Sample records for obesity-associated insulin resistance

  1. Association of Oxidative Stress and Obesity with Insulin Resistance in Type 2 Diabetes Mellitus.

    PubMed

    Das, P; Biswas, S; Mukherjee, S; Bandyopadhyay, S K

    2016-01-01

    Oxidative stress occurs due to delicate imbalance between pro-oxidant and anti oxidant forces in our system. It has been found to be associated with many morbidities but its association with obesity and insulin resistance is still controversial. Here in our study we examined 167 patients of recent onset type 2 diabetes mellitus and 60 age sex matched non-diabetic control. Body Mass Index (BMI), abdominal circumference, fasting blood glucose, serum insulin and plasma Malondealdehyde (MDA, marker for oxidative stress) were measured in them. On the basis of BMI, subjects were divided into obese (BMI≥25) and non obese (BMI<25) groups. Insulin resistance scores were calculated by Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) method. Physical parameters (BMI, abdominal circumference) as well as levels of insulin and MDA were found to be significantly higher in subjects with diabetes than their non diabetic controls. The said parameters also showed significant difference in obese and non-obese sub groups. Insulin resistance score showed positive correlation with BMI, abdominal circumference, and plasma MDA, strength of association being highest with abdominal circumference. Plasma MDA was found to have positive correlation with physical parameters. Study concludes that, obesity mainly central type may predispose to insulin resistance and oxidative stress may be a crucial factor in its pathogenesis. Thus, oxidative stress may be the connecting link between obesity and type 2 diabetes mellitus, two on going global epidemics.

  2. Whole-Body and Hepatic Insulin Resistance in Obese Children

    PubMed Central

    Ibarra-Reynoso, Lorena del Rocío; Pisarchyk, Liudmila; Pérez-Luque, Elva Leticia; Garay-Sevilla, Ma. Eugenia; Malacara, Juan Manuel

    2014-01-01

    Background Insulin resistance may be assessed as whole body or hepatic. Objective To study factors associated with both types of insulin resistance. Methods Cross-sectional study of 182 obese children. Somatometric measurements were registered, and the following three adiposity indexes were compared: BMI, waist-to-height ratio and visceral adiposity. Whole-body insulin resistance was evaluated using HOMA-IR, with 2.5 as the cut-off point. Hepatic insulin resistance was considered for IGFBP-1 level quartiles 1 to 3 (<6.67 ng/ml). We determined metabolite and hormone levels and performed a liver ultrasound. Results The majority, 73.1%, of obese children had whole-body insulin resistance and hepatic insulin resistance, while 7% did not have either type. HOMA-IR was negatively associated with IGFBP-1 and positively associated with BMI, triglycerides, leptin and mother's BMI. Girls had increased HOMA-IR. IGFBP-1 was negatively associated with waist-to-height ratio, age, leptin, HOMA-IR and IGF-I. We did not find HOMA-IR or IGFBP-1 associated with fatty liver. Conclusion In school-aged children, BMI is the best metric to predict whole-body insulin resistance, and waist-to-height ratio is the best predictor of hepatic insulin resistance, indicating that central obesity is important for hepatic insulin resistance. The reciprocal negative association of IGFBP-1 and HOMA-IR may represent a strong interaction of the physiological processes of both whole-body and hepatic insulin resistance. PMID:25411786

  3. Insulin resistance and its association with the components of the metabolic syndrome among obese children and adolescents.

    PubMed

    Juárez-López, Carlos; Klünder-Klünder, Miguel; Medina-Bravo, Patricia; Madrigal-Azcárate, Adrián; Mass-Díaz, Eliezer; Flores-Huerta, Samuel

    2010-06-07

    Insulin resistance is the primary metabolic disorder associated with obesity; yet little is known about its role as a determinant of the metabolic syndrome in obese children. The aim of this study is to assess the association between the degree of insulin resistance and the different components of the metabolic syndrome among obese children and adolescents. An analytical, cross-sectional and population-based study was performed in forty-four public primary schools in Campeche City, Mexico. A total of 466 obese children and adolescents between 11-13 years of age were recruited. Fasting glucose and insulin concentrations, high density lipoprotein cholesterol, triglycerides, waist circumference, systolic and diastolic blood pressures were measured; insulin resistance and metabolic syndrome were also evaluated. Out of the total population studied, 69% presented low values of high density lipoprotein cholesterol, 49% suffered from abdominal obesity, 29% had hypertriglyceridemia, 8% presented high systolic and 13% high diastolic blood pressure, 4% showed impaired fasting glucose, 51% presented insulin resistance and 20% metabolic syndrome. In spite of being obese, 13% of the investigated population did not present any metabolic disorder. For each one of the components of the metabolic syndrome, when insulin resistance increased so did odds ratios as cardiometabolic risk factors. Regardless of age and gender an increased degree of insulin resistance is associated with a higher prevalence of disorders in each of the components of the metabolic syndrome and with a heightened risk of suffering metabolic syndrome among obese children and adolescents.

  4. miRNA Signatures of Insulin Resistance in Obesity.

    PubMed

    Jones, Angela; Danielson, Kirsty M; Benton, Miles C; Ziegler, Olivia; Shah, Ravi; Stubbs, Richard S; Das, Saumya; Macartney-Coxson, Donia

    2017-10-01

    Extracellular microRNAs (miRNAs) represent functional biomarkers for obesity and related disorders; this study investigated plasma miRNAs in insulin resistance phenotypes in obesity. One hundred seventy-five miRNAs were analyzed in females with obesity (insulin sensitivity, n = 11; insulin resistance, n = 19; type 2 diabetes, n = 15) and without obesity (n = 12). Correlations between miRNA level and clinical parameters and levels of 15 miRNAs in a murine obesity model were investigated. One hundred six miRNAs were significantly (adjusted P ≤ 0.05) different between controls and at least one obesity phenotype, including miRNAs with the following attributes: previously reported roles in obesity and altered circulating levels (e.g., miR-122, miR-192); known roles in obesity but no reported changes in circulating levels (e.g., miR-378a); and no current reported role in, or association with, obesity (e.g., miR-28-5p, miR-374b, miR-32). The miRNAs in the latter group were found to be associated with extracellular vesicles. Forty-eight miRNAs showed significant correlations with clinical parameters; stepwise regression retained let-7b, miR-144-5p, miR-34a, and miR-532-5p in a model predictive of insulin resistance (R 2  = 0.57, P = 7.5 × 10 -8 ). Both miR-378a and miR-122 were perturbed in metabolically relevant tissues in a murine model of obesity. This study expands on the role of extracellular miRNAs in insulin-resistant phenotypes of obesity and identifies candidate miRNAs not previously associated with obesity. © 2017 The Obesity Society.

  5. 45Obesity, Insulin Resistance and Free Fatty Acids

    PubMed Central

    Boden, Guenther

    2011-01-01

    Purpose of Review to describe the role of FFA as a cause for insulin resistance in obese people. Recent Findings elevated plasma FFA levels can account for a large part of insulin resistance in obese patients with type 2 diabetes. Insulin resistance is clinically important because it is closely associated with several diseases including T2DM, hypertension, dyslipidemia and abnormalities in blood coagulation and fibrinolysis. These disorders are all independent risk factors for cardiovascular disease (heart attacks, strokes and peripheral arterial disease). The mechanism by which FFA can cause insulin resistance, although not completely known, include generation of lipid metabolites (diacylglycerol), proinflammatory cytokines (TNF-α, IL1β, IL6, MCP1) and cellular stress including oxidative and endoplasmic reticulum stress. Summary increased plasma FFA levels are an important cause of obesity associated insulin resistance and cardiovascular disease. Therapeutic application of this knowledge is hampered by the lack of readily accessible methods to measure FFA and by the lack of medications to lower plasma FFA levels. PMID:21297467

  6. Insulin resistance in obesity can be reliably identified from fasting plasma insulin.

    PubMed

    ter Horst, K W; Gilijamse, P W; Koopman, K E; de Weijer, B A; Brands, M; Kootte, R S; Romijn, J A; Ackermans, M T; Nieuwdorp, M; Soeters, M R; Serlie, M J

    2015-12-01

    Insulin resistance is the major contributor to cardiometabolic complications of obesity. We aimed to (1) establish cutoff points for insulin resistance from euglycemic hyperinsulinemic clamps (EHCs), (2) identify insulin-resistant obese subjects and (3) predict insulin resistance from routinely measured variables. We assembled data from non-obese (n=112) and obese (n=100) men who underwent two-step EHCs using [6,6-(2)H2]glucose as tracer (insulin infusion dose 20 and 60 mU m(-2) min(-1), respectively). Reference ranges for hepatic and peripheral insulin sensitivity were calculated from healthy non-obese men. Based on these reference values, obese men with preserved insulin sensitivity or insulin resistance were identified. Cutoff points for insulin-mediated suppression of endogenous glucose production (EGP) and insulin-stimulated glucose disappearance rate (Rd) were 46.5% and 37.3 μmol kg(-)(1) min(-)(1), respectively. Most obese men (78%) had EGP suppression within the reference range, whereas only 12% of obese men had Rd within the reference range. Obese men with Rd <37.3 μmol kg(-1) min(-1) did not differ from insulin-sensitive obese men in age, body mass index (BMI), body composition, fasting glucose or cholesterol, but did have higher fasting insulin (110±49 vs 63±29 pmol l(-1), P<0.001) and homeostasis model assessment of insulin resistance (HOMA-IR) (4.5±2.2 vs 2.7±1.4, P=0.004). Insulin-resistant obese men could be identified with good sensitivity (80%) and specificity (75%) from fasting insulin >74 pmol l(-1). Most obese men have hepatic insulin sensitivity within the range of non-obese controls, but below-normal peripheral insulin sensitivity, that is, insulin resistance. Fasting insulin (>74 pmol l(-1) with current insulin immunoassay) may be used for identification of insulin-resistant (or metabolically unhealthy) obese men in research and clinical settings.

  7. Tumor Progression Locus 2 (TPL2) Regulates Obesity-Associated Inflammation and Insulin Resistance

    PubMed Central

    Perfield, James W.; Lee, Yunkyoung; Shulman, Gerald I.; Samuel, Varman T.; Jurczak, Michael J.; Chang, Eugene; Xie, Chen; Tsichlis, Phillip N.; Obin, Martin S.; Greenberg, Andrew S.

    2011-01-01

    OBJECTIVE Obesity-associated low-grade systemic inflammation resulting from increased adipose mass is strongly related to the development of insulin resistance and type 2 diabetes as well as other metabolic complications. Recent studies have demonstrated that the obese metabolic state can be improved by ablating certain inflammatory signaling pathways. Tumor progression locus 2 (TPL2), a kinase that integrates signals from Toll receptors, cytokine receptors, and inhibitor of κ-B kinase-β is an important regulator of inflammatory pathways. We used TPL2 knockout (KO) mice to investigate the role of TPL2 in mediating obesity-associated inflammation and insulin resistance. RESEARCH DESIGN AND METHODS Male TPL2KO and wild-type (WT) littermates were fed a low-fat diet or a high-fat diet to investigate the effect of TPL2 deletion on obesity, inflammation, and insulin sensitivity. RESULTS We demonstrate that TPL2 deletion does not alter body weight gain or adipose depot weight. However, hyperinsulinemic euglycemic clamp studies revealed improved insulin sensitivity with enhanced glucose uptake in skeletal muscle and increased suppression of hepatic glucose output in obese TPL2KO mice compared with obese WT mice. Consistent with an improved metabolic phenotype, immune cell infiltration and inflammation was attenuated in the adipose tissue of obese TPL2KO mice coincident with reduced hepatic inflammatory gene expression and lipid accumulation. CONCLUSIONS Our results provide the first in vivo demonstration that TPL2 ablation attenuates obesity-associated metabolic dysfunction. These data suggest TPL2 is a novel target for improving the metabolic state associated with obesity. PMID:21346175

  8. Association between Myeloperoxidase Levels and Risk of Insulin Resistance in Egyptian Obese Women

    PubMed Central

    Zaki, Moushira; Basha, Walaa; Reyad, Hanaa; Mohamed, Ramy; Hassan, Naglaa; Kholousi, Shams

    2018-01-01

    BACKGROUND: Myeloperoxidase (MPO) is an enzyme involved in the pathogenesis of several diseases. AIM: The current study aimed to investigate serum MPO levels in obese Egyptian women and assess its relation with insulin resistance (IR) and other biochemical risk parameters. METHODS: The study included 80 obese women and 50 age-and-sex-matched healthy controls. Insulin resistance (IR) was evaluated by the Homeostasis Model Assessment-Insulin Resistance (HOMA-IR). Serum MPO, fasting glucose, insulin and blood lipids and anthropometry were measured. Obese cases were divided into three groups based on MPO tertiles. ROC analysis was performed to obtain the optimal cut-off values of MPO to predicate IR in obese women. RESULTS: The mean serum MPO was significantly higher in obese cases than controls. Cases in the highest MPO tertile had higher HOMA-IR, blood lipids and pressure levels compared with those in the lower tertile. The cutoff point of MPO was > 87.8 (ng/mL) and area under curves was 0.82 (p < 0.01) for diagnosis of IR. MPO levels were higher in obese Egyptian women than healthy controls. CONCLUSION: Elevation of MPO was associated with abnormal metabolic parameters. MPO might be used as an earlier biomarker for IR and metabolic disturbance in obese women. PMID:29731928

  9. Insulin resistance in obese children and adolescents.

    PubMed

    Romualdo, Monica Cristina dos Santos; Nóbrega, Fernando José de; Escrivão, Maria Arlete Meil Schimith

    2014-01-01

    To evaluate the presence of insulin resistance and its association with other metabolic abnormalities in obese children and adolescents. Retrospective study of 220 children and adolescents aged 5-14 years. Anthropometric measurements were performed (weight, height, and waist circumference) and clinical (gender, age, pubertal stage, and degree of obesity) and biochemical (glucose, insulin, total cholesterol, and fractions, triglycerides) data were analyzed. Insulin resistance was identified by the homeostasis model assessment for insulin resistance (HOMA-IR) index. The analysis of the differences between the variables of interest and the HOMA-IR quartiles was performed by ANOVA or Kruskal-Wallis tests. Insulin resistance was diagnosed in 33.20% of the sample. It was associated with low levels of high-density lipoprotein cholesterol (HDL-C; p=0.044), waist circumference measurement (p=0.030), and the set of clinical and metabolic (p=0.000) alterations. Insulin-resistant individuals had higher mean age (p=0.000), body mass index (BMI; p=0.000), abdominal circumference (p=0.000), median triglycerides (p=0.001), total cholesterol (p≤0.042), and low-density lipoprotein cholesterol (LDL-C; p≤0.027); and lower HDL-C levels (p=0.005). There was an increase in mean BMI (p=0.000), abdominal circumference (p=0.000), and median triglycerides (p=0.002) as the values of HOMA -IR increased, with the exception of HDL-C, which decreased (p=0.001). Those with the highest number of simultaneous alterations were between the second and third quartiles of the HOMA-IR index (p=0.000). The results confirmed that insulin resistance is present in many obese children and adolescents, and that this condition is associated with alterations that represent an increased risk for developing metabolic disorders in adulthood. Copyright © 2014 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

  10. Sexual dimorphism in interleukin 17A and adipocytokines and their association with insulin resistance among obese adolescents in Yogyakarta, Indonesia.

    PubMed

    Susilowati, Rina; Sulistyoningrum, Dian Caturini; Witari, Ni Putu Diah; Huriyati, Emy; Luglio, Harry Freitag; Julia, Madarina

    2016-12-01

    Pro-inflammatory cytokines interleukin 17A (IL-17), leptin, and adiponectin have been associated with obesity and insulin resistance. Moreover, differences in sex and ethnicity as well as plasma concentration of adipocytokines and cytokines have been associated with the risk of insulin resistance. This study was conducted to elucidate whether sex differences exist in the risk of insulin resistance in Indonesian adolescents and to determine how plasma leptin, adiponectin, and IL-17 predict insulin resistance. The study participants were 69 obese-overweight boys, 53 obese-overweight girls, 59 non-obese boys, and 50 non-obese girls aged 15-18 years. Insulin resistance was determined using the homeostatic model assessment of insulin resistance index. Plasma IL-17, leptin, and adiponectin were measured using ELISA. Data were analysed using one-way ANOVA and linear regression analysis. Odd ratios [ORs; 95% confidence intervals (CIs)] were analysed to estimate the risk of insulin resistance; the significance level was set at 95%. The OR (95% CI) for insulin resistance was higher in obese-overweight boys than in obese-overweight girls. The plasma IL-17 was higher in boys, whereas plasma adiponectin and leptin were significantly higher in girls. In all participants, obesity status and plasma leptin were the most efficient predictors of insulin resistance, whereas the IL-17 could not significantly predict insulin resistance. Sexual dimorphism exists in IL17 as well as leptin and adiponectin in adolescents. Plasma IL-17 cannot be used to predict insulin resistance in adolescents of both sex.

  11. IL-34 is associated with obesity, chronic inflammation, and insulin resistance.

    PubMed

    Chang, Eun-Ju; Lee, Seul Ki; Song, Young Sook; Jang, Yeon Jin; Park, Hye Soon; Hong, Joon Pio; Ko, A Ra; Kim, Dae Yeon; Kim, Jong-Hyeok; Lee, Yeon Ji; Heo, Yoon-Suk

    2014-07-01

    IL-34 is a recently identified alternative ligand for colony-stimulating factor-1 (CSF-1) receptor. IL-34 and CSF-1 are regulators of differentiation, proliferation, and survival in mononuclear phagocytes. Here, we investigated the IL-34 serum concentration and expression in human adipose tissues and any associations with insulin resistance. We recruited 19 nondiabetic obese women, 9 type 2 diabetic women, and 27 normal-weight women. Metabolic parameters, abdominal fat distribution, serum IL-34 concentration, and IL-34 mRNA expression were measured in abdominal sc adipose tissue (SAT) and visceral adipose tissue (VAT). In addition, the expression/secretion and putative effects of IL-34 were assessed in human differentiated adipocytes. Serum IL-34 concentration was measured before and 5 to 9 months after laparoscopic Roux-en-Y gastric bypass surgery was performed on the 20 obese patients. Regardless of diabetes status, obese patients demonstrated significantly higher serum IL-34 concentrations than controls. Serum IL-34 was significantly and positively correlated with insulin resistance-related metabolic parameters. IL-34 mRNA was significantly higher in VAT than SAT. IL-34 was expressed in adipocytes as well as nonadipocytes, and expression was significantly higher during adipogenesis. In differentiated adipocytes, the expression/secretion of IL-34 was enhanced by TNFα and IL-1β. In addition, IL-34 augmented fat accumulation and inhibited the stimulatory effects of insulin on glucose transport. Moreover, serum IL-34 was significantly decreased after Roux-en-Y gastric bypass-induced weight loss. The present study demonstrates, for the first time, that IL-34 is expressed in human adipose tissues and the circulating concentration is significantly elevated in obese patients. This suggests that IL-34 is associated with insulin resistance.

  12. Vitamin D insufficiency is associated with insulin resistance independently of obesity in primary schoolchildren. The healthy growth study.

    PubMed

    Moschonis, George; Androutsos, Odysseas; Hulshof, Toine; Dracopoulou, Maria; Chrousos, George P; Manios, Yannis

    2018-04-02

    To explore the associations of vitamin D status and obesity with insulin resistance (IR) in children. A sample of 2282 schoolchildren (9-13 years old) in Greece was examined. Sociodemographic, anthropometric (weight, height), biochemical (fasting plasma glucose, serum insulin and 25(OH)D), pubertal status and physical activity data were collected, using standard methods. The "Vitamin D Standardization Program" protocol was applied to standardize serum 25(OH)D values. The prevalence of vitamin D insufficiency (serum 25(OH)D < 50 nmol/L) was higher in obese children compared to their over- and normal-weight counterparts (60.5% vs 51.6% and 51%, P = .017). Furthermore, children with IR (both obese and non-obese) had higher prevalence of vitamin D insufficiency compared to non-obese, non-insulin resistant children (66% and 59.2% vs 49.8%, P < .05), possibly indicating that IR is associated with vitamin D insufficiency, independently of obesity. In line with the above, the results from logistic regression analyses controlled for several potential confounders, showed a 1.48 (95% C.I: 1.2-1.84) higher likelihood for vitamin D insufficiency for insulin resistant children compared to the non-insulin resistant ones, while no significant association was observed with obesity. The present study revealed a high prevalence of vitamin D insufficiency among schoolchildren in Greece, particularly among obese and insulin resistant ones. In addition, it highlighted that the significant association of vitamin D insufficiency with IR is possibly independent of obesity. Further clinical trials are needed to confirm this possible independent association but also explore the potential beneficial effect of vitamin D supplementation on IR and possibly on weight management too. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Skeletal muscle inflammation and insulin resistance in obesity.

    PubMed

    Wu, Huaizhu; Ballantyne, Christie M

    2017-01-03

    Obesity is associated with chronic inflammation, which contributes to insulin resistance and type 2 diabetes mellitus. Under normal conditions, skeletal muscle is responsible for the majority of insulin-stimulated whole-body glucose disposal; thus, dysregulation of skeletal muscle metabolism can strongly influence whole-body glucose homeostasis and insulin sensitivity. Increasing evidence suggests that inflammation occurs in skeletal muscle in obesity and is mainly manifested by increased immune cell infiltration and proinflammatory activation in intermyocellular and perimuscular adipose tissue. By secreting proinflammatory molecules, immune cells may induce myocyte inflammation, adversely regulate myocyte metabolism, and contribute to insulin resistance via paracrine effects. Increased influx of fatty acids and inflammatory molecules from other tissues, particularly visceral adipose tissue, can also induce muscle inflammation and negatively regulate myocyte metabolism, leading to insulin resistance.

  14. Skeletal muscle inflammation and insulin resistance in obesity

    PubMed Central

    Wu, Huaizhu; Ballantyne, Christie M.

    2017-01-01

    Obesity is associated with chronic inflammation, which contributes to insulin resistance and type 2 diabetes mellitus. Under normal conditions, skeletal muscle is responsible for the majority of insulin-stimulated whole-body glucose disposal; thus, dysregulation of skeletal muscle metabolism can strongly influence whole-body glucose homeostasis and insulin sensitivity. Increasing evidence suggests that inflammation occurs in skeletal muscle in obesity and is mainly manifested by increased immune cell infiltration and proinflammatory activation in intermyocellular and perimuscular adipose tissue. By secreting proinflammatory molecules, immune cells may induce myocyte inflammation, adversely regulate myocyte metabolism, and contribute to insulin resistance via paracrine effects. Increased influx of fatty acids and inflammatory molecules from other tissues, particularly visceral adipose tissue, can also induce muscle inflammation and negatively regulate myocyte metabolism, leading to insulin resistance. PMID:28045398

  15. Loss of prion protein is associated with the development of insulin resistance and obesity.

    PubMed

    de Brito, Giovanna; Lupinacci, Fernanda C; Beraldo, Flávio H; Santos, Tiago G; Roffé, Martín; Lopes, Marilene H; de Lima, Vladmir C; Martins, Vilma R; Hajj, Glaucia N

    2017-08-17

    Prion protein (PrP C ) was initially described due to its involvement in transmissible spongiform encephalopathies. It was subsequently demonstrated to be a cell surface molecule involved in many physiological processes, such as vesicle trafficking. Here, we investigated the roles of PrP C in the response to insulin and obesity development. Two independent PrP C knockout (KO) and one PrP C overexpressing (TG20) mouse models were fed high-fat diets, and the development of insulin resistance and obesity was monitored. PrP C KO mice fed high-fat diets presented all of the symptoms associated with the development of insulin resistance: hyperglycemia, hyperinsulinemia, and obesity. Conversely, TG20 animals fed high-fat diets showed reduced weight and insulin resistance. Accordingly, the expression of peroxisome proliferator-activated receptor gamma (PPARγ) was reduced in PrP C KO mice and increased in TG20 animals. PrP C KO cells also presented reduced glucose uptake upon insulin stimulation, due to reduced translocation of the glucose transporter Glut4. Thus, our results suggest that PrP C reflects susceptibility to the development of insulin resistance and metabolic syndrome. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

  16. Association between gamma glutamyl transferase and insulin resistance markers in healthy obese children.

    PubMed

    Kaushik, Girdhar Gopal; Sharm, Sonali; Sharma, Reenu; Mittal, Prerna

    2009-10-01

    To study the relationship of gamma glutamyl transferase (GGT) with insulin resistance markers [fasting insulin and Homeostasis Model Assessment of-insulin resistance (HOMA-IR)] and to assess the role of GGT as a determinant of insulin resistance in healthy obese children. Fifty healthy obese children (boys and girls with mean age 9.2 +/- 0.73 and 8.8 +/- 0.74 years) born to diabetic mothers were studied. In all the subjects, anthropometric measurements viz, BMI and body weight were studied. The biochemical parameters analysed in fasting samples of subjects were plasma glucose, plasma insulin, serum GGT and calculation of HOMA-IR. The fifty studied subjects belonged to age group 8 to12 years. The difference in mean age of boys and girls was not significant (p = 0.09). Body weight values in all subjects ranged from 20 to 78 kgs and BMI values ranged from 14.5 to 42.1 Kg/m2. No significant difference was observed between body weight and BMI values when compared between boys and girls. A similar trend was observed in the values of biochemical parameters viz, fasting glucose, fasting insulin and HOMA-IR levels when compared between boys and girls (p = 0.72, p = 0.80, p = 0.59). Serum GGT correlated significantly with age, body weight, BMI, fasting insulin and HOMA-IR levels. HOMA-IR values also showed significant correlation with body weight, BMI, fasting glucose and fasting insulin levels. The association of GGT with fasting insulin and HOMA-IR levels was considerably significant compared to its association with other variables. The serum activity of GGT remained correlated with HOMA-IR even after removing the effect of BMI, weight and age on GGT values. The results showed that GGT is a determinant of HOMA-IR independently of age, BMI and weight. A correlation exists between GGT and insulin resistance markers. The observed correlation indicates that monitoring GGT and fasting insulin levels in obese children might serve to help prevent the development of diabetes in

  17. Cytokines and their association with insulin resistance in obese pregnant women with different levels of physical activity.

    PubMed

    Nayak, Minakshi; Eekhoff, Marelise E W; Peinhaupt, Miriam; Heinemann, Akos; Desoye, Gernot; van Poppel, Mireille N M

    2016-01-01

    Cytokines contribute to insulin resistance in pregnancy, but the role of distinct cytokines is not fully understood. To study whether cytokines produced by tissues other than skeletal muscle are associated with glucose and insulin metabolism activity in overweight and obese women and to study whether these associations can be modified by physical activity. A longitudinal study with 44 overweight and obese pregnant women was conducted. Changes in cytokines levels (IFN-γ, IP-10, IL1-α, MIP1-α, adiponectin and leptin) and ICAM1 from early (15wk) to late (32wk) pregnancy were determined. Physical activity was measured objectively with accelerometers. In linear regression models, the associations between (changes in) cytokine levels and fasting glucose, fasting insulin and HOMA-IR were studied. Both IFN-γ and IP-10 levels increased from early to late pregnancy, and adiponectin levels decreased. IFN-γ and IP-10 were positively associated with fasting glucose, whereas IL-1α, ICAM1 and adiponectin were inversely associated with insulin and insulin resistance. The association of IL-1α with insulin and insulin resistance was only found in women with low levels of physical activity. IFN-γ, IP-10, IL1-α, ICAM1, and adiponectin may play a role in glucose and insulin metabolism in pregnancy. The relationship of IL-1α with insulin and insulin resistance might be moderated by levels of physical activity. Further studies are required to confirm the role of these cytokines in glucose and insulin metabolism in obese pregnant women. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. The role of dietary fat in obesity-induced insulin resistance.

    PubMed

    Lackey, Denise E; Lazaro, Raul G; Li, Pingping; Johnson, Andrew; Hernandez-Carretero, Angelina; Weber, Natalie; Vorobyova, Ivetta; Tsukomoto, Hidekazu; Osborn, Olivia

    2016-12-01

    Consumption of excess calories results in obesity and insulin resistance and has been intensively studied in mice and humans. The objective of this study was to determine the specific contribution of dietary fat rather than total caloric intake to the development of obesity-associated insulin resistance. We used an intragastric feeding method to overfeed excess calories from a low-fat diet (and an isocalorically matched high-fat diet) through a surgically implanted gastric feeding tube to generate obesity in wild-type mice followed by hyperinsulinemic-euglycemic clamp studies to assess the development of insulin resistance. We show that overfeeding a low-fat diet results in levels of obesity similar to high-fat diet feeding in mice. However, despite a similar body weight, obese high-fat diet-fed mice are more insulin resistant than mice fed an isocaloric low-fat diet. Therefore, increased proportion of calories from dietary fat further potentiates insulin resistance in the obese state. Furthermore, crossover diet studies revealed that reduction in dietary fat composition improves glucose tolerance in obesity. In the context of the current obesity and diabetes epidemic, it is particularly important to fully understand the role of dietary macronutrients in the potentiation and amelioration of disease. Copyright © 2016 the American Physiological Society.

  19. Metabolic syndrome and insulin resistance in obese adolescents.

    PubMed

    Gobato, Amanda Oliva; Vasques, Ana Carolina J; Zambon, Mariana Porto; Barros Filho, Antonio de Azevedo; Hessel, Gabriel

    2014-03-01

    To verify the prevalence of metabolic syndrome and insulin resistance in obese adolescents and its relationship with different body composition indicators. A cross-sectional study comprising 79 adolescents aged ten to 18 years old. The assessed body composition indicators were: body mass index (BMI), body fat percentage, abdominal circumference, and subcutaneous fat. The metabolic syndrome was diagnosed according to the criteria proposed by Cook et al. The insulin resistance was determined by the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) index for values above 3.16. The analysis of ROC curves was used to assess the BMI and the abdominal circumference, aiming to identify the subjects with metabolic syndrome and insulin resistance. The cutoff point corresponded to the percentage above the reference value used to diagnose obesity. The metabolic syndrome was diagnosed in 45.5% of the patients and insulin resistance, in 29.1%. Insulin resistance showed association with HDL-cholesterol (p=0.032) and with metabolic syndrome (p=0.006). All body composition indicators were correlated with insulin resistance (p<0.01). In relation to the cutoff point evaluation, the values of 23.5 and 36.3% above the BMI reference point allowed the identification of insulin resistance and metabolic syndrome. The best cutoff point for abdominal circumference to identify insulin resistance was 40%. All body composition indicators, HDL-cholesterol and metabolic syndrome showed correlation with insulin resistance. The BMI was the most effective anthropometric indicator to identify insulin resistance.

  20. Childhood obesity and insulin resistance: how should it be managed?

    PubMed

    Ho, Mandy; Garnett, Sarah P; Baur, Louise A

    2014-12-01

    Concomitant with the rise in global pediatric obesity in the past decades, there has been a significant increase in the number of children and adolescents with clinical signs of insulin resistance. Given insulin resistance is the important link between obesity and the associated metabolic abnormalities and cardiovascular risk, clinicians should be aware of high risk groups and treatment options. As there is no universally accepted biochemical definition of insulin resistance in children and adolescents, identification and diagnosis of insulin resistance usually relies on clinical features such as acanthosis nigricans, polycystic ovary syndrome, hypertension, dyslipidemia, and nonalcoholic fatty liver disease. Treatment for reducing insulin resistance and other obesity-associated comorbidities should focus on changes in health behaviors to achieve effective weight management. Lifestyle interventions incorporating dietary change, increased physical activity, and decreased sedentary behaviors, with the involvement of family and adoption of a developmentally appropriate approach, should be used as the first line treatment. Current evidence suggests that the primary objective of dietary interventions should be to reduce total energy intake and a combination of aerobic and resistance training should be encouraged. Metformin can be used in conjunction with a lifestyle intervention program in obese adolescents with clinical insulin resistance to achieve weight loss and to improve insulin sensitivity. Ongoing evaluation and research are required to explore optimal protocol and long-term effectiveness of lifestyle interventions, as well as to determine whether the improvements in insulin sensitivity induced by lifestyle interventions and weight loss will lead to a clinical benefit including reduced cardiovascular morbidity and mortality.

  1. Metabolic syndrome and insulin resistance in obese adolescents

    PubMed Central

    Gobato, Amanda Oliva; Vasques, Ana Carolina J.; Zambon, Mariana Porto; Barros, Antonio de Azevedo; Hessel, Gabriel

    2014-01-01

    Objective: To verify the prevalence of metabolic syndrome and insulin resistance in obese adolescents and its relationship with different body composition indicators. Methods: A cross-sectional study comprising 79 adolescents aged ten to 18 years old. The assessed body composition indicators were: body mass index (BMI), body fat percentage, abdominal circumference, and subcutaneous fat. The metabolic syndrome was diagnosed according to the criteria proposed by Cook et al. The insulin resistance was determined by the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) index for values above 3.16. The analysis of ROC curves was used to assess the BMI and the abdominal circumference, aiming to identify the subjects with metabolic syndrome and insulin resistance. The cutoff point corresponded to the percentage above the reference value used to diagnose obesity. Results: The metabolic syndrome was diagnosed in 45.5% of the patients and insulin resistance, in 29.1%. Insulin resistance showed association with HDL-cholesterol (p=0.032) and with metabolic syndrome (p=0.006). All body composition indicators were correlated with insulin resistance (p<0.01). In relation to the cutoff point evaluation, the values of 23.5 and 36.3% above the BMI reference point allowed the identification of insulin resistance and metabolic syndrome. The best cutoff point for abdominal circumference to identify insulin resistance was 40%. Conclusions: All body composition indicators, HDL-cholesterol and metabolic syndrome showed correlation with insulin resistance. The BMI was the most effective anthropometric indicator to identify insulin resistance. PMID:24676191

  2. Interleukin-6 induces impairment in human subcutaneous adipogenesis in obesity-associated insulin resistance.

    PubMed

    Almuraikhy, Shamma; Kafienah, Wael; Bashah, Moataz; Diboun, Ilhame; Jaganjac, Morana; Al-Khelaifi, Fatima; Abdesselem, Houari; Mazloum, Nayef A; Alsayrafi, Mohammed; Mohamed-Ali, Vidya; Elrayess, Mohamed A

    2016-11-01

    A subset of obese individuals remains insulin sensitive by mechanisms as yet unclear. The hypothesis that maintenance of normal subcutaneous (SC) adipogenesis accounts, at least partially, for this protective phenotype and whether it can be abrogated by chronic exposure to IL-6 was investigated. Adipose tissue biopsies were collected from insulin-sensitive (IS) and insulin-resistant (IR) individuals undergoing weight-reduction surgery. Adipocyte size, pre-adipocyte proportion of stromal vascular fraction (SVF)-derived cells, adipogenic capacity and gene expression profiles of isolated pre-adipocytes were determined, along with local in vitro IL-6 secretion. Adipogenic capacity was further assessed in response to exogenous IL-6 application. Despite being equally obese, IR individuals had significantly lower plasma leptin and adiponectin levels and higher IL-6 levels compared with age-matched IS counterparts. Elevated systemic IL-6 in IR individuals was associated with hyperplasia of adipose tissue-derived SVF cells, despite higher frequency of hypertrophied adipocytes. SC pre-adipocytes from these tissues exhibited lower adipogenic capacity accompanied by downregulation of PPARγ (also known as PPARG) and CEBPα (also known as CEBPA) and upregulation of GATA3 expression. Impaired adipogenesis in IR individuals was further associated with increased adipose secretion of IL-6. Treatment of IS-derived SC pre-adipocytes with IL-6 reduced their adipogenic capacity to levels of the IR group. Obesity-associated insulin resistance is marked by impaired SC adipogenesis, mediated, at least in a subset of individuals, by elevated local levels of IL-6. Understanding the molecular mechanisms underlying reduced adipogenic capacity in IR individuals could help target appropriate therapeutic strategies aimed at those at greatest risk of insulin resistance and type 2 diabetes mellitus.

  3. Role of intestinal inflammation as an early event in obesity and insulin resistance

    PubMed Central

    Ding, Shengli; Lund, Pauline K.

    2013-01-01

    Purpose of review To highlight recent evidence supporting a concept that intestinal inflammation is a mediator or contributor to development of obesity and insulin resistance. Recent findings Current views suggest that obesity-associated systemic and adipose tissue inflammation promote insulin resistance, which underlies many obesity-linked health risks. Diet-induced changes in gut microbiota also contribute to obesity. Recent findings support a concept that high fat diet and bacteria interact to promote early inflammatory changes in the small intestine that contribute to development of or susceptibility to obesity and insulin resistance. This review summarizes the evidence supporting a role of intestinal inflammation in diet-induced obesity and insulin resistance and discusses mechanisms. Summary The role of diet-induced intestinal inflammation as an early biomarker and mediator of obesity, and insulin resistance warrants further study. PMID:21587067

  4. Mechanisms of insulin resistance in obesity

    PubMed Central

    Ye, Jianping

    2014-01-01

    Obesity increases the risk for type 2 diabetes through induction of insulin resistance. Treatment of type 2 diabetes has been limited by little translational knowledge of insulin resistance although there have been several well-documented hypotheses for insulin resistance. In those hypotheses, inflammation, mitochondrial dysfunction, hyperinsulinemia and lipotoxicity have been the major concepts and have received a lot of attention. Oxidative stress, endoplasmic reticulum (ER) stress, genetic background, aging, fatty liver, hypoxia and lipodystrophy are active subjects in the study of these concepts. However, none of those concepts or views has led to an effective therapy for type 2 diabetes. The reason is that there has been no consensus for a unifying mechanism of insulin resistance. In this review article, literature is critically analyzed and reinterpreted for a new energy-based concept of insulin resistance, in which insulin resistance is a result of energy surplus in cells. The energy surplus signal is mediated by ATP and sensed by adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Decreasing ATP level by suppression of production or stimulation of utilization is a promising approach in the treatment of insulin resistance. In support, many of existing insulin sensitizing medicines inhibit ATP production in mitochondria. The effective therapies such as weight loss, exercise, and caloric restriction all reduce ATP in insulin sensitive cells. This new concept provides a unifying cellular and molecular mechanism of insulin resistance in obesity, which may apply to insulin resistance in aging and lipodystrophy. PMID:23471659

  5. AMP-activated Protein Kinase (AMPK): Does This Master Regulator of Cellular Energy State Distinguish Insulin Sensitive from Insulin Resistant Obesity?

    PubMed Central

    Valentine, Rudy J.; Ruderman, Neil B.

    2014-01-01

    Although a correlation exists between obesity and insulin resistance, roughly 25 % of obese individuals are insulin sensitive. AMP-activated protein kinase (AMPK) is a cellular energy sensor that among its many actions, integrates diverse physiological signals to restore energy balance. In addition, in many situations it also increases insulin sensitivity. In this context, AMPK activity is decreased in very obese individuals undergoing bariatric surgery who are insulin resistant compared to equally obese patients who are insulin sensitive. In this review, we will both explore what distinguishes these individuals, and evaluate the evidence that diminished AMPK is associated with insulin resistance and metabolic syndrome-associated disorders in other circumstances. PMID:24891985

  6. Effect of FTO rs9939609 variant on insulin resistance in obese female adolescents.

    PubMed

    Iskandar, Kristy; Patria, Suryono Yudha; Huriyati, Emy; Luglio, Harry Freitag; Julia, Madarina; Susilowati, Rina

    2018-05-15

    FTO rs9939609 variant has been shown to be associated with insulin resistance in Caucasian children. However, studies in Asia show inconsistent findings. We investigated the association between FTO rs9939609 polymorphisms and insulin resistance in obese female adolescents in Indonesia, a genetically distinct group within Asia. A total of 78 obese female adolescents participated in this study. The risk allele (A) frequency of FTO rs9939609 variant in Indonesian obese female adolescence was 44.2%. The frequency of insulin resistance was higher in the subjects with AA (54.6%) or AT (59.6%) than the subject with TT genotype (50%), but did not statistically different (p = 0.81 and p = 0.47, respectively). The insulin resistance rate was also higher in the risk allele (A) than the non-risk allele (T) subjects (0.58 vs. 0.55), but did not statistically different (p = 0.75). There was no association between FTO rs9939609 variant and body mass index, fasting glucose level, fasting insulin level, homeostatic model assessment of insulin resistance, and waist circumference (p > 0.05). In conclusion, FTO rs9939609 variant may not be associated with insulin resistance in Indonesian obese female adolescents. A multicenter study with a larger sample size is needed to clarify these findings.

  7. Vitamin D insufficiency and insulin resistance in obese adolescents

    PubMed Central

    Tosh, Aneesh K.; Belenchia, Anthony M.

    2014-01-01

    Obese adolescents represent a particularly vulnerable group for vitamin D deficiency which appears to have negative consequences on insulin resistance and glucose homeostasis. Poor vitamin D status is also associated with future risk of type 2 diabetes and metabolic syndrome in the obese. The biological mechanisms by which vitamin D influences glycemic control in obesity are not well understood, but are thought to involve enhancement of peripheral/hepatic uptake of glucose, attenuation of inflammation and/or regulation of insulin synthesis/secretion by pancreatic β cells. Related to the latter, recent data suggest that the active form of vitamin, 1,25-dihydroxyvitamin D, does not impact insulin release in healthy pancreatic islets; instead they require an environmental stressor such as inflammation or vitamin D deficiency to see an effect. To date, a number of observational studies exploring the relationship between the vitamin D status of obese adolescents and markers of glucose homeostasis have been published. Most, although not all, show significant associations between circulating 25-hydroxyvitamn D concentrations and insulin sensitivity/resistance indices. In interpreting the collective findings of these reports, significant considerations surface including the effects of pubertal status, vitamin D status, influence of parathyroid hormone status and the presence of nonalcoholic fatty liver disease. The few published clinical trials using vitamin D supplementation to improve insulin resistance and impaired glucose tolerance in obese adolescents have yielded beneficial effects. However, there is a need for more randomized controlled trials. Future investigations should involve larger sample sizes of obese adolescents with documented vitamin D deficiency, and careful selection of the dose, dosing regimen and achievement of target 25-hydroxyvitamn D serum concentrations. These trials should also include clamp-derived measures of in vivo sensitivity and

  8. Determinants of High Fasting Insulin and Insulin Resistance Among Overweight/Obese Adolescents.

    PubMed

    Ling, Jerri Chiu Yun; Mohamed, Mohd Nahar Azmi; Jalaludin, Muhammad Yazid; Rampal, Sanjay; Zaharan, Nur Lisa; Mohamed, Zahurin

    2016-11-08

    Hyperinsulinaemia is the earliest subclinical metabolic abnormality, which precedes insulin resistance in obese children. An investigation was conducted on the potential predictors of fasting insulin and insulin resistance among overweight/obese adolescents in a developing Asian country. A total of 173 overweight/obese (BMI > 85 th percentile) multi-ethnic Malaysian adolescents aged 13 were recruited from 23 randomly selected schools in this cross-sectional study. Waist circumference (WC), body fat percentage (BF%), physical fitness score (PFS), fasting glucose and fasting insulin were measured. Insulin resistance was calculated using homeostasis model assessment of insulin resistance (HOMA-IR). Adjusted stepwise multiple regression analysis was performed to predict fasting insulin and HOMA-IR. Covariates included pubertal stage, socioeconomic status, nutritional and physical activity scores. One-third of our adolescents were insulin resistant, with girls having significantly higher fasting insulin and HOMA-IR than boys. Gender, pubertal stage, BMI, WC and BF% had significant, positive moderate correlations with fasting insulin and HOMA-IR while PFS was inversely correlated (p < 0.05). Fasting insulin was primarily predicted by gender-girls (Beta = 0.305, p < 0.0001), higher BMI (Beta = -0.254, p = 0.02) and greater WC (Beta = 0.242, p = 0.03). This study demonstrated that gender, BMI and WC are simple predictors of fasting insulin and insulin resistance in overweight/obese adolescents.

  9. Expression of the central obesity and Type 2 Diabetes mellitus genes is associated with insulin resistance in young obese children.

    PubMed

    Skoczen, S; Wojcik, M; Fijorek, K; Siedlar, M; Starzyk, J B

    2015-04-01

    The assessment of the health consequences associated with obesity in young children is challenging. The aims of this study were: (1) to compare insulin resistance indices derived from OGTT in obese patients and healthy control (2) to analyze central obesity and Type 2 Diabetes genes expression in obese children, with special attention to the youngest group (< 10 years old). The study included 49 children with obesity (median age 13.5 years old), and 25 healthy peers. Biochemical blood tests and expression of 11 central obesity and 33 Type 2 Diabetes genes was assessed. A significant difference in insulin resistance between obese and non-obese adolescents was observed in all studied indices (mean values of the insulin levels: 24.9 vs. 9.71 mIU/L in T0, 128 vs. 54.7 mIU/L in T60 and 98.7 vs. 41.1 mIU/L in T120 respectively; AUC: 217 vs. 77.2 ng/ml*h, mean values of B% (state beta cell function), S% (insulin sensitivity), and IR were 255 (±97) vs. 135 (±37.8), 46.6 (±37.3) vs. 84.2 (±29.6) and 3 (±1.55) vs. 1.36 (±0,56); HIS, WBIS and ISIBel median 3.89, 44.7, 0.73 vs. 8.57, 110, 2.25. All comparisons differed significantly p<0.001). Moreover, insulin sensitivity was significantly better in the older obese group (>10 years old): median AUC 239 vs. 104 ng/ml*h, and HIS, WBIS and ISIBel 3.57, 38, 0.67 vs. 6.23, 75.6, 1.87 respectively in the obese older compared to the obese younger subgroup, p<0.05. The expression of 64% of the central obesity genes and 70% of Type 2 Diabetes genes was higher in the obese compared to control groups. The differences were more pronounced in the younger obese group. Insulin resistance may develop in early stage of childhood obesity and in very young children may be associated with higher expression of the central obesity and Type 2 Diabetes genes. © Georg Thieme Verlag KG Stuttgart · New York.

  10. Association Between Insulin Resistance and Oxidative Stress Parameters in Obese Adolescents with Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Pirgon, Özgür; Bilgin, Hüseyin; Çekmez, Ferhat; Kurku, Hüseyin; Dündar, Bumin Nuri

    2013-01-01

    Objective: Non-alcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases in children. The aim of this study was to investigate the associations of oxidative stress with insulin resistance and metabolic risk factors in obese adolescents with NAFLD. Methods: Forty-six obese adolescents (23 girls and 23 boys, mean age: 12.8±2.2 years) and 29 control subjects (15 girls and 14 boys, mean age: 12.7±2.7 years) were enrolled in the study. The obese subjects were divided into two groups (NAFLD group and non-NAFLD group) based on the elevated alanine aminotransferase levels (>30 IU/L) and the presence or absence of liver steatosis detected by ultrasonography. Insulin resistance was evaluated by homeostasis model assessment (HOMA-IR) from fasting samples. Plasma total antioxidant status (TAS) and total oxidant status (TOS) level measurements (REL Assay Diagnostics) were done in all participants. The ratio of TOS to TAS was regarded as an oxidative stress index (OSI), an indicator of the degree of OS. Results: Fasting insulin levels and HOMA-IR values in the NAFLD group were significantly higher than in the non-NAFLD and control groups. TAS measurements were decreased in both obese groups (NAFLD and non-NAFLD) in comparison with the control group. TOS and OSI measurements were higher in the NAFLD group than in the non-NAFLD and control groups. OSI was positively correlated with fasting insulin (r=0.67, p=0.01) and HOMA-IR (r=0.71, p=0.02) in the NAFLD obese group. Conclusions: In this cross-sectional study, elevated OS markers in obese adolescents with NAFLD were associated with insulin resistance. This data suggest that an antioxidant therapy might have a potential for treating NAFLD associated with insulin resistance. Conflict of interest:None declared. PMID:23367495

  11. Association between insulin resistance and oxidative stress parameters in obese adolescents with non-alcoholic fatty liver disease.

    PubMed

    Pirgon, Özgür; Bilgin, Hüseyin; Çekmez, Ferhat; Kurku, Hüseyin; Dündar, Bumin Nuri

    2013-01-01

    Non-alcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases in children. The aim of this study was to investigate the associations of oxidative stress with insulin resistance and metabolic risk factors in obese adolescents with NAFLD. Forty-six obese adolescents (23 girls and 23 boys, mean age: 12.8 ± 2.2 years) and 29 control subjects (15 girls and 14 boys, mean age: 12.7 ± 2.7 years) were enrolled in the study. The obese subjects were divided into two groups (NAFLD group and non-NAFLD group) based on the elevated alanine aminotransferase levels (>30 IU/L) and the presence or absence of liver steatosis detected by ultrasonography. Insulin resistance was evaluated by homeostasis model assessment (HOMA-IR) from fasting samples. Plasma total antioxidant status (TAS) and total oxidant status (TOS) level measurements (REL Assay Diagnostics) were done in all participants. The ratio of TOS to TAS was regarded as an oxidative stress index (OSI), an indicator of the degree of OS. Fasting insulin levels and HOMA-IR values in the NAFLD group were significantly higher than in the non-NAFLD and control groups. TAS measurements were decreased in both obese groups (NAFLD and non-NAFLD) in comparison with the control group. TOS and OSI measurements were higher in the NAFLD group than in the non-NAFLD and control groups. OSI was positively correlated with fasting insulin (r=0.67, p=0.01) and HOMA-IR (r=0.71, p=0.02) in the NAFLD obese group. In this cross-sectional study, elevated OS markers in obese adolescents with NAFLD were associated with insulin resistance. This data suggest that an antioxidant therapy might have a potential for treating NAFLD associated with insulin resistance.

  12. Intermittent hypoxia increases insulin resistance in genetically obese mice.

    PubMed

    Polotsky, Vsevolod Y; Li, Jianguo; Punjabi, Naresh M; Rubin, Arnon E; Smith, Philip L; Schwartz, Alan R; O'Donnell, Christopher P

    2003-10-01

    Obstructive sleep apnoea, a syndrome that leads to recurrent intermittent hypoxia, is associated with insulin resistance in obese individuals, but the mechanisms underlying this association remain unknown. We utilized a mouse model to examine the effects of intermittent hypoxia on insulin resistance in lean C57BL/6J mice and leptin-deficient obese (C57BL/6J-Lepob) mice. In lean mice, exposure to intermittent hypoxia for 5 days (short term) resulted in a decrease in fasting blood glucose levels (from 173 +/- 11 mg dl-1 on day 0 to 138 +/- 10 mg dl-1 on day 5, P < 0.01), improvement in glucose tolerance without a change in serum insulin levels and an increase in serum leptin levels in comparison with control (2.6 +/- 0.3 vs. 1.7 +/- 0.2 ng ml-1, P < 0.05). Microarray mRNA analysis of adipose tissue revealed that leptin was the only upregulated gene affecting glucose uptake. In obese mice, short-term intermittent hypoxia led to a decrease in blood glucose levels accompanied by a 607 +/- 136 % (P < 0.01) increase in serum insulin levels. This increase in insulin secretion after 5 days of intermittent hypoxia was completely abolished by prior leptin infusion. Obese mice exposed to intermittent hypoxia for 12 weeks (long term) developed a time-dependent increase in fasting serum insulin levels (from 3.6 +/- 1.1 ng ml-1 at baseline to 9.8 +/- 1.8 ng ml-1 at week 12, P < 0.001) and worsening glucose tolerance, consistent with an increase in insulin resistance. We conclude that the increase in insulin resistance in response to intermittent hypoxia is dependent on the disruption of leptin pathways.

  13. Intermittent Hypoxia Increases Insulin Resistance in Genetically Obese Mice

    PubMed Central

    Polotsky, Vsevolod Y; Li, Jianguo; Punjabi, Naresh M; Rubin, Arnon E; Smith, Philip L; Schwartz, Alan R; O'Donnell, Christopher P

    2003-01-01

    Obstructive sleep apnoea, a syndrome that leads to recurrent intermittent hypoxia, is associated with insulin resistance in obese individuals, but the mechanisms underlying this association remain unknown. We utilized a mouse model to examine the effects of intermittent hypoxia on insulin resistance in lean C57BL/6J mice and leptin-deficient obese (C57BL/6J−Lepob) mice. In lean mice, exposure to intermittent hypoxia for 5 days (short term) resulted in a decrease in fasting blood glucose levels (from 173 ± 11 mg dl−1 on day 0 to 138 ± 10 mg dl−1 on day 5, P < 0.01), improvement in glucose tolerance without a change in serum insulin levels and an increase in serum leptin levels in comparison with control (2.6 ± 0.3 vs. 1.7 ± 0.2 ng ml−1, P < 0.05). Microarray mRNA analysis of adipose tissue revealed that leptin was the only upregulated gene affecting glucose uptake. In obese mice, short-term intermittent hypoxia led to a decrease in blood glucose levels accompanied by a 607 ± 136 % (P < 0.01) increase in serum insulin levels. This increase in insulin secretion after 5 days of intermittent hypoxia was completely abolished by prior leptin infusion. Obese mice exposed to intermittent hypoxia for 12 weeks (long term) developed a time-dependent increase in fasting serum insulin levels (from 3.6 ± 1.1 ng ml−1 at baseline to 9.8 ± 1.8 ng ml−1 at week 12, P < 0.001) and worsening glucose tolerance, consistent with an increase in insulin resistance. We conclude that the increase in insulin resistance in response to intermittent hypoxia is dependent on the disruption of leptin pathways. PMID:12878760

  14. Roles of oxidative stress, adiponectin, and nuclear hormone receptors in obesity-associated insulin resistance and cardiovascular risk.

    PubMed

    Matsuda, Morihiro; Shimomura, Iichiro

    2014-08-01

    Obesity leads to the development of type 2 diabetes mellitus, which is a strong risk factor for cardiovascular disease. A better understanding of the molecular basis of obesity will lead to the establishment of effective prevention strategies for cardiovascular diseases. Adipocytes have been shown to generate a variety of endocrine factors termed adipokines/adipocytokines. Obesity-associated changes to these adipocytokines contribute to the development of cardiovascular diseases. Adiponectin, which is one of the most well-characterized adipocytokines, is produced exclusively by adipocytes and exerts insulin-sensitizing and anti-atherogenic effects. Obese subjects have lower levels of circulating adiponectin, and this is recognized as one of the factors involved in obesity-induced insulin resistance and atherosclerosis. Another pathophysiological feature of obesity may involve the low-grade chronic inflammation in adipose tissue. This inflammatory process increases oxidative stress in adipose tissue, which may affect remote organs, leading to the development of diabetes, hypertension, and atherosclerosis. Nuclear hormone receptors (NRs) regulate the transcription of the target genes in response to binding with their ligands, which include metabolic and nutritional substrates. Among the various NRs, peroxisome proliferator-activated receptor γ promotes the transcription of adiponectin and antioxidative enzymes, whereas mineralocorticoid receptor mediates the effects of aldosterone and glucocorticoid to induce oxidative stress in adipocytes. It is hypothesized that both play crucial roles in the pathophysiology of obesity-associated insulin resistance and cardiovascular diseases. Thus, reduced adiponectin and increased oxidative stress play pathological roles in obesity-associated insulin resistance to increase the cardiovascular disease risk, and various NRs may be involved in this pathogenesis.

  15. Circulating branched-chain amino acid concentrations are associated with obesity and future insulin resistance in children and adolescents.

    PubMed

    McCormack, S E; Shaham, O; McCarthy, M A; Deik, A A; Wang, T J; Gerszten, R E; Clish, C B; Mootha, V K; Grinspoon, S K; Fleischman, A

    2013-02-01

    What is already known about this subject Circulating concentrations of branched-chain amino acids (BCAAs) can affect carbohydrate metabolism in skeletal muscle, and therefore may alter insulin sensitivity. BCAAs are elevated in adults with diet-induced obesity, and are associated with their future risk of type 2 diabetes even after accounting for baseline clinical risk factors. What this study adds Increased concentrations of BCAAs are already present in young obese children and their metabolomic profiles are consistent with increased BCAA catabolism. Elevations in BCAAs in children are positively associated with insulin resistance measured 18 months later, independent of their initial body mass index. Branched-chain amino acid (BCAA) concentrations are elevated in response to overnutrition, and can affect both insulin sensitivity and secretion. Alterations in their metabolism may therefore play a role in the early pathogenesis of type 2 diabetes in overweight children. To determine whether paediatric obesity is associated with elevations in fasting circulating concentrations of BCAAs (isoleucine, leucine and valine), and whether these elevations predict future insulin resistance. Sixty-nine healthy subjects, ages 8-18 years, were enrolled as a cross-sectional cohort. A subset of subjects who were pre- or early-pubertal, ages 8-13 years, were enrolled in a prospective longitudinal cohort for 18 months (n = 17 with complete data). Elevations in the concentrations of BCAAs were significantly associated with body mass index (BMI) Z-score (Spearman's Rho 0.27, P = 0.03) in the cross-sectional cohort. In the subset of subjects that followed longitudinally, baseline BCAA concentrations were positively associated with homeostasis model assessment for insulin resistance measured 18 months later after controlling for baseline clinical factors including BMI Z-score, sex and pubertal stage (P = 0.046). Elevations in the concentrations of circulating BCAAs are significantly

  16. WNT5A-JNK regulation of vascular insulin resistance in human obesity.

    PubMed

    Farb, Melissa G; Karki, Shakun; Park, Song-Young; Saggese, Samantha M; Carmine, Brian; Hess, Donald T; Apovian, Caroline; Fetterman, Jessica L; Bretón-Romero, Rosa; Hamburg, Naomi M; Fuster, José J; Zuriaga, María A; Walsh, Kenneth; Gokce, Noyan

    2016-12-01

    Obesity is associated with the development of vascular insulin resistance; however, pathophysiological mechanisms are poorly understood. We sought to investigate the role of WNT5A-JNK in the regulation of insulin-mediated vasodilator responses in human adipose tissue arterioles prone to endothelial dysfunction. In 43 severely obese (BMI 44±11 kg/m 2 ) and five metabolically normal non-obese (BMI 26±2 kg/m 2 ) subjects, we isolated arterioles from subcutaneous and visceral fat during planned surgeries. Using videomicroscopy, we examined insulin-mediated, endothelium-dependent vasodilator responses and characterized adipose tissue gene and protein expression using real-time polymerase chain reaction and Western blot analyses. Immunofluorescence was used to quantify endothelial nitric oxide synthase (eNOS) phosphorylation. Insulin-mediated vasodilation was markedly impaired in visceral compared to subcutaneous vessels from obese subjects (p<0.001), but preserved in non-obese individuals. Visceral adiposity was associated with increased JNK activation and elevated expression of WNT5A and its non-canonical receptors, which correlated negatively with insulin signaling. Pharmacological JNK antagonism with SP600125 markedly improved insulin-mediated vasodilation by sixfold (p<0.001), while endothelial cells exposed to recombinant WNT5A developed insulin resistance and impaired eNOS phosphorylation (p<0.05). We observed profound vascular insulin resistance in the visceral adipose tissue arterioles of obese subjects that was associated with up-regulated WNT5A-JNK signaling and impaired endothelial eNOS activation. Pharmacological JNK antagonism markedly improved vascular endothelial function, and may represent a potential therapeutic target in obesity-related vascular disease. © The Author(s) 2016.

  17. WNT5A-JNK regulation of vascular insulin resistance in human obesity

    PubMed Central

    Farb, Melissa G; Karki, Shakun; Park, Song-Young; Saggese, Samantha M; Carmine, Brian; Hess, Donald T; Apovian, Caroline; Fetterman, Jessica L; Bretón-Romero, Rosa; Hamburg, Naomi M; Fuster, José J; Zuriaga, María A; Walsh, Kenneth; Gokce, Noyan

    2017-01-01

    Obesity is associated with the development of vascular insulin resistance; however, pathophysiological mechanisms are poorly understood. We sought to investigate the role of WNT5A-JNK in the regulation of insulin-mediated vasodilator responses in human adipose tissue arterioles prone to endothelial dysfunction. In 43 severely obese (BMI 44±11 kg/m2) and five metabolically normal non-obese (BMI 26±2 kg/m2) subjects, we isolated arterioles from subcutaneous and visceral fat during planned surgeries. Using videomicroscopy, we examined insulin-mediated, endothelium-dependent vasodilator responses and characterized adipose tissue gene and protein expression using real-time polymerase chain reaction and Western blot analyses. Immunofluorescence was used to quantify endothelial nitric oxide synthase (eNOS) phosphorylation. Insulin-mediated vasodilation was markedly impaired in visceral compared to subcutaneous vessels from obese subjects (p<0.001), but preserved in non-obese individuals. Visceral adiposity was associated with increased JNK activation and elevated expression of WNT5A and its non-canonical receptors, which correlated negatively with insulin signaling. Pharmacological JNK antagonism with SP600125 markedly improved insulin-mediated vasodilation by sixfold (p<0.001), while endothelial cells exposed to recombinant WNT5A developed insulin resistance and impaired eNOS phosphorylation (p<0.05). We observed profound vascular insulin resistance in the visceral adipose tissue arterioles of obese subjects that was associated with up-regulated WNT5A-JNK signaling and impaired endothelial eNOS activation. Pharmacological JNK antagonism markedly improved vascular endothelial function, and may represent a potential therapeutic target in obesity-related vascular disease. PMID:27688298

  18. Linking Gut Microbiota and Inflammation to Obesity and Insulin Resistance.

    PubMed

    Saad, M J A; Santos, A; Prada, P O

    2016-07-01

    Obesity and insulin resistance are the major predisposing factors to comorbidities, such as Type 2 diabetes, nonalcoholic fatty liver disease, cardiovascular and neurodegenerative diseases, and several types of cancer. The prevalence of obesity is still increasing worldwide and now affects a large number of individuals. Here, we review the role of the gut microbiota in the pathophysiology of insulin resistance/obesity. The human intestine is colonized by ∼100 trillion bacteria, which constitute the gut microbiota. Studies have shown that lean and overweight rodents and humans may present differences in the composition of their intestinal flora. Over the past 10 years, data from different sources have established a causal link between the intestinal microbiota and obesity/insulin resistance. It is important to emphasize that diet-induced obesity promotes insulin resistance by mechanisms independent and dependent on gut microbiota. In this review, we present several mechanisms that contribute to explaining the link between intestinal flora and insulin resistance/obesity. The LPS from intestinal flora bacteria can induce a chronic subclinical inflammatory process and obesity, leading to insulin resistance through activation of TLR4. The reduction in circulating SCFA may also have an essential role in the installation of reduced insulin sensitivity and obesity. Other mechanisms include effects of bile acids, branched-chain amino acids (BCAA), and some other lesser-known factors. In the near future, this area should open new therapeutic avenues for obesity/insulin resistance and its comorbidities. ©2016 Int. Union Physiol. Sci./Am. Physiol. Soc.

  19. Effect of android to gynoid fat ratio on insulin resistance in obese youth.

    PubMed

    Aucouturier, Julien; Meyer, Martine; Thivel, David; Taillardat, Michel; Duché, Pascale

    2009-09-01

    Upper body fat distribution is associated with the early development of insulin resistance in obese children and adolescents. To determine if an android to gynoid fat ratio is associated with the severity of insulin resistance in obese children and adolescents, whereas peripheral subcutaneous fat may have a protective effect against insulin resistance. The pediatric department of University Hospital, Clermont-Ferrand, France. A retrospective analysis using data from medical consultations between January 2005 and January 2007. Data from 66 obese children and adolescents coming to the hospital for medical consultation were used in this study. Subjects were stratified into tertiles of android to gynoid fat ratio determined by dual-energy x-ray absorptiometry. Insulin resistance was assessed by the homeostasis model of insulin resistance (HOMA-IR) index. There were no differences in weight, body mass index, and body fat percentage between tertiles. Values of HOMA-IR were significantly increased in the 2 higher tertiles (mean [SD], tertile 2, 2.73 [1.41]; tertile 3, 2.89 [1.28]) compared with the lower tertile (tertile 1, 1.67 [1.24]) of android to gynoid fat ratio (P < .001). The HOMA-IR value was significantly associated with android to gynoid fat ratio (r = 0.35; P < .01). Android fat distribution is associated with an increased insulin resistance in obese children and adolescents. An android to gynoid fat ratio based on dual-energy x-ray absorptiometry measurements is a useful and simple technique to assess distribution of body fat associated with an increased risk of insulin resistance.

  20. Insulin Resistance, Metabolic Syndrome, and Polycystic Ovary Syndrome in Obese Youth.

    PubMed

    Platt, Adrienne M

    2015-07-01

    School nurses are well aware of the childhood obesity epidemic in the United States, as one in three youth are overweight or obese. Co-morbidities found in overweight or obese adults were not commonly found in youth three decades ago but are now increasingly "normal" as the obesity epidemic continues to evolve. This article is the second of six related articles discussing the co-morbidities of childhood obesity and discusses the complex association between obesity and insulin resistance, metabolic syndrome, and polycystic ovary syndrome. Insulin resistance increases up to 50% during puberty, which may help to explain why youth are more likely to develop co-morbidities as teens. Treatment of these disorders is focused on changing lifestyle habits, as a child cannot change his or her pubertal progression, ethnicity, or family history. School nurses and other personnel can assist youth with insulin resistance, metabolic syndrome, and polycystic ovary syndrome by supporting their efforts to make changes, reinforcing that insulin resistance is not necessarily type 2 diabetes even if the child is taking medication, and intervening with negative peer pressure. © 2015 The Author(s).

  1. Obesity and insulin resistance are associated with reduced activity in core memory regions of the brain.

    PubMed

    Cheke, Lucy G; Bonnici, Heidi M; Clayton, Nicola S; Simons, Jon S

    2017-02-01

    Increasing research in animals and humans suggests that obesity may be associated with learning and memory deficits, and in particular with reductions in episodic memory. Rodent models have implicated the hippocampus in obesity-related memory impairments, but the neural mechanisms underlying episodic memory deficits in obese humans remain undetermined. In the present study, lean and obese human participants were scanned using fMRI while completing a What-Where-When episodic memory test (the "Treasure-Hunt Task") that assessed the ability to remember integrated item, spatial, and temporal details of previously encoded complex events. In lean participants, the Treasure-Hunt task elicited significant activity in regions of the brain known to be important for recollecting episodic memories, such as the hippocampus, angular gyrus, and dorsolateral prefrontal cortex. Both obesity and insulin resistance were associated with significantly reduced functional activity throughout the core recollection network. These findings indicate that obesity is associated with reduced functional activity in core brain areas supporting episodic memory and that insulin resistance may be a key player in this association. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  2. [The role of uric acid in the insulin resistance in children and adolescents with obesity].

    PubMed

    de Miranda, Josiane Aparecida; Almeida, Guilherme Gomide; Martins, Raissa Isabelle Leão; Cunha, Mariana Botrel; Belo, Vanessa Almeida; dos Santos, José Eduardo Tanus; Mourão-Júnior, Carlos Alberto; Lanna, Carla Márcia Moreira

    2015-12-01

    To investigate the association between serum uric acid levels and insulin resistance in children and adolescents with obesity. Cross-sectional study with 245 children and adolescents (134 obese and 111 controls), aged 8 to 18 years. The anthropometric variables (weight, height and waist circumference), blood pressure and biochemical parameters were collected. The clinical characteristics of the groups were analyzed by t-test or chi-square test. To evaluate the association between uric acid levels and insulin resistance the Pearson's test and logistic regression were applied. The prevalence of insulin resistance was 26.9%. The anthropometric variables, systolic and diastolic blood pressure and biochemical variables were significantly higher in the obese group (p<0.001), except for the high-density-lipoprotein cholesterol. There was a positive and significant correlation between anthropometric variables and uric acid with HOMA-IR in the obese and in the control groups, which was higher in the obese group and in the total sample. The logistic regression model that included age, gender and obesity, showed an odds ratio of uric acid as a variable associated with insulin resistance of 1.91 (95%CI 1.40 to 2.62; p<-0.001). The increase in serum uric acid showed a positive statistical correlation with insulin resistance and it is associated with and increased risk of insulin resistance in obese children and adolescents. Copyright © 2015 Sociedade de Pediatria de São Paulo. Publicado por Elsevier Editora Ltda. All rights reserved.

  3. Obesity, insulin resistance, and type 1 diabetes mellitus.

    PubMed

    Polsky, Sarit; Ellis, Samuel L

    2015-08-01

    To summarize recent studies about obesity, insulin resistance, and type 1 diabetes mellitus (T1DM). Overweight and obesity continue to be prevalent among individuals with T1DM. Obesity rates appear to have reached a plateau among children with T1DM in some parts of the world. The risk for development of T1DM is increased by obesity and may occur at an earlier age among obese individuals with a predisposition. Obesity increases the risk for comorbidities among individuals with T1DM, especially metabolic syndrome, and microvascular and macrovascular diseases. Metformin, glucagon-like peptide-1 agonist therapy, sodium glucose cotransporter-2 inhibitor therapy, and bariatric surgery may be beneficial therapies for glucose control, comorbidity management, and obesity among adults with T1DM. Insulin resistance may be improved among obese individuals with T1DM by biguanides (metformin) and glucagon-like peptide-1 agonists (exenatide). We review the last 18 months of literature on obesity, insulin resistance, and T1DM to highlight new epidemiologic results and treatments.

  4. SEX DIFFERENCES IN THE ASSOCIATION BETWEEN DIETARY RESTRAINT, INSULIN RESISTANCE AND OBESITY

    PubMed Central

    Jastreboff, Ania M.; Gaiser, Edward C.; Gu, Peihua; Sinha, Rajita

    2014-01-01

    Background & Aims Restrained food consumption may alter metabolic function and contribute to eventual weight gain; however, sex differences in these relationships have not been assessed. The objective of this study was to examine the relationship between restrained eating and insulin resistance and the influence of body mass index and sex on this relationship in a large community sample of both men and women. We hypothesized that restrained eating would be related to insulin resistance and this relationship would be influenced by sex and body mass index. Methods In this cross-sectional, observational study, we studied 487 individuals from the community (men N=222, women N=265), who ranged from lean (body mass index 18.5–24.9kg/m2, N=173), overweight (body mass index 25–29.9kg/m2, N=159) and obese (body mass index >30kg/m2, N=155) weight categories. We assessed restrained eating using the Dutch Eating Behavior Questionnaire and obtained fasting morning plasma insulin and glucose on all subjects. Results In men, but not in women, restrained eating was related to homeostatic model assessment of insulin resistance (HOMA-IR) (p<0.0001). Furthermore, homeostatic model assessment of insulin resistance levels were significantly higher in men who were high-versus low-restrained eaters (p=0.0006). Conclusions This study is the first to report sex differences with regard to the relationship between restrained eating and insulin resistance. Our results suggest that high restraint eating is associated with insulin resistance in men but not in women. PMID:24854820

  5. Association between insulin resistance and preeclampsia in obese non-diabetic women receiving metformin.

    PubMed

    Balani, Jyoti; Hyer, Steve; Syngelaki, Argyro; Akolekar, Ranjit; Nicolaides, Kypros H; Johnson, Antoinette; Shehata, Hassan

    2017-12-01

    To examine whether the reduced incidence of preeclampsia in non-diabetic obese pregnant women treated with metformin is mediated by changes in insulin resistance. This was a secondary analysis of obese pregnant women in a randomised trial (MOP trial). Fasting plasma glucose and insulin were measured in 384 of the 400 women who participated in the MOP trial. Homeostasis model assessment of insulin resistance (HOMA-IR) was compared in the metformin and placebo groups and in those that developed preeclampsia versus those that did not develop preeclampsia. At 28 weeks, median HOMA-IR was significantly lower in the metformin group. Logistic regression analysis demonstrated that there was a significant contribution in the prediction of preeclampsia from maternal history of chronic hypertension and gestational weight gain, but not HOMA-IR either at randomisation ( p  = 0.514) or at 28 weeks ( p  = 0.643). Reduced incidence of preeclampsia in non-diabetic obese pregnant women treated with metformin is unlikely to be due to changes in insulin resistance.

  6. Evaluation of Mn-superoxide dismutase and catalase gene expression in childhood obesity: its association with insulin resistance.

    PubMed

    Mohseni, Roohollah; Arab Sadeghabadi, Zahra; Goodarzi, Mohammad Taghi; Teimouri, Maryam; Nourbakhsh, Mitra; Razzaghy Azar, Maryam

    2018-06-28

    Obesity is associated with oxidative stress. Superoxide dismutase (SOD) is the first line of defense against reactive oxygen species (ROS), eliminating the strong superoxide radical and producing H2O2, which can then be degraded by catalase (CAT). The main objective of this study was to evaluate the gene expression antioxidant enzymes (Mn-SOD and CAT) in peripheral blood mononuclear cells (PBMCs) of obese and normal-weight children, and its association with anthropometric and biochemical parameters. Thirty obese and 30 control subjects between the ages of 8 and 16 years were enrolled in this study. Serum insulin levels were measured using enzyme-linked immunosorbent assay (ELISA), and insulin resistance was calculated using the homeostasis model assessment of insulin resistance (HOMA-IR). Biochemical parameters were also measured. PBMCs of the subjects were separated and Mn-SOD and CAT gene expression was measured using real-time polymerase chain reaction (PCR). Mn-SOD and CAT gene expression was significantly lower in the obese group compared with the control group (p<0.01). Also, a positive correlation was observed between the gene expression of Mn-SOD and CAT and body mass index (BMI), fasting blood sugar, insulin resistance, low density lipoprotein-cholesterol (LDL-C) cholesterol, triglycerides (TG) and systolic blood pressure (SBP). Induction of antioxidants, especially Mn-SOD and CAT, can lead to reduction of oxidative stress and prevent the complications of obesity in children.

  7. Familial juvenile autoimmune hypothyroidism, pituitary enlargement, obesity, and insulin resistance.

    PubMed

    Reutrakul, Sirimon; Hathout, Eba H; Janner, Donald; Hara, Manami; Donfack, Joseph; Bass, Joseph; Refetoff, Samuel

    2004-04-01

    The proband, a 9-year-old Hispanic female, presented with hair loss, strabismus, and weight gain. On magnetic resonance imaging (MRI) she was found to have severe primary hypothyroidism and a large pituitary mass. In addition, acanthosis nigricans, obesity, and hyperinsulinism were observed. Findings were similar in three of four siblings. Thyroid peroxidase antibodies were detected in the father and three of four siblings. Although all family members were obese, and hyperinsulinemia with high proinsulin and C-peptide was found in all except one sibling, only the mother and one child had overt type 2 diabetes mellitus. Because of the unusual association of autoimmune thyroid disease, insulin resistance and obesity rather than insulin deficiency, we searched for possible genetic abnormalities. The HLA haplotypes did not cosegregate with autoimmune thyroid disease or insulin resistance. Mutational analysis of known obesity genes was done. Leptin was not deficient, and sequencing of the proband's DNA showed no mutations in the perixisome proliferator activated receptor (PPAR)-gamma, PPAR-gamma(2), PPAR-alpha or melanocortin 4 receptor genes. Maternally inherited diabetes and deafness was ruled out since no mutations were found in mitochondria DNA. Insulin receptor antibodies were not detected. In conclusion, the remarkably high incidence of childhood autoimmune hypothyroidism, pituitary enlargement, insulin resistance and obesity in this family is not linked to known HLA types or known gene defects.

  8. Deletion of Skeletal Muscle SOCS3 Prevents Insulin Resistance in Obesity

    PubMed Central

    Jorgensen, Sebastian Beck; O’Neill, Hayley M.; Sylow, Lykke; Honeyman, Jane; Hewitt, Kimberly A.; Palanivel, Rengasamy; Fullerton, Morgan D.; Öberg, Lisa; Balendran, Anudharan; Galic, Sandra; van der Poel, Chris; Trounce, Ian A.; Lynch, Gordon S.; Schertzer, Jonathan D.; Steinberg, Gregory R.

    2013-01-01

    Obesity is associated with chronic low-grade inflammation that contributes to defects in energy metabolism and insulin resistance. Suppressor of cytokine signaling (SOCS)-3 expression is increased in skeletal muscle of obese humans. SOCS3 inhibits leptin signaling in the hypothalamus and insulin signal transduction in adipose tissue and the liver. Skeletal muscle is an important tissue for controlling energy expenditure and whole-body insulin sensitivity; however, the physiological importance of SOCS3 in this tissue has not been examined. Therefore, we generated mice that had SOCS3 specifically deleted in skeletal muscle (SOCS MKO). The SOCS3 MKO mice had normal muscle development, body mass, adiposity, appetite, and energy expenditure compared with wild-type (WT) littermates. Despite similar degrees of obesity when fed a high-fat diet, SOCS3 MKO mice were protected against the development of hyperinsulinemia and insulin resistance because of enhanced skeletal muscle insulin receptor substrate 1 (IRS1) and Akt phosphorylation that resulted in increased skeletal muscle glucose uptake. These data indicate that skeletal muscle SOCS3 does not play a critical role in regulating muscle development or energy expenditure, but it is an important contributing factor for inhibiting insulin sensitivity in obesity. Therapies aimed at inhibiting SOCS3 in skeletal muscle may be effective in reversing obesity-related glucose intolerance and insulin resistance. PMID:22961088

  9. NK cells link obesity-induced adipose stress to inflammation and insulin resistance.

    PubMed

    Wensveen, Felix M; Jelenčić, Vedrana; Valentić, Sonja; Šestan, Marko; Wensveen, Tamara Turk; Theurich, Sebastian; Glasner, Ariella; Mendrila, Davor; Štimac, Davor; Wunderlich, F Thomas; Brüning, Jens C; Mandelboim, Ofer; Polić, Bojan

    2015-04-01

    An important cause of obesity-induced insulin resistance is chronic systemic inflammation originating in visceral adipose tissue (VAT). VAT inflammation is associated with the accumulation of proinflammatory macrophages in adipose tissue, but the immunological signals that trigger their accumulation remain unknown. We found that a phenotypically distinct population of tissue-resident natural killer (NK) cells represented a crucial link between obesity-induced adipose stress and VAT inflammation. Obesity drove the upregulation of ligands of the NK cell-activating receptor NCR1 on adipocytes; this stimulated NK cell proliferation and interferon-γ (IFN-γ) production, which in turn triggered the differentiation of proinflammatory macrophages and promoted insulin resistance. Deficiency of NK cells, NCR1 or IFN-γ prevented the accumulation of proinflammatory macrophages in VAT and greatly ameliorated insulin sensitivity. Thus NK cells are key regulators of macrophage polarization and insulin resistance in response to obesity-induced adipocyte stress.

  10. Elevated circulating irisin is associated with lower risk of insulin resistance: association and path analyses of obese Chinese adults.

    PubMed

    Shi, Xiulin; Lin, Mingzhu; Liu, Changqin; Xiao, Fangsen; Liu, Yongwen; Huang, Peiying; Zeng, Xin; Yan, Bing; Liu, Suhuan; Li, Xiaoying; Yang, Shuyu; Li, Xuejun; Li, Zhibin

    2016-07-29

    Evidence on the role of irisin in insulin resistance is limited and controversial, and pathways between them remain unknown. We aimed to examine the independent effects of circulating irisin and different adiposity measurements, as well as their potential interactions, on insulin resistance. We also aimed to explore possible pathways among circulating irisin, adiposity, glucose and insulin levels and insulin resistance. A cross-sectional study of 1,115 community- living obese Chinese adults, with data collection on clinical characteristics, glucose and lipid metabolic parameters and circulating irisin levels. Among the 1,115 subjects, 667 (59.8 %) were identified as insulin-resistance, and showed significantly decreased serum irisin than their controls (log-transformed irisin: 1.19 ± 2.34 v.s. 1.46 ± 2.05 ng/ml, p = 0.042). With adjustment for potential confounders, elevated circulating irisin was significantly associated with reduced risk of insulin resistance, with adjusted odds ratio per standard deviation increase of irisin of 0.871 (0.765-0.991, p = 0.036). As for different adiposity measurements, body fat percentage, but neither BMI nor waist, was significantly associated with increased risk of insulin resistance (OR: 1.152 (1.041-1.275), p = 0.006). No significant interaction effect between serum irisin and adiposity on insulin resistance was found. A one pathway model about the relationship between serum irisin and insulin resistance fits well (χ (2) = 44.09, p < 0.001; CFI-0.994; TLI =0.986; and RMSEA = 0.067), and shows that elevated circulating irisin might improve insulin resistance indirectly through lowering fasting insulin levels (standardized path coefficient = -0.046, p = 0.032). Elevated circulating irisin is associated with lower risk of insulin resistance indirectly through lowering fasting insulin.

  11. Sex differences in the association between dietary restraint, insulin resistance and obesity.

    PubMed

    Jastreboff, Ania M; Gaiser, Edward C; Gu, Peihua; Sinha, Rajita

    2014-04-01

    Restrained food consumption may alter metabolic function and contribute to eventual weight gain; however, sex differences in these relationships have not been assessed. The objective of this study was to examine the relationship between restrained eating and insulin resistance and the influence of body mass index and sex on this relationship in a large community sample of both men and women. We hypothesized that restrained eating would be related to insulin resistance and this relationship would be influenced by sex and body mass index. In this cross-sectional, observational study, we studied 487 individuals from the community (men N = 222, women N = 265), who ranged from lean (body mass index 18.5-24.9 kg/m(2), N = 173), overweight (body mass index 25-29.9 kg/m(2), N = 159) to obese (body mass index >30 kg/m(2), N = 155) weight categories. We assessed restrained eating using the Dutch Eating Behavior Questionnaire and obtained fasting morning plasma insulin and glucose on all subjects. In men, but not in women, restrained eating was related to homeostatic model assessment of insulin resistance (HOMA-IR) (p < 0.0001). Furthermore, HOMA-IR was significantly higher in men who were high- versus low-restrained eaters (p = 0.0006). This study is the first to report sex differences with regard to the relationship between restrained eating and insulin resistance. Our results suggest that high restrained eating is associated with insulin resistance in men but not in women. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Differences in Cardiometabolic Risk between Insulin-Sensitive and Insulin-Resistant Overweight and Obese Children.

    PubMed

    Khan, Unab I; McGinn, Aileen P; Isasi, Carmen R; Groisman-Perelstein, Adriana; Diamantis, Pamela M; Ginsberg, Mindy; Wylie-Rosett, Judith

    2015-06-01

    It is known that 15-30% overweight/obese adults do not suffer cardiometabolic consequences. There is limited literature examining factors that can be used to assess cardiometabolic health in overweight/obese children. If such factors can be identified, they would aid in differentiating those most in need for aggressive management. Baseline data from 7- to 12-year-old, overweight, and obese children enrolled in a weight management program at an urban hospital were analyzed. Homeostatic model assessment for insulin resistance (HOMA-IR) <2.6 was used to define insulin-sensitive and HOMA-IR ≥2.6 was used to defined insulin-resistant participants. Demographics, physical activity measures, and cardiometabolic risk factors were compared between the two phenotypes. Odds ratios (ORs) examining the association between intermediate endpoints (metabolic syndrome [MetS], nonalcoholic fatty liver disease [NAFLD], systemic inflammation, and microalbuminuria) and the two metabolic phenotypes were evaluated. Of the 362 overweight/obese participants, 157 (43.5%) were insulin sensitive and 204 (56.5%) were insulin resistant. Compared to the insulin-sensitive group, the insulin-resistant group was older (8.6±1.6 vs. 9.9±1.7; p<0.001) and had a higher BMI z-score (1.89±0.42 vs. 2.04±0.42; p=0.001). After multivariable adjustment, compared to the insulin-sensitive group, the insulin-resistant group had higher odds of having MetS (OR, 5.47; 95% confidence interval [CI]: 1.72, 17.35; p=0.004) and NAFLD (OR, 8.66; 95% CI, 2.48, 30.31; p=0.001), but not systemic inflammation (OR, 1.06; 95% CI: 0.56, 2.03; p=0.86) or microalbuminuria (OR, 1.71; 95% CI, 0.49, 6.04; p=0.403). Using a HOMA-IR value of ≥2.6, clinical providers can identify prepubertal and early pubertal children most at risk. Focusing limited resources on aggressive weight interventions may lead to improvement in cardiometabolic health.

  13. Associations of vitamin D with insulin resistance, obesity, type 2 diabetes, and metabolic syndrome.

    PubMed

    Wimalawansa, Sunil J

    2018-01-01

    The aim of this study is to determine the relationships of vitamin D with diabetes, insulin resistance obesity, and metabolic syndrome. Intra cellular vitamin D receptors and the 1-α hydroxylase enzyme are distributed ubiquitously in all tissues suggesting a multitude of functions of vitamin D. It plays an indirect but an important role in carbohydrate and lipid metabolism as reflected by its association with type 2 diabetes (T2D), metabolic syndrome, insulin secretion, insulin resistance, polycystic ovarian syndrome, and obesity. Peer-reviewed papers, related to the topic were extracted using key words, from PubMed, Medline, and other research databases. Correlations of vitamin D with diabetes, insulin resistance and metabolic syndrome were examined for this evidence-based review. In addition to the well-studied musculoskeletal effects, vitamin D decreases the insulin resistance, severity of T2D, prediabetes, metabolic syndrome, inflammation, and autoimmunity. Vitamin D exerts autocrine and paracrine effects such as direct intra-cellular effects via its receptors and the local production of 1,25(OH) 2 D 3 , especially in muscle and pancreatic β-cells. It also regulates calcium homeostasis and calcium flux through cell membranes, and activation of a cascade of key enzymes and cofactors associated with metabolic pathways. Cross-sectional, observational, and ecological studies reported inverse correlations between vitamin D status with hyperglycemia and glycemic control in patients with T2D, decrease the rate of conversion of prediabetes to diabetes, and obesity. However, no firm conclusions can be drawn from current studies, because (A) studies were underpowered; (B) few were designed for glycemic outcomes, (C) the minimum (or median) serum 25(OH) D levels achieved are not measured or reported; (D) most did not report the use of diabetes medications; (E) some trials used too little (F) others used too large, unphysiological and infrequent doses of vitamin D; and

  14. Ordovas-Oxidized LDL is associated with metabolic syndrome traits independently of central obesity and insulin resistance

    USDA-ARS?s Scientific Manuscript database

    This study assesses whether oxidative stress, using oxidized LDL (ox-LDL) as a proxy, is associated with metabolic syndrome (MS), whether ox-LDL mediates the association between central obesity and MS, and whether insulin resistance mediates the association between ox-LDL and MS. We examined baselin...

  15. Lipocalin-2 Deficiency Attenuates Insulin Resistance Associated With Aging and Obesity

    PubMed Central

    Law, Ivy K.M.; Xu, Aimin; Lam, Karen S.L.; Berger, Thorsten; Mak, Tak W.; Vanhoutte, Paul M.; Liu, Jacky T.C.; Sweeney, Gary; Zhou, Mingyan; Yang, Bo; Wang, Yu

    2010-01-01

    OBJECTIVE The proinflammatory cytokines/adipokines produced from adipose tissue act in an autocrine and/or endocrine manner to perpetuate local inflammation and to induce peripheral insulin resistance. The present study investigates whether lipocalin-2 deficiency or replenishment with this adipokine has any impact on systemic insulin sensitivity and the underlying mechanisms. METHODS AND RESULTS Under conditions of aging or dietary-/genetic-induced obesity, lipocalin-2 knockout (Lcn2-KO) mice show significantly decreased fasting glucose and insulin levels and improved insulin sensitivity compared with their wild-type littermates. Despite enlarged fat mass, inflammation and the accumulation of lipid peroxidation products are significantly attenuated in the adipose tissues of Lcn2-KO mice. Adipose fatty acid composition of these mice varies significantly from that in wild-type animals. The amounts of arachidonic acid (C20:4 n6) are elevated by aging and obesity and are paradoxically further increased in adipose tissue, but not skeletal muscle and liver of Lcn2-KO mice. On the other hand, the expression and activity of 12-lipoxygenase, an enzyme responsible for metabolizing arachidonic acid, and the production of tumor necrosis factor-α (TNF-α), a critical insulin resistance–inducing factor, are largely inhibited by lipocalin-2 deficiency. Lipocalin-2 stimulates the expression and activity of 12-lipoxygenase and TNF-α production in fat tissues. Cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC), an arachidonate lipoxygenase inhibitor, prevents TNF-α expression induced by lipocalin-2. Moreover, treatment with TNF-α neutralization antibody or CDC significantly attenuated the differences of insulin sensitivity between wild-type and Lcn2-KO mice. CONCLUSIONS Lipocalin-2 deficiency protects mice from developing aging- and obesity-induced insulin resistance largely by modulating 12-lipoxygenase and TNF-α levels in adipose tissue. PMID:20068130

  16. Greater physical activity levels during pregnancy are associated with lower inflammation and insulin resistance in obese women

    USDA-ARS?s Scientific Manuscript database

    Compared to lean pregnant women, obese women develop greater insulin resistance and systemic inflammation during pregnancy. Identifying lifestyle factors that can reduce the metabolic effect of obesity during pregnancy is critical to protect both the mother and the fetus from insulin resistance and ...

  17. The relationship between insulin resistance and endothelial dysfunction in obese adolescents.

    PubMed

    Brar, Preneet Cheema; Patel, Payal; Katz, Stuart

    2017-05-24

    Insulin resistance and endothelial dysfunction share a reciprocal relationship that links the metabolic and cardiovascular sequelae of obesity. We characterized the brachial artery reactivity testing (BART) and carotid artery-intima media thickness (CIMT) in adolescents categorized as obese insulin resistant (OIR) and obese not insulin resistant (ONIR). Lipoprotein particle (p) analysis and inflammatory cytokines in OIR and ONIR groups were also analyzed. Obese adolescents (n=40; mean body mass index [BMI] 35.6) were categorized as ONIR and OIR based on their homeostatic model assessment of insulin resistance (HOMA-IR) calculation (≤or> than 3.4). Ultrasound measured conduit arterial function BART, microvascular function (post-ischemic hyperemia) and conduit artery structure CIMT. BART did not differ according to IR status (mean±SD: 7.0±4.3% vs. 5.9±3.4% in ONIR and OIR, respectively, p=0.3, but post-ischemic hyperemia was significantly greater in the ONIR group (4.5±2.2 vs. 3.5±3, p=0.04). Atherogenic lipoprotein particles; large VLDL particles and small LDL particles were higher in the OIR compared to ONIR group. OIR adolescents demonstrate an inflamed atherogenic milieu compared to the ONIR adolescents. Microvascular function, but not conduit vessel structure or function, was impaired in association with IR.

  18. Levels of eicosapentaenoic acid in obese schoolchildren with and without insulin resistance.

    PubMed

    Sánchez Meza, Karmina; Tene Pérez, Carlos Enrique; Sánchez Ramírez, Carmen Alicia; Muñiz Valencia, Roberto; Del Toro Equihua, Mario

    2014-09-12

    Obesity in children is now an increasing health risk worldwide in which the insulin-resistance can be present. Studies have linked a diet rich in n-3 fatty acids with a lower prevalence of insulin-resistance. To compare the levels of eicosapentaenoic acid among obese children with and without insulin-resistance. In 56 randomly school-age children with obesity, insulin-resistance was determined by the homeostasis model assessment for insulin-resistance index and the serum levels of eicosapentaenoic acid were determined by gas chromatography. Insulin-resistance was established when the index was >6.0, non- insulin- resistance when that index was within the range of 1.4-5.9. The serum levels of eicosapentaenoic acid were compared with the Kruskal-Wallis and Mann-Whitney U tests, as needed. No differences in age or sex were identified among the groups studied. The anthropometric parameters were significantly higher in the group of children with insulin-resistance than in the other two groups. The children with insulin- resistance had significantly lower levels of eicosapentaenoic acid than the non- insulin-resistance group [12.4% area under the curve vs. 37.4%, p = 0.031], respectively. Obese primary school-aged children with insulin-resistance had lower plasma levels of eicosapentaenoic acid. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

  19. Weight-adjusted lean body mass and calf circumference are protective against obesity-associated insulin resistance and metabolic abnormalities.

    PubMed

    Takamura, Toshinari; Kita, Yuki; Nakagen, Masatoshi; Sakurai, Masaru; Isobe, Yuki; Takeshita, Yumie; Kawai, Kohzo; Urabe, Takeshi; Kaneko, Shuichi

    2017-07-01

    To test the hypothesis that preserved muscle mass is protective against obesity-associated insulin resistance and metabolic abnormalities, we analyzed the relationship of lean body mass and computed tomography-assessed sectional areas of specific skeletal muscles with insulin resistance and metabolic abnormalities in a healthy cohort. A total of 195 subjects without diabetes who had completed a medical examination were included in this study. Various anthropometric indices such as circumferences of the arm, waist, hip, thigh, and calf were measured. Body composition (fat and lean body mass) was determined by bioelectrical impedance analysis. Sectional areas of specific skeletal muscles (iliopsoas, erector spinae, gluteus, femoris, and rectus abdominis muscles) were measured using computed tomography. Fat and lean body mass were significantly correlated with metabolic abnormalities and insulin resistance indices. When adjusted by weight, relationships of fat and lean body mass with metabolic parameters were mirror images of each other. The weight-adjusted lean body mass negatively correlated with systolic and diastolic blood pressures; fasting plasma glucose, HbA1c, alanine aminotransferase, and triglyceride, and insulin levels; and hepatic insulin resistance indices, and positively correlated with HDL-cholesterol levels and muscle insulin sensitivity indices. Compared with weight-adjusted lean body mass, weight-adjusted sectional areas of specific skeletal muscles showed similar, but not as strong, correlations with metabolic parameters. Among anthropometric measures, the calf circumference best reflected lean body mass, and weight-adjusted calf circumference negatively correlated with metabolic abnormalities and insulin resistance indices. Weight-adjusted lean body mass and skeletal muscle area are protective against weight-associated insulin resistance and metabolic abnormalities. The calf circumference reflects lean body mass and may be useful as a protective

  20. Recent Advances in Obesity-Induced Inflammation and Insulin Resistance

    PubMed Central

    Tateya, Sanshiro; Kim, Francis; Tamori, Yoshikazu

    2013-01-01

    It has been demonstrated in rodents and humans that chronic inflammation characterized by macrophage infiltration occurs mainly in adipose tissue or liver during obesity, in which activation of immune cells is closely associated with insulin sensitivity. Macrophages can be classified as classically activated (M1) macrophages that support microbicidal activity or alternatively activated (M2) macrophages that support allergic and antiparasitic responses. In the context of insulin action, M2 macrophages sustain insulin sensitivity by secreting IL-4 and IL-10, while M1 macrophages induce insulin resistance through the secretion of proinflammatory cytokines, such as TNFα. Polarization of M1/M2 is controlled by various dynamic functions of other immune cells. It has been demonstrated that, in a lean state, TH2 cells, Treg cells, natural killer T cells, or eosinophils contribute to the M2 activation of macrophages by secreting IL-4 or IL-10. In contrast, obesity causes alteration of the constituent immune cells, in which TH1 cells, B cells, neutrophils, or mast cells induce M1 activation of macrophages by the elevated secretion of TNFα and IFNγ. Increased secretion of TNFα and free fatty acids from hypertrophied adipocytes also contributes to the M1 activation of macrophages. Since obesity-induced insulin resistance is established by macrophage infiltration and the activation of immune cells inside tissues, identification of the factors that regulate accumulation and the intracellular signaling cascades that define polarization of M1/M2 would be indispensable. Regulation of these factors would lead to the pharmacological inhibition of obesity-induced insulin resistance. In this review, we introduce molecular mechanisms relevant to the pathophysiology and review the most recent studies of clinical applications targeting chronic inflammation. PMID:23964268

  1. The effect of insulin resistance and exercise on the percentage of CD16(+) monocyte subset in obese individuals.

    PubMed

    de Matos, Mariana A; Duarte, Tamiris C; Ottone, Vinícius de O; Sampaio, Pâmela F da M; Costa, Karine B; de Oliveira, Marcos F Andrade; Moseley, Pope L; Schneider, Suzanne M; Coimbra, Cândido C; Brito-Melo, Gustavo E A; Magalhães, Flávio de C; Amorim, Fabiano T; Rocha-Vieira, Etel

    2016-06-01

    Obesity is a low-grade chronic inflammation condition, and macrophages, and possibly monocytes, are involved in the pathological outcomes of obesity. Physical exercise is a low-cost strategy to prevent and treat obesity, probably because of its anti-inflammatory action. We evaluated the percentage of CD16(-) and CD16(+) monocyte subsets in obese insulin-resistant individuals and the effect of an exercise bout on the percentage of these cells. Twenty-seven volunteers were divided into three experimental groups: lean insulin sensitive, obese insulin sensitive and obese insulin resistant. Venous blood samples collected before and 1 h after an aerobic exercise session on a cycle ergometer were used for determination of monocyte subsets by flow cytometry. Insulin-resistant obese individuals have a higher percentage of CD16(+) monocytes (14.8 ± 2.4%) than the lean group (10.0 ± 1.3%). A positive correlation of the percentage of CD16(+) monocytes with body mass index and fasting plasma insulin levels was found. One bout of moderate exercise reduced the percentage of CD16(+) monocytes by 10% in all the groups evaluated. Also, the absolute monocyte count, as well as all other leukocyte populations, in lean and obese individuals, increased after exercise. This fact may partially account for the observed reduction in the percentage of CD16(+) cells in response to exercise. Insulin-resistant, but not insulin-sensitive obese individuals, have an increased percentage of CD16(+) monocytes that can be slightly modulated by a single bout of moderate aerobic exercise. These findings may be clinically relevant to the population studied, considering the involvement of CD16(+) monocytes in the pathophysiology of obesity. Copyright © 2016 John Wiley & Sons, Ltd. Obesity is now considered to be an inflammatory condition associated with many pathological consequences, including insulin resistance. It is proposed that insulin resistance contributes to the aggravation of the

  2. Insulin resistance in obesity as the underlying cause for the metabolic syndrome.

    PubMed

    Gallagher, Emily J; Leroith, Derek; Karnieli, Eddy

    2010-01-01

    The metabolic syndrome affects more than a third of the US population, predisposing to the development of type 2 diabetes and cardiovascular disease. The 2009 consensus statement from the International Diabetes Federation, American Heart Association, World Heart Federation, International Atherosclerosis Society, International Association for the Study of Obesity, and the National Heart, Lung, and Blood Institute defines the metabolic syndrome as 3 of the following elements: abdominal obesity, elevated blood pressure, elevated triglycerides, low high-density lipoprotein cholesterol, and hyperglycemia. Many factors contribute to this syndrome, including decreased physical activity, genetic predisposition, chronic inflammation, free fatty acids, and mitochondrial dysfunction. Insulin resistance appears to be the common link between these elements, obesity and the metabolic syndrome. In normal circumstances, insulin stimulates glucose uptake into skeletal muscle, inhibits hepatic gluconeogenesis, and decreases adipose-tissue lipolysis and hepatic production of very-low-density lipoproteins. Insulin signaling in the brain decreases appetite and prevents glucose production by the liver through neuronal signals from the hypothalamus. Insulin resistance, in contrast, leads to the release of free fatty acids from adipose tissue, increased hepatic production of very-low-density lipoproteins and decreased high-density lipoproteins. Increased production of free fatty acids, inflammatory cytokines, and adipokines and mitochondrial dysfunction contribute to impaired insulin signaling, decreased skeletal muscle glucose uptake, increased hepatic gluconeogenesis, and β cell dysfunction, leading to hyperglycemia. In addition, insulin resistance leads to the development of hypertension by impairing vasodilation induced by nitric oxide. In this review, we discuss normal insulin signaling and the mechanisms by which insulin resistance contributes to the development of the metabolic

  3. The triglyceride-to-HDL cholesterol ratio: association with insulin resistance in obese youths of different ethnic backgrounds.

    PubMed

    Giannini, Cosimo; Santoro, Nicola; Caprio, Sonia; Kim, Grace; Lartaud, Derek; Shaw, Melissa; Pierpont, Bridget; Weiss, Ram

    2011-08-01

    We evaluated whether the triglyceride-to-HDL cholesterol (TG/HDL-C) ratio is associated with insulin resistance (IR) in a large multiethnic cohort of obese youths. Obese youths (1,452) had an oral glucose tolerance test and a fasting lipid profile. Insulin sensitivity was estimated using the whole body insulin sensitivity index (WBISI) and homeostasis model assessment (HOMA)-IR and evaluated, in a subgroup of 146 obese youths, by the hyperinsulinemic-euglycemic clamp. The cohort was divided by ethnicity (612 whites, 357 Hispanics, and 483 African Americans) and then stratified into ethnicity-specific tertiles of TG/HDL-C ratio. Differences across tertiles were evaluated, and the association between the TG/HDL-C ratio and insulin sensitivity (WBISI) was defined by a multiple stepwise linear regression analysis. The area under the receiver operating characteristic (ROC) curve (AUC) was determined to calculate the TG/HDL-C ratio cutoff to identify insulin-resistant subjects by ethnicity. In each ethnic group and across rising tertiles of TG/HDL-C ratio, insulin sensitivity (WBISI) progressively decreased, whereas 2-h glucose and the AUC-glucose progressively increased. The cutoff for TG/HDL-C ratio was 2.27, and the odds of presenting with IR, in youths with TG/HDL-C ratio higher than the cutoff, was 6.023 (95% CI 2.798-12.964; P < 0.001) in white girls and boys, whereas for both Hispanics and African Americans the AUC-ROCs were not significant, thus not allowing the calculation of an optimal cutoff TG/HDL-C value. The TG/HDL-C ratio is associated with IR mainly in white obese boys and girls and thus may be used with other risk factors to identify subjects at increased risk of IR-driven morbidity.

  4. Obesity-induced DNA released from adipocytes stimulates chronic adipose tissue inflammation and insulin resistance.

    PubMed

    Nishimoto, Sachiko; Fukuda, Daiju; Higashikuni, Yasutomi; Tanaka, Kimie; Hirata, Yoichiro; Murata, Chie; Kim-Kaneyama, Joo-Ri; Sato, Fukiko; Bando, Masahiro; Yagi, Shusuke; Soeki, Takeshi; Hayashi, Tetsuya; Imoto, Issei; Sakaue, Hiroshi; Shimabukuro, Michio; Sata, Masataka

    2016-03-01

    Obesity stimulates chronic inflammation in adipose tissue, which is associated with insulin resistance, although the underlying mechanism remains largely unknown. Here we showed that obesity-related adipocyte degeneration causes release of cell-free DNA (cfDNA), which promotes macrophage accumulation in adipose tissue via Toll-like receptor 9 (TLR9), originally known as a sensor of exogenous DNA fragments. Fat-fed obese wild-type mice showed increased release of cfDNA, as determined by the concentrations of single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) in plasma. cfDNA released from degenerated adipocytes promoted monocyte chemoattractant protein-1 (MCP-1) expression in wild-type macrophages, but not in TLR9-deficient (Tlr9 (-/-) ) macrophages. Fat-fed Tlr9 (-/-) mice demonstrated reduced macrophage accumulation and inflammation in adipose tissue and better insulin sensitivity compared with wild-type mice, whereas bone marrow reconstitution with wild-type bone marrow restored the attenuation of insulin resistance observed in fat-fed Tlr9 (-/-) mice. Administration of a TLR9 inhibitory oligonucleotide to fat-fed wild-type mice reduced the accumulation of macrophages in adipose tissue and improved insulin resistance. Furthermore, in humans, plasma ssDNA level was significantly higher in patients with computed tomography-determined visceral obesity and was associated with homeostasis model assessment of insulin resistance (HOMA-IR), which is the index of insulin resistance. Our study may provide a novel mechanism for the development of sterile inflammation in adipose tissue and a potential therapeutic target for insulin resistance.

  5. Serum progranulin levels in relation to insulin resistance in childhood obesity.

    PubMed

    Alissa, Eman M; Sutaih, Rima H; Kamfar, Hayat Z; Alagha, Abdulmoeen E; Marzouki, Zuhair M

    2017-11-27

    Progranulin is an adipokine that is involved in the inflammatory response, glucose metabolism, insulin resistance, and may therefore be involved in chronic subclinical inflammation associated with the pathogenesis of childhood obesity. We aimed to investigate the association of circulating progranulin levels with metabolic parameters in children and to assess the importance of progranulin as a biomarker for metabolic diseases. A total of 150 children were consecutively recruited from the Pediatric Nutrition Clinics at King Abdulaziz University Hospital in Jeddah, Saudi Arabia. Children were classified into four groups based on quartile for serum progranulin. Anthropometric variables were measured in all study subjects. Fasting blood samples were collected for measurement of blood glucose, insulin and lipid profile. Children within the upper quartile for serum progranulin concentration were heavier, more insulin resistant and had higher concentrations of serum total cholesterol, triglycerides, insulin and high sensitivity C reactive protein compared to those in the lower quartile. On correlation analysis, serum progranulin concentrations were significantly related to general and central adiposity, metabolic parameters, markers of inflammation and insulin resistance. Stepwise multiple regression showed that 26.6% of the variability in serum progranulin could be explained by measures of adiposity. The increased serum progranulin concentrations were closely related to measures of adiposity, metabolic parameters, inflammatory marker and insulin resistance indices, suggesting that progranulin may be an excellent biomarker for obesity in childhood.

  6. Defective calcium inactivation causes long QT in obese insulin-resistant rat.

    PubMed

    Lin, Yen-Chang; Huang, Jianying; Kan, Hong; Castranova, Vincent; Frisbee, Jefferson C; Yu, Han-Gang

    2012-02-15

    The majority of diabetic patients who are overweight or obese die of heart disease. We suspect that the obesity-induced insulin resistance may lead to abnormal cardiac electrophysiology. We tested this hypothesis by studying an obese insulin-resistant rat model, the obese Zucker rat (OZR). Compared with the age-matched control, lean Zucker rat (LZR), OZR of 16-17 wk old exhibited an increase in QTc interval, action potential duration, and cell capacitance. Furthermore, the L-type calcium current (I(CaL)) in OZR exhibited defective inactivation and lost the complete inactivation back to the closed state, leading to increased Ca(2+) influx. The current density of I(CaL) was reduced in OZR, whereas the threshold activation and the current-voltage relationship of I(CaL) were not significantly altered. L-type Ba(2+) current (I(BaL)) in OZR also exhibited defective inactivation, and steady-state inactivation was not significantly altered. However, the current-voltage relationship and activation threshold of I(BaL) in OZR exhibited a depolarized shift compared with LZR. The total and membrane protein expression levels of Cav1.2 [pore-forming subunit of L-type calcium channels (LTCC)], but not the insulin receptors, were decreased in OZR. The insulin receptor was found to be associated with the Cav1.2, which was weakened in OZR. The total protein expression of calmodulin was reduced, but that of Cavβ2 subunit was not altered in OZR. Together, these results suggested that the 16- to 17-wk-old OZR has 1) developed cardiac hypertrophy, 2) exhibited altered electrophysiology manifested by the prolonged QTc interval, 3) increased duration of action potential in isolated ventricular myocytes, 4) defective inactivation of I(CaL) and I(BaL), 5) weakened the association of LTCC with the insulin receptor, and 6) decreased protein expression of Cav1.2 and calmodulin. These results also provided mechanistic insights into a remodeled cardiac electrophysiology under the condition of

  7. Liver attenuation, pericardial adipose tissue, obesity, and insulin resistance: the Multi-Ethnic Study of Atherosclerosis (MESA).

    PubMed

    McAuley, Paul A; Hsu, Fang-Chi; Loman, Kurt K; Carr, J Jeffrey; Budoff, Matthew J; Szklo, Moyses; Sharrett, A Richey; Ding, Jingzhong

    2011-09-01

    Insulin resistance is linked to general and abdominal obesity, but its relation to hepatic lipid content and pericardial adipose tissue is less clear. The purpose of this study was to examine cross-sectional associations of liver attenuation, pericardial adipose tissue, BMI, and waist circumference with insulin resistance. We measured liver attenuation and pericardial adipose tissue using the existing cardiac computed tomography scans in 5,291 individuals free of clinical cardiovascular disease and diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA) during the study's baseline visit (2000-2002). Low liver attenuation was defined as the lowest quartile and high pericardial adipose tissue as the upper quartile of volume (cm(3)). We used standard clinical definitions for obesity and abdominal obesity. Insulin resistance was assessed by the homeostasis model assessment of insulin resistance (HOMA(IR)) index. In multivariate linear regression with all adiposity measures in the model simultaneously, all adiposity measures were significantly (P < 0.0001) associated with insulin resistance: regression coefficients (±s.e.) were 0.31 (±0.02) for low liver attenuation, 0.27 (±0.02) for high pericardial adipose tissue, 0.27 (±0.02) for obesity, and 0.32 (±0.02) for abdominal obesity. We found significant differences (P = 0.003) between standardized liver attenuation and insulin resistance by ethnicity: regression coefficients per 1 s.d. increment were 0.10 ± 0.01 for whites, 0.11 ± 0.02 for Chinese, 0.08 ± 0.2 for blacks, and 0.14 ± 0.01 for Hispanics. Liver attenuation and pericardial adipose tissue were associated with insulin resistance, independent of BMI and waist circumference.

  8. Platelet activity in Chinese obese adolescents with and without insulin resistance.

    PubMed

    Lu, Huimin; Lei, Shundong; Zhao, Jiuming; Chen, Ni

    2014-01-01

    To investigate the platelet activity in Chinese obese adolescents with and without insulin resistance. A cross-sectional study was performed in 159 obese Chinese adolescents to investigate their platelet activity using anthropometrics and biochemical parameters, oral glucose tolerance test and platelet testing. An index of insulin sensitivity, homeostasis model assessment of insulin resistance (HOMA-IR), and plasma fibrinogen, prothrombin fragment 1.2 (PT 1.2), fibrinopeptide A (FPA) and the levels of aggregation to collagen 1 μg/ml, adenosine diphosphate (ADP) 10 μmol/L and arachidonic acid (AA) 0.5 mmol/L were measured. Obese adolescents with insulin resistance had significantly higher HOMA-IR, glucose response curve (AUC), insulin AUC, PT 1.2, FPA and fibrinogen and aggregation (to collagen 1 μg/ml, ADP 10 μmol/L and AA 0.5 mmol/L) comparison with obese adolescents without insulin resistance (P < 0.05). Moreover, a positive correlation was found between both aggregation (to collagen, ADP and AA) and HOMA-IR (ρ = 0.716; P < 0.01, ρ = 0.682; P < 0.01 and ρ = 0.699; P < 0.01, respectively), glucose AUC (ρ = 0.479; P < 0.01, ρ = 0.416; P < 0.01 and ρ = 0.458; P < 0.01, respectively) and insulin AUC (ρ = 0.585; P < 0.01, ρ = 0.511; P < 0.01 and ρ = 0.576; P < 0.01, respectively) in obese adolescents with insulin resistance. Insulin resistance is a major determinant of platelet activation in Chinese obese adolescents.

  9. The associations between VDR BsmI polymorphisms and risk of vitamin D deficiency, obesity and insulin resistance in adolescents residing in a tropical country.

    PubMed

    Rahmadhani, Rayinda; Zaharan, Nur Lisa; Mohamed, Zahurin; Moy, Foong Ming; Jalaludin, Muhammad Yazid

    2017-01-01

    The vitamin D receptor (VDR) gene is expressed abundantly in different tissues; including adipocytes and pancreatic beta cells. The rs1544410 or BsmI single nucleotide polymorphism (SNP) in the intronic region of the VDR gene has been previously associated with vitamin D levels, obesity and insulin resistance. This study was aimed to examine the association between BsmI polymorphism and risk of vitamin D deficiency, obesity and insulin resistance in adolescents living in a tropical country. Thirteen-year-old adolescents were recruited via multistage sampling from twenty-three randomly selected schools across the city of Kuala Lumpur, Malaysia (n = 941). Anthropometric measurements were obtained. Obesity was defined as body mass index higher than the 95th percentile of the WHO chart. Levels of fasting serum vitamin D (25-hydroxyvitamin D (25(OH)D)), glucose and insulin were measured. HOMA-IR was calculated as an indicator for insulin resistance. Genotyping was performed using the Sequenom MassARRAY platform (n = 807). The associations between BsmI and vitamin D, anthropometric parameters and HOMA-IR were examined using analysis of covariance and logistic regression. Those with AA genotype of BsmI had significantly lower levels of 25(OH)D (p = 0.001) compared to other genotypes. No significant differences was found across genotypes for obesity parameters. The AA genotype was associated with higher risk of vitamin D deficiency (p = 0.03) and insulin resistance (p = 0.03) compared to GG. The A allele was significantly associated with increased risk of vitamin D deficiency compared to G allele (adjusted odds ratio (OR) = 1.63 (95% Confidence Interval (CI) 1.03-2.59, p = 0.04). In those with concurrent vitamin D deficiency, having an A allele significantly increased their risk of having insulin resistance compared to G allele (adjusted OR = 2.66 (95% CI 1.36-5.19, p = 0.004). VDR BsmI polymorphism was significantly associated with vitamin D deficiency and insulin

  10. The associations between VDR BsmI polymorphisms and risk of vitamin D deficiency, obesity and insulin resistance in adolescents residing in a tropical country

    PubMed Central

    Mohamed, Zahurin; Moy, Foong Ming; Jalaludin, Muhammad Yazid

    2017-01-01

    Background The vitamin D receptor (VDR) gene is expressed abundantly in different tissues; including adipocytes and pancreatic beta cells. The rs1544410 or BsmI single nucleotide polymorphism (SNP) in the intronic region of the VDR gene has been previously associated with vitamin D levels, obesity and insulin resistance. Aims This study was aimed to examine the association between BsmI polymorphism and risk of vitamin D deficiency, obesity and insulin resistance in adolescents living in a tropical country. Methods Thirteen-year-old adolescents were recruited via multistage sampling from twenty-three randomly selected schools across the city of Kuala Lumpur, Malaysia (n = 941). Anthropometric measurements were obtained. Obesity was defined as body mass index higher than the 95th percentile of the WHO chart. Levels of fasting serum vitamin D (25-hydroxyvitamin D (25(OH)D)), glucose and insulin were measured. HOMA-IR was calculated as an indicator for insulin resistance. Genotyping was performed using the Sequenom MassARRAY platform (n = 807). The associations between BsmI and vitamin D, anthropometric parameters and HOMA-IR were examined using analysis of covariance and logistic regression. Result Those with AA genotype of BsmI had significantly lower levels of 25(OH)D (p = 0.001) compared to other genotypes. No significant differences was found across genotypes for obesity parameters. The AA genotype was associated with higher risk of vitamin D deficiency (p = 0.03) and insulin resistance (p = 0.03) compared to GG. The A allele was significantly associated with increased risk of vitamin D deficiency compared to G allele (adjusted odds ratio (OR) = 1.63 (95% Confidence Interval (CI) 1.03–2.59, p = 0.04). In those with concurrent vitamin D deficiency, having an A allele significantly increased their risk of having insulin resistance compared to G allele (adjusted OR = 2.66 (95% CI 1.36–5.19, p = 0.004). Conclusion VDR BsmI polymorphism was significantly associated

  11. Chromium picolinate enhances skeletal muscle cellular insulin signaling in vivo in obese, insulin-resistant JCR:LA-cp rats.

    PubMed

    Wang, Zhong Q; Zhang, Xian H; Russell, James C; Hulver, Matthew; Cefalu, William T

    2006-02-01

    Chromium is one of the few trace minerals for which a specific cellular mechanism of action has not been identified. Recent in vitro studies suggest that chromium supplementation may improve insulin sensitivity by enhancing insulin receptor signaling, but this has not been demonstrated in vivo. We investigated the effect of chromium supplementation on insulin receptor signaling in an insulin-resistant rat model, the JCR:LA-corpulent rat. Male JCR:LA-cp rats (4 mo of age) were randomly assigned to receive chromium picolinate (CrPic) (obese n=6, lean n=5) or vehicle (obese n=5, lean n=5) for 3 mo. The CrPic was provided in the water, and based on calculated water intake, rats randomized to CrPic received 80 microg/(kg.d). At the end of the study, skeletal muscle (vastus lateralis) biopsies were obtained at baseline and at 5, 15, and 30 min postinsulin stimulation to assess insulin signaling. Obese rats treated with CrPic had significantly improved glucose disposal rates and demonstrated a significant increase in insulin-stimulated phosphorylation of insulin receptor substrate (IRS)-1 and phosphatidylinositol (PI)-3 kinase activity in skeletal muscle compared with obese controls. The increase in cellular signaling was not associated with increased protein levels of the IRS proteins, PI-3 kinase or Akt. However, protein tyrosine phosphatase 1B (PTP1B) levels were significantly lower in obese rats administered CrPic than obese controls. When corrected for protein content, PTP1B activity was also significantly lower in obese rats administered CrPic than obese controls. Our data suggest that chromium supplementation of obese, insulin-resistant rats may improve insulin action by enhancing intracellular signaling.

  12. The Roles of IL-6, IL-10, and IL-1RA in Obesity and Insulin Resistance in African-Americans

    PubMed Central

    Doumatey, Ayo; Huang, Hanxia; Zhou, Jie; Chen, Guanjie; Shriner, Daniel; Adeyemo, Adebowale

    2011-01-01

    Objective: The aim of the study was to investigate the associations between IL-1 receptor antagonist (IL-1RA), IL-6, IL-10, measures of obesity, and insulin resistance in African-Americans. Research Design and Methods: Nondiabetic participants (n = 1025) of the Howard University Family Study were investigated for associations between serum IL (IL-1RA, IL-6, IL-10), measures of obesity, and insulin resistance, with adjustment for age and sex. Measures of obesity included body mass index, waist circumference, hip circumference, waist-to-hip ratio, and percent fat mass. Insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR). Data were analyzed with R statistical software using linear regression and likelihood ratio tests. Results: IL-1RA and IL-6 were associated with measures of obesity and insulin resistance, explaining 4–12.7% of the variance observed (P values < 0.001). IL-1RA was bimodally distributed and therefore was analyzed based on grouping those with low vs. high IL-1RA levels. High IL-1RA explained up to 20 and 12% of the variance in measures of obesity and HOMA-IR, respectively. Among the IL, only high IL-1RA improved the fit of models regressing HOMA-IR on measures of obesity. In contrast, all measures of obesity improved the fit of models regressing HOMA-IR on IL. IL-10 was not associated with obesity measures or HOMA-IR. Conclusions: High IL-1RA levels and obesity measures are associated with HOMA-IR in this population-based sample of African-Americans. The results suggest that obesity and increased levels of IL-1RA both contribute to the development of insulin resistance. PMID:21956416

  13. Reversal of diet-induced obesity and insulin resistance by inducible genetic ablation of GRK2

    PubMed Central

    Vila-Bedmar, Rocio; Cruces-Sande, Marta; Lucas, Elisa; Willemen, Hanneke L.D.M.; Heijnen, Cobi J.; Kavelaars, Annemieke; Mayor, Federico; Murga, Cristina

    2015-01-01

    Insulin resistance is a common feature of obesity and predisposes individuals to various prevalent pathological conditions. G protein-coupled receptor kinase 2 (GRK2) integrates several signal transduction pathways and is emerging as a physiologically relevant inhibitor of insulin signaling. GRK2 abundanceis increased in humans with metabolic syndrome and in different murine models of insulin resistance. To support GRK2 as a potential drug target in type 2 diabetes and obesity, we investigated whether lowering GRK2 abundance reversed an ongoing systemic insulin-resistant phenotype, using a mouse model of tamoxifen-induced GRK2 ablation after high fat diet-dependent obesity and insulin resistance. Tamoxifen-triggered GRK2 deletion impeded further body weight gain, normalized fa sting glycemia, improved glucose tolerance and was associated with preserved insulin sensitivity in skeletal muscle and liver, thereby maintaining whole body glucose homeostasis. Moreover, when continued to be fed a high fat diet, these animals displayed reduced fat mass and smaller adipocytes, were resistant to the development of liver steatosis, and showed reduced expression of pro-inflammatory markers in the liver. Our results indicate that GRK2 acts as a hub to control metabolic functions in different tissues, which is key to controlling insulin resistance development in vivo. These data suggest that inhibiting GRK2 could reverse an established insulin-resistant and obese phenotype, thereby putting forward this enzyme as a potential therapeutic target linking glucose homeostasis and regulation of adiposity. PMID:26198359

  14. Protein kinases: mechanisms and downstream targets in inflammation-mediated obesity and insulin resistance.

    PubMed

    Nandipati, Kalyana C; Subramanian, Saravanan; Agrawal, Devendra K

    2017-02-01

    Obesity-induced low-grade inflammation (metaflammation) impairs insulin receptor signaling. This has been implicated in the development of insulin resistance. Insulin signaling in the target tissues is mediated by stress kinases such as p38 mitogen-activated protein kinase, c-Jun NH2-terminal kinase, inhibitor of NF-kB kinase complex β (IKKβ), AMP-activated protein kinase, protein kinase C, Rho-associated coiled-coil containing protein kinase, and RNA-activated protein kinase. Most of these kinases phosphorylate several key regulators in glucose homeostasis. The phosphorylation of serine residues in the insulin receptor and IRS-1 molecule results in diminished enzymatic activity in the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. This has been one of the key mechanisms observed in the tissues that are implicated in insulin resistance especially in type 2 diabetes mellitus (T2-DM). Identifying the specific protein kinases involved in obesity-induced chronic inflammation may help in developing the targeted drug therapies to minimize the insulin resistance. This review is focused on the protein kinases involved in the inflammatory cascade and molecular mechanisms and their downstream targets with special reference to obesity-induced T2-DM.

  15. Obese adolescent girls with polycystic ovary syndrome (PCOS) have more severe insulin resistance measured by HOMA-IR score than obese girls without PCOS.

    PubMed

    Sawathiparnich, Pairunyar; Weerakulwattana, Linda; Santiprabhob, Jeerunda; Likitmaskul, Supawadee

    2005-11-01

    The prevalence of obesity in Thai children is increasing. These individuals are at increased risks of metabolic syndrome that includes insulin resistance, type 2 diabetes mellitus (T2DM), polycystic ovary syndrome (PCOS), dyslipidemia and hypertension. PCOS has been known to be associated with insulin resistance. To compare the insulin sensitivity between obese adolescent girls with PCOS and those without PCOS. We reviewed demographic and hormonal data of 6 obese adolescent girls with PCOS and compared with 6 age, weight and BMI-matched non-PCOS controls. Each subject underwent an oral glucose tolerance test. Homeostasis model assessment of insulin resistance score (HOMA-IR score) in obese adolescent girls with PCOS was significantly higher than in girls without PCOS with median and range as follows (16.5 [3.8, 21.8] vs. 4.1 [3.3, 6.9], p = 0.04). Our study demonstrates that obese adolescent girls with PCOS have more severe insulin resistance measured by HOMA-IR score than girls without PCOS independent of the degree of obesity. Since insulin resistance is a metabolic precursor of future cardiovascular diseases, obese adolescent girls with PCOS might be at greater risk of developing cardiovascular disease in later adulthood than their non-PCOS counterparts.

  16. Diet-induced obesity induces endoplasmic reticulum stress and insulin resistance in the amygdala of rats☆

    PubMed Central

    Castro, Gisele; C. Areias, Maria Fernanda; Weissmann, Lais; Quaresma, Paula G.F.; Katashima, Carlos K.; Saad, Mario J.A.; Prada, Patricia O.

    2013-01-01

    Insulin acts in the hypothalamus, decreasing food intake (FI) by the IR/PI3K/Akt pathway. This pathway is impaired in obese animals and endoplasmic reticulum (ER) stress and low-grade inflammation are possible mechanisms involved in this impairment. Here, we highlighted the amygdala as an important brain region for FI regulation in response to insulin. This regulation was dependent on PI3K/AKT pathway similar to the hypothalamus. Insulin was able to decrease neuropeptide Y (NPY) and increase oxytocin mRNA levels in the amygdala via PI3K, which may contribute to hypophagia. Additionally, obese rats did not reduce FI in response to insulin and AKT phosphorylation was decreased in the amygdala, suggesting insulin resistance. Insulin resistance was associated with ER stress and low-grade inflammation in this brain region. The inhibition of ER stress with PBA reverses insulin action/signaling, decreases NPY and increases oxytocin mRNA levels in the amygdala from obese rats, suggesting that ER stress is probably one of the mechanisms that induce insulin resistance in the amygdala. PMID:24251109

  17. DNA methylation of leptin and adiponectin promoters in children is reduced by the combined presence of obesity and insulin resistance.

    PubMed

    García-Cardona, M C; Huang, F; García-Vivas, J M; López-Camarillo, C; Del Río Navarro, B E; Navarro Olivos, E; Hong-Chong, E; Bolaños-Jiménez, F; Marchat, L A

    2014-11-01

    Epigenetic alterations have been suggested to be associated with obesity and related metabolic disorders. Here we examined the correlation between obesity and insulin resistance with the methylation frequency of the leptin (LEP) and adiponectin (ADIPOQ) promoters in obese adolescents with the aim to identify epigenetic markers that might be used as tools to predict and follow up the physiological alterations associated with the development of the metabolic syndrome. One hundred and six adolescents were recruited and classified according to body mass index and homeostasis model of assessment-insulin resistance index. The circulating concentrations of leptin, adiponectin and of several metabolic markers of obesity and insulin resistance were determined by standard methods. The methylation frequency of the LEP and ADIPOQ promoters was determined by methylation-specific PCR (MS-PCR) in DNA obtained from peripheral blood samples. Obese adolescents without insulin resistance showed higher and lower circulating levels of, respectively, leptin and adiponectin along with increased plasmatic concentrations of insulin and triglycerides. They also exhibited the same methylation frequency than lean subjects of the CpG sites located at -51 and -31 nt relative to the transcription start site of the LEP gene. However, the methylation frequency of these nucleotides dropped markedly in obese adolescents with insulin resistance. We found the same inverse relationship between the combined presence of obesity and insulin resistance and the methylation frequency of the CpG site located at -283 nt relative to the start site of the ADIPOQ promoter. These observations sustain the hypothesis that epigenetic modifications might underpin the development of obesity and related metabolic disorders. They also validate the use of blood leukocytes and MS-PCR as a reliable and affordable methodology for the identification of epigenetic modifications that could be used as molecular markers to

  18. Muramyl Dipeptide-Based Postbiotics Mitigate Obesity-Induced Insulin Resistance via IRF4.

    PubMed

    Cavallari, Joseph F; Fullerton, Morgan D; Duggan, Brittany M; Foley, Kevin P; Denou, Emmanuel; Smith, Brennan K; Desjardins, Eric M; Henriksbo, Brandyn D; Kim, Kalvin J; Tuinema, Brian R; Stearns, Jennifer C; Prescott, David; Rosenstiel, Philip; Coombes, Brian K; Steinberg, Gregory R; Schertzer, Jonathan D

    2017-05-02

    Intestinal dysbiosis contributes to obesity and insulin resistance, but intervening with antibiotics, prebiotics, or probiotics can be limited by specificity or sustained changes in microbial composition. Postbiotics include bacterial components such as lipopolysaccharides, which have been shown to promote insulin resistance during metabolic endotoxemia. We found that bacterial cell wall-derived muramyl dipeptide (MDP) is an insulin-sensitizing postbiotic that requires NOD2. Injecting MDP lowered adipose inflammation and reduced glucose intolerance in obese mice without causing weight loss or altering the composition of the microbiome. MDP reduced hepatic insulin resistance during obesity and low-level endotoxemia. NOD1-activating muropeptides worsened glucose tolerance. IRF4 distinguished opposing glycemic responses to different types of peptidoglycan and was required for MDP/NOD2-induced insulin sensitization and lower metabolic tissue inflammation during obesity and endotoxemia. IRF4 was dispensable for exacerbated glucose intolerance via NOD1. Mifamurtide, an MDP-based drug with orphan drug status, was an insulin sensitizer at clinically relevant doses in obese mice. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Potential epigenetic biomarkers of obesity-related insulin resistance in human whole-blood.

    PubMed

    Day, Samantha E; Coletta, Richard L; Kim, Joon Young; Garcia, Luis A; Campbell, Latoya E; Benjamin, Tonya R; Roust, Lori R; De Filippis, Elena A; Mandarino, Lawrence J; Coletta, Dawn K

    2017-04-03

    Obesity can increase the risk of complex metabolic diseases, including insulin resistance. Moreover, obesity can be caused by environmental and genetic factors. However, the epigenetic mechanisms of obesity are not well defined. Therefore, the identification of novel epigenetic biomarkers of obesity allows for a more complete understanding of the disease and its underlying insulin resistance. The aim of our study was to identify DNA methylation changes in whole-blood that were strongly associated with obesity and insulin resistance. Whole-blood was obtained from lean (n = 10; BMI = 23.6 ± 0.7 kg/m 2 ) and obese (n = 10; BMI = 34.4 ± 1.3 kg/m 2 ) participants in combination with euglycemic hyperinsulinemic clamps to assess insulin sensitivity. We performed reduced representation bisulfite sequencing on genomic DNA isolated from the blood. We identified 49 differentially methylated cytosines (DMCs; q < 0.05) that were altered in obese compared with lean participants. We identified 2 sites (Chr.21:46,957,981 and Chr.21:46,957,915) in the 5' untranslated region of solute carrier family 19 member 1 (SLC19A1) with decreased methylation in obese participants (lean 0.73 ± 0.11 vs. obese 0.09 ± 0.05; lean 0.68 ± 0.10 vs. obese 0.09 ± 0.05, respectively). These 2 DMCs identified by obesity were also significantly predicted by insulin sensitivity (r = 0.68, P = 0.003; r = 0.66; P = 0.004). In addition, we performed a differentially methylated region (DMR) analysis and demonstrated a decrease in methylation of Chr.21:46,957,915-46,958,001 in SLC19A1 of -34.9% (70.4% lean vs. 35.5% obese). The decrease in whole-blood SLC19A1 methylation in our obese participants was similar to the change observed in skeletal muscle (Chr.21:46,957,981, lean 0.70 ± 0.09 vs. obese 0.31 ± 0.11 and Chr.21:46,957,915, lean 0.72 ± 0.11 vs. obese 0.31 ± 0.13). Pyrosequencing analysis further demonstrated a decrease in methylation at Chr.21:46,957,915 in both whole-blood (lean 0.71 ± 0

  20. Association of abdominal obesity, insulin resistance, and oxidative stress in adipose tissue in women with polycystic ovary syndrome.

    PubMed

    Chen, Li; Xu, Wen Ming; Zhang, Dan

    2014-10-01

    To study the expression of insulin signaling-related genes and oxidative stress markers in the visceral adipose tissue obtained from polycystic ovary syndrome (PCOS) patients and healthy control subjects and to investigate the relationships among abdominal obesity, insulin resistance, and oxidative stress at the tissue level. Case-control study. University teaching hospital. In total, 30 PCOS patients and 30 healthy control subjects, who underwent laparoscopic surgery, were included in the study. Abdominal obesity was defined based on waist circumference (WC). The homeostasis model index was used to assess insulin resistance (HOMA-IR). Gene expression of glucose transporter 4 (GLUT4) and insulin receptor substrate 1 (IRS1) in visceral adipose tissue (VAT) and the parameters of oxidative stress, such as superoxide dismutase, enzyme glutathione reductase, and dimethylarginine, were measured, and the expression of protein oxidative damage product 3-nitro-tyrosine residues (nitrotyrosine) in VAT was identified with the use of immunohistochemistry. PCOS was associated with lower expression of GLUT4 and IRS1 and a higher level of oxidative stress in VAT, which was strongly correlated with WC and HOMA-IR. Presence of abdominal obesity further intensified the correlations observed in our measurements. The nitrotyrosine expression in VAT was stronger in PCOS patients. The strong correlation of insulin resistance with oxidative stress at the VAT level suggests that local oxidative stress and abnormalities of insulin signaling in adipose tissue play critical roles in the pathogenesis of PCOS. Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  1. Comparison of β-cell dysfunction and insulin resistance correlating obesity with type 2 diabetes: A cross-sectional study.

    PubMed

    Liu, Jia; Wang, Ying; Hu, Yanjin; Leng, Song; Wang, Guang

    2016-07-01

    To assess the contribution of β-cell dysfunction and insulin resistance to type 2 diabetes (T2D) in obese and non-obese Chinese people. In this cross-sectional study, we recruited 1384 newly diagnosed T2D patients and 1712 healthy controls. Insulin resistance was estimated by homeostasis model assessment of insulin resistance (HOMA-IR). β-cell function was estimated by homeostasis model assessment of β-cell function (HOMA-β) and 60min insulinogenic index (IGI60). We compared the insulin resistance and β-cell function of obese and non-obese Chinese patients with and without T2D. 50.18% of control participants and 62.28% of T2D patients were obese (BMI≥25kg/m(2)). HOMA-IR, HOMA-β and IGI60 were significantly higher in obese than non-obese, irrespective of T2D. Non-obese T2D patients had significantly greater HOMA-IR, and lower HOMA-β and IGI60 than non-obese control participants. The obese T2D group had lower HOMA-β and IGI60 than the obese control group. There was no significant difference in HOMA-IR between the obese T2D and obese control groups. Multivariate logistic regression analysis revealed that HOMA-IR was associated with T2D only in non-obese group, and HOMA-β and IGI60 were associated with T2D in both non-obese and obese groups. HOMA-β and IGI60 were associated with T2D in obese and non-obese patients, but HOMA-IR was associated with T2D in non-obese Chinese. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Adipose tissue oxygenation is associated with insulin sensitivity independently of adiposity in obese men and women.

    PubMed

    Goossens, Gijs H; Vogel, Max A A; Vink, Roel G; Mariman, Edwin C; van Baak, Marleen A; Blaak, Ellen E

    2018-04-23

    Adipose tissue (AT) dysfunction contributes to the pathophysiology of insulin resistance and type 2 diabetes. Previous studies have shown that altered AT oxygenation affects adipocyte functionality, but it remains to be elucidated whether altered AT oxygenation is more strongly related to obesity or insulin sensitivity. In the present study, we tested the hypothesis that AT oxygenation is associated with insulin sensitivity rather than adiposity in humans. Thirty-five lean and obese individuals (21 men and 14 women, aged 40-65 years) with either normal or impaired glucose metabolism participated in a cross-sectional single-centre study. We measured abdominal subcutaneous AT oxygenation, body composition and insulin sensitivity. AT oxygenation was higher in obese insulin resistant as compared to obese insulin sensitive (IS) individuals with similar age, body mass index and body fat percentage, both in men and women. No significant differences in AT oxygenation were found between obese IS and lean IS men. Moreover, AT oxygenation was positively associated with insulin resistance (r = 0.465; P = .005), even after adjustment for age, sex and body fat percentage (standardized β = 0.479; P = .005). In conclusion, abdominal subcutaneous AT oxygenation is associated with insulin sensitivity both in men and women, independently of adiposity. AT oxygenation may therefore be a promising target to improve insulin sensitivity. © 2018 John Wiley & Sons Ltd.

  3. The severity of nocturnal hypoxia but not abdominal adiposity is associated with insulin resistance in non-obese men with sleep apnea.

    PubMed

    Borel, Anne-Laure; Monneret, Denis; Tamisier, Renaud; Baguet, Jean-Philippe; Faure, Patrice; Levy, Patrick; Halimi, Serge; Pépin, Jean-Louis

    2013-01-01

    Beyond obesity, sleep apnea syndrome is frequently associated with excess abdominal adiposity that could contribute to the deteriorated cardiometabolic risk profile of apneic patients. The present study addressed the respective contribution of the severity of sleep apnea syndrome and excess abdominal adiposity to the cardiometabolic risk profile of 38 non obese men with polysomnography-diagnosed sleep apnea syndrome (apnea-hypopnea index >15 events/hour). These otherwise healthy men performed a 75g-oral glucose tolerance test (OGTT) with plasma lipid/inflammatory and redox profiles. Twenty-one apneic men with high-waist circumference (>94 cm) were compared to 17 apneic men with low-waist circumference. Apneic men with high-waist circumference had higher AUC glucose and AUC insulin than apneic men with low-waist circumference. Accordingly, apneic men with high-waist circumference had higher hepatic insulin resistance as reflected by higher HOMA-resistance index, and lower global insulin sensitivity as reflected by lower insulin sensitivity index of Matsuda (derived from OGTT). The sleep structure and the apnea-hypopnea index were not different between the two groups. However, apneic men with high-waist circumference presented with lower mean nocturnal oxyhemoglobin (SpO2). In the 38 men, waist circumference and mean nocturnal SpO2 were inversely correlated (r = -0.43, p = 0.011) and were both associated with plasma glucose/insulin homeostasis indices: the higher the waist circumference, the lower the mean nocturnal SpO2, the lower the insulin-sensitivity. Finally, in multivariable regression model, mean nocturnal SpO2 and not waist circumference was associated with insulin-resistance. Thus, excess abdominal adiposity in non obese apneic men was associated with a deteriorated insulin-sensitivity that could be driven by a more severe nocturnal hypoxemia.

  4. The Severity of Nocturnal Hypoxia but Not Abdominal Adiposity Is Associated with Insulin Resistance in Non-Obese Men with Sleep Apnea

    PubMed Central

    Borel, Anne-Laure; Monneret, Denis; Tamisier, Renaud; Baguet, Jean-Philippe; Faure, Patrice; Levy, Patrick; Halimi, Serge; Pépin, Jean-Louis

    2013-01-01

    Background Beyond obesity, sleep apnea syndrome is frequently associated with excess abdominal adiposity that could contribute to the deteriorated cardiometabolic risk profile of apneic patients. Methods The present study addressed the respective contribution of the severity of sleep apnea syndrome and excess abdominal adiposity to the cardiometabolic risk profile of 38 non obese men with polysomnography-diagnosed sleep apnea syndrome (apnea-hypopnea index >15 events/hour). These otherwise healthy men performed a 75g-oral glucose tolerance test (OGTT) with plasma lipid/inflammatory and redox profiles. Twenty-one apneic men with high-waist circumference (>94 cm) were compared to 17 apneic men with low-waist circumference. Results Apneic men with high-waist circumference had higher AUC glucose and AUC insulin than apneic men with low-waist circumference. Accordingly, apneic men with high-waist circumference had higher hepatic insulin resistance as reflected by higher HOMA-resistance index, and lower global insulin sensitivity as reflected by lower insulin sensitivity index of Matsuda (derived from OGTT). The sleep structure and the apnea-hypopnea index were not different between the two groups. However, apneic men with high-waist circumference presented with lower mean nocturnal oxyhemoglobin (SpO2). In the 38 men, waist circumference and mean nocturnal SpO2 were inversely correlated (r = −0.43, p = 0.011) and were both associated with plasma glucose/insulin homeostasis indices: the higher the waist circumference, the lower the mean nocturnal SpO2, the lower the insulin-sensitivity. Finally, in multivariable regression model, mean nocturnal SpO2 and not waist circumference was associated with insulin-resistance. Conclusion Thus, excess abdominal adiposity in non obese apneic men was associated with a deteriorated insulin-sensitivity that could be driven by a more severe nocturnal hypoxemia. PMID:23951064

  5. Circulating endocannabinoids in insulin sensitive vs. insulin resistant obese postmenopausal women. A MONET group study.

    PubMed

    Abdulnour, Joseph; Yasari, Siham; Rabasa-Lhoret, Rémi; Faraj, May; Petrosino, Stefania; Piscitelli, Fabiana; Prud' Homme, Denis; Di Marzo, Vincenzo

    2014-01-01

    To measure the circulating levels of endocannabinoids and related molecules at fasting, after acute hyperinsulinemia and after weight loss in insulin sensitive vs. insulin resistant obese postmenopausal women. The sample consisted of 30 obese postmenopausal women (age: 58.9 ± 5.2 yrs; BMI: 32.9 ± 3.6 kg/m(2) ). Subjects underwent a 3-hour hyperinsulinaemic-euglycaemic clamp (HEC) (glucose disposal rate (M-value): 10.7 ± 3.3 mg min(-1) kg(-1) FFM) and 6-month weight loss intervention. Participants were classified as insulin sensitive obese (ISO) or insulin resistant obese (IRO) based on a predefined cutoff. Plasma levels of the endocannabinoids, anandamide (AEA), 2-arachidonoylglycerol (2-AG), and of the AEA-related compounds, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), were measured by liquid chromatography-mass spectrometry. IRO presented higher levels of 2-AG (P < 0.05) independently of the HEC and weight loss, whereas the HEC had an independent inhibitory effect on AEA, PEA, and OEA levels (P < 0.05) in both groups. Furthermore, there was an independent stimulatory effect of weight loss only on PEA levels in both groups (P < 0.05). This study is the first to show that higher circulating levels of the endocannabinoid 2-AG are found in IRO compared to ISO postmenopausal women, and that weight loss is associated with an increase in PEA, a PPAR-α ligand. © 2013 The Obesity Society.

  6. The early origins of obesity and insulin resistance: timing, programming and mechanisms.

    PubMed

    Nicholas, L M; Morrison, J L; Rattanatray, L; Zhang, S; Ozanne, S E; McMillen, I C

    2016-02-01

    Maternal obesity is associated with an increased risk of developing gestational diabetes mellitus and it also results in an increased risk of giving birth to a large baby with increased fat mass. Furthermore, it is also contributes to an increased risk of obesity and insulin resistance in the offspring in childhood, adolescence and adult life. It has been proposed that exposure to maternal obesity may therefore result in an 'intergenerational cycle' of obesity and insulin resistance. There is significant interest in whether exposure to maternal obesity around the time of conception alone contributes directly to poor metabolic outcomes in the offspring and whether dieting in the obese mother before pregnancy or around the time of conception has metabolic benefits for the offspring. This review focusses on experimental and clinical studies that have investigated the specific impact of exposure to maternal obesity during the periconceptional period alone or extending beyond conception on adipogenesis, lipogenesis and on insulin signalling pathways in the fat, liver and muscle of the offspring. Findings from these studies highlight the need for a better evidence base for the development of dietary interventions in obese women before pregnancy and around the time of conception to maximize the metabolic benefits and minimize the metabolic costs for the next generation.

  7. Protein kinases: mechanisms and downstream targets in inflammation mediated obesity and insulin resistance

    PubMed Central

    Nandipati, Kalyana C; Subramanian, Saravanan; Agrawal, Devendra K

    2016-01-01

    Obesity induced low-grade inflammation (metaflammation) impairs insulin receptor signaling (IRS). This has been implicated in the development of insulin resistance. Insulin signaling in the target tissues is mediated by stress kinases such as p38 mitogen-activated protein kinase (MAPK), c-Jun NH2-terminal kinase (JNK), inhibitor of NF-kB kinase complex beta (IKKβ), AMP activated protein kinase (AMPK), protein kinase C (PKC), Rho associated coiled-coil containing protein kinase (ROCK) and RNA-activated protein kinase (PKR), etc. Most of these kinases phosphorylate several key regulators in glucose homeostasis. The phosphorylation of serine residues in the insulin receptor (IR) and IRS-1 molecule results in diminished enzymatic activity in the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. This has been one of the key mechanisms observed in the tissues that are implicated in insulin resistance especially in Type II Diabetes Mellitus (T2-DM). Identifying the specific protein kinases involved in obesity induced chronic inflammation may help in developing the targeted drug therapies to minimize the insulin resistance. This review is focused on the protein kinases involved in the inflammatory cascade and molecular mechanisms and their downstream targets with special reference to obesity induced T2-DM. PMID:27868170

  8. Effects of losartan on whole-body, skeletal muscle, and vascular insulin responses in obesity/insulin resistance without hypertension

    PubMed Central

    Lteif, AA; Chisholm, RL; Gilbert, K; Considine, RV; Mather, KJ

    2011-01-01

    Aims Renin-angiotensin system antagonists have been found to improve glucose metabolism in obese hypertensive and type 2 diabetic subjects. The mechanism of these effects is not well understood. We hypothesized that the angiotensin receptor antagonist losartan would improve insulin-mediated vasodilation, and thereby improve insulin-stimulated glucose uptake in skeletal muscle of insulin resistant subjects. Materials and Methods We studied subjects with obesity and insulin resistance but without hypertension, hypercholesterolemia or dysglycemia (age 39.0±9.6 yrs [mean±SD], BMI 33.2±5.9 kg/m2, BP 115.8±12.2/70.9±7.2 mmHg, LDL 2.1±0.5 mmol/L). Subjects were randomized to 12 weeks’ double-blind treatment with losartan 100 mg once daily (n=9) or matching placebo (n=8). Before and after treatment, under hyperinsulinemic euglycemic clamp conditions we measured whole-body insulin stimulated glucose disposal, insulin-mediated vasodilation, and insulin-stimulated leg glucose uptake by the limb balance technique. Results Whole-body insulin-stimulated glucose disposal was not significantly increased by losartan. Insulin-mediated vasodilation was augmented following both treatments (increase in leg vascular conductance: pre-treatment 0.7±0.3 L*min−1*mmHg−1[losartan, mean ±SEM] and 0.9±0.3 [placebo], post-treatment 1.0±0.4 [losartan] and 1.3±0.6 [placebo]) but not different between treatment groups (p=0.53). Insulin’s action to augment NO production and to augment endothelium-dependent vasodilation were also not improved. Leg glucose uptake was not significantly changed by treatments, and not different between groups (p=0.11). Conclusions These findings argue against the hypothesis that losartan might improve skeletal muscle glucose metabolism by improving insulin-mediated vasodilation in normotensive insulin resistant obese subjects. The metabolic benefits of angiotensin receptor blockers may require the presence of hypertension in addition to obesity-associated

  9. REGULATION OF OBESITY AND INSULIN RESISTANCE BY NITRIC OXIDE

    PubMed Central

    Sansbury, Brian E.; Hill, Bradford G.

    2014-01-01

    Obesity is a risk factor for developing type 2 diabetes and cardiovascular disease and has quickly become a world-wide pandemic with few tangible and safe treatment options. While it is generally accepted that the primary cause of obesity is energy imbalance, i.e., the calories consumed are greater than are utilized, understanding how caloric balance is regulated has proven a challenge. Many “distal” causes of obesity, such as the structural environment, occupation, and social influences, are exceedingly difficult to change or manipulate. Hence, molecular processes and pathways more proximal to the origins of obesity—those that directly regulate energy metabolism or caloric intake—appear to be more feasible targets for therapy. In particular, nitric oxide (NO) is emerging as a central regulator of energy metabolism and body composition. NO bioavailability is decreased in animal models of diet-induced obesity and in obese and insulin resistant patients, and increasing NO output has remarkable effects on obesity and insulin resistance. This review discusses the role of NO in regulating adiposity and insulin sensitivity and places its modes of action into context with the known causes and consequences of metabolic disease. PMID:24878261

  10. Inflammasome is a central player in the induction of obesity and insulin resistance

    PubMed Central

    Stienstra, Rinke; van Diepen, Janna A.; Tack, Cees J.; Zaki, Md. Hasan; van de Veerdonk, Frank L.; Perera, Deshani; Neale, Geoffrey A.; Hooiveld, Guido J.; Hijmans, Anneke; Vroegrijk, Irene; van den Berg, Sjoerd; Romijn, Johannes; Rensen, Patrick C. N.; Joosten, Leo A. B.; Netea, Mihai G.; Kanneganti, Thirumala-Devi

    2011-01-01

    Inflammation plays a key role in the pathogenesis of obesity. Chronic overfeeding leads to macrophage infiltration in the adipose tissue, resulting in proinflammatory cytokine production. Both microbial and endogenous danger signals trigger assembly of the intracellular innate immune sensor Nlrp3, resulting in caspase-1 activation and production of proinflammatory cytokines IL-1β and IL-18. Here, we showed that mice deficient in Nlrp3, apoptosis-associated speck-like protein, and caspase-1 were resistant to the development of high-fat diet-induced obesity, which correlated with protection from obesity-induced insulin resistance. Furthermore, hepatic triglyceride content, adipocyte size, and macrophage infiltration in adipose tissue were all reduced in mice deficient in inflammasome components. Monocyte chemoattractant protein (MCP)-1 is a key molecule that mediates macrophage infiltration. Indeed, defective inflammasome activation was associated with reduced MCP-1 production in adipose tissue. Furthermore, plasma leptin and resistin that affect energy use and insulin sensitivity were also changed by inflammasome-deficiency. Detailed metabolic and molecular phenotyping demonstrated that the inflammasome controls energy expenditure and adipogenic gene expression during chronic overfeeding. These findings reveal a critical function of the inflammasome in obesity and insulin resistance, and suggest inhibition of the inflammasome as a potential therapeutic strategy. PMID:21876127

  11. Relationship of obesity and insulin resistance with the cerebrovascular reactivity: a case control study

    PubMed Central

    2014-01-01

    Background Obesity is associated with increased risk for stroke. The breath-holding index (BHI) is a measure of vasomotor reactivity of the brain which can be measured with the transcranial Doppler (TCD). We aim to evaluate obesity as an independent factor for altered cerebrovascular reactivity. Methods Cerebrovascular hemodynamics (mean flow velocities MFV, pulsatility index, PI, resistance index, RI, and BHI) was determined in 85 non-obese (Body Mass Index, BMI ≤27 kg/m2) and 85 obese subjects (BMI ≥35 kg/m2) without diabetes mellitus and hypertension. Anthropometric and metabolic variables, and scores to detect risk for obstructive sleep apnea (OSA) were analyzed for their association with the cerebrovascular reactivity. Results The BHI was significantly lower in subjects with obesity according to BMI and in subjects with abdominal obesity, but the PI and RI were not different between groups. There was a linear association between the BMI, the HOMA-IR, the Matsuda index, the waist circumference, and the neck circumference, with the cerebrovascular reactivity. After adjusting for insulin resistance, neck circumference, and abdominal circumference, obesity according to BMI was negatively correlated with the cerebrovascular reactivity. Conclusions We found a diminished vasomotor reactivity in individuals with obesity which was not explained by the presence of insulin resistance. PMID:24383894

  12. [Studies of diet management and insulin resistance in obese pregnant women].

    PubMed

    Takeda, S; Saitoh, M; Kinoshita, K; Sakamoto, S

    1992-02-01

    In an attempt to determine the principles of diet management in obese pregnant women, the association between maternal weight gain during pregnancy (Group I; weight reduction, Group II; +0-4 kg, Group III; +5-9 kg, Group IV; +10 kg-) and the incidence of the complications was investigated in 151 obese pregnant women. Studies on glucose tolerance and insulin binding to erythrocytes were also undertaken. 1) In Group I, the incidences of C/S, forceps delivery, prolonged labor and complication of PIH were lower than those of other groups. There were no heavy-for-dates and light-for-dates babies in Group I, differing from the other three groups. 2) Plasma levels of glucose and insulin were high in obese pregnant women on 75 g OGTT in the second trimester. The binding sites of insulin to erythrocytes were significantly decreased in obese pregnant women. In conclusion, the risks of pregnancy complicated by obesity were high. Insulin resistance was a characteristic of obese pregnant women. The results of this study suggested that the nutritional requirements for very obese pregnant women should be restricted to maintaining the same weight or losing weight during the course of pregnancy to minimize maternal and perinatal risks.

  13. Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance

    USDA-ARS?s Scientific Manuscript database

    Chronic low-grade inflammation is a hallmark of obesity and thought to contribute to the development of obesity-related insulin resistance. Toll-like receptor 4 (Tlr4) is a key mediator of pro-inflammatory responses. Mice lacking Tlr4s are protected from diet-induced insulin resistance and inflammat...

  14. Leptin Receptor Gene Variant rs11804091 Is Associated with BMI and Insulin Resistance in Spanish Female Obese Children: A Case-Control Study

    PubMed Central

    Rupérez, Azahara I.; Gil-Campos, Mercedes; Leis, Rosaura; Cañete, Ramón; Tojo, Rafael

    2017-01-01

    Leptin is an endocrine hormone that has a critical role in body weight homoeostasis and mediates its effects via the leptin receptor (LEPR). Common polymorphisms in the genes coding leptin receptors have been associated with metabolic abnormalities. We assessed the association of 28 LEPR polymorphisms with body mass index (BMI) and their relationship with obesity-related phenotypes, inflammation and cardiovascular disease risk biomarkers. A multicentre case-control study was conducted in 522 children (286 with obesity and 236 with normal-BMI). All anthropometric, metabolic factors and biomarkers were higher in children with obesity except apolipoprotein (Apo)-AI, cholesterol, high-density lipoprotein cholesterol (HDL-c), and adiponectin, which were lower in the obesity group; and glucose, low-density lipoprotein cholesterol (LDL-c), and matrix metalloproteinase-9 that did not differ between groups. We identified the associations between rs11208659, rs11804091, rs10157275, rs9436303 and rs1627238, and BMI in the whole population, as well as the association of rs11804091, rs10157275, and rs1327118 with BMI in the female group, although only the rs11804091 remained associated after Bonferroni correction (p = 0.038). This single nucleotide polymorphisms (SNP) was also associated with insulin (p = 0.004), homeostasis model assessment for insulin resistance (HOMA-IR) (p = 0.006), quantitative insulin sensitivity check index (QUICKI) (p = 0.005) and adiponectin (p = 0.046) after adjusting for age, Tanner stage and BMI. Our results show a sex-specific association between the rs11804091 and obesity suggesting an influence of this SNP on insulin resistance. PMID:28771179

  15. [Factors associated with insulin resistence in rural populations].

    PubMed

    Mendes, Larissa Loures; Gazzinelli, Andréa; Velásquez-Meléndez, Gustavo

    2009-04-01

    This study explores the relations of anthropometric, body composition assessments, biochemical and hemodynamic parameters with insulin resistance in two rural communities. Sample was composed by adults aged 18 or older, both sexes. Participants were excluded if pregnant and diabetic. Data collection included demographic lifestyle, hemodynamic, anthropometric and biochemical variables. From the 567 subjects, 50.4% were men and 49.6%, women. Most of the sample was non-white (75.7%), lived with partner (69.3%) and had low educational level. Overweight and obesity prevalences were 17.4% and 5.5%, respectively. Multivariate analysis found risk factors associated to insulin resistance for non-diabetic adults with low income and educational level: overweight, obesity, elevated waist-to-hip ratio, C-reactive protein and skin color.

  16. Obesity is the main determinant of insulin resistance more than the circulating pro-inflammatory cytokines levels in rheumatoid arthritis patients.

    PubMed

    Castillo-Hernandez, Jesus; Maldonado-Cervantes, Martha Imelda; Reyes, Juan Pablo; Patiño-Marin, Nuria; Maldonado-Cervantes, Enrique; Solorzano-Rodriguez, Claudia; de la Cruz Mendoza, Esperanza; Alvarado-Sanchez, Brenda

    Systemic blockade of TNF-α in Rheumatoid arthritis with insulin resistance seems to produce more improvement in insulin sensitivity in normal weight patients with Rheumatoid arthritis than in obese patients with Rheumatoid arthritis, suggesting that systemic-inflammation and obesity are independent risk factors for insulin resistance in Rheumatoid arthritis patients. To evaluate the insulin resistance in: normal weight patients with Rheumatoid arthritis, overweight patients with Rheumatoid arthritis, obese Rheumatoid arthritis patients, and matched control subjects with normal weight and obesity; and its association with major cytokines involved in the pathogenesis of the disease. Assessments included: body mass index, insulin resistance by Homeostasis Model Assessment, ELISA method, and enzymatic colorimetric assay. Outstanding results from these studies include: (1) In Rheumatoid arthritis patients, insulin resistance was well correlated with body mass index, but not with levels of serum cytokines. In fact, levels of cytokines were similar in all Rheumatoid arthritis patients, regardless of being obese, overweight or normal weight (2) Insulin resistance was significantly higher in Rheumatoid arthritis with normal weight than in normal weight (3) No significant difference was observed between insulin resistances of Rheumatoid arthritis with obesity and obesity (4) As expected, levels of circulating cytokines were significantly higher in Rheumatoid arthritis patients than in obesity. Obesity appears to be a dominant condition above inflammation to produce IR in RA patients. The dissociation of the inflammation and obesity components to produce IR suggests the need of an independent therapeutic strategy in obese patients with RA. Copyright © 2017. Published by Elsevier Editora Ltda.

  17. Interplay between gut microbiota and p66Shc affects obesity-associated insulin resistance.

    PubMed

    Ciciliot, Stefano; Albiero, Mattia; Campanaro, Stefano; Poncina, Nicol; Tedesco, Serena; Scattolini, Valentina; Dalla Costa, Francesca; Cignarella, Andrea; Vettore, Monica; Di Gangi, Iole Maria; Bogialli, Sara; Avogaro, Angelo; Fadini, Gian Paolo

    2018-02-21

    The 66 kDa isoform of the mammalian Shc gene promotes adipogenesis, and p66Shc -/- mice accumulate less body weight than wild-type (WT) mice. As the metabolic consequences of the leaner phenotype of p66Shc -/- mice is debated, we hypothesized that gut microbiota may be involved. We confirmed that p66Shc -/- mice gained less weight than WT mice when on a high-fat diet (HFD), but they were not protected from insulin resistance and glucose intolerance. p66Shc deletion significantly modified the composition of gut microbiota and their modification after an HFD. This was associated with changes in gene expression of Il-1b and regenerating islet-derived protein 3 γ ( Reg3g) in the gut and in systemic trimethylamine N-oxide and branched chain amino acid levels, despite there being no difference in intestinal structure and permeability. Depleting gut microbiota at the end of HFD rendered both strains more glucose tolerant but improved insulin sensitivity only in p66Shc -/- mice. Microbiota-depleted WT mice cohoused with microbiota-competent p66Shc -/- mice became significantly more insulin resistant than WT mice cohoused with WT mice, despite no difference in weight gain. These findings reconcile previous inconsistent observations on the metabolic phenotype of p66Shc -/- mice and illustrate the complex microbiome-host-genotype interplay under metabolic stress.-Ciciliot, S., Albiero, M., Campanaro, S., Poncina, N., Tedesco, S., Scattolini, V., Dalla Costa, F., Cignarella, A., Vettore, M., Di Gangi, I. M., Bogialli, S., Avogaro, A., Fadini, G. P. Interplay between gut microbiota and p66Shc affects obesity-associated insulin resistance.

  18. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance.

    PubMed

    Vandanmagsar, Bolormaa; Youm, Yun-Hee; Ravussin, Anthony; Galgani, Jose E; Stadler, Krisztian; Mynatt, Randall L; Ravussin, Eric; Stephens, Jacqueline M; Dixit, Vishwa Deep

    2011-02-01

    The emergence of chronic inflammation during obesity in the absence of overt infection or well-defined autoimmune processes is a puzzling phenomenon. The Nod-like receptor (NLR) family of innate immune cell sensors, such as the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (Nlrp3, but also known as Nalp3 or cryopyrin) inflammasome are implicated in recognizing certain nonmicrobial originated 'danger signals' leading to caspase-1 activation and subsequent interleukin-1β (IL-1β) and IL-18 secretion. We show that calorie restriction and exercise-mediated weight loss in obese individuals with type 2 diabetes is associated with a reduction in adipose tissue expression of Nlrp3 as well as with decreased inflammation and improved insulin sensitivity. We further found that the Nlrp3 inflammasome senses lipotoxicity-associated increases in intracellular ceramide to induce caspase-1 cleavage in macrophages and adipose tissue. Ablation of Nlrp3 in mice prevents obesity-induced inflammasome activation in fat depots and liver as well as enhances insulin signaling. Furthermore, elimination of Nlrp3 in obese mice reduces IL-18 and adipose tissue interferon-γ (IFN-γ) expression, increases naive T cell numbers and reduces effector T cell numbers in adipose tissue. Collectively, these data establish that the Nlrp3 inflammasome senses obesity-associated danger signals and contributes to obesity-induced inflammation and insulin resistance.

  19. Lifecourse Childhood Adiposity Trajectories Associated With Adolescent Insulin Resistance

    PubMed Central

    Huang, Rae-Chi; de Klerk, Nicholas H.; Smith, Anne; Kendall, Garth E.; Landau, Louis I.; Mori, Trevor A.; Newnham, John P.; Stanley, Fiona J.; Oddy, Wendy H.; Hands, Beth; Beilin, Lawrence J.

    2011-01-01

    OBJECTIVE In light of the obesity epidemic, we aimed to characterize novel childhood adiposity trajectories from birth to age 14 years and to determine their relation to adolescent insulin resistance. RESEARCH DESIGN AND METHODS A total of 1,197 Australian children with cardiovascular/metabolic profiling at age 14 years were studied serially from birth to age 14 years. Semiparametric mixture modeling was applied to anthropometric data over eight time points to generate adiposity trajectories of z scores (weight-for-height and BMI). Fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) were compared at age 14 years between adiposity trajectories. RESULTS Seven adiposity trajectories were identified. Three (two rising and one chronic high adiposity) trajectories comprised 32% of the population and were associated with significantly higher fasting insulin and HOMA-IR compared with a reference trajectory group (with longitudinal adiposity z scores of approximately zero). There was a significant sex by trajectory group interaction (P < 0.001). Girls within a rising trajectory from low to moderate adiposity did not show increased insulin resistance. Maternal obesity, excessive weight gain during pregnancy, and gestational diabetes were more prevalent in the chronic high adiposity trajectory. CONCLUSIONS A range of childhood adiposity trajectories exist. The greatest insulin resistance at age 14 years is seen in those with increasing trajectories regardless of birth weight and in high birth weight infants whose adiposity remains high. Public health professionals should urgently target both excessive weight gain in early childhood across all birth weights and maternal obesity and excessive weight gain during pregnancy. PMID:21378216

  20. Circulating Branched-chain Amino Acid Concentrations Are Associated with Obesity and Future Insulin Resistance in Children and Adolescents

    PubMed Central

    McCormack, Shana E.; Shaham, Oded; McCarthy, Meaghan A.; Deik, Amy A.; Wang, Thomas J.; Gerszten, Robert E.; Clish, Clary B.; Mootha, Vamsi K.; Grinspoon, Steven K.; Fleischman, Amy

    2012-01-01

    Background Branched-chain amino acid (BCAA) concentrations are elevated in response to overnutrition, and can affect both insulin sensitivity and secretion. Alterations in their metabolism may therefore play a role in the early pathogenesis of type 2 diabetes in overweight children. Objective To determine whether pediatric obesity is associated with elevations in fasting circulating concentrations of branched-chain amino acids (isoleucine, leucine, and valine), and whether these elevations predict future insulin resistance. Research Design and Methods Sixty-nine healthy subjects, ages 8 to18 years, were enrolled as a cross-sectional cohort. A subset who were pre- or early-pubertal, ages 8 to 13 years, were enrolled in a prospective longitudinal cohort for 18 months (n=17 with complete data). Results Elevations in the concentrations of BCAA’s were significantly associated with BMI Z-score (Spearman’s Rho 0.27, p=0.03) in the cross-sectional cohort. In the subset of subjects followed longitudinally, baseline BCAA concentrations were positively associated with HOMA-IR measured 18 months later after controlling for baseline clinical factors including BMI Z-score, sex, and pubertal stage (p=0.046). Conclusions Elevations in the concentrations of circulating branched-chain amino acids are significantly associated with obesity in children and adolescents, and may independently predict future insulin resistance. PMID:22961720

  1. Obese but not normal-weight women with polycystic ovary syndrome are characterized by metabolic and microvascular insulin resistance.

    PubMed

    Ketel, Iris J G; Stehouwer, Coen D A; Serné, Erik H; Korsen, Ted J M; Hompes, Peter G A; Smulders, Yvo M; de Jongh, Renate T; Homburg, Roy; Lambalk, Cornelis B

    2008-09-01

    Polycystic ovary syndrome (PCOS) and obesity are associated with diabetes and cardiovascular disease, but it is unclear to what extent PCOS contributes independently of obesity. The objective of the study was to investigate whether insulin sensitivity and insulin's effects on the microcirculation are impaired in normal-weight and obese women with PCOS. Thirty-five women with PCOS (19 normal weight and 16 obese) and 27 age- and body mass index-matched controls (14 normal weight and 13 obese) were included. Metabolic Insulin sensitivity (isoglycemic-hyperinsulinemic clamp) and microvascular insulin sensitivity [endothelium dependent (acetylcholine [ACh])] and endothelium-independent [sodium nitroprusside (SNP)] vasodilation with laser Doppler flowmetry was assessed at baseline and during hyperinsulinemia. Metabolic insulin sensitivity (M/I value) and the area under the response curves to ACh and SNP curves were measured to assess microcirculatory function at baseline and during insulin infusion (microvascular insulin sensitivity). Obese women were more insulin resistant than normal-weight women (P < 0.001), and obese PCOS women were more resistant than obese controls (P = 0.02). In contrast, normal-weight women with PCOS had similar insulin sensitivity, compared with normal-weight women without PCOS. Baseline responses to ACh showed no difference in the four groups. ACh responses during insulin infusion were significantly greater in normal-weight PCOS and controls than in obese PCOS and controls. PCOS per se had no significant influence on ACh responses during insulin infusion. During hyperinsulinemia, SNP-dependent vasodilatation did not significantly increase, compared with baseline in the four groups. PCOS per se was not associated with impaired metabolic insulin sensitivity in normal-weight women but aggravates impairment of metabolic insulin sensitivity in obese women. In obese but not normal-weight women, microvascular and metabolic insulin sensitivity are

  2. Obesity, insulin resistance and comorbidities – Mechanisms of association

    PubMed Central

    Castro, Ana Valeria B.; Kolka, Cathryn M.; Kim, Stella P.; Bergman, Richard N.

    2015-01-01

    Overall excess of fat, usually defined by the body mass index, is associated with metabolic (e.g. glucose intolerance, type 2 diabetes mellitus (T2DM), dyslipidemia) and non-metabolic disorders (e.g. neoplasias, polycystic ovary syndrome, non-alcoholic fat liver disease, glomerulopathy, bone fragility etc.). However, more than its total amount, the distribution of adipose tissue throughout the body is a better predictor of the risk to the development of those disorders. Fat accumulation in the abdominal area and in non-adipose tissue (ectopic fat), for example, is associated with increased risk to develop metabolic and non-metabolic derangements. On the other hand, observations suggest that individuals who present peripheral adiposity, characterized by large hip and thigh circumferences, have better glucose tolerance, reduced incidence of T2DM and of metabolic syndrome. Insulin resistance (IR) is one of the main culprits in the association between obesity, particularly visceral, and metabolic as well as non-metabolic diseases. In this review we will highlight the current pathophysiological and molecular mechanisms possibly involved in the link between increased VAT, ectopic fat, IR and comorbidities. We will also provide some insights in the identification of these abnormalities. PMID:25211442

  3. Association of serum leptin and adiponectin with anthropomorphic indices of obesity, blood lipids and insulin resistance in a Sub-Saharan African population.

    PubMed

    Ayina, Clarisse Noël A; Noubiap, Jean Jacques N; Etoundi Ngoa, Laurent Serge; Boudou, Philippe; Gautier, Jean François; Mengnjo, Michel Karngong; Mbanya, Jean Claude; Sobngwi, Eugene

    2016-05-17

    There is little data on the metabolic effects of adipokines in sub-Saharan African populations. This study aimed to explore the potential relationship of leptin and adiponectin, with obesity, plasma lipids and insulin resistance in a Cameroonian population. We enrolled 167 men and 309 women aged ≥18 years from the general population in Cameroon. Data were collected on waist circumference (WC), body mass index (BMI), waist-to-hip ratio (WHR), body fat (BF%), fasting blood glucose, plasma lipids, adiponectin, leptin, insulin and homeostasis model for assessment of insulin resistance (HOMA-IR). Pearson's correlation and multiple stepwise linear regression analyses were used to determine correlates of leptin and adiponectin serum levels. The prevalence of obesity was higher in women compared to men (p < 0.0001), and Central obesity which is more prevalent particularly in women (WC = 42.4%, WHR = 42.3%), is almost for 90% comparable to %BF (42.7%). Adiponectin negatively with BMI (r = -0.294, p < 0.0001), WC (r = -0.294, p < 0.0001), %BF (r = -0.122, p = 0.028), WHR (r = -0.143, p = 0.009), triglycerides (r = -0.141, p = 0.011), HOMA-IR (r = -0.145, p = 0.027) and insulin (r = -0.130, p = 0.048). Leptin positively correlated with BMI (r = 0.628), WC (r = 0.530), BF% (r = 0.720), (all p < 0.0001); with DBP (r = 0.112, p = 0.043), total cholesterol (r = 0.324, p < 0.0001), LDL-cholesterol (r = 0.298, p < 0.0001), insulin (r = 0.320, p < 0.001 and HOMA-IR (r = 0.272, p < 0.0001). In multiple stepwise regression analysis, adiponectin was negatively associated with WC (β = -0.38, p = 0.001) and BF% (β = 0.33, p < 0.0001), while leptin was positively associated with BF% (β = 0.60, p < 0.0001), total cholesterol (β = 0.11, p = 0.02) and HOMA-IR (β = 0.11, p = 0.02). When controlled for gender, HOMA-IR was found significantly associated to adiponectin (β = 0.13, p = 0.046), but not BF%, while the association previously found between leptin and HOMA

  4. Insulin Resistance and Hunger in Childhood Obesity: A Patient and Physician's Perspective.

    PubMed

    Scinta, Wendy; Bayes, Harold; Smith, Nicole

    2017-10-01

    This article is co-authored by the mother of a child with obesity and insulin resistance, who gives her perspective. It is also co-authored by the treating Obesity Medicine clinician and an investigator in obesity clinical research (both certified in Obesity Medicine), who give their perspectives. The discussion focuses upon the potential clinical use of metformin in managing young patients with obesity and insulin resistance. The article integrates what is scientifically known about the mechanisms of actions of metformin and how these mechanisms are reflected in the clinical response of young patients.

  5. Dissecting the relationship between obesity and hyperinsulinemia: Role of insulin secretion and insulin clearance.

    PubMed

    Kim, Mee Kyoung; Reaven, Gerald M; Kim, Sun H

    2017-02-01

    The aim of this study was to better delineate the complex interrelationship among insulin resistance (IR), secretion rate (ISR), and clearance rate (ICR) to increase plasma insulin concentrations in obesity. Healthy volunteers (92 nondiabetic individuals) had an insulin suppression test to measure IR and graded-glucose infusion test to measure ISR and ICR. Obesity was defined as a body mass index (BMI) ≥30 kg/m 2 , and IR was defined as steady-state plasma glucose (SSPG) ≥10 mmol/L during the insulin suppression test. Plasma glucose and insulin concentrations, ISR, and ICR were compared in three groups: insulin sensitive/overweight; insulin sensitive/obesity; and insulin resistant/obesity. Compared with the insulin-sensitive/overweight group, the insulin-sensitive/obesity had significantly higher insulin area under the curve (AUC) and ISR AUC during the graded-glucose infusion test (P < 0.001). Glucose AUC and ICR were similar. The insulin-resistant/obesity group had higher insulin AUC and ISR AUC compared with the insulin-sensitive/obesity but also had higher glucose AUC and decreased ICR (P < 0.01). In multivariate analysis, both BMI and SSPG were significantly associated with ISR. Plasma insulin concentration and ISR are increased in individuals with obesity, irrespective of degree of IR, but a decrease in ICR is confined to the subset of individuals with IR. © 2016 The Obesity Society.

  6. Fanconi anemia links reactive oxygen species to insulin resistance and obesity.

    PubMed

    Li, Jie; Sipple, Jared; Maynard, Suzette; Mehta, Parinda A; Rose, Susan R; Davies, Stella M; Pang, Qishen

    2012-10-15

    Insulin resistance is a hallmark of obesity and type 2 diabetes. Reactive oxygen species (ROS) have been proposed to play a causal role in insulin resistance. However, evidence linking ROS to insulin resistance in disease settings has been scant. Since both oxidative stress and diabetes have been observed in patients with the Fanconi anemia (FA), we sought to investigate the link between ROS and insulin resistance in this unique disease model. Mice deficient for the Fanconi anemia complementation group A (Fanca) or Fanconi anemia complementation group C (Fancc) gene seem to be diabetes-prone, as manifested by significant hyperglycemia and hyperinsulinemia, and rapid weight gain when fed with a high-fat diet. These phenotypic features of insulin resistance are characterized by two critical events in insulin signaling: a reduction in tyrosine phosphorylation of the insulin receptor (IR) and an increase in inhibitory serine phosphorylation of the IR substrate-1 in the liver, muscle, and fat tissues from the insulin-challenged FA mice. High levels of ROS, spontaneously accumulated or generated by tumor necrosis factor alpha in these insulin-sensitive tissues of FA mice, were shown to underlie the FA insulin resistance. Treatment of FA mice with the natural anti-oxidant Quercetin restores IR signaling and ameliorates the diabetes- and obesity-prone phenotypes. Finally, pairwise screen identifies protein-tyrosine phosphatase (PTP)-α and stress kinase double-stranded RNA-dependent protein kinase (PKR) that mediate the ROS effect on FA insulin resistance. These findings establish a pathogenic and mechanistic link between ROS and insulin resistance in a unique human disease setting. ROS accumulation contributes to the insulin resistance in FA deficiency by targeting both PTP-α and PKR.

  7. Insulin resistance and endocrine-metabolic abnormalities in polycystic ovarian syndrome: Comparison between obese and non-obese PCOS patients.

    PubMed

    Layegh, Parvin; Mousavi, Zohreh; Farrokh Tehrani, Donya; Parizadeh, Seyed Mohammad Reza; Khajedaluee, Mohammad

    2016-04-01

    Insulin resistance has an important role in pathophysiology of polycystic ovarian syndrome (PCOS). Yet there are certain controversies regarding the presence of insulin resistance in non-obese patients. The aim was to compare the insulin resistance and various endocrine and metabolic abnormalities in obese and non-obese PCOS women. In this cross-sectional study which was performed from 2007-2010, 115 PCOS patients, aged 16-45 years were enrolled. Seventy patients were obese (BMI ≥25) and 45 patients were non-obese (BMI <25). Presence of insulin resistance and endocrine-metabolic abnormalities were compared between two groups. Collected data were analyzed with SPSS version 16.0 and p<0.05 was considered as statistically significant. There was no significant difference in presence of insulin resistance (HOMA-IR >2.3) between two groups (p=0.357). Waist circumference (p<0.001), waist/hip ratio (p<0.001), systolic (p<0.001) and diastolic (p<0.001) blood pressures, fasting blood sugar (p=0.003) and insulin (p=0.011), HOMA-IR (p=0.004), total cholesterol (p=0.001) and triglyceride (p<0.001) were all significantly higher in obese PCOS patients. There was no significant difference in total testosterone (p=0.634) and androstenedione (p=0.736) between groups whereas Dehydroepiandrotendione sulfate (DHEAS) was significantly higher in non-obese PCOS women (p=0.018). There was no case of fatty liver and metabolic syndrome in non-obese patients, whereas they were seen in 31.3% and 39.4% of obese PCOS women, respectively. Our study showed that metabolic abnormalities are more prevalent in obese PCOS women, but adrenal axis activity that is reflected in higher levels of DHEAS was more commonly pronounced in our non-obese PCOS patients.

  8. Metabolic consequences of obesity and insulin resistance in polycystic ovary syndrome: diagnostic and methodological challenges.

    PubMed

    Jeanes, Yvonne M; Reeves, Sue

    2017-06-01

    Women with polycystic ovary syndrome (PCOS) have a considerable risk of metabolic dysfunction. This review aims to present contemporary knowledge on obesity, insulin resistance and PCOS with emphasis on the diagnostic and methodological challenges encountered in research and clinical practice. Variable diagnostic criteria for PCOS and associated phenotypes are frequently published. Targeted searches were conducted to identify all available data concerning the association of obesity and insulin resistance with PCOS up to September 2016. Articles were considered if they were peer reviewed, in English and included women with PCOS. Obesity is more prevalent in women with PCOS, but studies rarely reported accurate assessments of adiposity, nor split the study population by PCOS phenotypes. Many women with PCOS have insulin resistance, though there is considerable variation reported in part due to not distinguishing subgroups known to have an impact on insulin resistance as well as limited methodology to measure insulin resistance. Inflammatory markers are positively correlated with androgen levels, but detailed interactions need to be identified. Weight management is the primary therapy; specific advice to reduce the glycaemic load of the diet and reduce the intake of pro-inflammatory SFA and advanced glycation endproducts have provided promising results. It is important that women with PCOS are educated about their increased risk of metabolic complications in order to make timely and appropriate lifestyle modifications. Furthermore, well-designed robust studies are needed to evaluate the mechanisms behind the improvements observed with dietary interventions.

  9. Adipocyte-Specific Deficiency of NADPH Oxidase 4 Delays the Onset of Insulin Resistance and Attenuates Adipose Tissue Inflammation in Obesity.

    PubMed

    Den Hartigh, Laura J; Omer, Mohamed; Goodspeed, Leela; Wang, Shari; Wietecha, Tomasz; O'Brien, Kevin D; Han, Chang Yeop

    2017-03-01

    Obesity is associated with insulin resistance and adipose tissue inflammation. Reactive oxygen species (ROS) increase in adipose tissue during the development of obesity. We previously showed that in response to excess nutrients like glucose and palmitate, adipocytes generated ROS via NADPH oxidase (NOX) 4, the major adipocyte isoform, instead of using mitochondrial oxidation. However, the role of NOX4-derived ROS in the development of whole body insulin resistance, adipocyte inflammation, and recruitment of macrophages to adipose tissue during the development of obesity is unknown. In this study, control C57BL/6 mice and mice in which NOX4 has been deleted specifically in adipocytes were fed a high-fat, high-sucrose diet. During the development of obesity in control mice, adipocyte NOX4 and pentose phosphate pathway activity were transiently increased. Primary adipocytes differentiated from mice with adipocytes deficient in NOX4 showed resistance against high glucose or palmitate-induced adipocyte inflammation. Mice with adipocytes deficient in NOX4 showed a delayed onset of insulin resistance during the development of obesity, with an initial reduction in adipose tissue inflammation that normalized with prolonged high-fat, high-sucrose feeding. These findings imply that NOX4-derived ROS may play a role in the onset of insulin resistance and adipose tissue inflammation. As such, therapeutics targeting NOX4-mediated ROS production could be effective in preventing obesity-associated conditions, such as insulin resistance. © 2016 American Heart Association, Inc.

  10. Maladaptive immune and inflammatory pathways lead to cardiovascular insulin resistance.

    PubMed

    Aroor, Annayya R; McKarns, Susan; Demarco, Vincent G; Jia, Guanghong; Sowers, James R

    2013-11-01

    Insulin resistance is a hallmark of obesity, the cardiorenal metabolic syndrome and type 2 diabetes mellitus (T2DM). The progression of insulin resistance increases the risk for cardiovascular disease (CVD). The significance of insulin resistance is underscored by the alarming rise in the prevalence of obesity and its associated comorbidities in the Unites States and worldwide over the last 40-50 years. The incidence of obesity is also on the rise in adolescents. Furthermore, premenopausal women have lower CVD risk compared to men, but this protection is lost in the setting of obesity and insulin resistance. Although systemic and cardiovascular insulin resistance is associated with impaired insulin metabolic signaling and cardiovascular dysfunction, the mechanisms underlying insulin resistance and cardiovascular dysfunction remain poorly understood. Recent studies show that insulin resistance in obesity and diabetes is linked to a metabolic inflammatory response, a state of systemic and tissue specific chronic low grade inflammation. Evidence is also emerging that there is polarization of macrophages and lymphocytes towards a pro-inflammatory phenotype that contributes to progression of insulin resistance in obesity, cardiorenal metabolic syndrome and diabetes. In this review, we provide new insights into factors, such as, the renin-angiotensin-aldosterone system, sympathetic activation and incretin modulators (e.g., DPP-4) and immune responses that mediate this inflammatory state in obesity and other conditions characterized by insulin resistance. © 2013.

  11. Role of immune cells in obesity induced low grade inflammation and insulin resistance.

    PubMed

    Asghar, Ambreen; Sheikh, Nadeem

    2017-05-01

    The frequency of obesity is enormously growing worldwide. Obesity results when energy intake exceeds, energy expenditure. Excess adiposity is a major risk factor in the progress of various metabolic disorders accounting insulin resistance, hypertension, Type 2 diabetes, nonalcoholic fatty liver disease, polycystic ovarian disease and several types of cancers. Obesity is characterized by pro-inflammatory condition in which hypertrophied adipose tissue along with immune cells contribute to increase the level of pro-inflammatory cytokines. Immune cells are the key players in inducing low grade chronic inflammation in obesity and are main factor responsible for pathogenesis of insulin resistance resulting Type 2 diabetes. The current review is aimed to investigate the mechanism of pro-inflammatory responses and insulin resistance involving immune cells and their products in obesity. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Fanconi Anemia Links Reactive Oxygen Species to Insulin Resistance and Obesity

    PubMed Central

    Li, Jie; Sipple, Jared; Maynard, Suzette; Mehta, Parinda A.; Rose, Susan R.; Davies, Stella M.

    2012-01-01

    Abstract Aims: Insulin resistance is a hallmark of obesity and type 2 diabetes. Reactive oxygen species (ROS) have been proposed to play a causal role in insulin resistance. However, evidence linking ROS to insulin resistance in disease settings has been scant. Since both oxidative stress and diabetes have been observed in patients with the Fanconi anemia (FA), we sought to investigate the link between ROS and insulin resistance in this unique disease model. Results: Mice deficient for the Fanconi anemia complementation group A (Fanca) or Fanconi anemia complementation group C (Fancc) gene seem to be diabetes-prone, as manifested by significant hyperglycemia and hyperinsulinemia, and rapid weight gain when fed with a high-fat diet. These phenotypic features of insulin resistance are characterized by two critical events in insulin signaling: a reduction in tyrosine phosphorylation of the insulin receptor (IR) and an increase in inhibitory serine phosphorylation of the IR substrate-1 in the liver, muscle, and fat tissues from the insulin-challenged FA mice. High levels of ROS, spontaneously accumulated or generated by tumor necrosis factor alpha in these insulin-sensitive tissues of FA mice, were shown to underlie the FA insulin resistance. Treatment of FA mice with the natural anti-oxidant Quercetin restores IR signaling and ameliorates the diabetes- and obesity-prone phenotypes. Finally, pairwise screen identifies protein-tyrosine phosphatase (PTP)-α and stress kinase double-stranded RNA-dependent protein kinase (PKR) that mediate the ROS effect on FA insulin resistance. Innovation: These findings establish a pathogenic and mechanistic link between ROS and insulin resistance in a unique human disease setting. Conclusion: ROS accumulation contributes to the insulin resistance in FA deficiency by targeting both PTP-α and PKR. Antioxid. Redox Signal. 00, 000–000. PMID:22482891

  13. FNDC5 attenuates adipose tissue inflammation and insulin resistance via AMPK-mediated macrophage polarization in obesity.

    PubMed

    Xiong, Xiao-Qing; Geng, Zhi; Zhou, Bing; Zhang, Feng; Han, Ying; Zhou, Ye-Bo; Wang, Jue-Jin; Gao, Xing-Ya; Chen, Qi; Li, Yue-Hua; Kang, Yu-Ming; Zhu, Guo-Qing

    2018-06-01

    Obesity-induced chronic inflammation is critical in the pathogenesis of insulin resistance, and the recruitment and proinflammatory activation of adipose tissue macrophages (ATMs) is important for the development of this process. Here, we examined the effects of fibronectin type III domain-containing 5 (FNDC5) on inflammation and insulin resistance in high-fat diet-induced obese mice. Male wild-type (WT) and FNDC5 -/- mice were fed with standard chow (Ctrl) or high fat diet (HFD) for 20 weeks to induce obesity and insulin resistance. Firstly, effects of FNDC5 gene deletion on obesity, insulin resistance, macrophage accumulation and polarization and adipose tissue inflammation were determined in mice. Secondly, the macrophage polarity shift was further examined with flow cytometry in isolated stromal vascular fraction (SVF). Thirdly, the effects of exogenous FNDC5 on lipopolysaccharide (LPS)-induced macrophage polarization, inflammation and the underlying signaling mechanism were investigated in RAW264.7 macrophages and primary mouse peritoneal cavity macrophages (PMs). Finally, the therapeutic effects of FNDC5 overexpression were examined in HFD-induced obese WT and FNDC5 -/- mice. FNDC5 gene deletion aggravated obesity, insulin resistance, fat accumulation and inflammation accompanied with enhanced AMPK inhibition, macrophages recruitment and M1 polarization in mice fed with HFD. Exogenous FNDC5 inhibited LPS-induced M1 macrophage polarization and inflammatory cytokine production via AMPK phosphorylation in both RAW264.7 macrophages and PMs. FNDC5 overexpression attenuated insulin resistance, AMPK inhibition, M1 macrophage polarization and inflammatory cytokine production in adipose tissue of obese WT and FNDC5 -/- mice. FNDC5 attenuates adipose tissue inflammation and insulin resistance via AMPK-mediated macrophage polarization in HFD-induced obesity. FNDC5 plays several beneficial roles in obesity and may be used as a therapeutic regimen for preventing

  14. Methods for quantifying adipose tissue insulin resistance in overweight/obese humans.

    PubMed

    Ter Horst, K W; van Galen, K A; Gilijamse, P W; Hartstra, A V; de Groot, P F; van der Valk, F M; Ackermans, M T; Nieuwdorp, M; Romijn, J A; Serlie, M J

    2017-08-01

    Insulin resistance of adipose tissue is an important feature of obesity-related metabolic disease. However, assessment of lipolysis in humans requires labor-intensive and expensive methods, and there is limited validation of simplified measurement methods. We aimed to validate simplified methods for the quantification of adipose tissue insulin resistance against the assessment of insulin sensitivity of lipolysis suppression during hyperinsulinemic-euglycemic clamp studies. We assessed the insulin-mediated suppression of lipolysis by tracer-dilution of [1,1,2,3,3- 2 H 5 ]glycerol during hyperinsulinemic-euglycemic clamp studies in 125 overweight or obese adults (85 men, 40 women; age 50±11 years; body mass index 38±7 kg m -2 ). Seven indices of adipose tissue insulin resistance were validated against the reference measurement method. Low-dose insulin infusion resulted in suppression of the glycerol rate of appearance ranging from 4% (most resistant) to 85% (most sensitive), indicating a good range of adipose tissue insulin sensitivity in the study population. The reference method correlated with (1) insulin-mediated suppression of plasma glycerol concentrations (r=0.960, P<0.001), (2) suppression of plasma non-esterified fatty acid (NEFA) concentrations (r=0.899, P<0.001), (3) the Adipose tissue Insulin Resistance (Adipo-IR) index (fasting plasma insulin-NEFA product; r=-0.526, P<0.001), (4) the fasting plasma insulin-glycerol product (r=-0.467, P<0.001), (5) the Adipose Tissue Insulin Resistance Index (fasting plasma insulin-basal lipolysis product; r=0.460, P<0.001), (6) the Quantitative Insulin Sensitivity Check Index (QUICKI)-NEFA index (r=0.621, P<0.001), and (7) the QUICKI-glycerol index (r=0.671, P<0.001). Bland-Altman plots showed no systematic errors for the suppression indices but proportional errors for all fasting indices. Receiver-operator characteristic curves confirmed that all indices were able to detect adipose tissue insulin resistance (area

  15. A review of obesity, insulin resistance, and the role of exercise in breast cancer patients.

    PubMed

    Ghose, Abhimanyu; Kundu, Ria; Toumeh, Anis; Hornbeck, Catherine; Mohamed, Iman

    2015-01-01

    Breast cancer, the most common female malignancy in the world, has a strong association with obesity and insulin resistance. The importance of these risk factors goes up significantly in patients already affected by this cancer as they negatively affect the prognosis, recurrence rate, and survival by various mechanisms. The literature on the role of physical activity and aerobic exercise on modifying the above risks is debatable with data both for and against it. In this article, we have reviewed the risks of obesity and insulin resistance in breast cancer patients and the controversy associated with the impact of exercise. Ultimately, we have concluded that a randomized control trial is necessary with an individualized aerobic exercise program for a minimum duration of 20 wk on breast cancer patients, who are undergoing or recently completed chemotherapy, to study its effects on insulin resistance, weight, and clinical outcome.

  16. Defect in skeletal muscle phosphatidylinositol-3-kinase in obese insulin-resistant mice.

    PubMed Central

    Heydrick, S J; Jullien, D; Gautier, N; Tanti, J F; Giorgetti, S; Van Obberghen, E; Le Marchand-Brustel, Y

    1993-01-01

    Activation of phosphatidylinositol-3-kinase (PI3K) is one of the earliest postreceptor events in the insulin signaling pathway. Incubation of soleus muscles from lean mice with 50 nM insulin caused a 3-10-fold increase in antiphosphotyrosine-immunoprecipitable PI3K (antiPTyr-PI3K) activity within 2 min in muscle homogenates as well as both the cytosolic and membrane fractions. Insulin did not affect total PI3K activity. Both the antiPTyr-PI3K stimulation and activation of insulin receptor tyrosine kinase were dependent on hormone concentration. In muscles from obese, insulin-resistant mice, there was a 40-60% decrease in antiPTyr-PI3K activity after 2 min of insulin that was present equally in the cytosolic and membrane fractions. A significant reduction in insulin sensitivity was also observed. The defect appears to result from alterations in both insulin receptor and postreceptor signaling. Starvation of obese mice for 48 h, which is known to reverse insulin resistance, normalized the insulin response of both PI3K and the receptor tyrosine kinase. The results demonstrate that: (a) antiPTyr-PI3K activity is responsive to insulin in mouse skeletal muscle, (b) both the insulin responsiveness and sensitivity of this activity are blunted in insulin-resistant muscles from obese mice, (c) these alterations result from a combination of insulin receptor and postreceptor defects, and (d) starvation restores normal insulin responses. Images PMID:8386184

  17. Glucose-6-Phosphate Dehydrogenase Deficiency Improves Insulin Resistance With Reduced Adipose Tissue Inflammation in Obesity.

    PubMed

    Ham, Mira; Choe, Sung Sik; Shin, Kyung Cheul; Choi, Goun; Kim, Ji-Won; Noh, Jung-Ran; Kim, Yong-Hoon; Ryu, Je-Won; Yoon, Kun-Ho; Lee, Chul-Ho; Kim, Jae Bum

    2016-09-01

    Glucose-6-phosphate dehydrogenase (G6PD), a rate-limiting enzyme of the pentose phosphate pathway, plays important roles in redox regulation and de novo lipogenesis. It was recently demonstrated that aberrant upregulation of G6PD in obese adipose tissue mediates insulin resistance as a result of imbalanced energy metabolism and oxidative stress. It remains elusive, however, whether inhibition of G6PD in vivo may relieve obesity-induced insulin resistance. In this study we showed that a hematopoietic G6PD defect alleviates insulin resistance in obesity, accompanied by reduced adipose tissue inflammation. Compared with wild-type littermates, G6PD-deficient mutant (G6PD(mut)) mice were glucose tolerant upon high-fat-diet (HFD) feeding. Intriguingly, the expression of NADPH oxidase genes to produce reactive oxygen species was alleviated, whereas that of antioxidant genes was enhanced in the adipose tissue of HFD-fed G6PD(mut) mice. In diet-induced obesity (DIO), the adipose tissue of G6PD(mut) mice decreased the expression of inflammatory cytokines, accompanied by downregulated proinflammatory macrophages. Accordingly, macrophages from G6PD(mut) mice greatly suppressed lipopolysaccharide-induced proinflammatory signaling cascades, leading to enhanced insulin sensitivity in adipocytes and hepatocytes. Furthermore, adoptive transfer of G6PD(mut) bone marrow to wild-type mice attenuated adipose tissue inflammation and improved glucose tolerance in DIO. Collectively, these data suggest that inhibition of macrophage G6PD would ameliorate insulin resistance in obesity through suppression of proinflammatory responses. © 2016 by the American Diabetes Association.

  18. Association of oxidative stress, insulin resistance, and diabetes risk phenotypes: the Framingham Offspring Study.

    PubMed

    Meigs, James B; Larson, Martin G; Fox, Caroline S; Keaney, John F; Vasan, Ramachandran S; Benjamin, Emelia J

    2007-10-01

    Systemic oxidative stress causes insulin resistance in rodents. We tested the hypothesis that oxidative stress and insulin resistance are associated in humans. We used cross-sectional data from 2,002 nondiabetic subjects of the community-based Framingham Offspring Study. We measured insulin resistance with the homeostasis model and defined categorical insulin resistance as homeostasis model assessment of insulin resistance (HOMA-IR) > 75th percentile. We measured oxidative stress using the ratio of urine 8-epi-prostaglandin F2alpha (8-epi-PGF2alpha) to creatinine and used age- and sex-adjusted regression models to test the association of oxidative stress with insulin resistance in individuals without diabetes and among subgroups at elevated risk of diabetes. Across 8-epi-PGF2alpha/creatinine tertiles, the prevalence of insulin resistance increased (18.0, 27.5, and 29.4% for the first, second, and third tertiles, respectively; P < 0.0001), as did mean levels of HOMA-IR (3.28, 3.83, and 4.06 units; P < 0.0001). The insulin resistance-oxidative stress association was attenuated by additional adjustment for BMI (P = 0.06 across tertiles for insulin resistance prevalence; P = 0.004 for mean HOMA-IR). Twenty-six percent of participants were obese (BMI > or = 30 kg/m2), 39% had metabolic syndrome (according to the Adult Treatment Panel III definition), and 37% had impaired fasting glucose (IFG) (fasting glucose 5.6-6.9 mmol/l). Among 528 obese participants, respectively, insulin resistance prevalence was 41.3, 60.6, and 54.2% across 8-epi-PGF2alpha/creatinine tertiles (P = 0.005); among 781 subjects with metabolic syndrome, insulin resistance prevalence was 41.3, 56.7, and 51.7% (P = 0.0025); and among 749 subjects with IFG, insulin resistance prevalence was 39.6, 47.2, and 51.6% (P = 0.04). Systemic oxidative stress is associated with insulin resistance in individuals at average or elevated risk of diabetes even after accounting for BMI.

  19. Adipocyte-specific deficiency of NADPH oxidase 4 delays the onset of insulin resistance and attenuates adipose tissue inflammation in obesity

    PubMed Central

    Den Hartigh, Laura J.; Omer, Mohamed; Goodspeed, Leela; Wang, Shari; Wietecha, Tomasz; O’Brien, Kevin D.; Han, Chang Yeop

    2017-01-01

    Objective Obesity is associated with insulin resistance and adipose tissue inflammation. Reactive oxygen species (ROS) increase in adipose tissue during the development of obesity. We previously showed that in response to excess nutrients like glucose and palmitate, adipocytes generated ROS via NADPH oxidase (NOX) 4, the major adipocyte isoform, instead of using mitochondrial oxidation. However, the role of NOX4-derived ROS in the development of whole body insulin resistance, adipocyte inflammation, and recruitment of macrophages to adipose tissue during the development of obesity is unknown. Approach and Results In this study, control C57BL/6 mice and mice in which NOX4 has been deleted specifically in adipocytes were fed a high fat, high sucrose (HFHS) diet. During the development of obesity in control mice, adipocyte NOX4 and PPP activity were transiently increased. Primary adipocytes differentiated form mice with adipocytes deficient in NOX4 showed resistance against high glucose or palmitate-induced adipocyte inflammation. Mice with adipocytes deficient in NOX4 showed a delayed onset of insulin resistance during the development of obesity, with an initial reduction in adipose tissue inflammation that normalized with prolonged HFHS feeding. Conclusions These findings imply that NOX4-derived ROS may play a role in the onset of insulin resistance and adipose tissue inflammation. As such, therapeutics targeting NOX4-mediated ROS production could be effective in preventing obesity-associated conditions such as insulin resistance. PMID:28062496

  20. Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independently of obesity

    PubMed Central

    Scott, Robert A; Fall, Tove; Pasko, Dorota; Barker, Adam; Sharp, Stephen J; Arriola, Larraitz; Balkau, Beverley; Barricarte, Aurelio; Barroso, Inês; Boeing, Heiner; Clavel-Chapelon, Françoise; Crowe, Francesca L; Dekker, Jacqueline M; Fagherazzi, Guy; Ferrannini, Ele; Forouhi, Nita G; Franks, Paul W; Gavrila, Diana; Giedraitis, Vilmantas; Grioni, Sara; Groop, Leif C; Kaaks, Rudolf; Key, Timothy J; Kühn, Tilman; Lotta, Luca A; Nilsson, Peter M; Overvad, Kim; Palli, Domenico; Panico, Salvatore; Quirós, J. Ramón; Rolandsson, Olov; Roswall, Nina; Sacerdote, Carlotta; Sala, Núria; Sánchez, María-José; Schulze, Matthias B; Siddiq, Afshan; Slimani, Nadia; Sluijs, Ivonne; Spijkerman, Annemieke MW; Tjonneland, Anne; Tumino, Rosario; van der A, Daphne L; Yaghootkar, Hanieh; McCarthy, Mark I; Semple, Robert K; Riboli, Elio; Walker, Mark; Ingelsson, Erik; Frayling, Tim M; Savage, David B

    2014-01-01

    We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterise their association with intermediate phenotypes, and to investigate their role in T2D risk among normal-weight, overweight and obese individuals.We investigated the association of genetic scores with euglycaemic-hyperinsulinaemic clamp- and OGTT-based measures of insulin resistance and secretion, and a range of metabolic measures in up to 18,565 individuals. We also studied their association with T2D risk among normal-weight, overweight and obese individuals in up to 8,124 incident T2D cases. The insulin resistance score was associated with lower insulin sensitivity measured by M/I value (β in SDs-per-allele [95%CI]:−0.03[−0.04,−0.01];p=0.004). This score was associated with lower BMI (−0.01[−0.01,−0.0;p=0.02) and gluteofemoral fat-mass (−0.03[−0.05,−0.02;p=1.4×10−6), and with higher ALT (0.02[0.01,0.03];p=0.002) and gamma-GT (0.02[0.01,0.03];p=0.001). While the secretion score had a stronger association with T2D in leaner individuals (pinteraction=0.001), we saw no difference in the association of the insulin resistance score with T2D among BMI- or waist-strata(pinteraction>0.31). While insulin resistance is often considered secondary to obesity, the association of the insulin resistance score with lower BMI and adiposity and with incident T2D even among individuals of normal weight highlights the role of insulin resistance and ectopic fat distribution in T2D, independently of body size. PMID:24947364

  1. The association among skeletal muscle phosphocreatine recovery, adiposity, and insulin resistance in children.

    PubMed

    Wells, Greg D; Banks, Laura; Caterini, Jessica E; Thompson, Sara; Noseworthy, Michael D; Rayner, Tammy; Syme, Catriona; McCrindle, Brian W; Hamilton, Jill

    2017-04-01

    Obesity is associated with cardiometabolic disturbances, which may have significant implications for musculoskeletal health and exercise tolerance. We sought to determine the association between muscle structure, function, and metabolism in adolescents across the weight spectrum. This cross-sectional case-control study included overweight and obese participants (n = 24) 8-18 years of age with a body mass index (BMI) ≥ 85th percentile for age and gender, and non-obese participants (n = 24) with a BMI < 85 th percentile. Body composition, physical activity, peak aerobic capacity, cardiometabolic blood markers and insulin resistance (measured by the homeostatic model assessment of insulin resistance, HOMA-IR), skeletal muscle mitochondrial oxidative capacity (via 31 Phosphorous-Magnetic Resonance Spectroscopy, 31 P-MRS, to assess phosphocreatine (PCr) recovery after exercise), and extramyocellular and intramyocellular lipid (IMCL) levels (via 1 Hydrogen-MRS) were assessed. Stepwise regression was performed to examine the factors associated with oxidative capacity. bese and overweight patients had similar age, height, and physical activity to non-obese controls, but obese and overweight participants exhibited higher insulin resistance. Obese and overweight participants had longer PCr recovery than non-obese controls following 5x30s of moderate-intensity exercise (51.2 ± 20.1 s vs. 23.9 ± 7.5 s, p = 0.004). In univariate correlation analysis, impaired PCr recovery was associated with a higher BMI z-score (r s  = 0.51, p < 0.001), circulating triglycerides (r s  = 0.41, p = 0.005), and HOMA-IR (r s  = 0.46, p = 0.001). In stepwise multivariate regression analysis, impaired PCr recovery was associated with a higher BMI z-score (β = 0.47, p = 0.002), but not insulin resistance (β = 0.07, p = 0.07) or circulating triglycerides (β = 0.16 p = 0.33). A slower phosphocreatine recovery

  2. Insulin resistance in obese children and adolescents: HOMA-IR cut-off levels in the prepubertal and pubertal periods.

    PubMed

    Kurtoğlu, Selim; Hatipoğlu, Nihal; Mazıcıoğlu, Mümtaz; Kendirici, Mustafa; Keskin, Mehmet; Kondolot, Meda

    2010-01-01

    Childhood obesity is associated with an increased risk for insulin resistance. The underlying mechanism for the physiological increase in insulin levels in puberty is not clearly understood. The aim of the present study was to determine the cut-off values for homeostasis model assessment for insulin resistance (HOMA-IR) in obese children and adolescents according to gender and pubertal status. Two hundred and eight obese children and adolescents (141 girls, 127 boys) aged between 5 and 18 years were included in the study. The children were divided into prepubertal and pubertal groups. A standard oral glucose tolerance test (OGTT) was carried out in all children. A total insulin level exceeding 300 μU/mL in the blood samples, collected during the test period, was taken as the insulin resistance criterion. Cut-off values for HOMA-IR were calculated by receiver operating characteristic (ROC) analysis. In the prepubertal period, the rate of insulin resistance was found to be 37% in boys and 27.8% in girls,while in the pubertal period, this rate was 61.7% in boys and 66.7% in girls. HOMA-IR cut-off values for insulin resistance in the prepubertal period were calculated to be 2.67 (sensitivity 88.2%, specificity 65.5%) in boys and 2.22 (sensitivity 100%, specificity 42.3%) in girls, and in the pubertal period, they were 5.22 (sensitivity 56%, specificity 93.3%) in boys and 3.82 (sensitivity 77.1%, specificity 71.4%) in girls. Since gender, obesity and pubertal status are factors affecting insulin resistance, cut-off values which depend on gender and pubertal status, should be used in evaluation of insulin resistance.

  3. Insulin resistance, body composition, and fat distribution in obese children with nonalcoholic fatty liver disease.

    PubMed

    Yang, Hye Ran; Chang, Eun Jae

    2016-01-01

    The aim of this study was to evaluate the influence of body composition, especially distribution of body fat, and insulin resistance on nonalcoholic fatty liver disease (NAFLD) in obese children. One hundred obese children (66 boys, 34 girls) with (n=60) and without NAFLD (n=40) were assessed. Anthropometry, laboratory tests, abdominal ultrasonography, and dual energy x-ray absorption metry (DXA) were evaluated in all subjects. Subject age and measurements of liver enzymes, γ- glutamyl transpeptidase (γGT), uric acid, high-density lipoprotein cholesterol, and insulin resistance were significantly different between the non-NAFLD group and NAFLD group. Body fat and trunk fat percentage were significantly different between the two groups (p<0.001 and p=0.003), whereas extremity fat percentage was not (p=0.683). Insulin resistance correlated significantly with body fat and trunk fat percentages, age, liver enzymes, γGT, and uric acid in obese children. Multiple logistic regression analysis indicated that insulin resistance and trunk fat percentage significantly affected the development of NAFLD in obese children. Body fat, especially abdominal fat, influences the development of insulin resistance and subsequent NAFLD in obese children. Therefore, body composition measurement using DXA, in conjunction with biochemical tests, may be beneficial in evaluating obese children with NAFLD.

  4. Associations of sarcopenic obesity with the metabolic syndrome and insulin resistance over five years in older men: The Concord Health and Ageing in Men Project.

    PubMed

    Scott, David; Cumming, Robert; Naganathan, Vasi; Blyth, Fiona; Le Couteur, David G; Handelsman, David J; Seibel, Markus; Waite, Louise M; Hirani, Vasant

    2018-07-15

    Previous cross-sectional studies investigating associations of sarcopenic obesity with metabolic syndrome (MetS) and insulin resistance have not utilised consensus definitions of sarcopenia. We aimed to determine associations of sarcopenic obesity with MetS and insulin resistance over five years in community-dwelling older men. 1231 men aged ≥70 years had appendicular lean mass (ALM) and body fat percentage assessed by dual-energy X-ray absorptiometry and hand grip strength and gait speed tests. Sarcopenia was defined as low ALM/height (m 2 ) and low hand grip strength or gait speed (European Working Group definition); obesity was defined as body fat percentage ≥30%. MetS was assessed at baseline and 5-years later. Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was assessed at 5-years only. Men with sarcopenic obesity (odds ratio, 95% CI: 2.07, 1.21-3.55) and non-sarcopenic obesity (4.19, 3.16-5.57) had higher MetS likelihood than those with non-sarcopenic non-obesity at baseline. Higher gait speed predicted lower odds for prevalent MetS (0.45, 0.21-0.96 per m/s). Higher body fat predicted increased odds for prevalent and incident MetS (1.14, 1.11-1.17 and 1.11, 1.02-1.20 per kg, respectively) and deleterious 5-year changes in MetS fasting glucose, high-density lipoprotein cholesterol and triglycerides (all P < 0.05). Compared with non-sarcopenic non-obesity, estimated marginal means for HOMA-IR at 5-years were higher in non-sarcopenic obesity only (1.0, 0.8-1.1 vs 1.3, 1.2-1.5; P < 0.001). Similar results were observed when sarcopenic obesity was defined by waist circumference. Sarcopenic obesity does not appear to confer greater risk for incident MetS or insulin resistance than obesity alone in community-dwelling older men. Copyright © 2018 Elsevier Inc. All rights reserved.

  5. Glucose alteration and insulin resistance in asymptomatic obese children and adolescents.

    PubMed

    Assunção, Silvana Neves Ferraz de; Boa Sorte, Ney Christian Amaral; Alves, Crésio de Aragão Dantas; Mendes, Patricia S Almeida; Alves, Carlos Roberto Brites; Silva, Luciana Rodrigues

    Obesity is associated with the abnormal glucose metabolism preceding type 2 diabetes mellitus. Thus, further investigation on the prediction of this lethal outcome must be sought. The objective was the profile glycemic assessment of asymptomatic obese children and adolescents from Salvador, Brazil. A fasting venous blood sample was obtained from 90 consecutive obese individuals aged 8-18 years, of both sexes, for laboratory determinations of glycated hemoglobin, basal insulin, and the Homeostasis Model Assessment Insulin Resistance index. The clinical evaluation included weight, height, waist circumference, assessment of pubertal development, and acanthosis nigricans research. The body mass index/age indicator was used for the severity of overweight assessment. Glycemic alterations were evidenced clinically and biochemically, although these individuals had no complaints or symptoms related to blood sugar levels. Quantitative and qualitative variables were respectively expressed measures of central tendency/dispersion and simple/relative frequency, using the SPSS, version 20.0. A p-value <0.05 was considered significant. Notably, this study found a high prevalence of glucose and insulin disorders in asymptomatic obese children and adolescents. Copyright © 2017 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

  6. Activation and regulation of the pattern recognition receptors in obesity-induced adipose tissue inflammation and insulin resistance.

    PubMed

    Watanabe, Yasuharu; Nagai, Yoshinori; Takatsu, Kiyoshi

    2013-09-23

    Obesity-associated chronic tissue inflammation is a key contributing factor to type 2 diabetes mellitus, and a number of studies have clearly demonstrated that the immune system and metabolism are highly integrated. Recent advances in deciphering the various immune cells and signaling networks that link the immune and metabolic systems have contributed to our understanding of the pathogenesis of obesity-associated inflammation. Other recent studies have suggested that pattern recognition receptors in the innate immune system recognize various kinds of endogenous and exogenous ligands, and have a crucial role in initiating or promoting obesity-associated chronic inflammation. Importantly, these mediators act on insulin target cells or on insulin-producing cells impairing insulin sensitivity and its secretion. Here, we discuss how various pattern recognition receptors in the immune system underlie the etiology of obesity-associated inflammation and insulin resistance, with a particular focus on the TLR (Toll-like receptor) family protein Radioprotective 105 (RP105)/myeloid differentiation protein-1 (MD-1).

  7. Insulin Resistance in Nondiabetic Peritoneal Dialysis Patients: Associations with Body Composition, Peritoneal Transport, and Peritoneal Glucose Absorption.

    PubMed

    Bernardo, Ana Paula; Oliveira, Jose C; Santos, Olivia; Carvalho, Maria J; Cabrita, Antonio; Rodrigues, Anabela

    2015-12-07

    Insulin resistance has been associated with cardiovascular disease in peritoneal dialysis patients. Few studies have addressed the impact of fast transport status or dialysis prescription on insulin resistance. The aim of this study was to test whether insulin resistance is associated with obesity parameters, peritoneal transport rate, and glucose absorption. Insulin resistance was evaluated with homeostasis model assessment method (HOMA-IR), additionally corrected by adiponectin (HOMA-AD). Enrolled patients were prevalent nondiabetics attending at Santo António Hospital Peritoneal Dialysis Unit, who were free of hospitalization or infectious events in the previous 3 months (51 patients aged 50.4 ± 15.9 years, 59% women). Leptin, adiponectin, insulin-like growth factor-binding protein 1 (IGFBP-1), and daily glucose absorption were also measured. Lean tissue index, fat tissue index (FTI), and relative fat mass (rel.FM) were assessed using multifrequency bioimpedance. Patients were categorized according to dialysate to plasma creatinine ratio at 4 hours, 3.86% peritoneal equilibration test, and obesity parameters. Obesity was present in 49% of patients according to rel.FM. HOMA-IR correlated better with FTI than with body mass index. Significant correlations were found in obese, but not in nonobese patients, between HOMA-IR and leptin, leptin/adiponectin ratio (LAR), and IGFBP-1. HOMA-IR correlated with HOMA-AD, but did not correlate with glucose absorption or transport rate. There were no significant differences in insulin resistance indices, glucose absorption, and body composition parameters between fast and nonfast transporters. A total of 18 patients (35.3%) who had insulin resistance presented with higher LAR and rel.FM (7.3 [12.3, interquartile range] versus 0.7 [1.4, interquartile range], P<0.001, and 39.4 ± 10.1% versus 27.2 ± 11.5%, P=0.002, respectively), lower IGFBP-1 (8.2 ± 7.2 versus 21.0 ± 16.3 ng/ml, P=0.002), but similar glucose absorption and

  8. Serum resistin correlates with central obesity but weakly with insulin resistance in Chinese children and adolescents.

    PubMed

    Li, M; Fisette, A; Zhao, X-Y; Deng, J-Y; Mi, J; Cianflone, K

    2009-04-01

    Resistin has been linked with obesity and hypothesized as a potential marker of insulin resistance in addition to being linked with acute inflammation. However, these links are still highly controversial in humans. Our goal was to examine resistin levels in relation to obesity, insulin resistance and inflammation markers in a large population of Asian children and adolescents. Children and adolescents (n=3472) aged 6-18 years, boys (n=1765) and girls (n=1707), were assessed for body size parameters, pubertal development, blood lipids, glucose, insulin, resistin, C-reactive protein (CRP), adiponectin and complement C3 (C3) levels. Resistin increased with central obesity in both genders but not with simple adiposity in boys. Several markers associated with central obesity correlated in a gender-specific fashion with plasma resistin. Waist circumference, fat-mass percentage, waist-to-height ratio and body mass index (BMI) positively correlated with resistin in both genders. Blood lipids such as triglycerides, nonesterified fatty acids (NEFA) and low-density lipoprotein cholesterol, diastolic and systolic blood pressure correlated positively with resistin in boys. NEFA, high-density lipoprotein cholesterol (negatively) and inflammation markers, such as CRP and C3, positively correlated with resistin in girls. There was no correlation between resistin and adiponectin, and no association of adiponectin with resistin quintiles in either boys or girls. In both boys and girls, resistin tended to decrease with age, with girls having higher levels than boys. Few indices of insulin resistance were linked with plasma resistin in either gender. In this population, plasma resistin levels are a weak biochemical marker of metabolic dysfunction defined by central obesity, adiposity and inflammation and does not predict insulin resistance. Only a small proportion of resistin variation can be explained by factors related to metabolic syndrome, suggesting that resistin is not strongly

  9. Adipose tissue CIDEA is associated, independently of weight variation, to change in insulin resistance during a longitudinal weight control dietary program in obese individuals.

    PubMed

    Montastier, Emilie; Déjean, Sébastien; Le Gall, Caroline; Saris, Wim H M; Langin, Dominique; Viguerie, Nathalie

    2014-01-01

    Weight loss reduces risk factors associated with obesity. However, long-term metabolic improvement remains a challenge. We investigated quantitative gene expression of subcutaneous adipose tissue in obese individuals and its relationship with low calorie diet and long term weight maintenance induced changes in insulin resistance. Three hundred eleven overweight and obese individuals followed a dietary protocol consisting of an 8-week low calorie diet followed by a 6-month ad libitum weight-maintenance diet. Individuals were clustered according to insulin resistance trajectories assessed using homeostasis model assessment of insulin resistance (HOMA-IR) index. Adipose tissue mRNA levels of 267 genes selected for regulation according to obesity, metabolic status and response to dieting was assessed using high throughput RT-qPCR. A combination of discriminant analyses was used to identify genes with regulation according to insulin resistance trajectories. Partial correlation was used to control for change in body mass index. Three different HOMA-IR profile groups were determined. HOMA-IR improved during low calorie diet in the 3 groups. At the end of the 6-month follow-up, groups A and B had reduced HOMA-IR by 50%. In group C, HOMA-IR had returned to baseline values. Genes were differentially expressed in the adipose tissue of individuals according to groups but a single gene, CIDEA, was common to all phases of the dietary intervention. Changes in adipose tissue CIDEA mRNA levels paralleled variations in insulin sensitivity independently of change in body mass index. Overall, CIDEA was up-regulated in adipose tissue of individuals with successful long term insulin resistance relapse and not in adipose tissue of unsuccessful individuals. The concomitant change in adipose tissue CIDEA mRNA levels and insulin sensitivity suggests a beneficial role of adipose tissue CIDEA in long term glucose homeostasis, independently of weight variation. ClinicalTrials.gov NCT00390637.

  10. Innate immunity, insulin resistance and type 2 diabetes.

    PubMed

    Fernández-Real, José Manuel; Pickup, John C

    2008-01-01

    Recent evidence has disclosed previously unrecognized links among insulin resistance, obesity, circulating immune markers, immunogenetic susceptibility, macrophage function and chronic infection. Genetic variations leading to altered production or function of circulating innate immune proteins, cellular pattern-recognition receptors and inflammatory cytokines have been linked with insulin resistance, type 2 diabetes, obesity and atherosclerosis. Cellular innate immune associations with obesity and insulin resistance include increased white blood cell count and adipose tissue macrophage numbers. The innate immune response is modulated possibly by both predisposition (genetic or fetal programming), perhaps owing to evolutionary pressures caused by acute infections at the population level (pandemics), and chronic low exposure to environmental products or infectious agents. The common characteristics shared among innate immunity activation, obesity and insulin resistance are summarized.

  11. [Contribution of leptin in the development of insulin resistance in pregnant women with obesity].

    PubMed

    Tarasenko, K

    2014-03-01

    The aim of the present study was to investigate contribution of leptin in the development of insulin resistance in obese pregnant women depending on the obesity class as well as its effect on the progression of pregnancy. 36 pregnant women of I and II obesity classes and 21 pregnant women with normal body mass participated in the study. Concentrations of insulin, leptin and C-reactive protein in blood serum were measured with immunoenzymatic assays. Insulin resistance (IR) was determined with the Caro index. Contribution of leptin to development of IR was assessed with the ratio "leptin/Caro index". An increase of leptin concentration in blood serum was found in pregnant women with obesity compared to healthy controls. Moreover, the ratio "leptin/Caro index" increased with IR progression and reached maximum in the group with obesity class II, where it was 5.8 times higher than in the control group. An increased frequency of gestoses and placentary dysfunction were manifestations of weakening of adaptive mechanisms of the organism associated with the IR progression and increased role of leptin in its development. Therefore, activation of adipocyte function through the increased leptin secretion and increased ratio "leptin/Caro index" reflects the important role of leptin in pathogenesis of IR in pregnant women with obesity.

  12. Abnormality of adipokines and endothelial dysfunction in Mexican obese adolescents with insulin resistance.

    PubMed

    Ortiz Segura, Maria Del Carmen; Del Río Navarro, Blanca Estela; Rodríguez Espino, Benjamín Antonio; Marchat, Laurence A; Sánchez Muñoz, Fausto; Villafaña, Santiago; Hong, Enrique; Meza-Cuenca, Fabián; Mailloux Salinas, Patrick; Bolaños-Jiménez, Francisco; Zambrano, Elena; Arredondo-López, Abel Armando; Bravo, Guadalupe; Huang, Fengyang

    2017-08-01

    The aim of this study was to investigate the possible relationship among insulin resistance (IR), endothelial dysfunction, and alteration of adipokines in Mexican obese adolescents and their association with metabolic syndrome (MetS). Two hundred and twenty-seven adolescents were classified according to the body mass index (BMI) (control: N=104; obese: N=123) and homeostasis model of the assessment-insulin resistance index (HOMA-IR) (obese with IR: N=65). The circulating concentrations of leptin, adiponectin, soluble intercellular adhesion molecule-1 (sICAM-1), and IR were determined by standard methods. The obese adolescents with IR presented increased presence of MetS and higher circulating concentrations in sICAM-1 in comparison with the obese subjects without IR. The lowest concentrations of adiponectin were observed in the obese with IR. In multivariate linear regression models, sICAM-1 along with triglycerides, total cholesterol, and waist circumference was strongly associated with HOMA-IR (R 2 =0.457, P=0.008). Similarly, after adjustment for age, BMI-SDS, lipids, and adipokines, HOMA-IR remained associated with sICAM-1 (R 2 =0.372, P=0.008). BMI-SDS was mildly associated with leptin (R 2 =0.176, P=0.002) and the waist circumference was mild and independent determinant of adiponectin (R 2 =0.136, P=0.007). Our findings demonstrated that the obese adolescents, particularly the obese subjects with IR exhibited increased presence of MetS, abnormality of adipokines, and endothelial dysfunction. The significant interaction between IR and endothelial dysfunction may suggest a novel therapeutic approach to prevent or delay systemic IR and the genesis of cardiovascular diseases in obese patients.

  13. Smad3 Deficiency in Mice Protects Against Insulin Resistance and Obesity Induced by a High-Fat Diet

    PubMed Central

    Tan, Chek Kun; Leuenberger, Nicolas; Tan, Ming Jie; Yan, Yew Wai; Chen, Yinghui; Kambadur, Ravi; Wahli, Walter; Tan, Nguan Soon

    2011-01-01

    OBJECTIVE Obesity and associated pathologies are major global health problems. Transforming growth factor-β/Smad3 signaling has been implicated in various metabolic processes, including adipogenesis, insulin expression, and pancreatic β-cell function. However, the systemic effects of Smad3 deficiency on adiposity and insulin resistance in vivo remain elusive. This study investigated the effects of Smad3 deficiency on whole-body glucose and lipid homeostasis and its contribution to the development of obesity and type 2 diabetes. RESEARCH DESIGN AND METHODS We compared various metabolic profiles of Smad3-knockout and wild-type mice. We also determined the mechanism by which Smad3 deficiency affects the expression of genes involved in adipogenesis and metabolism. Mice were then challenged with a high-fat diet to study the impact of Smad3 deficiency on the development of obesity and insulin resistance. RESULTS Smad3-knockout mice exhibited diminished adiposity with improved glucose tolerance and insulin sensitivity. Chromatin immunoprecipitation assay revealed that Smad3 deficiency increased CCAAT/enhancer-binding protein β-C/EBP homologous protein 10 interaction and exerted a differential regulation on proliferator-activated receptor β/δ and proliferator-activated receptor γ expression in adipocytes. Focused gene expression profiling revealed an altered expression of genes involved in adipogenesis, lipid accumulation, and fatty acid β-oxidation, indicative of altered adipose physiology. Despite reduced physical activity with no modification in food intake, these mutant mice were resistant to obesity and insulin resistance induced by a high-fat diet. CONCLUSIONS Smad3 is a multifaceted regulator in adipose physiology and the pathogenesis of obesity and type 2 diabetes, suggesting that Smad3 may be a potential target for the treatment of obesity and its associated disorders. PMID:21270259

  14. Obesity-related insulin resistance in adolescents: a systematic review and meta-analysis of observational studies.

    PubMed

    Thota, P; Perez-Lopez, F R; Benites-Zapata, V A; Pasupuleti, V; Hernandez, A V

    2017-03-01

    Insulin resistance is common among obese adolescents; however, the extent of this problem is not clear. We conducted a systematic review of PubMed-Medline, CINAHL, The Web of Science, EMBASE and Scopus for observational studies evaluating components defining insulin resistance (insulin, C-peptide and homeostatic model assessment-insulin resistance [HOMA-IR]) in obese adolescents (12-18 years) versus non-obese adolescents. Our systematic review and meta-analysis followed the PRISMA guidelines. Data were combined using a random-effects model and summary statistics were calculated using the mean differences (MDs). 31 studies were included (n = 8655). In 26 studies, fasting insulin levels were higher in obese adolescents when compared to non-obese adolescents (MD = 64.11 pmol/L, 95%CI 49.48-78.75, p < 0.00001). In three studies, fasting C-peptide levels were higher in obese adolescents when compared to non-obese adolescents (MD = 0.29 nmol/L, 95%CI 0.22-0.36, p < 0.00001). In 24 studies, HOMA-IR values were higher in obese adolescents when compared to non-obese adolescents (MD = 2.22, 95%CI 1.78-2.67, p < 0.00001). Heterogeneity of effects among studies was moderate to high. Subgroup analyses showed similar results to the main analyses. Circulating insulin and C-peptide levels and HOMA-IR values were significantly higher in obese adolescents compared to those non-obese.

  15. Accumulation of ceramide in slow-twitch muscle contributes to the development of insulin resistance in the obese JCR:LA-cp rat.

    PubMed

    Fillmore, Natasha; Keung, Wendy; Kelly, Sandra E; Proctor, Spencer D; Lopaschuk, Gary D; Ussher, John R

    2015-06-01

    What is the central question of this study? The aim was to determine whether the accumulation of ceramide contributes to skeletal muscle insulin resistance in the JCR obese rat. What is the main finding and its importance? Our main new finding is that ceramides accumulate only in slow-twitch skeletal muscle in the JCR obese rat and that reducing ceramide content in this muscle type by inhibition of serine palmitoyl transferase-1 halts the progression of insulin resistance in this rat model predisposed to early development of type 2 diabetes. Our findings highlight the importance of assessing insulin signalling/sensitivity and lipid intermediate accumulation in different muscle fibre types. It has been postulated that insulin resistance results from the accumulation of cytosolic lipid metabolites (i.e. diacylglycerol/ceramide) that impede insulin signalling and impair glucose homeostasis. De novo ceramide synthesis is catalysed by serine palmitoyl transferase-1. Our aim was to determine whether de novo ceramide synthesis plays a role during development of insulin resistance in the JCR:LA-cp obese rat. Ten-week-old JCR:LA-cp obese rats were supplemented with either vehicle or the serine palmitoyl transferase-1 inhibitor l-cycloserine (360 mg l(-1) ) in their drinking water for a 2 week period, and glycaemia was assessed by meal tolerance testing. Treatment of JCR:LA-cp obese rats with l-cycloserine improved their plasma glucose and insulin levels during a meal tolerance test. Examination of muscle lipid metabolites and protein phosphorylation patterns revealed differential signatures in slow-twitch (soleus) versus fast-twitch muscle (gastrocnemius), in that ceramide levels were increased in soleus but not gastrocnemius muscles of JCR:LA-cp obese rats. Likewise, improved glycaemia in l-cycloserine-treated JCR:LA-cp obese rats was associated with enhanced Akt and pyruvate dehydrogenase signalling in soleus but not gastrocnemius muscles, probably as a result of l

  16. Role of insulin resistance and adipocytokines on serum alanine aminotransferase in obese patients with type 2 diabetes mellitus.

    PubMed

    de Luis, D A; Aller, R; Izaola, O; Gonzalez Sagrado, M; Conde, R; de la Fuente, B

    2013-01-01

    The aim of our study was to study the association of insulin resistance expressed by HOMA and adipokines in obese type 2 diabetic patients with or without hyper-transaminasemia. A population of 72 obese patients with type 2 diabetes mellitus was analyzed. HOMA-IR was calculated as indicator of insulin-resistance. Adipocytokines blood levels were measured. Patients were classified as group I (n=37) when serum ALT activity was normal or group II (NAFLD patients: n=35) when serum ALT activity was greater than the median value of the group (≥ 28 UI/L). In NAFLD group, BMI, weight, fat mass, waist to hip ratio, waist circumference, triglycerides, HOMA and insulin levels were higher than control group. In the logistic regression analysis with a dependent variable (ALT) and the statistical univariant variables as independent variables, the HOMA-IR remained in the model, with an Odd's ratio of 1.21 (CI:95%: 1.11-1.35) to have a high ALT level with each 1 unit of HOMA-IR adjusted by age, sex, weight, and dietary intake. Some metabolic parameters are associated with elevated ALT in female obese patients. However, adjusted by other variables, only insulin resistance remained associated.

  17. Study of genetic variation in the STAT3 on obesity and insulin resistance in male adults.

    PubMed

    Gianotti, Tomas F; Sookoian, Silvia; Gemma, Carolina; Burgueño, Adriana L; González, Claudio D; Pirola, Carlos J

    2008-07-01

    Signal transducer and activator of transcription 3 (STAT3) plays an important role in hepatic glucose homeostasis and carbohydrate metabolism and has been implicated in the leptin-mediated energy homeostasis. We explored whether STAT3 gene variants are associated with obesity and insulin resistance in a well-characterized sample of 984 adult men (aged 34.4+/-8.6 years) of self-reported European ancestry from a population-based study. We analyzed three tagging single-nucleotide polymorphisms (tagSNPs), two intronic (rs2293152 and rs6503695) and one located in a noncoding region near the gene promoter (rs9891119). These variants were not associated with either obesity (in which 488 lean individuals were compared to 496 overweight/obese subjects) (P values: 0.68, 0.49, and 0.9 for rs2293152, rs6503695, and rs9891119, respectively) or BMI as a continuous trait (P values: 0.85, 0.73, and 0.58 for rs2293152, rs6503695, and rs9891119, respectively). We found no significant association between the three tagSNPs and fasting plasma glucose and insulin. Likewise, no association was observed between the homeostasis model assessment (HOMA) index and any of the tagSNPs. A significant association was observed with total cholesterol and rs6503695 (nominal P value 0.019), but after correcting for multiple testing by Bonferroni correction, the significance becomes marginal (P=0.057). In conclusion, although STAT3 is an excellent candidate gene for assessing obesity and insulin resistance susceptibility alleles, our results do not support a major role for STAT3 variants in BMI and insulin resistance in our male population.

  18. Bicycling but not walking is independently associated with fasting insulin in abdominally obese women.

    PubMed

    Hemmingsson, Erik; Ekelund, Ulf; Udden, Joanna

    2011-08-01

    The impact of walking and bicycling on insulin resistance (IR) in women with abdominal obesity is unclear. Pooled analysis of data from a randomized trial on physically active commuting (bicycling + walking vs walking only) in women with abdominal obesity [n = 98; age:47.3 ± 7.6 yrs; waist circumference (WC):103.1 ± 7.8 cm]. Bicycling and walking data were collected during 7 consecutive days by trip meters (Trelock FC-410) and pedometers (Yamax digiwalker SW-200) at baseline, 2, 4, and 6 months. Owing to a skew distribution we analyzed bicycling as a binary dummy variable with a 10 km/week cut-off. Fasting serum insulin and homeostatic model assessment - insulin resistance (HOMA-IR) were assessed at baseline and 6 months, as were body mass index (BMI), WC, and dual x-ray absorptiometry (DXA)-assessed % whole-body fat. Increased bicycling by 10 km/wk was associated with reductions in fasting serum insulin at follow-up independent of age, treatment allocation, baseline phenotype, Δ walking, and Δ % body fat (β = -10.9, P = .042), but not HOMA-IR (β = -2.0, P = .13). Increased walking was not associated with fasting serum insulin (P = .33) or HOMA-IR (P = .44) at follow-up, after adjustment for the same covariates and Δ bicycling. Increased bicycling but not walking was associated with reduced insulin levels at follow-up. Bicycling may be more effective than walking for reducing insulin levels in abdominally obese women.

  19. Impact of Bariatric Surgery on Heme Oxygenase-1, Inflammation, and Insulin Resistance in Morbid Obesity with Obstructive Sleep Apnea.

    PubMed

    Tirado, Raquel; Masdeu, Maria José; Vigil, Laura; Rigla, Mercedes; Luna, Alexis; Rebasa, Pere; Pareja, Rocío; Hurtado, Marta; Caixàs, Assumpta

    2017-09-01

    Morbid obesity and obstructive sleep apnea (OSA) interact at an inflammatory level. Bariatric surgery reduces inflammatory responses associated with obesity. Heme oxygenase-1 (HO-1) is an enzyme with anti-inflammatory properties, which might be increased in morbid obesity or OSA. We studied morbidly obese patients with OSA to determine: (a) HO-1 plasma concentrations according to OSA severity and their relationship with insulin resistance and inflammation and (b) the impact of bariatric surgery on HO-1 and parameters of insulin resistance and inflammation. We analyzed the homeostasis model insulin resistance index (HOMA) and plasma concentrations of HO-1, tumor necrosis factor alpha, interleukin-6, interleukin-1-beta, C reactive protein (CRP), and adiponectin according to polysomnography findings in 66 morbidly obese patients before bariatric surgery and 12 months after surgery. Before surgery, HO-1 plasma concentrations were similar in three groups of patients with mild, moderate, and severe OSA, and correlated with HOMA (r = 0.27, p = 0.02). Twelve months after surgery, low-grade inflammation and insulin resistance had decreased in all the groups, but HO-1 plasma concentration had decreased only in the severe OSA group (p = 0.02). In this group, the reduction in HO-1 correlated with a reduction in CRP concentrations (r = 0.43, p = 0.04) and with improved HOMA score (r = 0.37, p = 0.03). Bariatric surgery decreases HO-1 concentrations in morbid obesity with severe OSA, and this decrease is associated with decreases in insulin resistance and in inflammation.

  20. Insulin resistance and associated factors: a cross-sectional study of bank employees.

    PubMed

    Salaroli, Luciane Bresciani; Cattafesta, Monica; Molina, Maria Del Carmen Bisi; Zandonade, Eliana; Bissoli, Nazaré Souza

    2017-04-01

    Insulin resistance is characterized by the failure of target cells to respond to normal levels of circulating insulin, and this condition is related to cardiovascular disease. This study sought to evaluate the prevalence of insulin resistance and its association with markers of metabolic abnormalities and metabolic syndrome in bank employees. A cross-sectional study was performed on 498 working men and women aged ≥20 years old. The Homeostasis Model Assessment (HOMA-IR) was used to determine the presence of insulin resistance based on cut-off values of ≤2.71 for normal insulin levels and >2.71 for insulin resistance, as established for the adult Brazilian population. It was observed that the 52 (10.4%) overweight individuals with insulin resistance were 4.97 times (95%CI 1.31-18.83) more likely to have high HOMA-IR values than the normal-weight participants; among those who were obese, the likelihood increased to 17.87 (95%CI 4.36-73.21). Individuals with large waist circumferences were 3.27 times (95%CI 1.03-10.38) more likely to develop insulin resistance than those who were within normal parameters. The HOMA-IR values differed between subjects with and without metabolic syndrome, with values of 2.83±2.5 and 1.10±0.81 (p=0.001), respectively. The levels of insulin, ultrasensitive C-reactive protein and uric acid were also associated with insulin resistance. The prevalence of insulin resistance among bank employees is high, and insulin resistance is associated with and serves as a marker of metabolic syndrome. Cardiovascular disease and metabolic syndrome-associated metabolic abnormalities were observed, and insulin resistance may be a risk factor in this group of professionals.

  1. Insulin resistance and associated factors: a cross-sectional study of bank employees

    PubMed Central

    Salaroli, Luciane Bresciani; Cattafesta, Monica; Molina, Maria del Carmen Bisi; Zandonade, Eliana; Bissoli, Nazaré Souza

    2017-01-01

    OBJECTIVE: Insulin resistance is characterized by the failure of target cells to respond to normal levels of circulating insulin, and this condition is related to cardiovascular disease. This study sought to evaluate the prevalence of insulin resistance and its association with markers of metabolic abnormalities and metabolic syndrome in bank employees. METHODS: A cross-sectional study was performed on 498 working men and women aged ≥20 years old. The Homeostasis Model Assessment (HOMA-IR) was used to determine the presence of insulin resistance based on cut-off values of ≤2.71 for normal insulin levels and >2.71 for insulin resistance, as established for the adult Brazilian population. RESULTS: It was observed that the 52 (10.4%) overweight individuals with insulin resistance were 4.97 times (95%CI 1.31-18.83) more likely to have high HOMA-IR values than the normal-weight participants; among those who were obese, the likelihood increased to 17.87 (95%CI 4.36-73.21). Individuals with large waist circumferences were 3.27 times (95%CI 1.03-10.38) more likely to develop insulin resistance than those who were within normal parameters. The HOMA-IR values differed between subjects with and without metabolic syndrome, with values of 2.83±2.5 and 1.10±0.81 (p=0.001), respectively. The levels of insulin, ultrasensitive C-reactive protein and uric acid were also associated with insulin resistance. CONCLUSION: The prevalence of insulin resistance among bank employees is high, and insulin resistance is associated with and serves as a marker of metabolic syndrome. Cardiovascular disease and metabolic syndrome-associated metabolic abnormalities were observed, and insulin resistance may be a risk factor in this group of professionals. PMID:28492722

  2. Association between omentin levels and insulin resistance in pregnancy.

    PubMed

    Aktas, G; Alcelik, A; Ozlu, T; Tosun, M; Tekce, B K; Savli, H; Tekce, H; Dikbas, O

    2014-03-01

    Omentin is a new adipokine secreted mainly from visceral adipose tissue. Serum omentin is found to be reduced in patients with impaired glucose tolerance, type 2 diabetes mellitus, obesity and insulin resistant states. Despite the fact that pregnancy is also characterized with hyperinsulinemia, literature is lacking about data of omentin levels and its association with insulin resistance in pregnant women. We aimed to evaluate the association of omentin levels and insulin resistance in pregnant women and to compare these levels with those of non-pregnant, non-diabetic women. Uncomplicated pregnant women who admit to our outpatient clinics for routine follow-up were included in the study group. Non-pregnant women without diabetes mellitus were served as control group. Fasting glucose, insulin, omentin levels and HOMA IR were recorded. SPSS 15.0 for Windows was used for statistical analysis. There were 36 pregnant women in the study group and 37 healthy, non-pregnant women in the control group. Serum omentin and fasting glucose levels were significantly decreased and fasting insulin was significantly increased in the study group compared to control group. Omentin might be an indicator of insulin resistance in pregnant women. Larger prospective studies are needed to claim whether omentin can have a clinical use for diagnosis of gestational diabetes mellitus. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.

  3. Circulating MOTS-c levels are decreased in obese male children and adolescents and associated with insulin resistance.

    PubMed

    Du, Caiqi; Zhang, Cai; Wu, Wei; Liang, Yan; Wang, Anru; Wu, Shimin; Zhao, Yue; Hou, Ling; Ning, Qin; Luo, Xiaoping

    2018-04-25

    A novel bioactive peptide, mitochondrial-derived peptide (MOTS-c), has recently attracted attention as a potential prevention or therapeutic option for obesity and type 2 diabetes mellitus (T2DM). MOTS-c profiles have not yet been reported in human obesity and T2DM. We aimed to determine circulating MOTS-c levels in obesity and explore the association between MOTS-c levels and various metabolic parameters. In this case-control study, 40 obese children and adolescents (27 males) and 57 controls (40 males) were recruited in the Hubei Province of China in 2017. Circulating MOTS-c levels were measured, clinical data (e.g., glucose, insulin and lipid profile) were recorded, and anthropometric measurements were performed. Finally, we investigated correlations between MOTS-c levels and related variables. MOTS-c levels were significantly decreased in the obese group compared with the control group (472.61 ± 22.83 ng/mL vs. 561.64 ± 19.19 ng/mL, p < 0.01). After classification by sex, MOTS-c levels were significantly decreased in obese male children and adolescents compared to their counterparts (465.26 ± 24.53 ng/mL vs. 584.07 ± 21.18 ng/mL, p < 0.001), while they were comparable between the obese and healthy female subjects (487.89 ± 49.77 ng/mL vs. 508.85 ± 38.76 ng/mL, p > 0.05). Further, MOTS-c levels were negatively correlated with body mass index (BMI), BMI standard deviation score, waist circumference, waist-to-hip ratio, fasting insulin level, HOMA-IR, and HbA1c in the male cohort. Circulating MOTS-c levels were decreased in obese male children and adolescents and correlated with markers of insulin resistance and obesity. This article is protected by copyright. All rights reserved.

  4. Fibroblast growth factor-21 restores insulin sensitivity but induces aberrant bone microstructure in obese insulin-resistant rats.

    PubMed

    Charoenphandhu, Narattaphol; Suntornsaratoon, Panan; Krishnamra, Nateetip; Sa-Nguanmoo, Piangkwan; Tanajak, Pongpun; Wang, Xiaojie; Liang, Guang; Li, Xiaokun; Jiang, Chao; Chattipakorn, Nipon; Chattipakorn, Siriporn

    2017-03-01

    Fibroblast growth factor (FGF)-21 is a potent endocrine factor that improves insulin resistance and obesity-associated metabolic disorders. However, concomitant activation of peroxisome proliferator-activated receptor-γ by FGF-21 makes bone susceptible to osteopenia and fragility fracture. Since an increase in body weight often induced adaptive change in bone by making it resistant to fracture, it was unclear whether FGF-21 would still induce bone defects in overweight rats. Therefore, the present study aimed to investigate bone microstructure and its mechanical properties in high fat diet (HF)-fed rats treated with 0.1 mg/kg/day FGF-21. Eighteen male rats were divided into two groups to receive either a normal diet or HF for 12 weeks. HF rats were then divided into two subgroups to receive either vehicle or FGF-21 for 4 weeks. The results showed that HF led to obesity, dyslipidemia and insulin resistance, as indicated by hyperinsulinemia with euglycemia. In HF rats, there was an increase in tibial yield displacement (an indicator of ability to be deformed without losing toughness, as determined by 3-point bending) without changes in tibial trabecular volumetric bone mineral density (vBMD) or cortical bone parameters, e.g., cortical thickness and bone area. FGF-21 treatment strongly improved the metabolic parameters and increased insulin sensitivity in HF rats. However, FGF-21-treated HF rats showed lower yield displacement, trabecular vBMD, trabecular bone volume, trabecular thickness, and osteoblast surface compared with vehicle-treated HF rats. These findings suggest that, despite being a potent antagonist of insulin resistance and visceral fat accumulation, FGF-21 is associated with bone defects in HF rats.

  5. Grizzly bears exhibit augmented insulin sensitivity while obese prior to a reversible insulin resistance during hibernation.

    PubMed

    Nelson, O Lynne; Jansen, Heiko T; Galbreath, Elizabeth; Morgenstern, Kurt; Gehring, Jamie Lauren; Rigano, Kimberly Scott; Lee, Jae; Gong, Jianhua; Shaywitz, Adam J; Vella, Chantal A; Robbins, Charles T; Corbit, Kevin C

    2014-08-05

    The confluence of obesity and diabetes as a worldwide epidemic necessitates the discovery of new therapies. Success in this endeavor requires translatable preclinical studies, which traditionally employ rodent models. As an alternative approach, we explored hibernation where obesity is a natural adaptation to survive months of fasting. Here we report that grizzly bears exhibit seasonal tripartite insulin responsiveness such that obese animals augment insulin sensitivity but only weeks later enter hibernation-specific insulin resistance (IR) and subsequently reinitiate responsiveness upon awakening. Preparation for hibernation is characterized by adiposity coupled to increased insulin sensitivity via modified PTEN/AKT signaling specifically in adipose tissue, suggesting a state of "healthy" obesity analogous to humans with PTEN haploinsufficiency. Collectively, we show that bears reversibly cope with homeostatic perturbations considered detrimental to humans and describe a mechanism whereby IR functions not as a late-stage metabolic adaptation to obesity, but rather a gatekeeper of the fed-fasting transition. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Excessive Refined Carbohydrates and Scarce Micronutrients Intakes Increase Inflammatory Mediators and Insulin Resistance in Prepubertal and Pubertal Obese Children Independently of Obesity

    PubMed Central

    López-Alarcón, Mardia; Perichart-Perera, Otilia; Rodríguez-Cruz, Maricela; Armenta-Álvarez, Andrea; Bram-Falcón, María Teresa; Mayorga-Ochoa, Marielle

    2014-01-01

    Background. Low-grade inflammation is the link between obesity and insulin resistance. Because physiologic insulin resistance occurs at puberty, obese pubertal children are at higher risk for insulin resistance. Excessive diets in refined carbohydrates and saturated fats are risk factors for insulin resistance, but calcium, magnesium, vitamin-D, and the omega-3 fatty acids likely protect against inflammation and insulin resistance. Objective. To analyze interactions among dietary saturated fat, refined carbohydrates, calcium, magnesium, vitamin D, and omega-3 fatty acids on the risk of inflammation and insulin resistance in a sample of prepubertal and pubertal children. Methods. A sample of 229 children from Mexico City was analyzed in a cross-sectional design. Anthropometric measurements, 24 h recall questionnaires, and blood samples were obtained. Serum insulin, glucose, calcium, magnesium, 25-OHD3, C-reactive protein, leptin, adiponectin, and erythrocytes fatty acids were measured. Parametric and nonparametric statistics were used for analysis. Results. While mean macronutrients intake was excessive, micronutrients intake was deficient (P < 0.01). Inflammation determinants were central obesity and magnesium-deficient diets. Determinants of insulin resistance were carbohydrates intake and circulating magnesium and adiponectin. Conclusions. Magnesium-deficient diets are determinants of inflammation, while high intake of refined carbohydrates is a risk factor for insulin resistance, independently of central adiposity. PMID:25477716

  7. Serum visfatin in relation to insulin resistance and markers of hyperandrogenism in lean and obese women with polycystic ovary syndrome.

    PubMed

    Kowalska, Irina; Straczkowski, Marek; Nikolajuk, Agnieszka; Adamska, Agnieszka; Karczewska-Kupczewska, Monika; Otziomek, Elzbieta; Wolczynski, Slawomir; Gorska, Maria

    2007-07-01

    Visfatin, a protein secreted by adipose tissue, is suggested to play a role in pathogenesis of insulin resistance. In polycystic ovary syndrome (PCOS), insulin resistance might be involved in the development of endocrine and metabolic abnormalities. The aim of the study was to asses the relation between serum visfatin concentration and insulin sensitivity and markers of hyperandrogenism in lean and obese PCOS patients. The study group consisted of 70 women with PCOS (23 lean and 47 obese) and 45 healthy women (25 lean and 20 obese). Euglycemic hyperinsulinemic clamp and the measurements of serum visfatin, sex hormones were performed. The PCOS group had lower insulin sensitivity (P=0.00049) and higher serum visfatin (P=0.047) in comparison to the control group. The decrease in insulin sensitivity was present in both the lean (P=0.019) and obese (P=0.0077) PCOS subjects, whereas increase in serum visfatin was observed only in lean PCOS subjects (P=0.012). In the whole group, serum visfatin was negatively correlated with insulin sensitivity (r=-0.27, P=0.004). This relationship was also observed in the subgroup of lean (r=-0.30, P=0.038), but not obese women. Additionally, in lean women, visfatin was associated with serum testosterone (r=0.47, P=0.002) and free androgen index (r=0.48, P=0.002), independently of other potential confounding factors. Visfatin is associated with insulin resistance and markers of hyperandrogenism in lean PCOS patients.

  8. Insulin resistance and associated factors among HIV-infected patients in sub-Saharan Africa: a cross sectional study from Cameroon.

    PubMed

    Noumegni, Steve Raoul Ngongang; Nansseu, Jobert Richie; Ama, Vicky Jocelyne Moor; Bigna, Jean Joel; Assah, Felix Kembe; Guewo-Fokeng, Magellan; Leumi, Steve; Katte, Jean-Claude; Dehayem, Mesmin; Kengne, Andre Pascal; Sobngwi, Eugene

    2017-08-10

    Little is known on the magnitude and correlates of insulin resistance in HIV-infected people in Africa. We determined the prevalence of insulin resistance and investigated associated factors in HIV-infected adult Cameroonians. We conducted a cross-sectional study at the Yaoundé Central Hospital, Cameroon; during which we enrolled HIV-infected people aged 30 to 74 years with no previous history of cardiovascular disease. An homeostatic model assessment of insulin resistance (HOMA-IR) like index served to assess insulin sensitivity with insulin resistance defined by values of 2.1 or higher. We included 452 patients (20% men). Their mean age was 44.4 ± 9.8 years and 88.5% of them were on antiretroviral therapy (93.3% on first line regimen including Zidovudine, lamivudine and Efavirenz/Nevirapine). Of all participants, 28.5% were overweight, 19.5% had obesity and 2.0% had diabetes. The prevalence of insulin resistance was 47.3% without any difference between patients on ART and those ART-naïve (48.5% vs. 38.5%; p = 0.480). Obesity was the only factor independently associated with insulin resistance (adjusted odds ratio: 2.28; 95% confidence interval: 1.10-4.72). Insulin resistance is present in nearly half of HIV-infected patients in Cameroon despite a low prevalence rate of diabetes, and is associated with obesity.

  9. Disruption of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Integrity Contributes to Muscle Insulin Resistance in Mice and Humans.

    PubMed

    Tubbs, Emily; Chanon, Stéphanie; Robert, Maud; Bendridi, Nadia; Bidaux, Gabriel; Chauvin, Marie-Agnès; Ji-Cao, Jingwei; Durand, Christine; Gauvrit-Ramette, Daphné; Vidal, Hubert; Lefai, Etienne; Rieusset, Jennifer

    2018-04-01

    Modifications of the interactions between endoplasmic reticulum (ER) and mitochondria, defined as mitochondria-associated membranes (MAMs), were recently shown to be involved in the control of hepatic insulin action and glucose homeostasis, but with conflicting results. Whereas skeletal muscle is the primary site of insulin-mediated glucose uptake and the main target for alterations in insulin-resistant states, the relevance of MAM integrity in muscle insulin resistance is unknown. Deciphering the importance of MAMs on muscle insulin signaling could help to clarify this controversy. Here, we show in skeletal muscle of different mice models of obesity and type 2 diabetes (T2D) a marked disruption of ER-mitochondria interactions as an early event preceding mitochondrial dysfunction and insulin resistance. Furthermore, in human myotubes, palmitate-induced insulin resistance is associated with a reduction of structural and functional ER-mitochondria interactions. Importantly, experimental increase of ER-mitochondria contacts in human myotubes prevents palmitate-induced alterations of insulin signaling and action, whereas disruption of MAM integrity alters the action of the hormone. Lastly, we found an association between altered insulin signaling and ER-mitochondria interactions in human myotubes from obese subjects with or without T2D compared with healthy lean subjects. Collectively, our data reveal a new role of MAM integrity in insulin action of skeletal muscle and highlight MAM disruption as an essential subcellular alteration associated with muscle insulin resistance in mice and humans. Therefore, reduced ER-mitochondria coupling could be a common alteration of several insulin-sensitive tissues playing a key role in altered glucose homeostasis in the context of obesity and T2D. © 2018 by the American Diabetes Association.

  10. Cardiometabolic risk factors and insulin resistance in obese children and adolescents: relation to puberty.

    PubMed

    Tobisch, B; Blatniczky, L; Barkai, L

    2015-02-01

    The prevalence of obesity with concomitant increasing risk for having cardiometabolic diseases is rising in the childhood population. Insulin resistance has a key role in metabolic changes in these children. Insulin levels elevate as puberty commences in every individual. Children with increased risk for cardiometabolic diseases show significant differences in insulin levels even before the onset of puberty compared with those without risks. The pattern of appearance of dyslipidaemia also varies in children with risk factors even in the pre-pubertal group from those without risk. Children with metabolic syndrome display considerably pronounced changes in their metabolic parameters before the onset of puberty, which become more pronounced as puberty passes. Insulin resistance (IR) has a key role in the metabolic changes in obese children. In commencing puberty, the insulin levels elevate. It is not clear, however, how insulin levels develop if the metabolic syndrome appears. Metabolic changes were assessed in obese children before, during and after puberty to analyse the relationship between IR and puberty in subjects with and without metabolic syndrome. Three hundred thirty-four obese children (5-19 years) attended the study. The criteria of the International Diabetes Federation were used to assess the presence of cardiometabolic risks (CMRs). Subjects with increased CMR were compared with those without risk (nCMR). Pubertal staging, lipid levels, plasma glucose and insulin levels during oral glucose tolerance test were determined in each participant. IR was expressed by homeostasis model assessment (HOMA-IR) and the ratio of glucose and insulin areas under the curve (AUC-IR). Significantly higher AUC-IR were found in pre-pubertal CMR children compared with nCMR subjects (11.84 ± 1.03 vs. 8.00 ± 0.69; P < 0.01), but no difference was discovered during and after puberty. HOMA-IR differs between CMR and nCMR only in post-puberty (6.03 ± 1.26 vs. 2

  11. Lack of association between the fatty acid binding protein 2 (FABP2) polymorphism with obesity and insulin resistance in two aboriginal populations from Chile.

    PubMed

    Pérez-Bravo, F; Fuentes, M; Angel, B; Sanchez, H; Carrasco, E; Santos, J L; Lera, L; Albala, C

    2006-12-01

    The aim of this study was to assess the frequency of fatty acid binding protein 2 (FABP2) Ala54Thr genetic polymorphism and to evaluate its association with obesity and insulin resistance in Chilean aboriginal populations. A sample of 96 urban Aymara and 111 urban Mapuche subjects aged 20-80 years were recruited for this cross-sectional study. Glucose, insulin and lipid profile were measured in fasting plasma samples. Insulin resistance was estimated through the HOMA-IR model. FABP2 Ala54Thr genotypes were determined by PCR followed by RFLP analysis. The allele frequency of Thr54 variant was estimated as 18.2% in Aymara subjects, which is one of the lowest reported to date. The corresponding frequency in Mapuche subjects was 31.9% (p<0.002). Regarding genotype-phenotype associations, no significant differences were found in any of the anthropometric or metabolic variables according to Ala54Thr genotypes. After adjustment by BMI and metabolic variables through a logistic regression analysis, the association of the FABP2 polymorphism with ethnic group persisted (Mapuche group: OR=2.37, 95% CI 1.319-4.277, p=0.004) It is unlikely that Ala54Thr polymorphism of the FABP2 gene plays a relevant role in obesity and insulin resistance in Chilean ethnic groups.

  12. Independent associations of insulin resistance with high whole-body intermuscular and low leg subcutaneous adipose tissue distribution in obese HIV-infected women123

    PubMed Central

    Albu, Jeanine B; Kenya, Sonjia; He, Qing; Wainwright, Marsha; Berk, Evan S; Heshka, Stanley; Kotler, Donald P; Engelson, Ellen S

    2009-01-01

    Background Obesity and insulin resistance are growing problems in HIV-positive (HIV+) women receiving highly active antiretroviral therapy (HAART). Objective The objective was to determine the contribution of adipose tissue (AT) enlargement and distribution to the presence of insulin resistance in obese HIV+ women. Design Whole-body intermuscular AT (IMAT), visceral AT (VAT), subcutaneous AT (SAT), and SAT distribution (leg versus upper body) were measured by whole-body magnetic resonance imaging. Insulin sensitivity (SI) was measured with an intravenous glucose tolerance test in obese HIV+ women recruited because of their desire to lose weight (n = 17) and in obese healthy controls (n = 32). Results The HIV+ women had relatively less whole-body SAT and more VAT and IMAT than did the controls (P < 0.05 for all). A significant interaction by HIV status was observed for the relation of total SAT with SI (P < 0.001 for the regression’s slope interactions after adjustment for age, height, and weight). However, relations of IMAT, VAT, and SAT distribution (leg SAT as a percentage of total SAT; leg SAT%) with SI did not differ significantly between groups. For both groups combined, the best model predicting a low SI included significant contributions by both high IMAT and low leg SAT%, independent of age, height, and weight, and no interaction between groups was observed (overall r2 = 0.44, P = 0.0003). Conclusion In obese HIV+ women, high whole-body IMAT and low leg SAT% distribution are independently associated with insulin resistance. PMID:17616768

  13. The gut microbiota, obesity and insulin resistance.

    PubMed

    Shen, Jian; Obin, Martin S; Zhao, Liping

    2013-02-01

    The human gut is densely populated by commensal and symbiotic microbes (the "gut microbiota"), with the majority of the constituent microorganisms being bacteria. Accumulating evidence indicates that the gut microbiota plays a significant role in the development of obesity, obesity-associated inflammation and insulin resistance. In this review we discuss molecular and cell biological mechanisms by which the microbiota participate in host functions that impact the development and maintenance of the obese state, including host ingestive behavior, energy harvest, energy expenditure and fat storage. We additionally explore the diverse signaling pathways that regulate gut permeability and bacterial translocation to the host and how these are altered in the obese state to promote the systemic inflammation ("metabolic endotoxemia") that is a hallmark of obesity and its complications. Fundamental to our discussions is the concept of "crosstalk", i.e., the biochemical exchange between host and microbiota that maintains the metabolic health of the superorganism and whose dysregulation is a hallmark of the obese state. Differences in community composition, functional genes and metabolic activities of the gut microbiota appear to distinguish lean vs obese individuals, suggesting that gut 'dysbiosis' contributes to the development of obesity and/or its complications. The current challenge is to determine the relative importance of obesity-associated compositional and functional changes in the microbiota and to identify the relevant taxa and functional gene modules that promote leanness and metabolic health. As diet appears to play a predominant role in shaping the microbiota and promoting obesity-associated dysbiosis, parallel initiatives are required to elucidate dietary patterns and diet components (e.g., prebiotics, probiotics) that promote healthy gut microbiota. How the microbiota promotes human health and disease is a rich area of investigation that is likely to generate

  14. Nesfatin-1 in childhood and adolescent obesity and its association with food intake, body composition and insulin resistance.

    PubMed

    Anwar, Ghada M; Yamamah, Gamal; Ibrahim, Amani; El-Lebedy, Dalia; Farid, Tarek M; Mahmoud, Rasha

    2014-01-10

    Nesfatin-1 is an anorexigenic peptide that controls feeding behavior and glucose homeostasis. However, there is little data that exists regarding nesfatin-1 secretion in obese children and young adolescents. The aim of this study is to investigate serum nesfatin-1 in childhood and adolescent obesity and to study potential correlations with food intake, anthropometric indices, body composition and insulin resistance. Forty obese children and adolescents and 40 healthy control subjects were studied. Anthropometric measurements were assessed, dietary food intake was evaluated based on 3-days food record and body composition indices were evaluated using bioelectrical impedance analysis. Lipid profile, fasting blood sugar, fasting insulin and HOMA-IR were measured. Fasting serum nesfatin-1 was quantitatively assayed by ELISA. Serum nesfatin-1 was significantly higher in obese group (2.49±1.96 ng/ml) than in control group (0.70±0.81 ng/ml), P=0.001. Positive correlations with serum insulin (P=0.001), HOMA-IR (P=0.000), BMI-SDS (P=0.04), body fat % (P=0.000), fat mass (P=0.000), fat free mass (P=0.03), CHO % (P=0.000), and saturated fat % (P=0.01) were found. While significant negative correlation with protein % (P=0.000) was observed. In conclusion, our results denote that nesfatin-1 might have an important role in regulation of food intake and pathogenesis of insulin resistance in obese children and young adolescents. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Comprehensive assessment of insulin resistance in non-obese Asian Indian and Chinese men.

    PubMed

    Tan, Hong Chang; Yew, Tong Wei; Chacko, Shaji; Tai, E Shyong; Kovalik, Jean-Paul; Ching, Jianhong; Myo Thant, Sandi; Khoo, Chin Meng

    2018-03-27

    Indian individuals are more insulin resistant (IR) than Chinese individuals, even among those with a non-obese body mass index (BMI). However, BMI often underestimates body fat in Indian individuals, and it remains unclear whether Indians would remain more IR than Chinese individuals when both BMI and body fat are equally matched. Using the hyperinsulinemic-euglycemic clamp with stable-isotope infusion, we comprehensively assessed IR between 13 non-obese Indian men with 13 Chinese men matched for age, BMI and body fat. We further compared the differences in insulin metabolic clearance rate (MCR) between the two groups and its relationship with various metabolic parameters. The response of lipid and amino acid metabolism to insulin stimulation was also evaluated using metabolomic profiling. The rates of endogenous glucose production during fasting were similar, and endogenous glucose production was completely suppressed during insulin clamp for both ethnic groups. Glucose disappearance during insulin clamp was also similar between the two groups, even after accounting for differences in insulin concentration. Metabolomic profiles of amino acids and various acylcarnitines were similar during both fasting and insulin clamp. However, plasma insulin during clamp was significantly higher in Indian men, indicating that insulin MCR was lower. Insulin MCR correlated significantly with total adiposity and skeletal muscle insulin sensitivity. When equally matched for body fat, non-obese Indian men had similar skeletal muscle insulin sensitivity and endogenous glucose production to Chinese men. The effects of insulin on lipid and amino acid metabolism were also similar. Low insulin MCR is associated with greater adiposity and lower skeletal muscle insulin sensitivity. © 2018 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

  16. Exercise rescues obese mothers' insulin sensitivity, placental hypoxia and male offspring insulin sensitivity.

    PubMed

    Fernandez-Twinn, Denise S; Gascoin, Geraldine; Musial, Barbara; Carr, Sarah; Duque-Guimaraes, Daniella; Blackmore, Heather L; Alfaradhi, Maria Z; Loche, Elena; Sferruzzi-Perri, Amanda N; Fowden, Abigail L; Ozanne, Susan E

    2017-03-14

    The prevalence of obesity during pregnancy continues to increase at alarming rates. This is concerning as in addition to immediate impacts on maternal wellbeing, obesity during pregnancy has detrimental effects on the long-term health of the offspring through non-genetic mechanisms. A major knowledge gap limiting our capacity to develop intervention strategies is the lack of understanding of the factors in the obese mother that mediate these epigenetic effects on the offspring. We used a mouse model of maternal-diet induced obesity to define predictive correlations between maternal factors and offspring insulin resistance. Maternal hyperinsulinemia (independent of maternal body weight and composition) strongly associated with offspring insulin resistance. To test causality, we implemented an exercise intervention that improved maternal insulin sensitivity without changing maternal body weight or composition. This maternal intervention prevented excess placental lipid deposition and hypoxia (independent of sex) and insulin resistance in male offspring. We conclude that hyperinsulinemia is a key programming factor and therefore an important interventional target during obese pregnancy, and propose moderate exercise as a promising strategy to improve metabolic outcome in both the obese mother and her offspring.

  17. Vitamin D deficiency and insulin resistance as risk factors for dyslipidemia in obese children.

    PubMed

    Erol, Meltem; Bostan Gayret, Özlem; Hamilçıkan, Şahin; Can, Emrah; Yiğit, Özgu L

    2017-04-01

    Dyslipidemia is one of the major complications of obesity; vitamin D deficiency and insulin resistance are attending metabolic complications in dyslipidemic obese children. Objective. To determine if vitamin D deficiency and insulin resistance are risk factors for dyslipidemia in obese children. This study was conducted in the Department of Pediatrics at Bagcilar Training and Research Hospital in Istanbul, Turkey between 2014 and 2015. Obese patients whose age range was 8-14 were included in the study. The serum triglyceride, total cholesterol, low-density lipoprotein cholesterol, highdensity lipoprotein cholesterol, fasting glucose, insulin, alanine aminotransferase, vitamin D levels were measured; a liver ultrasonography was performed. Homeostatic model assessment (HOMA-IR), was used to calculate insulin resistance. 108 obese children were included; 39 (36.11%) had dyslipidemia. The average fasting blood glucose (88.74 ± 7.58 vs. 95.31 ± 6.82; p= 0.0001), insulin level (14.71 ± 12.44 vs. 24.39 ± 15.02; p= 0.0001) and alanine aminotransferase level (23.45 ± 11.18 vs. 30.4 ± 18.95; p= 0.018) were significantly higher in the children with dyslipidemia. In the dyslipidemic obese children, the average hepatosteatosis rate and HOMA-IR level were higher; 28 (71.9%) had hepatosteatosis, 37 (94.87%) had insulin resistance; the vitamin D levels were <20 ng/ml in 69.3%. Vitamin D deficiency was significantly more common (p= 0.033). The multivariate regression analysis confirmed that the increase in the HOMA-IR level (p= 0.015) and the low vitamin D level (p= 0.04) were important risk factors for dyslipidemia. Obese children in our region exhibit low vitamin D and increased HOMA-IR levels, which are efficient risk factors of dyslipidemia.

  18. Irisin and its relation to insulin resistance and puberty in obese children: a longitudinal analysis.

    PubMed

    Reinehr, Thomas; Elfers, Clinton; Lass, Nina; Roth, Christian L

    2015-05-01

    Irisin is a recently identified myokine affecting metabolic and glucose homeostasis. However, the role of irisin in obesity and its metabolic consequences are controversial, and data in children are scarce. To study the relationships between irisin, insulin resistance, and puberty before and after weight loss in obese children with and without impaired glucose tolerance. One-year follow-up study in obese children participating in a lifestyle intervention. Primary care. Forty obese children and 20 normal-weight children of similar age, gender, and pubertal stage. A 1-year outpatient intervention program based on exercise, behavior, and nutrition therapy. Fasting serum irisin, weight status (body mass index [BMI] SD score), and the following parameters of the metabolic syndrome: insulin resistance index (homeostasis model of assessment), blood pressure, and lipids. The irisin levels were the highest in obese children with impaired glucose tolerance, followed by obese children with normal glucose tolerance, and levels were lowest in normal-weight children (P < .001). In a multiple linear regression analysis, baseline irisin was significantly associated with pubertal stage, high-density lipoprotein-cholesterol, and homeostasis model of assessment, but not to age, gender, BMI, or any other parameter of the metabolic syndrome. The irisin concentrations were significantly (P = .010) lower in the prepubertal compared to the pubertal children. In longitudinal analyses, changes of irisin were significantly associated with entry into puberty, change of fasting glucose, and 2-hour glucose in an oral glucose tolerance test, but not with change of BMI or any other parameter. Irisin levels are related to pubertal stage and insulin resistance but not to weight status in childhood.

  19. A Branched-Chain Amino Acid-Related Metabolic Signature that Differentiates Obese and Lean Humans and Contributes to Insulin Resistance

    PubMed Central

    Newgard, Christopher B; An, Jie; Bain, James R; Muehlbauer, Michael J; Stevens, Robert D; Lien, Lillian F; Haqq, Andrea M; Shah, Svati H.; Arlotto, Michelle; Slentz, Cris A; Rochon, James; Gallup, Dianne; Ilkayeva, Olga; Wenner, Brett R; Yancy, William E; Eisenson, Howard; Musante, Gerald; Surwit, Richard; Millington, David S; Butler, Mark D; Svetkey, Laura P

    2009-01-01

    Summary Metabolomic profiling of obese versus lean humans reveals a branched-chain amino acid (BCAA)-related metabolite signature that is suggestive of increased catabolism of BCAA and correlated with insulin resistance. To test its impact on metabolic homeostasis, we fed rats on high-fat (HF), HF with supplemented BCAA (HF/BCAA) or standard chow (SC) diets. Despite having reduced food intake and weight gain equivalent to the SC group, HF/BCAA rats were equally insulin resistant as HF rats. Pair-feeding of HF diet to match the HF/BCAA animals or BCAA addition to SC diet did not cause insulin resistance. Insulin resistance induced by HF/BCAA feeding was accompanied by chronic phosphorylation of mTOR, JNK, and IRS1(ser307), accumulation of multiple acylcarnitines in muscle, and was reversed by the mTOR inhibitor, rapamycin. Our findings show that in the context of a poor dietary pattern that includes high fat consumption, BCAA contributes to development of obesity-associated insulin resistance. PMID:19356713

  20. Association Between Insulin Resistance and Bone Structure in Nondiabetic Postmenopausal Women.

    PubMed

    Shanbhogue, Vikram V; Finkelstein, Joel S; Bouxsein, Mary L; Yu, Elaine W

    2016-08-01

    The clinical consequences of insulin resistance and hyperinsulinemia on bone remain largely unknown. The objective of the study was to evaluate the effect of insulin resistance on peripheral bone geometry, volumetric bone mineral density (vBMD), bone microarchitecture, and estimated bone strength. This cross-sectional study included 146 postmenopausal, nondiabetic Caucasian women (mean age 60.3 ± 2.7 y) who were participating in the Study of Women's Health Across the Nation. There were no interventions. High-resolution peripheral quantitative computed tomography was used to assess bone density and microstructure at the distal radius and tibia. Fasting insulin and glucose were measured and insulin resistance was estimated using homeostasis model assessment of insulin resistance (HOMA-IR), with higher values indicating greater insulin resistance. There was a negative association between HOMA-IR and bone size and a positive association between HOMA-IR and total vBMD, trabecular vBMD, trabecular thickness, and cortical thickness at the radius and tibia. These relationships remained, even after adjusting for body weight and other potential covariates (eg, time since menopause, cigarette smoking, physical activity, prior use of osteoporosis medications or glucocorticoids). In nondiabetic, postmenopausal women, insulin resistance was associated with smaller bone size, greater volumetric bone mineral density, and generally favorable bone microarchitecture at weight-bearing and nonweight-bearing skeletal sites. These associations were independent of body weight and other potential covariates, suggesting that hyperinsulinemia directly affects bone structure independent of obesity and may explain, in part, the higher trabecular bone density and favorable trabecular microarchitecture seen in individuals with type 2 diabetes mellitus.

  1. Short Chain Fatty Acids in the Colon and Peripheral Tissues: A Focus on Butyrate, Colon Cancer, Obesity and Insulin Resistance

    PubMed Central

    McNabney, Sean M.

    2017-01-01

    Increased dietary fiber consumption has been associated with many beneficial effects, including amelioration of obesity and insulin resistance. These effects may be due to the increased production of short chain fatty acids, including propionate, acetate and butyrate, during fermentation of the dietary fiber in the colon. Indeed, oral and dietary supplementation of butyrate alone has been shown to prevent high fat-diet induced obesity and insulin resistance. This review focuses on sources of short chain fatty acids, with emphasis on sources of butyrate, mechanisms of fiber and butyrate metabolism in the gut and its protective effects on colon cancer and the peripheral effects of butyrate supplementation in peripheral tissues in the prevention and reversal of obesity and insulin resistance. PMID:29231905

  2. [Cyanidin-3-glucoside attenuates body weight gain, serum lipid concentrations and insulin resistance in high-fat diet-induced obese rats].

    PubMed

    Yu, Ren-Qiang; Wu, Xiao-You; Zhou, Xiang; Zhu, Jing; Ma, Lu-Yi

    2014-05-01

    Cyanidin-3-glucoside (C3G) is the main active ingredient of anthocyanidin. This study aimed to evaluate the effects of C3G on body weight gain, visceral adiposity, lipid profiles and insulin resistance in high-fat diet-induced obese rats. Thirty male Sprague-Dawley rats were randomly divided into a control group (n=8) and a high fat diet group (n=22), and were fed with standard diet or high fat diet. Five weeks later, 17 high-fat diet-induced obese rats were randomly given C3G [100 mg/(kg·d)] or normal saline via intragastric administration for 5 weeks. Five weeks later, body weight, visceral adiposity and food intake were measured. Blood samples were collected for detecting fasting glucose, serum insulin, lipid profiles and adiponectin. Insulin resistance index, atherosclerosis index and average feed efficiency ratio were calculated. C3G supplementation markedly decreased body weight, visceral adiposity, average feed efficiency ratio, triglyceride, total cholesterol, low density lipoprotein cholesterol, fasting glucose, serum insulin, insulin resistance index and atherosclerosis index in high-fat diet-induced obese rats. C3G supplementation normalized serum adiponectin and high density lipoprotein cholesterol levels in high-fat diet-induced obese rats. Cyanidin-3-glucoside can reduce body weight gain, and attenuate obesity-associated dyslipidemia and insulin resistance in high-fat diet-fed rats via up-regulating serum adiponectin level.

  3. Fatty liver disease, glucose tolerance and insulin resistance in obese adolescents.

    PubMed

    Slyper, A H; Rosenberg, H; Kabra, A; Huang, W-M; Blech, B; Matsumura, M M

    2015-12-01

    Adult studies suggest that intra-hepatic fat predicts 2-h blood glucose levels and type 2 diabetes, and may have a role in the development of insulin resistance. Our study objective was to explore relationships between intra-hepatic fat and (i) blood glucose levels and (ii) insulin resistance determined by homeostasis model assessment (HOMA) in a group of obese adolescents. Subjects were 61 obese non-diabetic male and female volunteers aged 12-18 years inclusive with a body mass index >95th percentile for age and 2-h blood glucose <200 mg dL(-1) . Each subject underwent 2-h glucose tolerance testing and measurement of haemoglobin A1c, ultrasensitive C-reactive protein and fasting insulin. Visceral, subcutaneous abdominal and intra-hepatic fat were determined by magnetic resonance imaging. Intra-hepatic fat was measured by gradient echo chemical shift imaging. Alanine aminotransferase levels and hepatic phase difference were not significant correlates of fasting or 2-h glucose. In a multiple regression model including hepatic phase difference and visceral fat volume, visceral fat volume was the sole predictor of HOMA. This study provides no support to the notion that intra-hepatic fat has a role in the regulation of fasting blood glucose, 2-h postprandial blood glucose or systemic insulin resistance. © 2014 World Obesity.

  4. Estrogen has opposing effects on vascular reactivity in obese, insulin-resistant male Zucker rats

    NASA Technical Reports Server (NTRS)

    Brooks-Asplund, Esther M.; Shoukas, Artin A.; Kim, Soon-Yul; Burke, Sean A.; Berkowitz, Dan E.

    2002-01-01

    We hypothesized that estradiol treatment would improve vascular dysfunction commonly associated with obesity, hyperlipidemia, and insulin resistance. A sham operation or 17beta-estradiol pellet implantation was performed in male lean and obese Zucker rats. Maximal vasoconstriction (VC) to phenylephrine (PE) and potassium chloride was exaggerated in control obese rats compared with lean rats, but estradiol significantly attenuated VC in the obese rats. Estradiol reduced the PE EC50 in all groups. This effect was cyclooxygenase independent, because preincubation with indomethacin reduced VC response to PE similarly in a subset of control and estrogen-treated lean rats. Endothelium-independent vasodilation (VD) to sodium nitroprusside was similar among groups, but endothelium-dependent VD to ACh was significantly impaired in obese compared with lean rats. Estradiol improved VD in lean and obese rats by decreasing EC50 but impaired function by decreasing maximal VD. The shift in EC50 corresponded to an upregulation in nitric oxide synthase III protein expression in the aorta of the estrogen-treated obese rats. In summary, estrogen treatment improves vascular function in male insulin-resistant, obese rats, partially via an upregulation of nitric oxide synthase III protein expression. These effects are counteracted by adverse factors, such as hyperlipidemia and, potentially, a release of an endothelium-derived contractile agent.

  5. Is salivary gland function altered in noninsulin-dependent diabetes mellitus and obesity-insulin resistance?

    PubMed

    Ittichaicharoen, Jitjiroj; Chattipakorn, Nipon; Chattipakorn, Siriporn C

    2016-04-01

    Salivary gland dysfunction in several systemic diseases has been shown to decrease the quality of life in patients. In non-insulin dependent diabetes mellitus (NIDDM), inadequate salivary gland function has been evidenced to closely associate with this abnormal glycemic control condition. Although several studies demonstrated that NIDDM has a positive correlation with impaired salivary gland function, including decreased salivary flow rate, some studies demonstrated contradictory findings. Moreover, the changes of the salivary gland function in pre-diabetic stage known as insulin resistance are still unclear. The aim of this review is to comprehensively summarize the current evidence from in vitro, in vivo and clinical studies regarding the relationship between NIDDM and salivary gland function, as well as the correlation between obesity and salivary gland function. Consistent findings as well as controversial reports and the mechanistic insights regarding the effect of NIDDM and obesity-insulin resistance on salivary gland function are also presented and discussed. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Effects of intranasal insulin on endogenous glucose production in insulin-resistant men.

    PubMed

    Xiao, Changting; Dash, Satya; Stahel, Priska; Lewis, Gary F

    2018-03-14

    The effects of intranasal insulin on the regulation of endogenous glucose production (EGP) in individuals with insulin resistance were assessed in a single-blind, crossover study. Overweight or obese insulin-resistant men (n = 7; body mass index 35.4 ± 4.4 kg/m 2 , homeostatic model assessment of insulin resistance 5.6 ± 1.6) received intranasal spray of either 40 IU insulin lispro or placebo in 2 randomized visits. Acute systemic spillover of intranasal insulin into the circulation was matched with a 30-minute intravenous infusion of insulin lispro in the nasal placebo arm. EGP was assessed under conditions of a pancreatic clamp with a primed, constant infusion of glucose tracer. Under these experimental conditions, compared with placebo, intranasal administration of insulin did not significantly affect plasma glucose concentrations, EGP or glucose disposal in overweight/obese, insulin-resistant men, in contrast to our previous study, in which an equivalent dose of intranasal insulin significantly suppressed EGP in lean, insulin-sensitive men. Insulin resistance is probably associated with impairment in centrally mediated insulin suppression of EGP. © 2018 John Wiley & Sons Ltd.

  7. Aldosterone Is Not Associated With Metabolic and Microvascular Insulin Sensitivity in Abdominally Obese Men.

    PubMed

    Schütten, Monica T J; Kusters, Yvo H A M; Houben, Alfons J H M; Scheijen, Jean L J M; van de Waarenburg, Marjo P H; Schalkwijk, Casper G; Joris, Peter J; Plat, Jogchum; Mensink, Ronald P; de Leeuw, Peter W; Stehouwer, Coen D A

    2018-02-01

    Impaired insulin-mediated muscle microvascular recruitment (IMMR) may add to the development of insulin resistance and hypertension. Increased aldosterone levels have been linked to these obesity-related complications in severely to morbidly obese individuals and to impaired microvascular function in experimental studies. To investigate whether aldosterone levels are associated with IMMR, insulin sensitivity, and blood pressure in lean and moderately abdominally obese men, and to study the effect of weight loss. In 25 lean and 53 abdominally obese men, 24-hour blood pressure measurement was performed, and aldosterone levels were measured using ultra-performance liquid chromatography tandem mass spectrometry. Insulin sensitivity was assessed by determining whole-body glucose disposal during a hyperinsulinemic clamp. IMMR in forearm skeletal muscle was measured with contrast-enhanced ultrasonography. These assessments were repeated in the abdominally obese men following an 8-week weight loss or weight stable period. Sodium excretion and aldosterone levels were similar in lean and abdominally obese participants, but sodium excretion was inversely associated with aldosterone concentration only in the lean individuals [lean, β/100 mmol sodium excretion (adjusted for age and urinary potassium excretion) = -0.481 (95% confidence interval, -0.949 to -0.013); abdominally obese, β/100 mmol sodium excretion = -0.081 (95% confidence interval, -0.433 to 0.271); P for interaction = 0.02]. Aldosterone was not associated with IMMR, insulin sensitivity, or blood pressure and was unaffected by weight loss. In moderately abdominally obese men, the inverse relationship between sodium excretion and aldosterone concentration is less than that in lean men but does not translate into higher aldosterone levels. The absolute aldosterone level does not explain differences in microvascular and metabolic insulin sensitivity and blood pressure between lean and moderately abdominally obese men

  8. Sex Differences in Biomarkers Associated With Insulin Resistance in Obese Adolescents: Metabolomic Profiling and Principal Components Analysis

    PubMed Central

    Newbern, Dorothee; Balikcioglu, Metin; Bain, James; Muehlbauer, Michael; Stevens, Robert; Ilkayeva, Olga; Dolinsky, Diana; Armstrong, Sarah; Irizarry, Krystal; Freemark, Michael

    2014-01-01

    Objective: Obesity and insulin resistance (IR) predispose to type 2 diabetes mellitus. Yet only half of obese adolescents have IR and far fewer progress to type 2 diabetes mellitus. We hypothesized that amino acid and fatty acid metabolites may serve as biomarkers or determinants of IR in obese teens. Research Design and Methods: Fasting blood samples were analyzed by tandem mass spectrometry in 82 obese adolescents. A principal components analysis and multiple linear regression models were used to correlate metabolic components with surrogate measures of IR: homeostasis model assessment index of insulin resistance (HOMA-IR), adiponectin, and triglyceride (TG) to high-density lipoprotein (HDL) ratio. Results: Branched-chain amino acid (BCAA) levels and products of BCAA catabolism were higher (P < .01) in males than females with comparable body mass index (BMI) z-score. In multivariate analyses, HOMA-IR in males correlated positively with BMI z-score and a metabolic signature containing BCAA, uric acid, and long-chain acylcarnitines and negatively with byproducts of complete fatty acid oxidation (R2 = 0.659, P < .0001). In contrast, only BMI z-score correlated with HOMA-IR in females. Adiponectin correlated inversely with BCAA and uric acid (R2 = 0.268, P = .0212) in males but not females. TG to HDL ratio correlated with BMI z-score and the BCAA signature in females but not males. Conclusions: BCAA levels and byproducts of BCAA catabolism are higher in obese teenage boys than girls of comparable BMI z-score. A metabolic signature comprising BCAA and uric acid correlates positively with HOMA-IR in males and TG to HDL ratio in females and inversely with adiponectin in males but not females. Likewise, byproducts of fatty acid oxidation associate inversely with HOMA-IR in males but not females. Our findings underscore the roles of sex differences in metabolic function and outcomes in pediatric obesity. PMID:25202817

  9. Compensation for obesity-induced insulin resistance in dogs: assessment of the effects of leptin, adiponectin, and glucagon-like peptide-1 using path analysis.

    PubMed

    Verkest, K R; Fleeman, L M; Morton, J M; Ishioka, K; Rand, J S

    2011-07-01

    The hormonal mediators of obesity-induced insulin resistance and compensatory hyperinsulinemia in dogs have not been identified. Plasma samples were obtained after a 24-h fast from 104 client-owned lean, overweight, and obese dogs. Plasma glucose and insulin concentrations were used to calculate insulin sensitivity and β-cell function with the use of the homeostasis model assessment (HOMA(insulin sensitivity) and HOMA(β-cell function), respectively). Path analysis with multivariable linear regression was used to identify whether fasting plasma leptin, adiponectin, or glucagon-like peptide-1 concentrations were associated with adiposity, insulin sensitivity, and basal insulin secretion. None of the dogs were hyperglycemic. In the final path model, adiposity was positively associated with leptin (P < 0.01) and glucagon-like peptide-1 (P = 0.04) concentrations. No significant total effect of adiposity on adiponectin in dogs (P = 0.24) was observed. If there is a direct effect of leptin on adiponectin, then our results indicate that this is a positive relationship, which at least partly counters a negative direct relationship between adiposity and adiponectin. Fasting plasma leptin concentration was directly negatively associated with fasting insulin sensitivity (P = 0.01) and positively associated with β-cell function (P < 0.01), but no direct association was observed between adiponectin concentration and either insulin sensitivity or β-cell function (P = 0.42 and 0.11, respectively). We conclude that dogs compensate effectively for obesity-induced insulin resistance. Fasting plasma leptin concentrations appear to be associated with obesity-associated changes in insulin sensitivity and compensatory hyperinsulinemia in naturally occurring obese dogs. Adiponectin does not appear to be involved in the pathophysiology of obesity-associated changes in insulin sensitivity. Copyright © 2011 Elsevier Inc. All rights reserved.

  10. Dietary Aloe QDM Complex Reduces Obesity-Induced Insulin Resistance and Adipogenesis in Obese Mice Fed a High-Fat Diet.

    PubMed

    Shin, Seulmee; Kim, Seulah; Oh, Hee-Eun; Kong, Hyunseok; Shin, Eunju; Do, Seon-Gil; Jo, Tae Hyung; Park, Young-In; Lee, Chong-Kil; Kim, Kyungjae

    2012-06-01

    Obesity-induced disorders contribute to the development of metabolic diseases such as insulin resistance, fatty liver diseases, and type 2 diabetes (T2D). In this study, we evaluated whether the Aloe QDM complex could improve metabolic disorders related to blood glucose levels and insulin resistance. Male C57BL/6 obese mice fed a high-fat diet for 54 days received a supplement of Aloe QDM complex or pioglitazone (PGZ) or metformin (Met) and were compared with unsupplemented controls (high-fat diet; HFD) or mice fed a regular diet (RD). RT-PCR and western blot analysis were used to quantify the expression of obesity-induced inflammation. Dietary Aloe QDM complex lowered body weight, fasting blood glucose, plasma insulin, and leptin levels, and markedly reduced the impairment of glucose tolerance in obese mice. Also, Aloe QDM complex significantly enhanced plasma adiponectin levels and insulin sensitivity via AMPK activity in muscles. At the same time, Aloe QDM decreased the mRNA and protein of PPARγ/LXRα and scavenger receptors in white adipose tissue (WAT). Dietary Aloe QDM complex reduces obesity-induced glucose tolerance not only by suppressing PPARγ/LXRα but also by enhancing AMPK activity in the WAT and muscles, both of which are important peripheral tissues affecting insulin resistance. The Aloe QDM complex could be used as a nutritional intervention against T2D.

  11. Dietary Aloe QDM Complex Reduces Obesity-Induced Insulin Resistance and Adipogenesis in Obese Mice Fed a High-Fat Diet

    PubMed Central

    Shin, Seulmee; Kim, Seulah; Oh, Hee-Eun; Kong, Hyunseok; Shin, Eunju; Do, Seon-Gil; Jo, Tae Hyung; Park, Young-In; Lee, Chong-Kil

    2012-01-01

    Obesity-induced disorders contribute to the development of metabolic diseases such as insulin resistance, fatty liver diseases, and type 2 diabetes (T2D). In this study, we evaluated whether the Aloe QDM complex could improve metabolic disorders related to blood glucose levels and insulin resistance. Male C57BL/6 obese mice fed a high-fat diet for 54 days received a supplement of Aloe QDM complex or pioglitazone (PGZ) or metformin (Met) and were compared with unsupplemented controls (high-fat diet; HFD) or mice fed a regular diet (RD). RT-PCR and western blot analysis were used to quantify the expression of obesity-induced inflammation. Dietary Aloe QDM complex lowered body weight, fasting blood glucose, plasma insulin, and leptin levels, and markedly reduced the impairment of glucose tolerance in obese mice. Also, Aloe QDM complex significantly enhanced plasma adiponectin levels and insulin sensitivity via AMPK activity in muscles. At the same time, Aloe QDM decreased the mRNA and protein of PPARγ/LXRα and scavenger receptors in white adipose tissue (WAT). Dietary Aloe QDM complex reduces obesity-induced glucose tolerance not only by suppressing PPARγ/LXRα but also by enhancing AMPK activity in the WAT and muscles, both of which are important peripheral tissues affecting insulin resistance. The Aloe QDM complex could be used as a nutritional intervention against T2D. PMID:22916045

  12. Intermuscular and perimuscular fat expansion in obesity correlates with skeletal muscle T cell and macrophage infiltration and insulin resistance

    PubMed Central

    Khan, Ilvira M.; Dai Perrard, Xiao-Yuan; Brunner, Gerd; Lui, Hua; Sparks, Lauren M.; Smith, Steven R.; Wang, Xukui; Shi, Zheng-Zheng; Lewis, Dorothy E.; Wu, Huaizhu; Ballantyne, Christie M.

    2015-01-01

    Background/Objectives Limited numbers of studies demonstrated obesity-induced macrophage infiltration in skeletal muscle (SM), but dynamics of immune cell accumulation and contribution of T cells to SM insulin resistance are understudied. Subjects/Methods T cells and macrophage markers were examined in SM of obese humans by RT-PCR. Mice were fed high-fat diet (HFD) for 2–24 weeks, and time course of macrophage and T cell accumulation was assessed by flow cytometry and quantitative RT-PCR. Extramyocellular adipose tissue (EMAT) was quantified by high-resolution micro-CT, and correlation to T cell number in SM was examined. CD11a−/− mice and C57BL/6 mice were treated with CD11a-neutralizing antibody to determine the role of CD11a in T cell accumulation in SM. To investigate the involvement JAK/STAT, the major pathway for T helper I (TH1) cytokine IFNγ? in SM and adipose tissue inflammation and insulin resistance, mice were treated with a JAK1/JAK2 inhibitor, baricitinib. Results Macrophage and T cells markers were upregulated in SM of obese compared with lean humans. SM of obese mice had higher expression of inflammatory cytokines, with macrophages increasing by 2 weeks on HFD and T cells increasing by 8 weeks. The immune cells were localized in EMAT. Micro-CT revealed that EMAT expansion in obese mice correlated with T cell infiltration and insulin resistance. Deficiency or neutralization of CD11a reduced T cell accumulation in SM of obese mice. T cells polarized into a proinflammatory TH1 phenotype, with increased STAT1 phosphorylation in SM of obese mice. In vivo inhibition of JAK/STAT pathway with baricitinib reduced T cell numbers and activation markers in SM and adipose tissue and improved insulin resistance in obese mice. Conclusions Obesity-induced expansion of EMAT in SM was associated with accumulation and proinflammatory polarization of T cells, which may regulate SM metabolic functions through paracrine mechanisms. Obesity-associated SM

  13. Inflammation and insulin/IGF-1 resistance as the possible link between obesity and neurodegeneration.

    PubMed

    Spielman, Lindsay J; Little, Jonathan P; Klegeris, Andis

    2014-08-15

    Obesity is a growing epidemic that contributes to several brain disorders including Alzheimer's, Parkinson's, and Huntington's diseases. Obesity could promote these diseases through several different mechanisms. Here we review evidence supporting the involvement of two recently recognized factors linking obesity with neurodegeneration: the induction of pro-inflammatory cytokines and onset of insulin and insulin-like growth factor 1 (IGF-1) resistance. Excess peripheral pro-inflammatory mediators, some of which can cross the blood brain barrier, may trigger neuroinflammation, which subsequently exacerbates neurodegeneration. Insulin and IGF-1 resistance leads to weakening of neuroprotective signaling by these molecules and can contribute to onset of neurodegenerative diseases. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. Insulin Resistance of Puberty.

    PubMed

    Kelsey, Megan M; Zeitler, Philip S

    2016-07-01

    Puberty is a time of considerable metabolic and hormonal change. Notably, puberty is associated with a marked decrease in insulin sensitivity, on par with that seen during pregnancy. In otherwise healthy youth, there is a nadir in insulin sensitivity in mid-puberty, and then it recovers at puberty completion. However, there is evidence that insulin resistance (IR) does not resolve in youth who are obese going into puberty and may result in increased cardiometabolic risk. Little is known about the underlying pathophysiology of IR in puberty, and how it might contribute to increased disease risk (e.g., type 2 diabetes). In this review, we have outlined what is known about the IR in puberty in terms of pattern, potential underlying mechanisms and other mediating factors. We also outline other potentially related metabolic changes that occur during puberty, and effects of underlying insulin resistant states (e.g., obesity) on pubertal changes in insulin sensitivity.

  15. CTLA-4Ig immunotherapy of obesity-induced insulin resistance by manipulation of macrophage polarization in adipose tissues

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Fujii, Masakazu, E-mail: masakazu731079@yahoo.co.jp; Inoguchi, Toyoshi, E-mail: toyoshi@intmed3.med.kyushu-u.ac.jp; Innovation Center for Medical Redox Navigation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582

    Highlights: •CTLA-4Ig completely alleviates HFD-induced insulin resistance. •CTLA-4Ig reduces epididymal and subcutaneous fat tissue weight and adipocyte size. •CTLA-4Ig alters ATM polarization from inflammatory M1 to anti-inflammatory M2. •CTLA-4Ig may lead to a novel anti-obesity/inflammation/insulin resistance agent. •We identified the mechanism of the novel favorable effects of CTLA-4lg. -- Abstract: It has been established that obesity alters the metabolic and endocrine function of adipose tissue and, together with accumulation of adipose tissue macrophages, contributes to insulin resistance. Although numerous studies have reported that shifting the polarization of macrophages from M1 to M2 can alleviate adipose tissue inflammation, manipulation of macrophagemore » polarization has not been considered as a specific therapy. Here, we determined whether cytotoxic T-lymphocyte-associated antigen-4IgG1 (CTLA-4Ig) can ameliorate insulin resistance by induction of macrophages from proinflammatory M1 to anti-inflammatory M2 polarization in the adipose tissues of high fat diet-induced insulin-resistant mice. CTLA4-Ig treatment prevented insulin resistance by changing gene expression to M2 polarization, which increased the levels of arginase 1. Furthermore, flow cytometric analysis confirmed the alteration of polarization from CD11c (M1)- to CD206 (M2)-positive cells. Concomitantly, CTLA-4Ig treatment resulted in weight reductions of epididymal and subcutaneous adipose tissues, which may be closely related to overexpression of apoptosis inhibitors in macrophages. Moreover, proinflammatory cytokine and chemokine levels decreased significantly. In contrast, CCAAT enhancer binding protein α, peroxisome proliferator-activated receptor γ, and adiponectin expression increased significantly in subcutaneous adipose tissue. This novel mechanism of CTLA-4lg immunotherapy may lead to an ideal anti-obesity/inflammation/insulin resistance agent.« less

  16. Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance.

    PubMed

    Gaggini, Melania; Carli, Fabrizia; Rosso, Chiara; Buzzigoli, Emma; Marietti, Milena; Della Latta, Veronica; Ciociaro, Demetrio; Abate, Maria Lorena; Gambino, Roberto; Cassader, Maurizio; Bugianesi, Elisabetta; Gastaldelli, Amalia

    2018-01-01

    Plasma concentrations of amino acids (AAs), in particular, branched chain AAs (BCAAs), are often found increased in nonalcoholic fatty liver disease (NAFLD); however, if this is due to increased muscular protein catabolism, obesity, and/or increased insulin resistance (IR) or impaired tissue metabolism is unknown. Thus, we evaluated a) if subjects with NAFLD without obesity (NAFLD-NO) compared to those with obesity (NAFLD-Ob) display altered plasma AAs compared to controls (CTs); and b) if AA concentrations are associated with IR and liver histology. Glutamic acid, serine, and glycine concentrations are known to be altered in NAFLD. Because these AAs are involved in glutathione synthesis, we hypothesized they might be related to the severity of NAFLD. We therefore measured the AA profile of 44 subjects with NAFLD without diabetes and who had a liver biopsy (29 NAFLD-NO and 15 NAFLD-Ob) and 20 CTs without obesity, by gas chromatography-mass spectrometry, homeostasis model assessment of insulin resistance, hepatic IR (Hep-IR; Hep-IR = endogenous glucose production × insulin), and the new glutamate-serine-glycine (GSG) index (glutamate/[serine + glycine]) and tested for an association with liver histology. Most AAs were increased only in NAFLD-Ob subjects. Only alanine, glutamate, isoleucine, and valine, but not leucine, were increased in NAFLD-NO subjects compared to CTs. Glutamate, tyrosine, and the GSG-index were correlated with Hep-IR. The GSG-index correlated with liver enzymes, in particular, gamma-glutamyltransferase (R = 0.70), independent of body mass index. Ballooning and/or inflammation at liver biopsy were associated with increased plasma BCAAs and aromatic AAs and were mildly associated with the GSG-index, while only the new GSG-index was able to discriminate fibrosis F3-4 from F0-2 in this cohort. Increased plasma AA concentrations were observed mainly in subjects with obesity and NAFLD, likely as a consequence of increased IR and protein catabolism

  17. Evidence in obese children: contribution of hyperlipidemia, obesity-inflammation, and insulin sensitivity.

    PubMed

    Chang, Chi-Jen; Jian, Deng-Yuan; Lin, Ming-Wei; Zhao, Jun-Zhi; Ho, Low-Tone; Juan, Chi-Chang

    2015-01-01

    Evidence shows a high incidence of insulin resistance, inflammation and dyslipidemia in adult obesity. The aim of this study was to assess the relevance of inflammatory markers, circulating lipids, and insulin sensitivity in overweight/obese children. We enrolled 45 male children (aged 6 to 13 years, lean control = 16, obese = 19, overweight = 10) in this study. The plasma total cholesterol, HDL cholesterol, triglyceride, glucose and insulin levels, the circulating levels of inflammatory factors, such as TNF-α, IL-6, and MCP-1, and the high-sensitive CRP level were determined using quantitative colorimetric sandwich ELISA kits. Compared with the lean control subjects, the obese subjects had obvious insulin resistance, abnormal lipid profiles, and low-grade inflammation. The overweight subjects only exhibited significant insulin resistance and low-grade inflammation. Both TNF-α and leptin levels were higher in the overweight/obese subjects. A concurrent correlation analysis showed that body mass index (BMI) percentile and fasting insulin were positively correlated with insulin resistance, lipid profiles, and inflammatory markers but negatively correlated with adiponectin. A factor analysis identified three domains that explained 74.08% of the total variance among the obese children (factor 1: lipid, 46.05%; factor 2: obesity-inflammation, 15.38%; factor 3: insulin sensitivity domains, 12.65%). Our findings suggest that lipid, obesity-inflammation, and insulin sensitivity domains predominantly exist among obese children. These factors might be applied to predict the outcomes of cardiovascular diseases in the future.

  18. The association between insulin resistance, metabolic variables, and depressive symptoms in Mexican-American elderly: A population-based study.

    PubMed

    Diniz, Breno S; Fisher-Hoch, Susan; McCormick, Joseph

    2018-02-01

    Depressive symptoms are common among older adults with obesity and diabetes. Nonetheless, the mechanisms for this association are not clear but may involve changes in the insulin cascade signaling. We aimed to investigate the association, and potential mediators, between obesity, insulin resistance, and depressive symptoms among older adults from a homogenous cohort of Mexican-Americans. We included a total of 500 Mexican-American older adults assessed in the Cameron County Health Study. We evaluated depressive symptoms using the Center for Epidemiologic Survey Depression Scale (CES-D). Central obesity was defined by waist circumference. Insulin resistance was evaluated by the HOMA-IR index. We estimated the association between obesity, insulin resistance, and depressive symptoms by carrying out univariate and multivariate regression analyses. In unadjusted regression analysis, HOMA-IR (unstandardized β = 0.31 ± 0.12, P = 0.007), waist circumference (unstandardized β = 0.066 ± 0.0.028, P = 0.017), and Hb1Ac levels (unstandardized β = 0.52 ± 0.24, P = 0.03) were significantly associated with CES-D scores. The association of HOMA-IR and CES-D remained statistically significant after controlling for socio-demographic and clinical variables in multivariate analysis (unstandardized β = 0.28 ± 0.11, P = 0.01). Our results suggest that depressive symptoms are associated with insulin resistance in older Mexican-American adults. In addition, poorer glucose control and obesity are important mediators of this relationship. Additional studies are needed to evaluate whether interventions that increase insulin sensitivity can also reduce depressive symptoms in this population. Copyright © 2017 John Wiley & Sons, Ltd.

  19. Association Between Insulin Resistance and Bone Structure in Nondiabetic Postmenopausal Women

    PubMed Central

    Finkelstein, Joel S.; Bouxsein, Mary L.; Yu, Elaine W.

    2016-01-01

    Context: The clinical consequences of insulin resistance and hyperinsulinemia on bone remain largely unknown. Objective: The objective of the study was to evaluate the effect of insulin resistance on peripheral bone geometry, volumetric bone mineral density (vBMD), bone microarchitecture, and estimated bone strength. Design, Setting, and Participants: This cross-sectional study included 146 postmenopausal, nondiabetic Caucasian women (mean age 60.3 ± 2.7 y) who were participating in the Study of Women's Health Across the Nation. Interventions: There were no interventions. Main Outcome Measures: High-resolution peripheral quantitative computed tomography was used to assess bone density and microstructure at the distal radius and tibia. Fasting insulin and glucose were measured and insulin resistance was estimated using homeostasis model assessment of insulin resistance (HOMA-IR), with higher values indicating greater insulin resistance. Results: There was a negative association between HOMA-IR and bone size and a positive association between HOMA-IR and total vBMD, trabecular vBMD, trabecular thickness, and cortical thickness at the radius and tibia. These relationships remained, even after adjusting for body weight and other potential covariates (eg, time since menopause, cigarette smoking, physical activity, prior use of osteoporosis medications or glucocorticoids). Conclusions: In nondiabetic, postmenopausal women, insulin resistance was associated with smaller bone size, greater volumetric bone mineral density, and generally favorable bone microarchitecture at weight-bearing and nonweight-bearing skeletal sites. These associations were independent of body weight and other potential covariates, suggesting that hyperinsulinemia directly affects bone structure independent of obesity and may explain, in part, the higher trabecular bone density and favorable trabecular microarchitecture seen in individuals with type 2 diabetes mellitus. PMID:27243136

  20. Importance of hepatitis C virus-associated insulin resistance: Therapeutic strategies for insulin sensitization

    PubMed Central

    Kawaguchi, Takumi; Sata, Michio

    2010-01-01

    Insulin resistance is one of the pathological features in patients with hepatitis C virus (HCV) infection. Generally, persistence of insulin resistance leads to an increase in the risk of life-threatening complications such as cardiovascular diseases. However, these complications are not major causes of death in patients with HCV-associated insulin resistance. Indeed, insulin resistance plays a crucial role in the development of various complications and events associated with HCV infection. Mounting evidence indicates that HCV-associated insulin resistance may cause (1) hepatic steatosis; (2) resistance to anti-viral treatment; (3) hepatic fibrosis and esophageal varices; (4) hepatocarcinogenesis and proliferation of hepatocellular carcinoma; and (5) extrahepatic manifestations. Thus, HCV-associated insulin resistance is a therapeutic target at any stage of HCV infection. Although the risk of insulin resistance in HCV-infected patients has been documented, therapeutic guidelines for preventing the distinctive complications of HCV-associated insulin resistance have not yet been established. In addition, mechanisms for the development of HCV-associated insulin resistance differ from lifestyle-associated insulin resistance. In order to ameliorate HCV-associated insulin resistance and its complications, the efficacy of the following interventions is discussed: a late evening snack, coffee consumption, dietary iron restriction, phlebotomy, and zinc supplements. Little is known regarding the effect of anti-diabetic agents on HCV infection, however, a possible association between use of exogenous insulin or a sulfonylurea agent and the development of HCC has recently been reported. On the other hand, insulin-sensitizing agents are reported to improve sustained virologic response rates. In this review, we summarize distinctive complications of, and therapeutic strategies for, HCV-associated insulin resistance. Furthermore, we discuss supplementation with branched

  1. Bioactives in blueberries improve insulin sensitivity in obese, insulin-resistant men and women.

    PubMed

    Stull, April J; Cash, Katherine C; Johnson, William D; Champagne, Catherine M; Cefalu, William T

    2010-10-01

    Dietary supplementation with whole blueberries in a preclinical study resulted in a reduction in glucose concentrations over time. We sought to evaluate the effect of daily dietary supplementation with bioactives from blueberries on whole-body insulin sensitivity in men and women. A double-blinded, randomized, and placebo-controlled clinical study design was used. After screening to resolve study eligibility, baseline (wk 0) insulin sensitivity was measured on 32 obese, nondiabetic, and insulin-resistant subjects using a high-dose hyperinsulinemic-euglycemic clamp (insulin infusion of 120 mU(861 pmol)⋅m(-2)⋅min(-1)). Serum inflammatory biomarkers and adiposity were measured at baseline. At the end of the study, insulin sensitivity, inflammatory biomarkers, and adiposity were reassessed. Participants were randomized to consume either a smoothie containing 22.5 g blueberry bioactives (blueberry group, n = 15) or a smoothie of equal nutritional value without added blueberry bioactives (placebo group, n = 17) twice daily for 6 wk. Both groups were instructed to maintain their body weight by reducing ad libitum intake by an amount equal to the energy intake of the smoothies. Participants' body weights were evaluated weekly and 3-d food records were collected at baseline, the middle, and end of the study. The mean change in insulin sensitivity improved more in the blueberry group (1.7 ± 0.5 mg⋅kg FFM(-1)⋅min(-1)) than in the placebo group (0.4 ± 0.4 mg⋅kg FFM(-1)⋅min(-1)) (P = 0.04). Insulin sensitivity was enhanced in the blueberry group at the end of the study without significant changes in adiposity, energy intake, and inflammatory biomarkers. In conclusion, daily dietary supplementation with bioactives from whole blueberries improved insulin sensitivity in obese, nondiabetic, and insulin-resistant participants.

  2. Hematopoietic Kit Deficiency, rather than Lack of Mast Cells, Protects Mice from Obesity and Insulin Resistance.

    PubMed

    Gutierrez, Dario A; Muralidhar, Sathya; Feyerabend, Thorsten B; Herzig, Stephan; Rodewald, Hans-Reimer

    2015-05-05

    Obesity, insulin resistance, and related pathologies are associated with immune-mediated chronic inflammation. Kit mutant mice are protected from diet-induced obesity and associated co-morbidities, and this phenotype has previously been attributed to their lack of mast cells. We performed a comprehensive metabolic analysis of Kit-dependent Kit(W/Wv) and Kit-independent Cpa3(Cre/+) mast-cell-deficient mouse strains, employing diet-induced or genetic (Lep(Ob/Ob) background) models of obesity. Our results show that mast cell deficiency, in the absence of Kit mutations, plays no role in the regulation of weight gain or insulin resistance. Moreover, we provide evidence that the metabolic phenotype observed in Kit mutant mice, while independent of mast cells, is immune regulated. Our data underscore the value of definitive mast cell deficiency models to conclusively test the involvement of this enigmatic cell in immune-mediated pathologies and identify Kit as a key hematopoietic factor in the pathogenesis of metabolic syndrome. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Proteasome Dysfunction Associated to Oxidative Stress and Proteotoxicity in Adipocytes Compromises Insulin Sensitivity in Human Obesity

    PubMed Central

    Díaz-Ruiz, Alberto; Guzmán-Ruiz, Rocío; Moreno, Natalia R.; García-Rios, Antonio; Delgado-Casado, Nieves; Membrives, Antonio; Túnez, Isaac; El Bekay, Rajaa; Fernández-Real, José M.; Tovar, Sulay; Diéguez, Carlos; Tinahones, Francisco J.; Vázquez-Martínez, Rafael; López-Miranda, José

    2015-01-01

    Abstract Aims: Obesity is characterized by a low-grade systemic inflammatory state and adipose tissue (AT) dysfunction, which predispose individuals to the development of insulin resistance (IR) and metabolic disease. However, a subset of obese individuals, referred to as metabolically healthy obese (MHO) individuals, are protected from obesity-associated metabolic abnormalities. Here, we aim at identifying molecular factors and pathways in adipocytes that are responsible for the progression from the insulin-sensitive to the insulin-resistant, metabolically unhealthy obese (MUHO) phenotype. Results: Proteomic analysis of paired samples of adipocytes from subcutaneous (SC) and omental (OM) human AT revealed that both types of cells are altered in the MUHO state. Specifically, the glutathione redox cycle and other antioxidant defense systems as well as the protein-folding machinery were dysregulated and endoplasmic reticulum stress was increased in adipocytes from IR subjects. Moreover, proteasome activity was also compromised in adipocytes of MUHO individuals, which was associated with enhanced accumulation of oxidized and ubiquitinated proteins in these cells. Proteasome activity was also impaired in adipocytes of diet-induced obese mice and in 3T3-L1 adipocytes exposed to palmitate. In line with these data, proteasome inhibition significantly impaired insulin signaling in 3T3-L1 adipocytes. Innovation: This study provides the first evidence of the occurrence of protein homeostasis deregulation in adipocytes in human obesity, which, together with oxidative damage, interferes with insulin signaling in these cells. Conclusion: Our results suggest that proteasomal dysfunction and impaired proteostasis in adipocytes, resulting from protein oxidation and/or misfolding, constitute major pathogenic mechanisms in the development of IR in obesity. Antioxid. Redox Signal. 23, 597–612. PMID:25714483

  4. Consumption of a liquid high-fat meal increases triglycerides but decreases high-density lipoprotein cholesterol in abdominally obese subjects with high postprandial insulin resistance.

    PubMed

    Wang, Feng; Lu, Huixia; Liu, Fukang; Cai, Huizhen; Xia, Hui; Guo, Fei; Xie, Yulan; Huang, Guiling; Miao, Miao; Shu, Guofang; Sun, Guiju

    2017-07-01

    Abdominal obesity is associated with an increased risk of insulin resistance, which may be a potential contributor to dyslipidemia. However, the relationship between postprandial insulin resistance and lipid metabolism in abdominally obese subjects remains unknown. We hypothesized that postprandial dyslipidemia would be exaggerated in abdominally obese subjects with high postprandial insulin resistance. To test this hypothesis, serum glucose, insulin, triglycerides, total cholesterol, high-density lipoprotein cholesterol, and apolipoprotein B were measured at baseline and postprandial state at 0.5, 1, 2, 4, 6, and 8 hours after a liquid high-fat meal in non-abdominally obese controls (n=44) and abdominally obese subjects with low (AO-LPIR, n=40), middle (n=40), and high postprandial insulin resistance (AO-HPIR, n=40) based on the tertiles ratio of the insulin to glucose areas under the curve (AUC). Their serum adipokines were tested at baseline only. Fasting serum leptin was higher (P<.05) in AO-HPIR than that in AO-LPIR and controls. Postprandial triglycerides AUC was higher (P<.05), whereas high-density lipoprotein cholesterol AUC was lower (P<.05), in AO-HPIR than those in AO-LPIR and controls. Postprandial AUCs for total cholesterol and apolipoprotein B were similar in abdominally obese subjects with different degrees of postprandial insulin resistance and controls. The present study indicated that the higher degree of postprandial insulin resistance, the more adverse lipid profiles in abdominally obese subjects, which provides insight into opportunity for screening in health. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Contributions of dysglycemia, obesity and insulin resistance to impaired endothelium-dependent vasodilation in humans

    PubMed Central

    Han, KA; Patel, Y; Lteif, AA; Chisholm, R; Mather, KJ

    2011-01-01

    Background Individual effects of hyperglycemia and obesity to impair vascular health are recognized. However, the relative contributions of dysglycemia versus other obesity-related traits to vascular dysfunction have not been systematically evaluated. Methods We undertook a cross-sectional evaluation of factors contributing to vascular function in 271 consecutive subjects, categorized as non-obese normal glucose tolerant (n=115), non-obese dysglycemic (n=32), obese normal glucose tolerant (n=57), obese dysglycemic (n=38), or type 2 diabetic (n=29). Vascular function was measured invasively as leg blood flow responses to methacholine chloride, an endothelium-dependent vasodilator. Categorical and continuous analyses were used to assess the contributions of hyperglycemia to vascular dysfunction. Results Even among normoglycemic subjects, obese subjects had impaired vascular function compared to non-obese subjects (p=0.004). Vascular function was also impaired in non-obese dysglycemic subjects (p=0.04 versus non-obese normoglycemic subjects), to a level comparable to normoglycemic obese subjects. Within obese subject groups, gradations of dysglycemia including the presence of diabetes were not associated with further worsening of these vascular responses beyond the effect of obesity alone (p=NS comparing all obese groups, p<0.001 versus lean normoglycemic subjects). In univariate and multivariable modeling analyses we found that effects of glycemia were less powerful than effects of insulin resistance and obesity on vascular dysfunction. Conclusions Dysglycemia contributes to impaired vascular function in non-obese subjects, but obesity and insulin resistance are more important determinants of vascular function in obese and diabetic subjects. PMID:21309061

  6. Abdominal obesity in older women: potential role for disrupted fatty acid reesterification in insulin resistance.

    PubMed

    Yeckel, Catherine W; Dziura, James; DiPietro, Loretta

    2008-04-01

    Excess abdominal adiposity is a primary factor for insulin resistance in older age. Our objectives were to examine the role of abdominal obesity on adipose tissue, hepatic, and peripheral insulin resistance in aging, and to examine impaired free fatty acid metabolism as a mechanism in these relations. This was a cross-sectional study. The study was performed at a General Clinical Research Center. Healthy, inactive older (>60 yr) women (n = 25) who were not on hormone replacement therapy or glucose-lowering medication were included in the study. Women with abdominal circumference values above the median (>97.5 cm) were considered abdominally obese. Whole-body peripheral glucose utilization, adipose tissue lipolysis, and hepatic glucose production were measured using in vivo techniques according to a priori hypotheses. In the simple analysis, glucose utilization at the 40 mU insulin dose (6.3 +/- 2.8 vs. 9.1 +/- 3.4; P < 0.05), the index of the insulin resistance of basal hepatic glucose production (23.6 +/- 13.0 vs. 15.1 +/- 6.0; P < 0.05), and insulin-stimulated suppression of lipolysis (35 vs. 54%; P < 0.05) were significantly different between women with and without abdominal obesity, respectively. Using the glycerol appearance rate to free fatty acid ratio as an index of fatty acid reesterification revealed markedly blunted reesterification in the women with abdominal adiposity under all conditions: basal (0.95 +/- 0.29 vs. 1.35 +/- 0.47; P < 0.02); low- (2.58 +/- 2.76 vs. 6.95 +/- 5.56; P < 0.02); and high-dose (4.46 +/- 3.70 vs. 12.22 +/- 7.13; P < 0.01) hyperinsulinemia. Importantly, fatty acid reesterification was significantly (P < 0.01) associated with abdominal circumference and hepatic and peripheral insulin resistance, regardless of total body fat. These findings support the premise of dysregulated fatty acid reesterification with abdominal obesity as a pathophysiological link to perturbed glucose metabolism across multiple tissues in aging.

  7. Association of lipid parameters and insulin resistance with bone health in South Korean adolescents.

    PubMed

    Park, S-W; Nam, G-E; Jung, D-W; Yoon, S-J; Han, K; Park, Y-G; Choi, J-S; Lee, J-E; Sang, J-E; Yoon, Y-J; Kim, D-H

    2016-02-01

    This study investigated the association between lipid profiles and insulin resistance and bone mineral content (BMC) in Korean adolescents and found that BMC was inversely associated with triglyceride (TG) and homeostasis model assessment of insulin resistance (HOMA-IR). This association did not differ according to obesity status in either boys or girls. To prevent future osteoporosis, it is important to identify factors that affect bone health in adolescents as well as adults. This study aimed to examine the association between lipid profiles and insulin resistance and BMC in Korean adolescents. Data from 706 boys and 621 girls, who participated in the Korea National Health and Nutrition Examination Survey from 2008 to 2011, were analyzed. Lipid profiles were measured, and HOMA-IR was calculated to assess insulin resistance. BMC was measured for the total femur, femur neck, and lumbar spine by using whole-body dual-energy X-ray absorptiometry (DXA). TG level and HOMA-IR were negatively correlated with BMC at all three sites in boys. In girls, TG level showed a negative correlation with BMC at the femur neck and lumbar spine, and HOMA-IR was negatively associated with BMC at the femur neck only. These inverse associations did not differ according to obesity status in either sex. Adjusted means of BMC at the three sites in boys tended to decrease in the higher tertile groups of TG and HOMA-IR, and the adjusted means of BMC for the total femur in girls tended to decrease in the higher tertile groups of TG and HOMA-IR. BMC was inversely associated with TG and HOMA-IR in Korean adolescents, and this association was more pronounced in boys. This association did not differ according to obesity status in either sex.

  8. PGRN is a key adipokine mediating high fat diet-induced insulin resistance and obesity through IL-6 in adipose tissue.

    PubMed

    Matsubara, Toshiya; Mita, Ayako; Minami, Kohtaro; Hosooka, Tetsuya; Kitazawa, Sohei; Takahashi, Kenichi; Tamori, Yoshikazu; Yokoi, Norihide; Watanabe, Makoto; Matsuo, Ei-Ichi; Nishimura, Osamu; Seino, Susumu

    2012-01-04

    Adipose tissue secretes adipokines that mediate insulin resistance, a characteristic feature of obesity and type 2 diabetes. By differential proteome analysis of cellular models of insulin resistance, we identified progranulin (PGRN) as an adipokine induced by TNF-α and dexamethasone. PGRN in blood and adipose tissues was markedly increased in obese mouse models and was normalized with treatment of pioglitazone, an insulin-sensitizing agent. Ablation of PGRN (Grn(-/-)) prevented mice from high fat diet (HFD)-induced insulin resistance, adipocyte hypertrophy, and obesity. Grn deficiency blocked elevation of IL-6, an inflammatory cytokine, induced by HFD in blood and adipose tissues. Insulin resistance induced by chronic administration of PGRN was suppressed by neutralizing IL-6 in vivo. Thus, PGRN is a key adipokine that mediates HFD-induced insulin resistance and obesity through production of IL-6 in adipose tissue, and may be a promising therapeutic target for obesity. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. Deficiency in plasmacytoid dendritic cells and type I interferon signalling prevents diet-induced obesity and insulin resistance in mice.

    PubMed

    Hannibal, Tine D; Schmidt-Christensen, Anja; Nilsson, Julia; Fransén-Pettersson, Nina; Hansen, Lisbeth; Holmberg, Dan

    2017-10-01

    Obesity is associated with glucose intolerance and insulin resistance and is closely linked to the increasing prevalence of type 2 diabetes. In mouse models of diet-induced obesity (DIO) and type 2 diabetes, an increased fat intake results in adipose tissue expansion and the secretion of proinflammatory cytokines. The innate immune system not only plays a crucial role in obesity-associated chronic low-grade inflammation but it is also proposed to play a role in modulating energy metabolism. However, little is known about how the modulation of metabolism by the immune system may promote increased adiposity in the early stages of increased dietary intake. Here we aimed to define the role of type I IFNs in DIO and insulin resistance. Mice lacking the receptor for IFN-α (IFNAR -/- ) and deficient in plasmacytoid dendritic cells (pDCs) (B6.E2-2 fl/fl .Itgax-cre) were fed a diet with a high fat content or normal chow. The mice were analysed in vivo and in vitro using cellular, biochemical and molecular approaches. We found that the development of obesity was inhibited by an inability to respond to type I IFNs. Furthermore, the development of obesity and insulin resistance in this model was associated with pDC recruitment to the fatty tissues and liver of obese mice (a 4.3-fold and 2.7-fold increase, respectively). Finally, we demonstrated that the depletion of pDCs protects mice from DIO and from developing obesity-associated metabolic complications. Our results provide genetic evidence that pDCs, via type I IFNs, regulate energy metabolism and promote the development of obesity.

  10. Gender differences in the association between food insecurity and insulin resistance among U.S. adults: National Health and Nutrition Examination Survey, 2005-2010.

    PubMed

    Liu, Junxiu; Park, Yong-Moon Mark; Berkowitz, Seth A; Hu, Qingwei; Han, Kyungdo; Ortaglia, Andrew; McKeown, Robert E; Liese, Angela D

    2015-09-01

    To examine gender-specific associations between food insecurity and insulin resistance in a representative U.S. Data on 5533 adults of 20 years of age or more (2742 men and 2791 women) without diabetes from the 2005-2010 National Health and Nutrition Examination Survey were analyzed. Respondents were categorized as having full, marginal, low, or very low food security using a validated scale. Insulin-resistant individuals were defined as those with a homeostasis model assessment of insulin resistance value 2.5 or more. Insulin resistance was higher in both normal-weight (P = .001) and overweight or obese (P < .001) women with lower food security, but no linear trend was found in men. In multiple logistic regression analyses, however, very low food security-compared with full food security-was associated with insulin resistance in normal-weight men (odds ratio, 3.99; 95% confidence interval, 1.71-9.33), and marginal food insecurity was associated with insulin resistance in overweight or obese men (odds ratio, 2.07; 95% confidence interval, 1.18-3.64) after adjusting for potential confounders. In women, the association between food insecurity and insulin resistance was no longer significant after adjustment. Food insecurity is associated with insulin resistance in adults without diabetes, and this effect varies by gender in normal-weight and overweight or obese populations. Improving food security status may help reduce insulin resistance, an underlying risk factor for diabetes and cardiovascular disease. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. White Pitaya (Hylocereus undatus) Juice Attenuates Insulin Resistance and Hepatic Steatosis in Diet-Induced Obese Mice.

    PubMed

    Song, Haizhao; Zheng, Zihuan; Wu, Jianan; Lai, Jia; Chu, Qiang; Zheng, Xiaodong

    2016-01-01

    Insulin resistance and hepatic steatosis are the most common complications of obesity. Pitaya is an important source of phytochemicals such as polyphenols, flavonoid and vitamin C which are related to its antioxidant activity. The present study was conducted to evaluate the influence of white pitaya juice (WPJ) on obesity-related metabolic disorders (e.g. insulin resistance and hepatic steatosis) in high-fat diet-fed mice. Forty-eight male C57BL/6J mice were assigned into four groups and fed low-fat diet with free access to water or WPJ, or fed high-fat diet with free access to water or WPJ for 14 weeks. Our results showed that administration of WPJ improved high-fat diet-induced insulin resistance, hepatic steatosis and adipose hypertrophy, but it exerted no influence on body weight gain in mice. Hepatic gene expression analysis indicated that WPJ supplement not only changed the expression profile of genes involved in lipid and cholesterol metabolism (Srebp1, HMGCoR, Cpt1b, HL, Insig1 and Insig2) but also significantly increased the expression levels of FGF21-related genes (Klb, FGFR2, Egr1 and cFos). In conclusion, WPJ protected from diet-induced hepatic steatosis and insulin resistance, which was associated with the improved FGF21 resistance and lipid metabolism.

  12. Emerging perspectives on essential amino acid metabolism in obesity and the insulin-resistant state.

    PubMed

    Adams, Sean H

    2011-11-01

    Dysregulation of insulin action is most often considered in the context of impaired glucose homeostasis, with the defining feature of diabetes mellitus being elevated blood glucose concentration. Complications arising from the hyperglycemia accompanying frank diabetes are well known and epidemiological studies point to higher risk toward development of metabolic disease in persons with impaired glucose tolerance. Although the central role of proper blood sugar control in maintaining metabolic health is well established, recent developments have begun to shed light on associations between compromised insulin action [obesity, prediabetes, and type 2 diabetes mellitus (T2DM)] and altered intermediary metabolism of fats and amino acids. For amino acids, changes in blood concentrations of select essential amino acids and their derivatives, in particular BCAA, sulfur amino acids, tyrosine, and phenylalanine, are apparent with obesity and insulin resistance, often before the onset of clinically diagnosed T2DM. This review provides an overview of these changes and places recent observations from metabolomics research into the context of historical reports in the areas of biochemistry and nutritional biology. Based on this synthesis, a model is proposed that links the FFA-rich environment of obesity/insulin resistance and T2DM with diminution of BCAA catabolic enzyme activity, changes in methionine oxidation and cysteine/cystine generation, and tissue redox balance (NADH/NAD+).

  13. Dietary fiber, plasma insulin, and obesity.

    PubMed

    Albrink, M J

    1978-10-01

    The relationship between obesity, insulin resistance, and hyperinsulinemia is briefly reviewed. The possibility is considered that excess insulin secretion is the cause rather than the result of insulin resistance and obesity. Glucose administration is one of the most frequently studied of those factors known to stimulate insulin secretion. Much less well documented is the fact that meals of equal protein, fat, and carbohydrate content may cause different responses of plasma glucose and insulin. An experiment is reported in which the effects of a high-carbohydrate, high-fiber meal administered to seven healthy young adults were compared with the effects of a meal equally high in carbohydrate but composed largely of glucose in liquid formula form. The high-fiber meal caused an insulin rise less than half that caused by the liquid formula meal although the plasma glucose response to the two meals was not significantly different. The hypothesis is proposed that a high-carbohydrate, fiber-depleted diet, high in simple sugars, by repeatedly stimulating an excessive insulin response, may lead to insulin resistance and obesity in susceptible individuals and may play a role in the common occurrence of obesity in industrialized societies.

  14. Cardiovascular fitness, insulin resistance and metabolic syndrome in severely obese prepubertal Italian children.

    PubMed

    Brufani, Claudia; Grossi, Armando; Fintini, Danilo; Fiori, Rossana; Ubertini, Graziamaria; Colabianchi, Diego; Ciampalini, Paolo; Tozzi, Alberto; Barbetti, Fabrizio; Cappa, Marco

    2008-01-01

    To evaluate if insulin resistance (IR) and metabolic syndrome (MS) were associated with poor cardiovascular fitness in very obese prepubertal Italian subjects. Children referred to the Endocrinology and Diabetes Unit of Bambino Gesù Children's Hospital underwent an OGTT with glucose and insulin assays. QUICKI, ISI and HOMA-IR were calculated. Total and HDL cholesterol, triglycerides and percentage of body fat (DEXA) were determined. Cardiovascular fitness (maximal treadmill time) was evaluated using a treadmill protocol. The MS was defined as having 3 or more of following risk factors: obesity, impaired glucose tolerance, high blood pressure, low HDL-cholesterol, high triglycerides. Fifty-five very obese prepubertal Italian children were enrolled in the study. Unadjusted correlation revealed maximal treadmill time negatively related to fasting insulin (r = -0.53, p < 0.0001) and HOMA-IR (r = -0.57, p < 0.0001) and positively to QUICKI (r = 0.51, p < 0.0001) and ISI (r = 0.46, p = 0.0035). These relationships remained significant when in multivariate analysis age, gender, BMI SD and body composition were accounted for (all p < 0.01). The presence of the MS was independently associated with maximal treadmill time. Poorcardiovascular fitness, IR and MS were independently related, suggesting that the relationship between fitness and insulin action develops early in life. Copyright 2008 S. Karger AG, Basel.

  15. Metabolic signatures of insulin resistance in 7,098 young adults.

    PubMed

    Würtz, Peter; Mäkinen, Ville-Petteri; Soininen, Pasi; Kangas, Antti J; Tukiainen, Taru; Kettunen, Johannes; Savolainen, Markku J; Tammelin, Tuija; Viikari, Jorma S; Rönnemaa, Tapani; Kähönen, Mika; Lehtimäki, Terho; Ripatti, Samuli; Raitakari, Olli T; Järvelin, Marjo-Riitta; Ala-Korpela, Mika

    2012-06-01

    Metabolite associations with insulin resistance were studied in 7,098 young Finns (age 31 ± 3 years; 52% women) to elucidate underlying metabolic pathways. Insulin resistance was assessed by the homeostasis model (HOMA-IR) and circulating metabolites quantified by high-throughput nuclear magnetic resonance spectroscopy in two population-based cohorts. Associations were analyzed using regression models adjusted for age, waist, and standard lipids. Branched-chain and aromatic amino acids, gluconeogenesis intermediates, ketone bodies, and fatty acid composition and saturation were associated with HOMA-IR (P < 0.0005 for 20 metabolite measures). Leu, Ile, Val, and Tyr displayed sex- and obesity-dependent interactions, with associations being significant for women only if they were abdominally obese. Origins of fasting metabolite levels were studied with dietary and physical activity data. Here, protein energy intake was associated with Val, Phe, Tyr, and Gln but not insulin resistance index. We further tested if 12 genetic variants regulating the metabolites also contributed to insulin resistance. The genetic determinants of metabolite levels were not associated with HOMA-IR, with the exception of a variant in GCKR associated with 12 metabolites, including amino acids (P < 0.0005). Nonetheless, metabolic signatures extending beyond obesity and lipid abnormalities reflected the degree of insulin resistance evidenced in young, normoglycemic adults with sex-specific fingerprints.

  16. High serum fasting peptide YY (3-36) is associated with obesity-associated insulin resistance and type 2 diabetes.

    PubMed

    Ukkola, Olavi H; Puurunen, Veli-Pekka; Piira, Olli-Pekka; Niva, Jarkko T; Lepojärvi, E Samuli; Tulppo, Mikko P; Huikuri, Heikki V

    2011-10-10

    We studied whether serum fasting levels of active form of peptide YY (PYY), PYY(3-36), are associated with obesity and related phenotypes. The study population consisted of 428 patients with coronary artery disease and diagnosed type 2 diabetes and 440 patients with coronary artery disease but without evidence of diabetes from the ARTEMIS study. The patients were recruited from the consecutive series of patients undergoing coronary angiography in the Oulu University Hospital. The patients without diabetes underwent a 2-hour oral glucose tolerance test. PYY(3-36) levels were analyzed by human PYY(3-36) specific radioimmunoassay. Result suggested that when PYY(3-36) tertiles were considered, high serum fasting PYY(3-36) concentration was associated with high body mass index, waist circumference, hemoglobin A1c, fasting blood glucose, leptin, triglyceride (p for all p ≤ 0.001), serum insulin (p=0.013) and with a low high-density lipoprotein cholesterol (p=0.004) concentrations in the analyses adjusted for age, sex and study group. The link high PYY(3-36)-high insulin level was evident in subjects with normal glucose tolerance (p<0.05). The prevalence of diabetes was 72%, 46% and 30% in the highest, medium and lowest PYY(3-36) tertile (p<0.001). The PYY(3-36) concentrations (after adjustment for age, sex and body mass index) were higher in type 2 diabetics compared to subjects with impaired fasting glucose, impaired glucose tolerance and normal glucose tolerance (p<0.001 for trend). In conclusion, fasting PYY(3-36) concentrations in type 2 diabetic subjects are high. Although high PYY(3-36) is strongly linked to obesity and associated insulin resistance, the relation between PYY(3-36) and type 2 diabetes is independent of body fatness. Copyright © 2011 Elsevier B.V. All rights reserved.

  17. GH Receptor Deficiency in Ecuadorian Adults Is Associated With Obesity and Enhanced Insulin Sensitivity

    PubMed Central

    Rosenbloom, Arlan L.; Balasubramanian, Priya; Teran, Enrique; Guevara-Aguirre, Marco; Guevara, Carolina; Procel, Patricio; Alfaras, Irene; De Cabo, Rafael; Di Biase, Stefano; Narvaez, Luis; Saavedra, Jannette

    2015-01-01

    Context: Ecuadorian subjects with GH receptor deficiency (GHRD) have not developed diabetes, despite obesity. Objective: We sought to determine the metabolic associations for this phenomenon. Design: Four studies were carried out: 1) glucose, lipid, adipocytokine concentrations; 2) metabolomics evaluation; 3) metabolic responses to a high-calorie meal; and 4) oral glucose tolerance tests. Setting: Clinical Research Institute in Quito, Ecuador. Subjects: Adults homozygous for the E180 splice mutation of the GH receptor (GHRD) were matched for age, gender, and body mass index with unaffected control relatives (C) as follows: study 1, 27 GHRD and 35 C; study 2, 10 GHRD and 10 C; study 3, seven GHRD and 11 C; and study 4, seven GHRD and seven C. Results: Although GHRD subjects had greater mean percentage body fat than controls, their fasting insulin, 2-hour blood glucose, and triglyceride levels were lower. The indicator of insulin sensitivity, homeostasis model of assessment 2%S, was greater (P < .0001), and the indicator of insulin resistance, homeostasis model of assessment 2-IR, was lower (P = .0025). Metabolomic differences between GHRD and control subjects were consistent with their differing insulin sensitivity, including postprandial decreases of branched-chain amino acids that were more pronounced in controls. High molecular weight and total adiponectin concentrations were greater in GHRD (P = .0004 and P = .0128, respectively), and leptin levels were lower (P = .02). Although approximately 65% the weight of controls, GHRD subjects consumed an identical high-calorie meal; nonetheless, their mean glucose concentrations were lower, with mean insulin levels one-third those of controls. Results of the 2-hour oral glucose tolerance test were similar. Main Outcome Measures: Measures of insulin sensitivity, adipocytokines, and energy metabolites. Conclusions: Without GH counter-regulation, GHRD is associated with insulin efficiency and obesity. Lower leptin levels

  18. Insulin resistance, metabolic syndrome, and lung function in US adolescents with and without asthma.

    PubMed

    Forno, Erick; Han, Yueh-Ying; Muzumdar, Radhika H; Celedón, Juan C

    2015-08-01

    Obesity increases both the risk of asthma and asthma severity and is a well-known risk factor for insulin resistance and the metabolic syndrome (MS) in children and adolescents. We aimed to examine the association among obesity, insulin sensitivity, MS, and lung function in US adolescents with and without asthma. We performed a cross-sectional study of 1429 adolescents aged 12 to 17 years in the 2007-2010 National Health and Nutrition Examination Survey. Adjusted regression was used to assess the relationships among obesity, insulin sensitivity/resistance, MS, and lung function in children with and without asthma. Insulin resistance was negatively associated with FEV1 and forced vital capacity (FVC) in adolescents with and without asthma, whereas MS was associated with lower FEV1/FVC ratios, with a more pronounced decrease found among asthmatic patients; these associations were driven by overweight/obese adolescents. Higher body mass index was associated with a decrease in FEV1/FVC ratios among adolescents with insulin resistance. Compared with healthy participants, adolescents with MS had an approximately 2% decrease in FEV1/FVC ratios, adolescents with asthma had an approximately 6% decrease, and those with MS and asthma had approximately 10% decreased FEV1/FVC ratios (P < .05). Insulin resistance and MS are associated with worsened lung function in overweight/obese adolescents. Asthma and MS synergistically decrease lung function, as do obesity and insulin resistance. These factors might contribute to the pathogenesis of asthma severity in obese patients and warrant further investigation. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  19. Inflammation-induced microvascular insulin resistance is an early event in diet-induced obesity.

    PubMed

    Zhao, Lina; Fu, Zhuo; Wu, Jing; Aylor, Kevin W; Barrett, Eugene J; Cao, Wenhong; Liu, Zhenqi

    2015-12-01

    Endothelial dysfunction and vascular insulin resistance usually coexist and chronic inflammation engenders both. In the present study, we investigate the temporal relationship between vascular insulin resistance and metabolic insulin resistance. We assessed insulin responses in all arterial segments, including aorta, distal saphenous artery and the microvasculature, as well as the metabolic insulin responses in muscle in rats fed on a high-fat diet (HFD) for various durations ranging from 3 days to 4 weeks with or without sodium salicylate treatment. Compared with controls, HFD feeding significantly blunted insulin-mediated Akt (protein kinase B) and eNOS [endothelial nitric oxide (NO) synthase] phosphorylation in aorta in 1 week, blunted vasodilatory response in small resistance vessel in 4 weeks and microvascular recruitment in as early as 3 days. Insulin-stimulated whole body glucose disposal did not begin to progressively decrease until after 1 week. Salicylate treatment fully inhibited vascular inflammation, prevented microvascular insulin resistance and significantly improved muscle metabolic responses to insulin. We conclude that microvascular insulin resistance is an early event in diet-induced obesity and insulin resistance and inflammation plays an essential role in this process. Our data suggest microvascular insulin resistance contributes to the development of metabolic insulin resistance in muscle and muscle microvasculature is a potential therapeutic target in the prevention and treatment of diabetes and its related complications. © 2015 Authors; published by Portland Press Limited.

  20. Inflammation-induced microvascular insulin resistance is an early event in diet-induced obesity

    PubMed Central

    Zhao, Lina; Fu, Zhuo; Wu, Jing; Aylor, Kevin W.; Barrett, Eugene J.; Cao, Wenhong

    2015-01-01

    Endothelial dysfunction and vascular insulin resistance usually coexist and chronic inflammation engenders both. In the present study, we investigate the temporal relationship between vascular insulin resistance and metabolic insulin resistance. We assessed insulin responses in all arterial segments, including aorta, distal saphenous artery and the microvasculature, as well as the metabolic insulin responses in muscle in rats fed on a high-fat diet (HFD) for various durations ranging from 3 days to 4 weeks with or without sodium salicylate treatment. Compared with controls, HFD feeding significantly blunted insulin-mediated Akt (protein kinase B) and eNOS [endothelial nitric oxide (NO) synthase] phosphorylation in aorta in 1 week, blunted vasodilatory response in small resistance vessel in 4 weeks and microvascular recruitment in as early as 3 days. Insulin-stimulated whole body glucose disposal did not begin to progressively decrease until after 1 week. Salicylate treatment fully inhibited vascular inflammation, prevented microvascular insulin resistance and significantly improved muscle metabolic responses to insulin. We conclude that microvascular insulin resistance is an early event in diet-induced obesity and insulin resistance and inflammation plays an essential role in this process. Our data suggest microvascular insulin resistance contributes to the development of metabolic insulin resistance in muscle and muscle microvasculature is a potential therapeutic target in the prevention and treatment of diabetes and its related complications. PMID:26265791

  1. Triglyceride to HDL-C Ratio is Associated with Insulin Resistance in Overweight and Obese Children

    PubMed Central

    Iwani, Nur Ahmad Kamil Zati; Jalaludin, Muhammad Yazid; Zin, Ruziana Mona Wan Mohd; Fuziah, Md Zain; Hong, Janet Yeow Hua; Abqariyah, Yahya; Mokhtar, Abdul Halim; Wan Nazaimoon, Wan Mohamud

    2017-01-01

    The purpose of this study was to investigate the usefulness of triglyceride to hdl-c ratio (TG:HDL-C) as an insulin resistance (IR) marker for overweight and obese children. A total of 271 blood samples of obese and overweight children aged 9–16 years were analysed for fasting glucose, lipids and insulin. Children were divided into IR and non-insulin resistance, using homeostasis model assessment (HOMA). The children were then stratified by tertiles of TG: HDL-C ratio. The strength between TG:HDL-C ratio and other parameters of IR were quantified using Pearson correlation coefficient (r). Odds ratio was estimated using multiple logistic regression adjusted for age, gender, pubertal stages and IR potential risk factors. Children with IR had significantly higher TG:HDL-C ratio (2.48) (p = 0.01). TG:HDL-C ratio was significantly correlated with HOMA-IR (r = 0.104, p < 0.005) and waist circumference (r = 0.134, p < 0.001). Increasing tertiles of TG:HDL-C ratio showed significant increase in mean insulin level (p = 0.03), HOMA-IR (p = 0.04) and significantly higher number of children with acanthosis nigricans and metabolic syndrome. The odds of having IR was about 2.5 times higher (OR = 2.47; 95% CI 1.23, 4.95; p = 0.01) for those in the highest tertiles of TG:HDL-C ratio. Hence, TG:HDL-C may be a useful tool to identify high risk individuals. PMID:28059134

  2. Expanded Normal Weight Obesity and Insulin Resistance in US Adults of the National Health and Nutrition Examination Survey

    PubMed Central

    Martinez, Keilah E.; Bailey, Bruce W.

    2017-01-01

    This study aims to expand the evaluation of normal weight obesity (NWO) and its association with insulin resistance using an NHANES (1999–2006) sample of US adults. A cross-sectional study including 5983 men and women (50.8%) was conducted. Body fat percentage (BF%) was assessed using dual-energy X-ray absorptiometry. Expanded normal weight obesity (eNWO) categories, pairings of BMI and body fat percentage classifications, were created using standard cut-points for BMI and sex-specific median for BF%. Homeostatic model assessment-insulin resistance (HOMA-IR) levels were used to index insulin resistance. Mean ± SE values were BMI: 27.9 ± 0.2 (women) and 27.8 ± 0.1 (men); body fat percentage: 40.5 ± 0.2 (women) and 27.8 ± 0.2 (men); and HOMA-IR: 2.04 ± 0.05 (women) and 2.47 ± 0.09 (men). HOMA-IR differed systematically and in a dose-response fashion across all levels of the eNWO categories (F = 291.3, P < 0.0001). As BMI levels increased, HOMA-IR increased significantly, and within each BMI category, higher levels of body fat were associated with higher levels of HOMA-IR. Both high BMI and high BF% were strongly related to insulin resistance. Insulin resistance appears to increase incrementally according to BMI levels primarily and body fat levels secondarily. Including a precise measure of body fat with BMI adds little to the utility of BMI in the prediction of insulin resistance. PMID:28812029

  3. Immunity as a link between obesity and insulin resistance

    USDA-ARS?s Scientific Manuscript database

    Type-2 diabetes mellitus (T2DM) is a major health problem in the United States and worldwide. Obesity is causally linked to the pathogenesis of insulin resistance, metabolic syndrome and T2DM. A chronic low-grade inflammation occurring in adipose tissue is at least in part responsible for the obesit...

  4. Weight-loss changes PPAR expression, reduces atherosclerosis and improves cardiovascular function in obese insulin-resistant mice

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Verreth, Wim; Verhamme, Peter; Pelat, Michael

    2003-09-01

    Weight-loss in obese insulin-resistant, but not in insulin-sensitive, persons reduces CHD risk. It is not known to what extent changes in the adipose gene expression profile are important for reducing CHD risk. We studied the effect of diet restriction-induced weight-loss on gene expression in adipose tissue, atherosclerosis and cardiovascular function in mice with combined leptin and LDL-receptor deficiency. Obesity, hypertriglyceridemia and insulin-resistance are associated with hypertension, impaired left ventricle function and accelerated atherosclerosis in those mice. Diet restriction during 12 weeks caused a 45% weight-loss and changes in the gene expression in adipose tissue of PPARa and PPAR? and ofmore » key genes regulating glucose transport and insulin sensitivity, lipid metabolism, oxidative stress and inflammation, most of which are under the transcriptional control of PPARs. These changes were associated with increased insulin-sensitivity, decreased hypertriglyceridemia, reduced mean 24-hour blood pressure and heart rate, restored circadian variations of blood pressure and heart rate, increased ejection fraction, and reduced atherosclerosis. Thus, induction of PPARa and PPAR? in adipose tissue is a key mechanism for reducing atherosclerosis and improving cardiovascular function resulting from weight-loss. Our observations point to the critical role of PPARs in the pathogenesis of cardiovascular features of the metabolic syndrome.« less

  5. Dipeptidyl Peptidase-4 Inhibitor, Vildagliptin, Improves Trabecular Bone Mineral Density and Microstructure in Obese, Insulin-Resistant, Pre-diabetic Rats.

    PubMed

    Charoenphandhu, Narattaphol; Suntornsaratoon, Panan; Sa-Nguanmoo, Piangkwan; Tanajak, Pongpan; Teerapornpuntakit, Jarinthorn; Aeimlapa, Ratchaneevan; Chattipakorn, Nipon; Chattipakorn, Siriporn

    2018-02-02

    Obese insulin resistance and type 2 diabetes mellitus profoundly impair bone mechanical properties and bone quality. However, because several antidiabetes drugs, especially thiazolidinediones, further aggravate bone loss in individuals with diabetes, diabetic osteopathy should not be treated by using simply any glucose-lowering agents. Recently, incretins have been reported to affect osteoblast function positively. The present study aimed to investigate the effects of vildagliptin, an inhibitor of dipeptidyl peptidase-4, on bone of rats with high-fat-diet-induced prediabetes. Male rats were fed a high-fat diet for 12 weeks to induce obese insulin resistance and then treated with vildagliptin for 4 weeks. The effects of the drug on bone were determined by microcomputed tomography and bone histomorphometry. Vildagliptin markedly improved insulin resistance in these obese insulin-resistant rats. It also significantly increased volumetric bone mineral density. Specifically, vildagliptin-treated obese insulin-resistant rats exhibited higher trabecular volumetric bone mineral density than vehicle-treated obese insulin-resistant rats, whereas cortical volumetric bone mineral density, cortical thickness and area were not changed. Bone histomorphometric analysis in a trabecular-rich area (i.e. tibial metaphysis) revealed greater trabecular bone volume and number and less trabecular separation without change in trabecular thickness, osteocyte lacunar area or cortical thickness in the vildagliptin-treated group. Vildagliptin had a beneficial effect on the bone of obese insulin-resistant rats with prediabetes, particularly at the trabecular site. Such benefit probably results from enhanced bone formation rather than from suppressed bone resorption. Copyright © 2018 Diabetes Canada. Published by Elsevier Inc. All rights reserved.

  6. Insulin-sensitive obese children display a favorable metabolic profile.

    PubMed

    Vukovic, Rade; Mitrovic, Katarina; Milenkovic, Tatjana; Todorovic, Sladjana; Soldatovic, Ivan; Sipetic-Grujicic, Sandra; Zdravkovic, Dragan

    2013-02-01

    Most of what is known about the metabolically healthy obese phenomenon is derived from studies in the adult population and no standardized criteria to identify these individuals exist to date. The aim of this study was to determine if the preserved insulin sensitivity evaluated by homeostatic model assessment of insulin resistance (HOMA-IR) index is associated with favorable metabolic profile in the obese children. We studied a group of 248 children and adolescents (150 female, 98 male), aged 5.9-18.9 years with diet-induced obesity (BMI >95th percentile). The entire cohort was divided into quartiles based on levels of insulin resistance determined by HOMA-IR index. Subjects in the lower quartile of HOMA-IR were classified as insulin-sensitive group (ISG), whereas children in the upper quartile were categorized as insulin-resistant group (IRG). The ISG subjects had values of HOMA-IR ≤2.75 while the children from the IRG group had HOMA-IR ≥6.16. Subjects from ISG group had lower basal β-cell activity and were less likely to have impaired fasting glucose or impaired glucose tolerance. Concentrations of LDL and total cholesterol, triglycerides, and transaminases were lower and HDL cholesterol levels were higher in ISG subjects. Findings obtained by the use of Matsuda index correlated well with the findings obtained by the use of HOMA-IR. Lower HOMA-IR values were significantly associated with favorable metabolic profile in studied children, which correlates with findings in the adult population and emphasizes the need for further, longitudinal studies of insulin resistance development in childhood obesity.

  7. Obesity does not aggravate osteoporosis or osteoblastic insulin resistance in orchiectomized rats.

    PubMed

    Potikanond, Saranyapin; Rattanachote, Pinyada; Pintana, Hiranya; Suntornsaratoon, Panan; Charoenphandhu, Narattaphol; Chattipakorn, Nipon; Chattipakorn, Siriporn

    2016-02-01

    The present study aimed to test the hypothesis that testosterone deprivation impairs osteoblastic insulin signaling, decreases osteoblast survival, reduces bone density, and that obesity aggravates those deleterious effects in testosterone-deprived rats. Twenty four male Wistar rats underwent either a bilateral orchiectomy (O, n=12) or a sham operation (S, n=12). Then the rats in each group were further divided into two subgroups fed with either a normal diet (ND) or a high-fat diet (HF) for 12 weeks. At the end of the protocol, blood samples were collected to determine metabolic parameters and osteocalcin ratios. The tibiae were collected to determine bone mass using microcomputed tomography and for osteoblast isolation. The results showed that rats fed with HF (sham-operated HF-fed rats (HFS) and ORX HF-fed rats (HFO)) developed peripheral insulin resistance and had decreased trabecular bone density. In ND-fed rats, only the ORX ND-fed rats (NDO) group had decreased trabecular bone density. In addition, osteoblastic insulin resistance, as indicated by a decrease in tyrosine phosphorylation of the insulin receptor and Akt, were observed in all groups except the sham-operated ND-fed rats (NDS) rats. Those groups, again with the exception of the NDS rats, also had decreased osteoblastic survival. No differences in the levels of osteoblastic insulin resistance and osteoblastic survival were found among the NDO, HFS, and HFO groups. These findings suggest that either testosterone deprivation or obesity alone can impair osteoblastic insulin signaling and decrease osteoblastic survival leading to the development of osteoporosis. However, obesity does not aggravate those deleterious effects in the bone of testosterone-deprived rats. © 2016 Society for Endocrinology.

  8. Common variants in SOCS7 gene predict obesity, disturbances in lipid metabolism and insulin resistance.

    PubMed

    Tellechea, M L; Steinhardt, A Penas; Rodriguez, G; Taverna, M J; Poskus, E; Frechtel, G

    2013-05-01

    Specific Suppressor of Cytokine Signaling (SOCS) members, such as SOCS7, may play a role in the development of insulin resistance (IR) owing to their ability to inhibit insulin signaling pathways. The objective was to explore the association between common variants and related haplotypes in SOCS7 gene and metabolic traits related to obesity, lipid metabolism and IR. 780 unrelated men were included in a cross-sectional study. We selected three tagged SNPs that capture 100% of SNPs with minor allele frequency ≥ 0.10. Analyses were done separately for each SNP and followed up by haplotype analysis. rs8074124C was associated with both obesity (p = 0.005) and abdominal obesity (p = 0.002) and allele C carriers showed, in comparison with TT carriers, lower BMI (p = 0.001) and waist circumference (p = 0.001). rs8074124CC- carriers showed lower fasting insulin (p = 0.017) and HOMA-IR (p = 0.018) than allele T carriers. rs12051836C was associated with hypertriglyceridemia (p = 0.009) and hypertriglyceridemic waist (p = 0.006). rs12051836CC- carriers showed lower fasting insulin (p = 0.043) and HOMA-IR (p = 0.042). Haplotype-based association analysis (rs8074124 and rs12051836 in that order) showed associations with lipid and obesity -related phenotypes, consistent with single locus analysis. Haplotype analysis also revealed association between haplotype CT and both decreased HDL-C (p = 0.026) and HDL-C (p = 0.014) as a continuous variable. We found, for the first time, significant associations between SOCS7 common variants and related haplotypes and obesity, IR and lipid metabolism disorders. Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.

  9. Negative association between trunk fat, insulin resistance and skeleton in obese women.

    PubMed

    Greco, Emanuela A; Francomano, Davide; Fornari, Rachele; Marocco, Chiara; Lubrano, Carla; Papa, Vincenza; Wannenes, Francesca; Di Luigi, Luigi; Donini, Lorenzo M; Lenzi, Andrea; Aversa, Antonio; Migliaccio, Silvia

    2013-04-15

    To evaluate the potential interference of trunk fat (TF) mass on metabolic and skeletal metabolism. In this cross-sectional study, 340 obese women (mean age: 44.8 ± 14 years; body mass index: 36.0 ± 5.9 kg/m(2)) were included. Patients were evaluated for serum vitamin D, osteocalcin (OSCA), inflammatory markers, lipids, glucose and insulin (homeostasis model assessment of insulin resistance, HOMA-IR) levels, and hormones profile. Moreover, all patients underwent measurements of bone mineral density (BMD; at lumbar and hip site) and body composition (lean mass, total and trunk fat mass) by dual-energy X-ray absorptiometry. Data showed that: (1) high TF mass was inversely correlated with low BMD both at lumbar (P < 0.001) and hip (P < 0.01) sites and with serum vitamin D (P < 0.0005), OSCA (P < 0.0001) and insulin-like growth factor-1 (IGF-1; P < 0.0001) levels; (2) a positive correlation was found between TF and HOMA-IR (P < 0.01), fibrinogen (P < 0.0001) and erythrocyte sedimentation rate (P < 0.0001); (3) vitamin D levels were directly correlated with IGF-1 (P < 0.0005), lumbar (P < 0.006) and hip (P < 0.01) BMD; and (4) inversely with HOMA-IR (P < 0.001) and fibrinogen (P < 0.0005).Multivariate analysis demonstrated that only vitamin D was independent of TF variable. In obese women, TF negatively correlates with BMD independently from vitamin D levels. Reduced IGF-1 and increased inflammatory markers might be some important determinants that account for this relationship.

  10. Negative association between trunk fat, insulin resistance and skeleton in obese women

    PubMed Central

    Greco, Emanuela A; Francomano, Davide; Fornari, Rachele; Marocco, Chiara; Lubrano, Carla; Papa, Vincenza; Wannenes, Francesca; Di Luigi, Luigi; Donini, Lorenzo M; Lenzi, Andrea; Aversa, Antonio; Migliaccio, Silvia

    2013-01-01

    AIM: To evaluate the potential interference of trunk fat (TF) mass on metabolic and skeletal metabolism. METHODS: In this cross-sectional study, 340 obese women (mean age: 44.8 ± 14 years; body mass index: 36.0 ± 5.9 kg/m2) were included. Patients were evaluated for serum vitamin D, osteocalcin (OSCA), inflammatory markers, lipids, glucose and insulin (homeostasis model assessment of insulin resistance, HOMA-IR) levels, and hormones profile. Moreover, all patients underwent measurements of bone mineral density (BMD; at lumbar and hip site) and body composition (lean mass, total and trunk fat mass) by dual-energy X-ray absorptiometry. RESULTS: Data showed that: (1) high TF mass was inversely correlated with low BMD both at lumbar (P < 0.001) and hip (P < 0.01) sites and with serum vitamin D (P < 0.0005), OSCA (P < 0.0001) and insulin-like growth factor-1 (IGF-1; P < 0.0001) levels; (2) a positive correlation was found between TF and HOMA-IR (P < 0.01), fibrinogen (P < 0.0001) and erythrocyte sedimentation rate (P < 0.0001); (3) vitamin D levels were directly correlated with IGF-1 (P < 0.0005), lumbar (P < 0.006) and hip (P < 0.01) BMD; and (4) inversely with HOMA-IR (P < 0.001) and fibrinogen (P < 0.0005).Multivariate analysis demonstrated that only vitamin D was independent of TF variable. CONCLUSION: In obese women, TF negatively correlates with BMD independently from vitamin D levels. Reduced IGF-1 and increased inflammatory markers might be some important determinants that account for this relationship. PMID:23593534

  11. Bioactives in Blueberries Improve Insulin Sensitivity in Obese, Insulin-Resistant Men and Women1234

    PubMed Central

    Stull, April J.; Cash, Katherine C.; Johnson, William D.; Champagne, Catherine M.; Cefalu, William T.

    2010-01-01

    Dietary supplementation with whole blueberries in a preclinical study resulted in a reduction in glucose concentrations over time. We sought to evaluate the effect of daily dietary supplementation with bioactives from blueberries on whole-body insulin sensitivity in men and women. A double-blinded, randomized, and placebo-controlled clinical study design was used. After screening to resolve study eligibility, baseline (wk 0) insulin sensitivity was measured on 32 obese, nondiabetic, and insulin-resistant subjects using a high-dose hyperinsulinemic-euglycemic clamp (insulin infusion of 120 mU(861 pmol)⋅m−2⋅min−1). Serum inflammatory biomarkers and adiposity were measured at baseline. At the end of the study, insulin sensitivity, inflammatory biomarkers, and adiposity were reassessed. Participants were randomized to consume either a smoothie containing 22.5 g blueberry bioactives (blueberry group, n = 15) or a smoothie of equal nutritional value without added blueberry bioactives (placebo group, n = 17) twice daily for 6 wk. Both groups were instructed to maintain their body weight by reducing ad libitum intake by an amount equal to the energy intake of the smoothies. Participants’ body weights were evaluated weekly and 3-d food records were collected at baseline, the middle, and end of the study. The mean change in insulin sensitivity improved more in the blueberry group (1.7 ± 0.5 mg⋅kg FFM−1⋅min−1) than in the placebo group (0.4 ± 0.4 mg⋅kg FFM−1⋅min−1) (P = 0.04). Insulin sensitivity was enhanced in the blueberry group at the end of the study without significant changes in adiposity, energy intake, and inflammatory biomarkers. In conclusion, daily dietary supplementation with bioactives from whole blueberries improved insulin sensitivity in obese, nondiabetic, and insulin-resistant participants. PMID:20724487

  12. High Dietary Magnesium Intake Is Associated with Low Insulin Resistance in the Newfoundland Population

    PubMed Central

    Shea, Jennifer; Wadden, Danny; Gulliver, Wayne; Randell, Edward; Vasdev, Sudesh; Sun, Guang

    2013-01-01

    Background Magnesium plays a role in glucose and insulin homeostasis and evidence suggests that magnesium intake is associated with insulin resistance (IR). However, data is inconsistent and most studies have not adequately controlled for critical confounding factors. Objective The study investigated the association between magnesium intake and IR in normal-weight (NW), overweight (OW) and obese (OB) along with pre- and post- menopausal women. Design A total of 2295 subjects (590 men and 1705 women) were recruited from the CODING study. Dietary magnesium intake was computed from the Willett Food Frequency Questionnaire (FFQ). Adiposity (NW, OW and OB) was classified by body fat percentage (%BF) measured by Dual-energy X-ray absorptiometry according to the Bray criteria. Multiple regression analyses were used to test adiposity-specific associations of dietary magnesium intake on insulin resistance adjusting for caloric intake, physical activity, medication use and menopausal status. Results Subjects with the highest intakes of dietary magnesium had the lowest levels of circulating insulin, HOMA-IR, and HOMA-ß and subjects with the lowest intake of dietary magnesium had the highest levels of these measures, suggesting a dose effect. Multiple regression analysis revealed a strong inverse association between dietary magnesium with IR. In addition, adiposity and menopausal status were found to be critical factors revealing that the association between dietary magnesium and IR was stronger in OW and OB along with Pre-menopausal women. Conclusion The results of this study indicate that higher dietary magnesium intake is strongly associated with the attenuation of insulin resistance and is more beneficial for overweight and obese individuals in the general population and pre-menopausal women. Moreover, the inverse correlation between insulin resistance and dietary magnesium intake is stronger when adjusting for %BF than BMI. PMID:23472169

  13. Relation of insulin resistance to neurocognitive function and electroencephalography in obese children.

    PubMed

    Akın, Onur; Eker, İbrahim; Arslan, Mutluay; Yavuz, Süleyman Tolga; Akman, Sevil; Taşçılar, Mehmet Emre; Ünay, Bülent

    2017-10-26

    Childhood obesity may lead to neuronal impairment in both the peripheral and the central nervous system. This study aimed to investigate the impact of obesity and insulin resistance (IR) on the central nervous system and neurocognitive functions in children. Seventy-three obese children (38 male and 35 female) and 42 healthy children (21 male and 21 female) were recruited. Standard biochemical indices and IR were evaluated. The Wechsler Intelligence Scale for Children-Revised (WISC-R) and electroencephalography (EEG) were administered to all participants. The obese participants were divided into two groups based on the presence or absence of IR, and the data were compared between the subgroups. Only verbal scores on the WISC-R in the IR+ group were significantly lower than those of the control and IR- groups. There were no differences between the groups with respect to other parameters of the WISC-R or the EEG. Verbal scores of the WISC-R were negatively correlated with obesity duration and homeostatic model assessment-insulin resistance (HOMA-IR) values. EEGs showed significantly more frequent 'slowing during hyperventilation' (SDHs) in obese children than non-obese children. Neurocognitive functions, particularly verbal abilities, were impaired in obese children with IR. An early examination of cognitive functions may help identify and correct such abnormalities in obese children.

  14. Childhood obesity, thyroid function, and insulin resistance – is there a link? A longitudinal study.

    PubMed

    Santos, Maria Inês; Limbert, Catarina; Marques, Filipa Carlota; Rosário, Frederico; Lopes, Lurdes

    2015-05-01

    Serum thyroid stimulating hormone (TSH) levels are frequently elevated in obese children and are most likely to be associated with insulin resistance. However, clinical relevance of this association remains unclear. To assess the prevalence of hyperthyrotropinemia; to analyze the relationship between TSH and homeostasis model assessment - insulin resistance (HOMA-IR); and to verify whether TSH levels and HOMA-IR vary with weight loss in obese children. Retrospective longitudinal study with data from baseline and 1 year after lifestyle intervention in a pediatric obese group (344 children were recruited and 100 among them completed follow-up). For postintervention analysis, three groups were considered according to body mass index-standard deviation score (BMI-SDS) variations: ≤-0.5 (significant weight loss); 0.5-0 (weight loss); and >0 (weight gain). Statistical analysis was performed using SPSS 19.0®. The prevalence of increased TSH levels was 9.3%. At baseline TSH (p=0.007), fT4 (p=0.006), and HOMA-IR (p<0.001) were positively correlated to BMI-SDS (n=344). Weight reduction was verified in 67 out of 100 cases but significant loss was present in only 21 cases. Decreases in both TSH and BMI-SDS were independently associated with decreases in HOMA-IR (p=0.005 and p=0.016, respectively). There was no correlation between TSH and BMI-SDS variation. Significant decreases in the HOMA-IR (p=0.006) were only achieved in the significant weight loss group. The prevalence of hyperthyrotropinemia was lower than previously reported. However, cutoff values were adjusted to pubertal stage, suggesting an over report in other studies. Insulin resistance and TSH were positively correlated, independent of body status. Although weight loss was not associated with TSH variation, a decrease in TSH levels was independently associated with decreases in HOMA-IR.

  15. Insulin resistance and self-perceived scholastic competence in inner-city, overweight and obese, African American children.

    PubMed

    Fyfe, Molly; Raman, Aarthi; Sharma, Sushma; Hudes, Mark L; Fleming, Sharon E

    2011-01-10

    scholastic competence is a predictor of future achievement, yet there is little research about health factors that influence the development of self-perceived scholastic competence (SPSC). This study examined the relationship of insulin resistance and body fatness with SPSC in low-income, overweight and obese, African American children. data were analyzed from a convenience sample of 9-10years old African American children (89 boys and 113 girls) enrolled in a type 2 diabetes prevention study. Health variables analyzed for their influence on SPSC (Harter scale) included insulin resistance (Homeostatic model-derived insulin sensitivity, HOMA-IR) and body fatness (% body fat). Adjustments were made for self-esteem (Global Self Worth). there was a significant gender by insulin resistance interaction effect on the child's SPSC, so separate regression models were developed for each gender. In boys, neither insulin resistance nor body fatness was related to SPSC. In girls, however, insulin resistance was negatively related to SPSC scores, and the significance of the relationship increased further after adjusting for body fatness. Body fatness alone was not significantly related to SPSC in girls, but after adjusting for insulin resistance, body fatness was positively related to SPSC. Thus, insulin resistance and body fatness mutually suppressed SPSC in girls. high SPSC was associated with lower insulin resistance and, with insulin resistance held constant, with higher body fatness in girls but not in boys. These relationships were not influenced by self-esteem in these children. 2010 Elsevier Inc. All rights reserved.

  16. Characterization of beta-cell mass and insulin resistance in diet-induced obese and diet-resistant rats.

    PubMed

    Paulsen, Sarah J; Jelsing, Jacob; Madsen, Andreas N; Hansen, Gitte; Lykkegaard, Kirsten; Larsen, Leif K; Larsen, Philip J; Levin, Barry E; Vrang, Niels

    2010-02-01

    The selectively bred diet-induced obese (DIO) and diet-resistant (DR) rats represent a polygenetic animal model mimicking most clinical variables characterizing the human metabolic syndrome. When fed a high-energy (HE) diet DIO rats develop visceral obesity, dyslipidemia, hyperinsulinemia, and insulin resistance but never frank diabetes. To improve our understanding of the underlying cause for the deteriorating glucose and insulin parameters, we have investigated possible adaptive responses in DIO and DR rats at the level of the insulin-producing beta-cells. At the time of weaning, DR rats were found to have a higher body weight and beta-cell mass compared to DIO rats, and elevated insulin and glucose responses to an oral glucose load. However, at 2.5 months of age, and for the remaining study period, the effect of genotype became evident: the chow-fed DIO rats steadily increased their body weight and beta-cell mass, as well as insulin and glucose levels compared to the DR rats. HE feeding affected both DIO and DR rats leading to an increased body weight and an increased beta-cell mass. Interestingly, although the beta-cell mass in DR rats and chow-fed DIO rats appeared to constantly increase with age, the beta-cell mass in the HE-fed DIO rats did not continue to do so. This might constitute part of an explanation for their reduced glucose tolerance. Collectively, the data support the use of HE-fed DIO rats as a model of human obesity and insulin resistance, and accentuate its relevance for studies examining the benefit of pharmaceutical compounds targeting this disease complex.

  17. Mid-arm muscle circumference as a surrogate in predicting insulin resistance in non-obese elderly individuals

    PubMed Central

    Chao, Yuan-Ping; Lai, Yi-Fen; Kao, Tung-Wei; Peng, Tao-Chun; Lin, Yuan-Yung; Shih, Mu-Tsun; Chen, Wei-Liang; Wu, Li-Wei

    2017-01-01

    The homeostatic model assessment of insulin resistance (HOMA-IR) was used to measure the degree of insulin resistance (IR). Previous literature revealed that mid-arm muscle circumference (MAMC) is one of the anthropometric indicators for nutritional status and the relationship between MAMC and HOMA-IR remains uncertain in the obese and non-obese elderly individuals. The present study included 5,607 participants aged between 60 to 84 years old, using data from the 1999 to 2006 National Health and Nutrition Examination Survey (NHANES). To further explore the association between HOMA-IR and MAMC in the obese and non-obese elderly population using multivariate Cox regression analyses, we divided the participants into obese (BMI ≥ 30 kg/m2) group and non-obese (19 ≤ BMI < 30 kg/m2) group in this study; each group was then divided into quartiles based on their MAMC levels. A positive association was noted between the MAMC and HOMA-IR in all of the designed models initially. After adjusting for multiple covariates, a higher level of the MAMC was significantly associated with elevated HOMA-IR (P < 0.05) in the non-obesity group, which was not the case in the obesity group. Additionally, subjects in the higher quartiles of MAMC tended to have higher HOMA-IR with a significant association (P for trend = 0.003 in model 1; P for trend < 0.001 in model 2, 3, and 4). These results demonstrated that the MAMC can be an auxiliary indicator of HOMA-IR in non-obese elderly individuals and may have substantial additional value in screening for IR if well extrapolated. PMID:29108358

  18. White Pitaya (Hylocereus undatus) Juice Attenuates Insulin Resistance and Hepatic Steatosis in Diet-Induced Obese Mice

    PubMed Central

    Song, Haizhao; Zheng, Zihuan; Wu, Jianan; Lai, Jia; Chu, Qiang; Zheng, Xiaodong

    2016-01-01

    Insulin resistance and hepatic steatosis are the most common complications of obesity. Pitaya is an important source of phytochemicals such as polyphenols, flavonoid and vitamin C which are related to its antioxidant activity. The present study was conducted to evaluate the influence of white pitaya juice (WPJ) on obesity-related metabolic disorders (e.g. insulin resistance and hepatic steatosis) in high-fat diet-fed mice. Forty-eight male C57BL/6J mice were assigned into four groups and fed low-fat diet with free access to water or WPJ, or fed high-fat diet with free access to water or WPJ for 14 weeks. Our results showed that administration of WPJ improved high-fat diet-induced insulin resistance, hepatic steatosis and adipose hypertrophy, but it exerted no influence on body weight gain in mice. Hepatic gene expression analysis indicated that WPJ supplement not only changed the expression profile of genes involved in lipid and cholesterol metabolism (Srebp1, HMGCoR, Cpt1b, HL, Insig1 and Insig2) but also significantly increased the expression levels of FGF21-related genes (Klb, FGFR2, Egr1 and cFos). In conclusion, WPJ protected from diet-induced hepatic steatosis and insulin resistance, which was associated with the improved FGF21 resistance and lipid metabolism. PMID:26914024

  19. The serum concentration of tumor necrosis factor alpha is not an index of growth-hormone- or obesity-induced insulin resistance.

    PubMed

    Pincelli, A I; Brunani, A; Scacchi, M; Dubini, A; Borsotti, R; Tibaldi, A; Pasqualinotto, L; Maestri, E; Cavagnini, F

    2001-01-01

    The tumor necrosis factor alpha (TNF-alpha) might play a central role in insulin resistance, a frequent correlate of obesity likely contributing to some obesity-associated complications. Adult growth hormone (GH) deficiency syndrome (GHDA) shares with obesity excessive fat mass, hyperlipidemia, increased cardiovascular risk, and insulin resistance. On the other hand, GH has been shown to induce transient deterioration of glucose metabolism and insulin resistance when administered in normal humans and in GHDA patients. No information is presently available on the relationship between serum TNF-alpha levels and insulin sensitivity in GHDA. We compared the serum TNF-alpha levels found in 10 GHDA patients before and after a 6-month recombinant human GH therapy (Genotropin), in an insulin resistance prone population of 16 obese (OB) patients and in 38 normal-weight healthy blood donors (controls). The insulin sensitivity was assessed by a euglycemic-hyperinsulinemic glucose clamp in all the GHDA patients and in 10 OB and in 6 control subjects. The serum TNF-alpha levels were not significantly different in OB patients (42.2 +/- 12.81 pg/ml), in GHDA patients at baseline (71.3 +/- 23.97 pg/ml), and in controls (55.3 +/- 14.28 pg/ml). A slight decrease of TNF-alpha values was noted in GHDA patients after 6 months of recombinant human GH treatment (44.5 +/- 20.19 pg/ml; NS vs. baseline). The insulin sensitivity (M) was significantly reduced in OB patients (2.4 +/- 0.30 mg/kg/min) as compared with control subjects (7.5 +/- 0.39 mg/kg/min) and in GHDA patients both at baseline (6.6 +/- 0.6 mg/kg/min) and after recombinant human GH therapy (5.6 +/- 0.7 mg/kg/min). The insulin sensitivity in the GHDA patients, similar to that of controls at baseline, worsened after recombinant human GH treatment (p < 0.05 vs. baseline; p = 0.05 vs. controls). Linear regression analysis showed no correlation between TNF-alpha and M values (see text) in all patient groups. These data indicate

  20. Polycystic ovary syndrome: insight into pathogenesis and a common association with insulin resistance.

    PubMed

    Barber, Thomas M; Dimitriadis, George K; Andreou, Avgi; Franks, Stephen

    2015-12-01

    Polycystic ovary syndrome (PCOS) is a common condition that typically develops in reproductive-age women. The cardinal clinical and biochemical characteristics of PCOS include reproductive dysfunction and hyperandrogenic features. PCOS is also strongly associated with obesity based on data from epidemiological and genetic studies. Accordingly, PCOS often becomes manifest in those women who carry a genetic predisposition to its development, and who also gain weight. The role of weight gain and obesity in the development of PCOS is mediated at least in part, through worsening of insulin resistance. Compensatory hyperinsulinaemia that develops in this context disrupts ovarian function, with enhanced androgen production and arrest of ovarian follicular development. Insulin resistance also contributes to the strong association of PCOS with adverse metabolic risk, including dysglycaemia, dyslipidaemia and fatty liver. Conversely, modest weight loss of just 5% body weight with improvement in insulin sensitivity, frequently results in clinically meaningful improvements in hyperandrogenic, reproductive and metabolic features. Future developments of novel therapies for obese women with PCOS should focus on promotion of weight loss and improvement in insulin sensitivity. In this context, therapies that complement lifestyle changes such as dietary modification and exercise, particularly during the maintenance phase of weight loss are important. Putative novel targets for therapy in PCOS include human brown adipose tissue. © Royal College of Physicians 2015. All rights reserved.

  1. Polycystic ovary syndrome: insight into pathogenesis and a common association with insulin resistance.

    PubMed

    Barber, Thomas M; Dimitriadis, George K; Andreou, Avgi; Franks, Stephen

    2016-06-01

    Polycystic ovary syndrome (PCOS) is a common condition that typically develops in reproductive-age women. The cardinal clinical and biochemical characteristics of PCOS include reproductive dysfunction and hyperandrogenic features. PCOS is also strongly associated with obesity based on data from epidemiological and genetic studies. Accordingly, PCOS often becomes manifest in those women who carry a genetic predisposition to its development, and who also gain weight. The role of weight gain and obesity in the development of PCOS is mediated at least in part, through worsening of insulin resistance. Compensatory hyperinsulinaemia that develops in this context disrupts ovarian function, with enhanced androgen production and arrest of ovarian follicular development. Insulin resistance also contributes to the strong association of PCOS with adverse metabolic risk, including dysglycaemia, dyslipidaemia and fatty liver. Conversely, modest weight loss of just 5% body weight with improvement in insulin sensitivity, frequently results in clinically meaningful improvements in hyperandrogenic, reproductive and metabolic features. Future developments of novel therapies for obese women with PCOS should focus on promotion of weight loss and improvement in insulin sensitivity. In this context, therapies that complement lifestyle changes such as dietary modification and exercise, particularly during the maintenance phase of weight loss are important. Putative novel targets for therapy in PCOS include human brown adipose tissue. © 2016 Royal College of Physicians.

  2. Response of osteocalcin and insulin resistance after a hypocaloric diet in obese patients.

    PubMed

    de Luis, D A; Perez Castrillon, J L; Aller, R; Izaola, O; Bachiller, C

    2015-06-01

    Osteocalcin is a hormone with a complex cross-talk between adipose tissue and the skeleton. The aim of the present study was to explore the change of osteocalcin, insulin resistance, and adipocytokines after hypocaloric diet in obese patients. A population of 178 obese patients was analyzed. At basal time and 2 months after the dietary intervention, weight, fat mass, body mass index, basal glucose, insulin, insulin resistance (HOMA), total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, leptin, adiponectin, IL-6, TNF alpha and osteocalcin levels were measured. After dietary treatment, BMI, weight, fat mass, waist circumference, waist to hip ratio, systolic pressure, glucose, HOMA, triglycerides, total cholesterol, leptin and LDL cholesterol decreased significantly. Osteocalcin levels have a significant decrease after weight loss (Osteocalcin (ng/ml); 9.76 ± 5.3 vs 9.31 ± 4.1: p < 0.05). In correlation analysis, a negative association was detected among osteocalcin and age, BMI, fat mass, glucose, C reactive protein, interleukin-6. In the linear regression with age-, sex-, BMI, fat mass- and insulin- adjusted, only C reactive protein concentrations are related with osteocalcin levels -0.21 (CI 95%: -0.40 -0.009). Osteocalcin decreased after a weight loss treatment. Moreover, osteocalcin levels, before and after treatment, were related in a negative way with CRP fat mass, body mass index, age and glucose levels.

  3. Evaluating the evidence for macrophage presence in skeletal muscle and its relation to insulin resistance in obese mice and humans: a systematic review protocol.

    PubMed

    Bhatt, Meha; Rudrapatna, Srikesh; Banfield, Laura; Bierbrier, Rachel; Wang, Pei-Wen; Wang, Kuan-Wen; Thabane, Lehana; Samaan, M Constantine

    2017-08-08

    The current global rates of obesity and type 2 diabetes are staggering. In order to implement effective management strategies, it is imperative to understand the mechanisms of obesity-induced insulin resistance and diabetes. Macrophage infiltration and inflammation of the adipose tissue in obesity is a well-established paradigm, yet the role of macrophages in muscle inflammation, insulin resistance and diabetes is not adequately studied. In this systematic review, we will examine the evidence for the presence of macrophages in skeletal muscle of obese humans and mice, and will assess the association between muscle macrophages and insulin resistance. We will identify published studies that address muscle macrophage content and phenotype, and its association with insulin resistance. We will search MEDLINE/PubMed, EMBASE, and Web of Science for eligible studies. Grey literature will be searched in ProQuest. Quality assessment will be conducted using the Systematic Review Centre for Laboratory Animal Experimentation risk of bias Tool for animal studies. The findings of this systematic review will shed light on immune-metabolic crosstalk in obesity, and allow the consideration of targeted therapies to modulate muscle macrophages in the treatment and prevention of diabetes. The review will be published in a peer-reviewed journal and presented at conferences.

  4. The influence of puberty on vitamin D status in obese children and the possible relation between vitamin D deficiency and insulin resistance.

    PubMed

    Gutiérrez Medina, Sonsoles; Gavela-Pérez, Teresa; Domínguez-Garrido, María Nieves; Gutiérrez-Moreno, Elisa; Rovira, Adela; Garcés, Carmen; Soriano-Guillén, Leandro

    2015-01-01

    Puberty can affect vitamin D levels. The goal of this study was to analyze the relation between vitamin D deficiency and puberty in obese Spanish children, along with the possible interrelation between vitamin D status and degree of insulin resistance. A cross-sectional study was carried out, in which clinical and biochemical data were gathered from 120 obese and 50 normal weight children between January 2011 and January 2013. Mean vitamin D levels were 19.5 and 31.6 ng/mL in obese pubertal and obese prepubertal children, respectively. About 75% of the obese pubertal subjects and 46% of the obese prepubertal subjects had vitamin D deficiency. Vitamin D levels were significantly lower in pubescent subjects compared with pre-pubescent subjects in summer, fall, and winter. There was no apparent relation between vitamin D levels and homeostasis model assessment index for insulin resistence (expressed in standard deviation score for sex and Tanner stage) in either puberty or pre-puberty. Puberty may be a risk factor for the vitamin D deficiency commonly found in the obese child population. This deficiency is not associated with higher insulin resistance in obese pubertal children compared with obese prepubertal children.

  5. Fast-food restaurants, park access, and insulin resistance among Hispanic youth.

    PubMed

    Hsieh, Stephanie; Klassen, Ann C; Curriero, Frank C; Caulfield, Laura E; Cheskin, Lawrence J; Davis, Jaimie N; Goran, Michael I; Weigensberg, Marc J; Spruijt-Metz, Donna

    2014-04-01

    Evidence of associations between the built environment and obesity risk has been steadily building, yet few studies have focused on the relationship between the built environment and aspects of metabolism related to obesity's most tightly linked comorbidity, type 2 diabetes. To examine the relationship between aspects of the neighborhood built environment and insulin resistance using accurate laboratory measures to account for fat distribution and adiposity. Data on 453 Hispanic youth (aged 8-18 years) from 2001 to 2011 were paired with neighborhood built environment and 2000 Census data. Analyses were conducted in 2011. Walking-distance buffers were built around participants' residential locations. Body composition and fat distribution were assessed using dual x-ray absorptiometry and waist circumference. Variables for park space, food access, walkability, and neighborhood sociocultural aspects were entered into a multivariate regression model predicting insulin resistance as determined by the homeostasis model assessment. Independent of obesity measures, greater fast-food restaurant density was associated with higher insulin resistance. Increased park space and neighborhood linguistic isolation were associated with lower insulin resistance among boys. Among girls, park space was associated with lower insulin resistance, but greater neighborhood linguistic isolation was associated with higher insulin resistance. A significant interaction between waist circumference and neighborhood linguistic isolation indicated that the negative association between neighborhood linguistic isolation and insulin resistance diminished with increased waist circumference. Reducing access to fast food and increasing public park space may be valuable to addressing insulin resistance and type 2 diabetes, but effects may vary by gender. Copyright © 2014 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

  6. Emerging Perspectives on Essential Amino Acid Metabolism in Obesity and the Insulin-Resistant State12

    PubMed Central

    Adams, Sean H.

    2011-01-01

    Dysregulation of insulin action is most often considered in the context of impaired glucose homeostasis, with the defining feature of diabetes mellitus being elevated blood glucose concentration. Complications arising from the hyperglycemia accompanying frank diabetes are well known and epidemiological studies point to higher risk toward development of metabolic disease in persons with impaired glucose tolerance. Although the central role of proper blood sugar control in maintaining metabolic health is well established, recent developments have begun to shed light on associations between compromised insulin action [obesity, prediabetes, and type 2 diabetes mellitus (T2DM)] and altered intermediary metabolism of fats and amino acids. For amino acids, changes in blood concentrations of select essential amino acids and their derivatives, in particular BCAA, sulfur amino acids, tyrosine, and phenylalanine, are apparent with obesity and insulin resistance, often before the onset of clinically diagnosed T2DM. This review provides an overview of these changes and places recent observations from metabolomics research into the context of historical reports in the areas of biochemistry and nutritional biology. Based on this synthesis, a model is proposed that links the FFA-rich environment of obesity/insulin resistance and T2DM with diminution of BCAA catabolic enzyme activity, changes in methionine oxidation and cysteine/cystine generation, and tissue redox balance (NADH/NAD+). PMID:22332087

  7. [Diagnosis of insulin resistance by indirect methods in obese school children].

    PubMed

    Angulo, Nerkis; de Szarvas, Sobeida Barbella; Mathison, Yaira; Hadad, Erika; González, Dora; Hernández, Ana; Guevara, Harold

    2013-06-01

    Obesity leads to a deterioration of glucose tolerance and the action of insulin. The purpose of this study was to determine insulin resistance (IR) by indirect methods, and its correlation with clinical, anthropometric and biochemical variables in obese normoglycemic school children. This was a descriptive-correlational study of 72 school prepubescent children, who attended the ambulatory "El Concejo" of the University of Carabobo (UC) and at the Gastroenterology and Pediatric Nutrition service of the city hospital "Enrique Tejera" (CHET), in Valencia, Venezuela, between January-April 2011. exogenous obesity. We assessed personal and family history, presence of Acanthosis Nigricans and nutritional and biochemical status. We found a higher percentage of IR, through the use of the QUICKI method (66.7%), followed by the HOMA (55.6%) and basal insulin (45.9%). The mean (chi) indexes of body mass and waist circumference were significantly greater (p < 0.05) in patients with IR, by HOMA and QUICKI techniques. The QUICKI method detected significant differences (p < 0.05) in the values of glycemia, basal insulin and postprandial insulin, among patients with diminished and normal insulin sensitivities. While HOMA, detected these differences (p < 0.05) in the values of glycemia and basal insulin. A statistically significant relationship was observed (p < 0.05), between the presence of Acanthosis Nigricans and IR, by the HOMA, QUICKI and basal insulin methods. In conclusion, the evaluated techniques, QUICKI, HOMA and basal insulin indexes, were most effective for detecting the IR.

  8. Association between insulin resistance and plasma amino acid profile in non-diabetic Japanese subjects.

    PubMed

    Yamada, Chizumi; Kondo, Masumi; Kishimoto, Noriaki; Shibata, Takeo; Nagai, Yoko; Imanishi, Tadashi; Oroguchi, Takashige; Ishii, Naoaki; Nishizaki, Yasuhiro

    2015-07-01

    Elevation of the branched-chain amino acids (BCAAs), valine, leucine and isoleucine; and the aromatic amino acids, tyrosine and phenylalanine, has been observed in obesity-related insulin resistance. However, there have been few studies on Asians, who are generally less obese and less insulin-resistant than Caucasian or African-Americans. In the present study, we investigated the relationship between homeostasis model assessment of insulin resistance (HOMA-IR) and plasma amino acid concentration in non-diabetic Japanese participants. A total of 94 healthy men and women were enrolled, and plasma amino acid concentration was measured by liquid chromatography/mass spectrometry after overnight fasting. The associations between HOMA-IR and 20 amino acid concentrations, and anthropometric and clinical parameters of lifestyle-related diseases were evaluated. The mean age and body mass index were 40.1 ± 9.6 years and 22.7 ± 3.9, respectively. Significantly positive correlations were observed between HOMA-IR and valine, isoleucine, leucine, tyrosine, phenylalanine and total BCAA concentration. Compared with the HOMA-IR ≤ 1.6 group, the HOMA-IR > 1.6 group showed significantly exacerbated anthropometric and clinical parameters, and significantly elevated levels of valine, isoleucine, leucine, tyrosine, phenylalanine and BCAA. The present study shows that the insulin resistance-related change in amino acid profile is also observed in non-diabetic Japanese subjects. These amino acids include BCAAs (valine, isoleucine and leucine) and aromatic amino acids (tyrosine and phenylalanine), in agreement with previous studies carried out using different ethnic groups with different degrees of obesity and insulin resistance.

  9. Sea cucumber saponin liposomes ameliorate obesity-induced inflammation and insulin resistance in high-fat-diet-fed mice.

    PubMed

    Chen, Cheng; Han, Xiuqing; Dong, Ping; Li, Zhaojie; Yanagita, Teruyoshi; Xue, Changhu; Zhang, Tiantian; Wang, Yuming

    2018-02-21

    Obesity has become a worldwide concern in recent years, which may cause many diseases. Much attention has been paid to food components that are considered to be beneficial in preventing chronic metabolic diseases. The present study was conducted to investigate the effects of sea cucumber saponin liposomes on certain metabolic markers associated with obesity. C57/BL6 mice fed with high-fat diet were treated with different forms of sea cucumber saponins for eight weeks. The results showed that liposomes exhibited better effects on anti-obesity and anti-hyperlipidemia activities than the common form of sea cucumber saponins. Sea cucumber saponin liposomes could also effectively alleviate adipose tissue inflammation by reducing pro-inflammatory cytokine releases and macrophage infiltration. Moreover, sea cucumber saponin liposomes improved insulin resistance by altering the uptake and utilization of glucose. Taken together, our results indicated that the intake of sea cucumber saponin liposomes might be able to ameliorate obesity-induced inflammation and insulin resistance.

  10. Physical characteristics, blood hormone concentrations, and plasma lipid concentrations in obese horses with insulin resistance.

    PubMed

    Frank, Nicholas; Elliott, Sarah B; Brandt, Laura E; Keisler, Duane H

    2006-05-01

    To compare obese horses with insulin resistance (IR) with nonobese horses and determine whether blood resting glucose, insulin, leptin, and lipid concentrations differed between groups and were correlated with combined glucose-insulin test (CGIT) results. 7 obese adult horses with IR (OB-IR group) and 5 nonobese mares. Physical measurements were taken, and blood samples were collected after horses had acclimated to the hospital for 3 days. Response to insulin was assessed by use of the CGIT, and maintenance of plasma glucose concentrations greater than the preinjection value for > or = 45 minutes was used to define IR. Area under the curve values for glucose (AUC(g)) and insulin (AUC(i)) concentrations were calculated. Morgan, Paso Fino, Quarter Horse, and Tennessee Walking Horse breeds were represented in the OB-IR group. Mean neck circumference and BCS differed significantly between groups and were positively correlated with AUC values. Resting insulin and leptin concentrations were 6 and 14 times as high, respectively, in the OB-IR group, compared with the nonobese group, and were significantly correlated with AUC(g) and AUC(i). Plasma nonesterified fatty acid, very low-density lipoprotein, and high-density lipoprotein-cholesterol (HDL-C) concentrations were significantly higher (86%, 104%, and 29%, respectively) in OB-IR horses, and HDL-C concentrations were positively correlated with AUC values. Measurements of neck circumference and resting insulin and leptin concentrations can be used to screen obese horses for IR. Dyslipidemia is associated with IR in obese horses.

  11. Suppressive Effects of Insulin on Tumor Necrosis Factor-Dependent Early Osteoarthritic Changes Associated With Obesity and Type 2 Diabetes Mellitus.

    PubMed

    Hamada, Daisuke; Maynard, Robert; Schott, Eric; Drinkwater, Christopher J; Ketz, John P; Kates, Stephen L; Jonason, Jennifer H; Hilton, Matthew J; Zuscik, Michael J; Mooney, Robert A

    2016-06-01

    Obesity is a state of chronic inflammation that is associated with insulin resistance and type 2 diabetes mellitus (DM), as well as an increased risk of osteoarthritis (OA). This study was undertaken to define the links between obesity-associated inflammation, insulin resistance, and OA, by testing the hypotheses that 1) tumor necrosis factor (TNF) is critical in mediating these pathologic changes in OA, and 2) insulin has direct effects on the synovial joint that are compromised by insulin resistance. The effects of TNF and insulin on catabolic gene expression were determined in fibroblast-like synoviocytes (FLS) isolated from human OA synovium. Synovial TNF expression and OA progression were examined in 2 mouse models, high-fat (HF) diet-fed obese mice with type 2 DM and TNF-knockout mice. Insulin resistance was investigated in synovium from patients with type 2 DM. Insulin receptors (IRs) were abundant in both mouse and human synovial membranes. Human OA FLS were insulin responsive, as indicated by the dose-dependent phosphorylation of IRs and Akt. In cultures of human OA FLS with exogenous TNF, the expression and release of MMP1, MMP13, and ADAMTS4 by FLS were markedly increased, whereas after treatment with insulin, these effects were selectively inhibited by >50%. The expression of TNF and its abundance in the synovium were elevated in samples from obese mice with type 2 DM. In TNF-knockout mice, increases in osteophyte formation and synovial hyperplasia associated with the HF diet were blunted. The synovium from OA patients with type 2 DM contained markedly more macrophages and showed elevated TNF levels as compared to the synovium from OA patients without diabetes. Moreover, insulin-dependent phosphorylation of IRs and Akt was blunted in cultures of OA FLS from patients with type 2 DM. TNF appears to be involved in mediating the advanced progression of OA seen in type 2 DM. While insulin plays a protective, antiinflammatory role in the synovium, insulin

  12. Inhibition of 11β-hydroxysteroid dehydrogenase type 1 ameliorates obesity-related insulin resistance.

    PubMed

    Shao, Shiying; Zhang, Xiaojie; Zhang, Muxun

    2016-09-09

    Excess 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) may be implicated in the development of obesity related metabolic disorders. The present study measured the expression level of 11β-HSD1 in visceral adipose tissues from 23 patients undergoing abdominal operation. Correlation of 11β-HSD1 expression with BMI, waist-to-hip ratio (WHR), HOMA-IR, and serum lipids was evaluated by spearman correlation analysis. High-fat diet-induced obese (DIO) rats were orally dosed with BVT.2733 for 4 weeks. Weight, plasma insulin, and lipids were detected at the end of the treatment. The effects of 11β-HSD1 inhibition on the key insulin-signaling cascade and adipocytokines were measured by western blot and ELISA respectively. 11β-HSD1 was increased in patients with central obesity, the expression level of which was closely related with WHR (r = 0.5851), BMI (r = 0.4952), and HOMA-IR (r = 0.4637). Obesity related insulin resistance in high-fat DIO rats, as reflected by a marked decrease in IRS-1, IRS-2, GLUT4, and PI3K, could be attenuated by 11β-HSD1 inhibition. Furthermore, the down-regulation of 11β-HSD1 could correct the disordered profiles of adipocytokines including adiponectin, IL-6, and TNF-α. These findings indicated that 11β-HSD1 inhibition can give a potential benefit in reducing obesity and lowering insulin resistance by modulating the insulin-signaling pathway and adipocytokine production. Copyright © 2016. Published by Elsevier Inc.

  13. Unusual Suspects in the Development of Obesity-Induced Inflammation and Insulin Resistance: NK cells, iNKT cells, and ILCs.

    PubMed

    Bonamichi, Beatriz Dal Santo Francisco; Lee, Jongsoon

    2017-08-01

    The notion that obesity-induced inflammation mediates the development of insulin resistance in animal models and humans has been gaining strong support. It has also been shown that immune cells in local tissues, in particular in visceral adipose tissue, play a major role in the regulation of obesity-induced inflammation. Specifically, obesity increases the numbers and activation of proinflammatory immune cells, including M1 macrophages, neutrophils, Th1 CD4 T cells, and CD8 T cells, while simultaneously suppressing anti-inflammatory cells such as M2 macrophages, CD4 regulatory T cells, regulatory B cells, and eosinophils. Recently, however, new cell types have been shown to participate in the development of obesity-induced inflammation and insulin resistance. Some of these cell types also appear to regulate obesity. These cells are natural killer (NK) cells and innate lymphoid cells (ILCs), which are closely related, and invariant natural killer T (iNKT) cells. It should be noted that, although iNKT cells resemble NK cells in name, they are actually a completely different cell type in terms of their development and functions in immunity and metabolism. In this review, we will focus on the roles that these relatively new players in the metabolism field play in obesity-induced insulin resistance and the regulation of obesity. Copyright © 2017 Korean Diabetes Association.

  14. Programming of Fetal Insulin Resistance in Pregnancies with Maternal Obesity by ER Stress and Inflammation

    PubMed Central

    Sáez, Pablo J.; Villalobos-Labra, Roberto; Farías-Jofré, Marcelo

    2014-01-01

    The global epidemics of obesity during pregnancy and excessive gestational weight gain (GWG) are major public health problems worldwide. Obesity and excessive GWG are related to several maternal and fetal complications, including diabetes (pregestational and gestational diabetes) and intrauterine programming of insulin resistance (IR). Maternal obesity (MO) and neonatal IR are associated with long-term development of obesity, diabetes mellitus, and increased global cardiovascular risk in the offspring. Multiple mechanisms of insulin signaling pathway impairment have been described in obese individuals, involving complex interactions of chronically elevated inflammatory mediators, adipokines, and the critical role of the endoplasmic reticulum (ER) stress-dependent unfolded protein response (UPR). However, the underlying cellular processes linking MO and IR in the offspring have not been fully elucidated. Here, we summarize the state-of-the-art evidence supporting the possibility that adverse metabolic postnatal outcomes such as IR in the offspring of pregnancies with MO and/or excessive GWG may be related to intrauterine activation of ER stress response. PMID:25093191

  15. Combined Vildagliptin and Metformin Exert Better Cardioprotection than Monotherapy against Ischemia-Reperfusion Injury in Obese-Insulin Resistant Rats

    PubMed Central

    Apaijai, Nattayaporn; Chinda, Kroekkiat; Palee, Siripong; Chattipakorn, Siriporn; Chattipakorn, Nipon

    2014-01-01

    Background Obese-insulin resistance caused by long-term high-fat diet (HFD) consumption is associated with left ventricular (LV) dysfunction and increased risk of myocardial infarction. Metformin and vildagliptin have been shown to exert cardioprotective effects. However, the effect of these drugs on the hearts under obese-insulin resistance with ischemia-reperfusion (I/R) injury is unclear. We hypothesized that combined vildagliptin and metformin provide better protective effects against I/R injury than monotherapy in obese-insulin resistant rats. Methodology Male Wistar rats were fed either HFD or normal diet. Rats in each diet group were divided into 4 subgroups to receive vildagliptin, metformin, combined vildagliptin and metformin, or saline for 21 days. Ischemia due to left anterior descending artery ligation was allowed for 30-min, followed by 120-min reperfusion. Metabolic parameters, heart rate variability (HRV), LV function, infarct size, mitochondrial function, calcium transient, Bax and Bcl-2, and Connexin 43 (Cx43) were determined. Rats developed insulin resistance after 12 weeks of HFD consumption. Vildagliptin, metformin, and combined drugs improved metabolic parameters, HRV, and LV function. During I/R, all treatments improved LV function, reduced infarct size and Bax, increased Bcl-2, and improved mitochondrial function in HFD rats. However, only combined drugs delayed the time to the first VT/VF onset, reduced arrhythmia score and mortality rate, and increased p-Cx43 in HFD rats. Conclusion Although both vildagliptin and metformin improved insulin resistance and attenuate myocardial injury caused by I/R, combined drugs provided better outcomes than single therapy by reducing arrhythmia score and mortality rate. PMID:25036861

  16. Obesity, Insulin Resistance and Diabetes: Sex Differences and Role of Estrogen Receptors

    PubMed Central

    Meyer, Matthias R.; Clegg, Deborah J.; Prossnitz, Eric R.; Barton, Matthias

    2010-01-01

    Obesity increases the risk of coronary artery disease through insulin resistance, diabetes, arterial hypertension, and dyslipidemia. The prevalence of obesity has increased worldwide and is particularly high among middle-aged women and men. After menopause, women are at an increased risk to develop visceral obesity due to the loss of endogenous ovarian hormone production. Effects of estrogens are classically mediated by the two nuclear estrogen receptors (ERs) α and β. In addition, more recent research has shown that the intracellular transmembrane G protein-coupled estrogen receptor, GPER, originally designated as GPR30, also mediates some of the actions attributed to estrogens. Estrogen and its receptors are important regulators of body weight and insulin sensitivity not only in women, but also in men as demonstrated by ER mutations in rodents and humans. This article reviews the role of sex hormones and estrogen receptors in the context of obesity, insulin sensitivity and diabetes as well as the related clinical issues in females and males. PMID:21281456

  17. Insulin resistance and the metabolism of branched-chain amino acids in humans.

    PubMed

    Adeva, María M; Calviño, Jesús; Souto, Gema; Donapetry, Cristóbal

    2012-07-01

    Peripheral resistance to insulin action is the major mechanism causing the metabolic syndrome and eventually type 2 diabetes mellitus. The metabolic derangement associated with insulin resistance is extensive and not restricted to carbohydrates. The branched-chain amino acids (BCAAs) are particularly responsive to the inhibitory insulin action on amino acid release by skeletal muscle and their metabolism is profoundly altered in conditions featuring insulin resistance, insulin deficiency, or both. Obesity, the metabolic syndrome and diabetes mellitus display a gradual increase in the plasma concentration of BCAAs, from the obesity-related low-grade insulin-resistant state to the severe deficiency of insulin action in diabetes ketoacidosis. Obesity-associated hyperinsulinemia succeeds in maintaining near-normal or slightly elevated plasma concentration of BCAAs, despite the insulin-resistant state. The low circulating levels of insulin and/or the deeper insulin resistance occurring in diabetes mellitus are associated with more marked elevation in the plasma concentration of BCAAs. In diabetes ketoacidosis, the increase in plasma BCAAs is striking, returning to normal when adequate metabolic control is achieved. The metabolism of BCAAs is also disturbed in other situations typically featuring insulin resistance, including kidney and liver dysfunction. However, notwithstanding the insulin-resistant state, the plasma level of BCAAs in these conditions is lower than in healthy subjects, suggesting that these organs are involved in maintaining BCAAs blood concentration. The pathogenesis of the decreased BCAAs plasma level in kidney and liver dysfunction is unclear, but a decreased afflux of these amino acids into the blood stream has been observed.

  18. Obesity and Insulin Resistance Screening Tools in American Adolescents: National Health and Nutrition Examination Survey (NHANES) 1999 to 2010.

    PubMed

    Lee, Joey A; Laurson, Kelly R

    2016-08-01

    To identify which feasible obesity and insulin resistance (IR) screening tools are most strongly associated in adolescents by using a nationally representative sample. Adolescents aged 12.0 to 18.9 years who were participating in the National Health and Nutrition Examination Survey (NHANES) (n=3584) and who were measured for height, weight, waist circumference (WC), triceps and subscapular skinfold thickness, glycated hemoglobin, fasting glucose (FG) and fasting insulin (FI) level were included. Adolescents were split by gender and grouped by body mass index (BMI) percentile. Age- and gender-specific classifications were constructed for each obesity screening tool measure to account for growth and maturation. General linear models were used to establish groups objectively for analysis based on when IR began to increase. Additional general linear models were used to identify when IR significantly increased for each IR measure as obesity group increased and to identify the variance accounted for among each obesity-IR screening tool relationship. As the obesity group increased, homeostasis model assessment-insulin resistance (HOMA-IR) and FI significantly increased, while FG increased only (above the referent) in groups with BMI percentiles ≥95.0, and glycated hemoglobin level did not vary across obesity groups. The most strongly associated screening tools were WC and FI in boys (R(2)=0.253) and girls (R(2)=0.257). FI had the strongest association with all of the obesity measures. BMI associations were slightly weaker than WC in each in relation to IR. Our findings show that WC and FI are the most strongly associated obesity and IR screening tool measures in adolescents. These feasible screening tools should be utilized in screening practices for at-risk adolescents. Copyright © 2015 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

  19. Vitamin D deficiency in childhood obesity is associated with high levels of circulating inflammatory mediators, and low insulin sensitivity.

    PubMed

    Reyman, M; Verrijn Stuart, A A; van Summeren, M; Rakhshandehroo, M; Nuboer, R; de Boer, F K; van den Ham, H J; Kalkhoven, E; Prakken, B; Schipper, H S

    2014-01-01

    Childhood obesity is accompanied by low-grade systemic inflammation, which contributes to the development of insulin resistance and cardiovascular complications later in life. As vitamin D exhibits profound immunomodulatory functions and vitamin D deficiency is highly prevalent in childhood obesity, we hypothesized that vitamin D deficiency in childhood obesity coincides with enhanced systemic inflammation and reduced insulin sensitivity. In a cross-sectional study of 64 obese and 32 healthy children aged 6-16 years, comprehensive profiling of 32 circulating inflammatory mediators was performed, together with assessment of 25-hydroxyvitamin D (25(OH)D) levels and measures for insulin sensitivity. Severe vitamin D insufficiency, which is further referred to as vitamin D deficiency, was defined as a 25(OH)D level ≤37.5 nmol l(-1), and was highly prevalent in obese (56%) versus healthy control children (16%). Throughout the study, 25(OH)D-deficient children were compared with the other children, including 25(OH)D insufficient (37.5-50 nmol l(-1)) and 25(OH)D sufficient children (≥50 nmol l(-1)). First, 25(OH)D-deficient obese children showed a lower insulin sensitivity than other obese children, as measured by a lower quantitative insulin sensitivity check index. Second, the association between 25(OH)D deficiency and insulin resistance in childhood obesity was confirmed with multiple regression analysis. Third, 25(OH)D-deficient obese children showed higher levels of the inflammatory mediators cathepsin S, chemerin and soluble vascular adhesion molecule (sVCAM), compared with the other obese children. Finally, hierarchical cluster analysis revealed an over-representation of 25(OH)D deficiency in obese children expressing inflammatory mediator clusters with high levels of cathepsin S, sVCAM and chemerin. 25(OH)D deficiency in childhood obesity was associated with enhanced systemic inflammation and reduced insulin sensitivity. The high cathepsin S and sVCAM levels

  20. Association between Insulin Resistance and Cardiovascular Risk Factors in Polycystic Ovary Syndrome Patients.

    PubMed

    Wanderley, Miriam da Silva; Pereira, Lara Cristina Ribeiro; Santos, Carla Borges; Cunha, Vinícius Santos da; Neves, Mariam Viviane Jovino

    2018-04-01

     To analyze the association between the indirect methods of evaluating insulin resistance (IR) and blood pressure, anthropometric and biochemical parameters in a population of polycystic ovary syndrome (PCOS) patients.  Cross-sectional study performed at the Hospital Universitário de Brasília (HUB, in the Portuguese acronym) involving PCOS patients diagnosed from January 2011 to January 2013. Four indirect methods, namely, fasting blood insulin level, fasting glucose/insulin ratio (G/I), homeostatic model-assessment-insulin resistance (HOMA-IR), and the quantitative insulin sensitivity check index (QUICKI), were used to obtain the IR diagnosis. The data were analyzed using the test of proportions, the Chi-square test, and Fisher exact test, when indicated.  Out of the 83 patients assessed, aged 28.79 ± 5.85, IR was found in 51.81-66.2% of them using the G/I ratio and the QUICKI, respectively. The test of proportions did not show a significant difference between the methods analyzed. The proportion of IR diagnoses was statistically higher in obese women than in women with normal body mass index (BMI). We observed a statistically significant association between all the methods for diagnosing IR and BMI, waist circumference (WC) and lipid accumulation product (LAP). With regards to arterial hypertension (AH), we observed a significant association according to three methods, with the exception of the ratio G/I.  Insulin resistance prevalence varied according to the diagnostic method employed, with no statistical difference between them. The proportion of IR diagnoses was statistically higher in obese women than in women with normal BMI. We observed a significant association between IR and WC, BMI, LAP, as well as dyslipidemia and AH in a high proportion of patients. Thieme Revinter Publicações Ltda Rio de Janeiro, Brazil.

  1. Flaxseed Oil Alleviates Chronic HFD-Induced Insulin Resistance through Remodeling Lipid Homeostasis in Obese Adipose Tissue.

    PubMed

    Yu, Xiao; Tang, Yuhan; Liu, Peiyi; Xiao, Lin; Liu, Liegang; Shen, Ruiling; Deng, Qianchun; Yao, Ping

    2017-11-08

    Emerging evidence suggests that higher circulating long-chain n-3 polyunsaturated fatty acids (n-3PUFA) levels were intimately associated with lower prevalence of obesity and insulin resistance. However, the understanding of bioactivity and potential mechanism of α-linolenic acid-rich flaxseed oil (ALA-FO) against insulin resistance was still limited. This study evaluated the effect of FO on high-fat diet (HFD)-induced insulin resistance in C57BL/6J mice focused on adipose tissue lipolysis. Mice after HFD feeding for 16 weeks (60% fat-derived calories) exhibited systemic insulin resistance, which was greatly attenuated by medium dose of FO (M-FO), paralleling with differential accumulation of ALA and its n-3 derivatives across serum lipid fractions. Moreover, M-FO was sufficient to effectively block the metabolic activation of adipose tissue macrophages (ATMs), thereby improving adipose tissue insulin signaling. Importantly, suppression of hypoxia-inducible factors HIF-1α and HIF-2α were involved in FO-mediated modulation of adipose tissue lipolysis, accompanied by specific reconstitution of n-3PUFA within adipose tissue lipid fractions.

  2. Body fat mass and the proportion of very large adipocytes in pregnant women are associated with gestational insulin resistance.

    PubMed

    Svensson, H; Wetterling, L; Bosaeus, M; Odén, B; Odén, A; Jennische, E; Edén, S; Holmäng, A; Lönn, M

    2016-04-01

    Pregnancy is accompanied by fat gain and insulin resistance. Changes in adipose tissue morphology and function during pregnancy and factors contributing to gestational insulin resistance are incompletely known. We sought to characterize adipose tissue in trimesters 1 and 3 (T1/T3) in normal weight (NW) and obese pregnant women, and identify adipose tissue-related factors associated with gestational insulin resistance. Twenty-two NW and 11 obese women were recruited early in pregnancy for the Pregnancy Obesity Nutrition and Child Health study. Examinations and sampling of blood and abdominal adipose tissue were performed longitudinally in T1/T3 to determine fat mass (air-displacement plethysmography); insulin resistance (homeostasis model assessment of insulin resistance, HOMA-IR); size, number and lipolytic activity of adipocytes; and adipokine release and density of immune cells and blood vessels in adipose tissue. Fat mass and HOMA-IR increased similarly between T1 and T3 in the groups; all remained normoglycemic. Adipocyte size increased in NW women. Adipocyte number was not influenced, but proportions of small and large adipocytes changed oppositely in the groups. Lipolytic activity and circulating adipocyte fatty acid-binding protein increased in both groups. Adiponectin release was reduced in NW women. Fat mass and the proportion of very large adipocytes were most strongly associated with T3 HOMA-IR by multivariable linear regression (R(2)=0.751, P<0.001). During pregnancy, adipose tissue morphology and function change comprehensively. NW women accumulated fat in existing adipocytes, accompanied by reduced adiponectin release. In comparison with the NW group, obese women had signs of adipocyte recruitment and maintained adiponectin levels. Body fat and large adipocytes may contribute significantly to gestational insulin resistance.

  3. Physical Training Improves Insulin Resistance Syndrome Markers in Obese Adolescents.

    ERIC Educational Resources Information Center

    Kang, Hyun-Sik; Gutin, Bernard; Barbeau, Paule; Owens, Scott; Lemmon, Christian R.; Allison, Jerry; Litaker, Mark S.; Le, Ngoc-Anh

    2002-01-01

    Tested the hypothesis that physical training (PT), especially high-intensity PT, would favorably affect components of the insulin resistance syndrome (IRS) in obese adolescents. Data on teens randomized into lifestyle education (LSE) alone, LSE plus moderate -intensity PT, and LSE plus high-intensity PT indicated that PT, especially high-intensity…

  4. Latent associations of low serum amylase with decreased plasma insulin levels and insulin resistance in asymptomatic middle-aged adults

    PubMed Central

    2012-01-01

    Background Low serum amylase is likely to be associated with obesity and metabolic abnormalities, which are often accompanied by impaired insulin action. However, it is unclear whether low serum amylase is associated with impaired insulin action in clinical settings. Therefore, we investigated the associations of low serum amylase with plasma insulin levels, and obesity-related parameters, including leptin. Research design and methods We measured serum amylase, plasma insulin, obesity-related parameters such as leptin, cardiometabolic risk factors, and anthropometric parameters in a cross-sectional study of 54 asymptomatic subjects (mean age 48.6 ± 7.6 years) who were not being treated for diabetes. Results Body mass index (BMI) and plasma glucose at 120 min after a 75-g oral glucose tolerance test (OGTT) were significantly higher in subjects with low serum amylase (< 60 IU/l, n = 21) than in those with normal-to-high serum amylase (n = 33) (P = 0.04 and P = 0.004, respectively). In univariate correlation analysis, serum amylase was significantly correlated with BMI alone (r = –0.39, P = 0.004). By contrast, multivariate logistic analysis showed that each 1-SD increase in quantitative insulin sensitivity check index, and each 1-SD decrease in plasma insulin OGTT at 0 and 60 min, homeostasis model assessment of insulin resistance (HOMA)-R, and HOMA-β were significantly associated with low serum amylase, particularly after adjusting for BMI. When subjects were divided into three groups according to HOMA-R, serum amylase levels were significantly lower in subjects with HOMA-R > 2.5 (n = 23) compared with subjects with HOMA-R 1.6–2.5 (n = 10) (61.1 ± 13.6 U/ml versus 76.9 ± 20.5 U/ml, Bonferroni test, P = 0.02), but not compared with subjects with HOMA-R<1.6 (n = 21; 62.7 ± 17.6 U/ml). Similar trends were observed when subjects were divided according to plasma leptin and fasting plasma

  5. Blocking CXCR7-mediated adipose tissue macrophages chemotaxis attenuates insulin resistance and inflammation in obesity.

    PubMed

    Peng, Hongxia; Zhang, Hu; Zhu, Honglei

    2016-10-28

    Adipose tissue macrophages (ATMs) have been considered to have a pivotal role in the chronic inflammation development during obesity. Although chemokine-chemokine receptor interaction has been studied in ATMs infiltration, most chemokine receptors remain incompletely understood and little is known about their mechanism of actions that lead to ATMs chemotaxis and pathogenesis of insulin resistance during obesity. In this study, we reported that CXCR7 expression is upregulated in adipose tissue, and specifically in ATMs during obesity. In addition, CXCL11 or CXCL12-induced ATMs chemotaxis is mediated by CXCR7 in obesity but not leanness, whereas CXCR3 and CXCR4 are not involved. Additional mechanism study shows that NF-κB activation is essential in ATMs chemotaxis, and manipulates chemotaxis of ATMs via CXCR7 expression regulation in obesity. Most importantly, CXCR7 neutralizing therapy dose dependently leads to less infiltration of macrophages into adipose tissue and thus reduces inflammation and improves insulin sensitivity in obesity. In conclusion, these findings demonstrated that blocking CXCR7-mediated ATMs chemotaxis ameliorates insulin resistance and inflammation in obesity. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Adipose Expression of Tumor Necrosis Factor-α: Direct Role in Obesity-Linked Insulin Resistance

    NASA Astrophysics Data System (ADS)

    Hotamisligil, Gokhan S.; Shargill, Narinder S.; Spiegelman, Bruce M.

    1993-01-01

    Tumor necrosis factor-α (TNF-α) has been shown to have certain catabolic effects on fat cells and whole animals. An induction of TNF-α messenger RNA expression was observed in adipose tissue from four different rodent models of obesity and diabetes. TNF-α protein was also elevated locally and systemically. Neutralization of TNF-α in obese fa/fa rats caused a significant increase in the peripheral uptake of glucose in response to insulin. These results indicate a role for TNF-α in obesity and particularly in the insulin resistance and diabetes that often accompany obesity.

  7. Neural correlates of stress- and food cue-induced food craving in obesity: association with insulin levels.

    PubMed

    Jastreboff, Ania M; Sinha, Rajita; Lacadie, Cheryl; Small, Dana M; Sherwin, Robert S; Potenza, Marc N

    2013-02-01

    Obesity is associated with alterations in corticolimbic-striatal brain regions involved in food motivation and reward. Stress and the presence of food cues may each motivate eating and engage corticolimibic-striatal neurocircuitry. It is unknown how these factors interact to influence brain responses and whether these interactions are influenced by obesity, insulin levels, and insulin sensitivity. We hypothesized that obese individuals would show greater responses in corticolimbic-striatal neurocircuitry after exposure to stress and food cues and that brain activations would correlate with subjective food craving, insulin levels, and HOMA-IR. Fasting insulin levels were assessed in obese and lean subjects who were exposed to individualized stress and favorite-food cues during functional MRI. Obese, but not lean, individuals exhibited increased activation in striatal, insular, and hypothalamic regions during exposure to favorite-food and stress cues. In obese but not lean individuals, food craving, insulin, and HOMA-IR levels correlated positively with neural activity in corticolimbic-striatal brain regions during favorite-food and stress cues. The relationship between insulin resistance and food craving in obese individuals was mediated by activity in motivation-reward regions including the striatum, insula, and thalamus. These findings demonstrate that obese, but not lean, individuals exhibit increased corticolimbic-striatal activation in response to favorite-food and stress cues and that these brain responses mediate the relationship between HOMA-IR and food craving. Improving insulin sensitivity and in turn reducing corticolimbic-striatal reactivity to food cues and stress may diminish food craving and affect eating behavior in obesity.

  8. Roles of the Chemokine System in Development of Obesity, Insulin Resistance, and Cardiovascular Disease

    PubMed Central

    Yao, Longbiao; Herlea-Pana, Oana; Heuser-Baker, Janet; Chen, Yitong; Barlic-Dicen, Jana

    2014-01-01

    The escalating epidemic of obesity has increased the incidence of obesity-induced complications to historically high levels. Adipose tissue is a dynamic energy depot, which stores energy and mobilizes it during nutrient deficiency. Excess nutrient intake resulting in adipose tissue expansion triggers lipid release and aberrant adipokine, cytokine and chemokine production, and signaling that ultimately lead to adipose tissue inflammation, a hallmark of obesity. This low-grade chronic inflammation is thought to link obesity to insulin resistance and the associated comorbidities of metabolic syndrome such as dyslipidemia and hypertension, which increase risk of type 2 diabetes and cardiovascular disease. In this review, we focus on and discuss members of the chemokine system for which there is clear evidence of participation in the development of obesity and obesity-induced pathologies. PMID:24741577

  9. Structural Equation Modeling for the Associations between the Home Environment and Obesity-related Cardiovascular Fitness and Insulin Resistance among Hispanic Children

    PubMed Central

    Santiago-Torres, Margarita; Cui, Yuchen; Adams, Alexandra K.; Allen, David B.; Carrel, Aaron L.; Guo, Jessica Y.; LaRowe, Tara L.; Schoeller, Dale A.

    2017-01-01

    Objective To use the Structural Equation Modeling (SEM) to examined the associations between the home environment (HE), diet and physical activity (PA) factors with Hispanic children’s obesity, cardiovascular fitness (CVF), and insulin resistance (IR) measures. Design Cross-sectional analyses of the HE, diet and PA factors with children’s metabolic health. Setting Urban Community School, Wisconsin, USA. Subjects A total of 187 Hispanic children and their parents participated. Methods Children’s reported their diet and PA, and parents reported on the HE through self-administered questionnaires. Outcome variables were measured anthropometrics, CVF assessed using the Progressive Aerobic Cardiovascular Endurance Run (PACER). IR was determined with the homeostasis model assessment of insulin resistance (HOMAIR) in a subgroup of children (n=99) who participated in a one-time blood draw for fasting glucose and insulin concentrations. Results Parents exercise (β=0.33), home availability of PA equipment (β=0.20) and sugar-sweetened beverages (SSB) (β=0.19) were all associated with children’s PA and SSB consumption, respectively. Children’s SSB consumption (β=0.15) was associated with BMI z-score, which in turn, was associated with HOMAIR (β=0.61). In contrast, children’s PA (β=0.17) was associated with PACER z-score, which in turn was inversely associated with HOMAIR (β=−0.18). The SEM indices suggested a satisfactory model fit (Chi-square, Χ2 =53.1, comparative fix index=0.92, root-mean-squared error associated=0.04). Conclusions The SEM findings confirm the need to focus intervention efforts at the family level where parents are educated on making a healthier HE targeting poor diet and low levels of PA among Hispanic children who are disproportionally affected by obesity-related IR. PMID:26850309

  10. Rapid development of cardiac dysfunction in a canine model of insulin resistance and moderate obesity.

    PubMed

    Broussard, Josiane L; Nelson, Michael D; Kolka, Cathryn M; Bediako, Isaac Asare; Paszkiewicz, Rebecca L; Smith, Laura; Szczepaniak, Edward W; Stefanovski, Darko; Szczepaniak, Lidia S; Bergman, Richard N

    2016-01-01

    The worldwide incidence of obesity and diabetes continues to rise at an alarming rate. A major cause of the morbidity and mortality associated with obesity and diabetes is heart disease, yet the mechanisms that lead to cardiovascular complications remain unclear. We performed cardiac MRI to assess left ventricular morphology and function during the development of moderate obesity and insulin resistance in a well-established canine model (n = 26). To assess the influence of dietary fat composition, we randomised animals to a traditional lard diet (rich in saturated and monounsaturated fat; n = 12), a salmon oil diet (rich in polyunsaturated fat; n = 8) or a control diet (n = 6). High-fat feeding with lard increased body weight and fasting insulin and markedly reduced insulin sensitivity. Lard feeding also significantly reduced left ventricular function, evidenced by a worsening of circumferential strain and impairment in left ventricular torsion. High-fat feeding with salmon oil increased body weight; however, salmon oil feeding did not impair insulin sensitivity or cardiac function. These data emphasise the importance of dietary fat composition on both metabolic and cardiac function, and have important implications for the relationship between diet and health.

  11. Treatment with the 3-ketoacyl-CoA thiolase inhibitor trimetazidine does not exacerbate whole-body insulin resistance in obese mice.

    PubMed

    Ussher, John R; Keung, Wendy; Fillmore, Natasha; Koves, Timothy R; Mori, Jun; Zhang, Liyan; Lopaschuk, David G; Ilkayeva, Olga R; Wagg, Cory S; Jaswal, Jagdip S; Muoio, Deborah M; Lopaschuk, Gary D

    2014-06-01

    There is a growing need to understand the underlying mechanisms involved in the progression of cardiovascular disease during obesity and diabetes. Although inhibition of fatty acid oxidation has been proposed as a novel approach to treat ischemic heart disease and heart failure, reduced muscle fatty acid oxidation rates may contribute to the development of obesity-associated insulin resistance. Our aim was to determine whether treatment with the antianginal agent trimetazidine, which inhibits fatty acid oxidation in the heart secondary to inhibition of 3-ketoacyl-CoA thiolase (3-KAT), may have off-target effects on glycemic control in obesity. We fed C57BL/6NCrl mice a high-fat diet (HFD) for 10 weeks before a 22-day treatment with the 3-KAT inhibitor trimetazidine (15 mg/kg per day). Insulin resistance was assessed via glucose/insulin tolerance testing, and lipid metabolite content was assessed in gastrocnemius muscle. Trimetazidine-treatment led to a mild shift in substrate preference toward carbohydrates as an oxidative fuel source in obese mice, evidenced by an increase in the respiratory exchange ratio. This shift in metabolism was accompanied by an accumulation of long-chain acyl-CoA and a trend to an increase in triacylglycerol content in gastrocnemius muscle, but did not exacerbate HFD-induced insulin resistance compared with control-treated mice. It is noteworthy that trimetazidine treatment reduced palmitate oxidation rates in the isolated working mouse heart and neonatal cardiomyocytes but not C2C12 skeletal myotubes. Our findings demonstrate that trimetazidine therapy does not adversely affect HFD-induced insulin resistance, suggesting that treatment with trimetazidine would not worsen glycemic control in obese patients with angina.

  12. Pre-sarcopenia is associated with renal hyperfiltration independent of obesity or insulin resistance: Nationwide Surveys (KNHANES 2008-2011).

    PubMed

    Han, Eugene; Lee, Yong-Ho; Lee, Byung-Wan; Kang, Eun Seok; Cha, Bong-Soo

    2017-06-01

    Renal hyperfiltration is closely linked to cardiometabolic disorders, and it may increase the mortality risk of the general population. Despite the well-established association between cardiometabolic diseases and sarcopenia, the relationship between renal hyperfiltration and sarcopenia has not yet been assessed.This population-based, cross-sectional study used a nationally representative sample of 13,800 adults from the 2008 to 2011 Korea National Health and Nutrition Examination Survey. Renal hyperfiltration was defined as the age- and sex-specific glomerular filtration rate above the 90th percentile in subjects with normal kidney function (>60 mL/min/1.73 m). Appendicular skeletal muscle (ASM), measured by dual-energy x-ray absorptiometry, was used to assess pre-sarcopenia, which the international consensus defines as both ASM per se and ASM that was adjusted for the body mass index and the height.A total of 1402 (10.2%) participants were classified as having renal hyperfiltration. The prevalence of pre-sarcopenia ranged from 11.6% to 33.0%, by definition. Individuals with pre-sarcopenia had higher risks of renal hyperfiltration compared to those without pre-sarcopenia (10.9% vs 17.4%, P < .001; odds ratio [OR] = 1.71, 95% confidential interval [CI] = 1.48-1.99, P < .001). Multiple logistic regression analyses also demonstrated this independent association between pre-sarcopenia and renal hyperfiltration, following adjustment for confounding factors such as insulin resistance and obesity (OR = 1.84, 95% CI = 1.57-2.15, P < .001).In the general population of healthy individuals, pre-sarcopenia might be associated with renal hyperfiltration independent of obesity or insulin resistance.

  13. Biochanin A improves hepatic steatosis and insulin resistance by regulating the hepatic lipid and glucose metabolic pathways in diet-induced obese mice.

    PubMed

    Park, Hee-Sook; Hur, Haeng Jeon; Kim, Soon-Hee; Park, Su-Jin; Hong, Moon Ju; Sung, Mi Jeong; Kwon, Dae Young; Kim, Myung-Sunny

    2016-09-01

    Natural compounds that regulate peroxisome proliferator-activated receptor alpha (PPARα) have been reported to have beneficial effects in obesity-mediated metabolic disorders. In this study, we demonstrated that biochanin A (BA), an agonist of PPAR-α, improved hepatic steatosis and insulin resistance by regulating hepatic lipid and glucose metabolism. C57BL/6 mice were fed a normal chow diet, a high-fat diet (HFD), and an HFD supplemented with 0.05% BA for 12 weeks. Histological and biochemical examinations indicated that BA prevented obesity-induced hepatic steatosis and insulin resistance in HFD-fed mice. BA stimulated the transcriptional activation of PPAR-α in vitro and increased the expression of PPAR-α and its regulatory proteins in the liver. CE-TOF/MS analyses indicated that BA administration promoted the recovery of metabolites involved in phosphatidylcholine synthesis, lipogenesis, and beta-oxidation in the livers of obese mice. BA also suppressed the levels of gluconeogenesis-related metabolites and the expression of the associated enzymes, glucose 6-phosphatase and pyruvate kinase. Taken together, these results showed that BA ameliorated metabolic disorders such as hepatic steatosis and insulin resistance by modulating lipid and glucose metabolism in diet-induced obesity. Thus, BA may be a potential therapeutic agent for the prevention of obesity-mediated hepatic steatosis and insulin resistance. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Endoplasmic reticulum chaperone GRP78 regulates macrophage function and insulin resistance in diet-induced obesity.

    PubMed

    Kim, Jong Hun; Lee, Eunjung; Friedline, Randall H; Suk, Sujin; Jung, Dae Young; Dagdeviren, Sezin; Hu, Xiaodi; Inashima, Kunikazu; Noh, Hye Lim; Kwon, Jung Yeon; Nambu, Aya; Huh, Jun R; Han, Myoung Sook; Davis, Roger J; Lee, Amy S; Lee, Ki Won; Kim, Jason K

    2018-04-01

    Obesity-mediated inflammation is a major cause of insulin resistance, and macrophages play an important role in this process. The 78-kDa glucose-regulated protein (GRP78) is a major endoplasmic reticulum chaperone that modulates unfolded protein response (UPR), and mice with GRP78 heterozygosity were resistant to diet-induced obesity. Here, we show that mice with macrophage-selective ablation of GRP78 (Lyz- GRP78 -/- ) are protected from skeletal muscle insulin resistance without changes in obesity compared with wild-type mice after 9 wk of high-fat diet. GRP78-deficient macrophages demonstrated adapted UPR with up-regulation of activating transcription factor (ATF)-4 and M2-polarization markers. Diet-induced adipose tissue inflammation was reduced, and bone marrow-derived macrophages from Lyz- GRP78 -/- mice demonstrated a selective increase in IL-6 expression. Serum IL-13 levels were elevated by >4-fold in Lyz- GRP78 -/- mice, and IL-6 stimulated the myocyte expression of IL-13 and IL-13 receptor. Lastly, recombinant IL-13 acutely increased glucose metabolism in Lyz- GRP78 -/- mice. Taken together, our data indicate that GRP78 deficiency activates UPR by increasing ATF-4, and promotes M2-polarization of macrophages with a selective increase in IL-6 secretion. Macrophage-derived IL-6 stimulates the myocyte expression of IL-13 and regulates muscle glucose metabolism in a paracrine manner. Thus, our findings identify a novel crosstalk between macrophages and skeletal muscle in the modulation of obesity-mediated insulin resistance.-Kim, J. H., Lee, E., Friedline, R. H., Suk, S., Jung, D. Y., Dagdeviren, S., Hu, X., Inashima, K., Noh, H. L., Kwon, J. Y., Nambu, A., Huh, J. R., Han, M. S., Davis, R. J., Lee, A. S., Lee, K. W., Kim, J. K. Endoplasmic reticulum chaperone GRP78 regulates macrophage function and insulin resistance in diet-induced obesity.

  15. Labrador tea (Rhododendron groenlandicum) attenuates insulin resistance in a diet-induced obesity mouse model.

    PubMed

    Ouchfoun, Meriem; Eid, Hoda M; Musallam, Lina; Brault, Antoine; Li, Shilin; Vallerand, Diane; Arnason, John T; Haddad, Pierre S

    2016-04-01

    Using a diet-induced obesity (DIO) mouse model, we investigated the antidiabetic effect of Labrador tea [Rhododendron groenlandicum (Oeder) Kron and Judd], a beverage and medicinal tea used by the Cree Nations of northern Quebec. C57BL6 mice were divided into five groups and given standard chow (~4 % of lipids) or high-fat diet (~35 % of lipids) for 8 weeks until they became obese and insulin resistant. Treatment began by adding the plant extract at three doses (125, 250 and 500 mg/kg) to the high-fat diet for another 8 weeks. At the end of the study, insulin-sensitive tissues (liver, skeletal muscle, adipose tissue) were collected to investigate the plant's molecular mechanisms. Labrador tea significantly reduced blood glucose (13 %), the response to an oral glucose tolerance test (18.2 %) and plasma insulin (65 %) while preventing hepatic steatosis (42 % reduction in hepatic triglyceride levels) in DIO mice. It stimulated insulin-dependent Akt pathway (55 %) and increased the expression of GLUT4 (53 %) in skeletal muscle. In the liver, Labrador tea stimulated the insulin-dependent Akt and the insulin-independent AMP-activated protein kinase pathways. The improvement in hepatic steatosis observed in DIO-treated mice was associated with a reduction in inflammation (through the IKK α/β) and a decrease in the hepatic content of SREBP-1 (39 %). Labrador tea exerts potential antidiabetic action by improving insulin sensitivity and mitigating high-fat diet-induced obesity and hyperglycemia. They validate the safety and efficacy of this plant, a promising candidate for culturally relevant complementary treatment in Cree diabetics.

  16. Familial and individual predictors of obesity and insulin resistance in urban Hispanic children.

    PubMed

    Santiago-Torres, M; Cui, Y; Adams, A K; Allen, D B; Carrel, A L; Guo, J Y; Delgado-Rendon, A; LaRowe, T L; Schoeller, D A

    2016-02-01

    High intake of sugar-sweetened beverages (SSB) has been suggested to contribute to the pediatric obesity epidemic, however, how the home food environment influence children's intake of SSB among Hispanic families is still poorly understood. To evaluate the relationships between the home food environment and Hispanic children's diet in relation to weight status and insulin resistance (IR). A food frequency questionnaire was administered to 187 Hispanic children (ages 10 to 14 years) and anthropometrics were measured. IR was estimated from fasting insulin and glucose levels using the homeostasis model assessment of insulin resistance (HOMAIR ). Parents reported on family demographics and the home food environment. A structural equation modelling approach was applied to examine the hypothesized relationships among variables. The prevalence of childhood overweight and obesity was 52.8% and it was positively associated with HOMAIR (β = 0.687, P < .0001). Children's SSB consumption was positively associated with children's body mass index z-score (β = 0.151, P < 0.05) and subsequently to HOMAIR . Children's SSB consumption was predicted by home availability (β = 0.191) and parental intake of SSB (β = 0.419) (P < 0.05). The model fit indices [χ(2)  = 45.821 (d.f. = 30, P > 0.01 and < 0.05), χ(2) /d.f. = 1.53, root mean square error of approximation = 0.053 (90% confidence interval = 0.016, 0.082), comparative fit index = 0.904] suggested a satisfactory goodness-of-fit. The home food environment and parental diet seem to play an important role in the children's access to and intake of SSB, which in turn predicted children's weight status. © 2015 World Obesity.

  17. Laparoscopic sleeve gastrectomy improves body composition and alleviates insulin resistance in obesity related acanthosis nigricans.

    PubMed

    Zhang, Yi; Zhu, Cuiling; Wen, Xin; Wang, Xingchun; Li, Liang; Rampersad, Sharvan; Lu, Liesheng; Zhou, Donglei; Qian, Chunhua; Cui, Ran; Zhang, Manna; Yang, Peng; Qu, Shen; Bu, Le

    2017-11-07

    Acanthosis nigricans (AN) has a close relationship with obesity. It is believed that obesity and AN have the common pathophysiological basis such as hyperinsulinism. This study is aimed to observe the effect of laparoscopic sleeve gastrectomy (LSG) on body composition and insulin resistance in Chinese obese patients with acanthosis nigricans. A total of 37 obese patients who underwent LSG in our hospital were selected for analysis. They were divided into simple obesity (OB n = 14) and obesity with acanthosis nigricans (AN n = 23) group respectively. Body composition was measured by dual-energy X-ray absorptiometry (DEXA). Anthropometric measurements and glucolipid metabolism before and 3 months post LSG were collected for analysis. Patients with AN got noticeable improvement in skin condition and their AN score was significantly decreased (3.52 ± 0.79 vs. 1.48 ± 0.73, P < 0.001).Alleviated insulin resistance and more trunk fat loss than limbs' were observed in both groups (P value < 0.01). In AN group, preoperative android fat mass (FM) was positively correlated with fasting insulin and natural logarithm of HOMA-IR (LNIR) (r = 0.622, 0.608, respectively; all P < 0.01). Besides, changes in android FM and visceral adipose tissue (VAT) also showed significantly positive correlation with changes in LNIR (r = 0.588, r = 0.598, respectively; all P < 0.01). LSG had a positive impact on body composition and skin condition in Chinese obese patients with AN. Loss of android FM and VAT might result in the alleviation of insulin resistance in AN patients. Android fat distribution seems to be a potential indicator of postoperative metabolic benefits for obese patients with AN.

  18. Obesity, insulin resistance and diabetes: sex differences and role of oestrogen receptors.

    PubMed

    Meyer, M R; Clegg, D J; Prossnitz, E R; Barton, M

    2011-09-01

    Obesity increases the risk of coronary artery disease through insulin resistance, diabetes, arterial hypertension and dyslipidemia. The prevalence of obesity has increased worldwide and is particularly high among middle-aged women and men. After menopause, women are at an increased risk to develop visceral obesity due to the loss of endogenous ovarian hormone production. Effects of oestrogens are classically mediated by the two nuclear oestrogen receptors (ERs) α and β. In addition, more recent research has shown that the intracellular transmembrane G-protein-coupled oestrogen receptor (GPER) originally designated as GPR30 also mediates some of the actions attributed to oestrogens. Oestrogen and its receptors are important regulators of body weight and insulin sensitivity not only in women but also in men as demonstrated by ER mutations in rodents and humans. This article reviews the role of sex hormones and ERs in the context of obesity, insulin sensitivity and diabetes as well as the related clinical issues in women and men. © 2011 The Authors. Acta Physiologica © 2011 Scandinavian Physiological Society.

  19. Body fat mass and the proportion of very large adipocytes in pregnant women are associated with gestational insulin resistance

    PubMed Central

    Svensson, H; Wetterling, L; Bosaeus, M; Odén, B; Odén, A; Jennische, E; Edén, S; Holmäng, A; Lönn, M

    2016-01-01

    Background/Objectives: Pregnancy is accompanied by fat gain and insulin resistance. Changes in adipose tissue morphology and function during pregnancy and factors contributing to gestational insulin resistance are incompletely known. We sought to characterize adipose tissue in trimesters 1 and 3 (T1/T3) in normal weight (NW) and obese pregnant women, and identify adipose tissue-related factors associated with gestational insulin resistance. Subjects/Methods: Twenty-two NW and 11 obese women were recruited early in pregnancy for the Pregnancy Obesity Nutrition and Child Health study. Examinations and sampling of blood and abdominal adipose tissue were performed longitudinally in T1/T3 to determine fat mass (air-displacement plethysmography); insulin resistance (homeostasis model assessment of insulin resistance, HOMA-IR); size, number and lipolytic activity of adipocytes; and adipokine release and density of immune cells and blood vessels in adipose tissue. Results: Fat mass and HOMA-IR increased similarly between T1 and T3 in the groups; all remained normoglycemic. Adipocyte size increased in NW women. Adipocyte number was not influenced, but proportions of small and large adipocytes changed oppositely in the groups. Lipolytic activity and circulating adipocyte fatty acid-binding protein increased in both groups. Adiponectin release was reduced in NW women. Fat mass and the proportion of very large adipocytes were most strongly associated with T3 HOMA-IR by multivariable linear regression (R2=0.751, P<0.001). Conclusions: During pregnancy, adipose tissue morphology and function change comprehensively. NW women accumulated fat in existing adipocytes, accompanied by reduced adiponectin release. In comparison with the NW group, obese women had signs of adipocyte recruitment and maintained adiponectin levels. Body fat and large adipocytes may contribute significantly to gestational insulin resistance. PMID:26563815

  20. KSR2 Mutations Are Associated with Obesity, Insulin Resistance, and Impaired Cellular Fuel Oxidation

    PubMed Central

    Pearce, Laura R.; Atanassova, Neli; Banton, Matthew C.; Bottomley, Bill; van der Klaauw, Agatha A.; Revelli, Jean-Pierre; Hendricks, Audrey; Keogh, Julia M.; Henning, Elana; Doree, Deon; Jeter-Jones, Sabrina; Garg, Sumedha; Bochukova, Elena G.; Bounds, Rebecca; Ashford, Sofie; Gayton, Emma; Hindmarsh, Peter C.; Shield, Julian P.H.; Crowne, Elizabeth; Barford, David; Wareham, Nick J.; O’Rahilly, Stephen; Murphy, Michael P.; Powell, David R.; Barroso, Ines; Farooqi, I. Sadaf

    2013-01-01

    Summary Kinase suppressor of Ras 2 (KSR2) is an intracellular scaffolding protein involved in multiple signaling pathways. Targeted deletion of Ksr2 leads to obesity in mice, suggesting a role in energy homeostasis. We explored the role of KSR2 in humans by sequencing 2,101 individuals with severe early-onset obesity and 1,536 controls. We identified multiple rare variants in KSR2 that disrupt signaling through the Raf-MEK-ERK pathway and impair cellular fatty acid oxidation and glucose oxidation in transfected cells; effects that can be ameliorated by the commonly prescribed antidiabetic drug, metformin. Mutation carriers exhibit hyperphagia in childhood, low heart rate, reduced basal metabolic rate and severe insulin resistance. These data establish KSR2 as an important regulator of energy intake, energy expenditure, and substrate utilization in humans. Modulation of KSR2-mediated effects may represent a novel therapeutic strategy for obesity and type 2 diabetes. PaperFlick PMID:24209692

  1. The incidence of metabolic syndrome in obese Czech children: the importance of early detection of insulin resistance using homeostatic indexes HOMA-IR and QUICKI.

    PubMed

    Pastucha, D; Filipčíková, R; Horáková, D; Radová, L; Marinov, Z; Malinčíková, J; Kocvrlich, M; Horák, S; Bezdičková, M; Dobiáš, M

    2013-01-01

    Common alimentary obesity frequently occurs on a polygenic basis as a typical lifestyle disorder in the developed countries. It is associated with characteristic complex metabolic changes, which are the cornerstones for future metabolic syndrome development. The aims of our study were 1) to determine the incidence of metabolic syndrome (based on the diagnostic criteria defined by the International Diabetes Federation for children and adolescents) in Czech obese children, 2) to evaluate the incidence of insulin resistance according to HOMA-IR and QUICKI homeostatic indexes in obese children with and without metabolic syndrome, and 3) to consider the diagnostic value of these indexes for the early detection of metabolic syndrome in obese children. We therefore performed anthropometric and laboratory examinations to determine the incidence of metabolic syndrome and insulin resistance in the group of 274 children with obesity (128 boys and 146 girls) aged 9-17 years. Metabolic syndrome was found in 102 subjects (37 %). On the other hand, the presence of insulin resistance according to QUICKI <0.357 was identified in 86 % and according to HOMA-IR >3.16 in 53 % of obese subjects. This HOMA-IR limit was exceeded by 70 % children in the MS(+) group, but only by 43 % children in the MS(-) group (p<0.0001). However, a relatively high incidence of insulin resistance in obese children without metabolic syndrome raises a question whether the existing diagnostic criteria do not falsely exclude some cases of metabolic syndrome. On the basis of our results we suggest to pay a preventive attention also to obese children with insulin resistance even if they do not fulfill the actual diagnostic criteria for metabolic syndrome.

  2. Regulation of obesity-related insulin resistance with gut anti-inflammatory agents.

    PubMed

    Luck, Helen; Tsai, Sue; Chung, Jason; Clemente-Casares, Xavier; Ghazarian, Magar; Revelo, Xavier S; Lei, Helena; Luk, Cynthia T; Shi, Sally Yu; Surendra, Anuradha; Copeland, Julia K; Ahn, Jennifer; Prescott, David; Rasmussen, Brittany A; Chng, Melissa Hui Yen; Engleman, Edgar G; Girardin, Stephen E; Lam, Tony K T; Croitoru, Kenneth; Dunn, Shannon; Philpott, Dana J; Guttman, David S; Woo, Minna; Winer, Shawn; Winer, Daniel A

    2015-04-07

    Obesity has reached epidemic proportions, but little is known about its influence on the intestinal immune system. Here we show that the gut immune system is altered during high-fat diet (HFD) feeding and is a functional regulator of obesity-related insulin resistance (IR) that can be exploited therapeutically. Obesity induces a chronic phenotypic pro-inflammatory shift in bowel lamina propria immune cell populations. Reduction of the gut immune system, using beta7 integrin-deficient mice (Beta7(null)), decreases HFD-induced IR. Treatment of wild-type HFD C57BL/6 mice with the local gut anti-inflammatory, 5-aminosalicyclic acid (5-ASA), reverses bowel inflammation and improves metabolic parameters. These beneficial effects are dependent on adaptive and gut immunity and are associated with reduced gut permeability and endotoxemia, decreased visceral adipose tissue inflammation, and improved antigen-specific tolerance to luminal antigens. Thus, the mucosal immune system affects multiple pathways associated with systemic IR and represents a novel therapeutic target in this disease. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Paediatrics, insulin resistance and the kidney.

    PubMed

    Marlais, Matko; Coward, Richard J

    2015-08-01

    Systemic insulin resistance is becoming more prevalent in the young due to modern lifestyles predisposing to the metabolic syndrome and obesity. There is also evidence that there are critical insulin-resistant phases for the developing child, including puberty, and that renal disease per se causes systemic insulin resistance. This review considers the factors that render children insulin resistant, as well as the accumulating evidence that the kidney is an insulin-responsive organ and could be affected by insulin resistance.

  4. Adipose extracellular matrix remodelling in obesity and insulin resistance☆

    PubMed Central

    Lin, De; Chun, Tae-Hwa; Kang, Li

    2016-01-01

    The extracellular matrix (ECM) of adipose tissues undergoes constant remodelling to allow adipocytes and their precursor cells to change cell shape and function in adaptation to nutritional cues. Abnormal accumulation of ECM components and their modifiers in adipose tissues has been recently demonstrated to cause obesity-associated insulin resistance, a hallmark of type 2 diabetes. Integrins and other ECM receptors (e.g. CD44) that are expressed in adipose tissues have been shown to regulate insulin sensitivity. It is well understood that a hypoxic response is observed in adipose tissue expansion during obesity progression and that hypoxic response accelerates fibrosis and inflammation in white adipose tissues. The expansion of adipose tissues should require angiogenesis; however, the excess deposition of ECM limits the angiogenic response of white adipose tissues in obesity. While recent studies have focused on the metabolic consequences and the mechanisms of adipose tissue expansion and remodelling, little attention has been paid to the role played by the interaction between peri-adipocyte ECM and their cognate cell surface receptors. This review will address what is currently known about the roles played by adipose ECM, their modifiers, and ECM receptors in obesity and insulin resistance. Understanding how excess ECM deposition in the adipose tissue deteriorates insulin sensitivity would provide us hints to develop a new therapeutic strategy for the treatment of insulin resistance and type 2 diabetes. PMID:27179976

  5. Effects of clenbuterol on insulin resistance in conscious obese Zucker rats.

    PubMed

    Pan, S J; Hancock, J; Ding, Z; Fogt, D; Lee, M; Ivy, J L

    2001-04-01

    The present study was conducted to determine the effect of chronic administration of the long-acting beta(2)-adrenergic agonist clenbuterol on rats that are genetically prone to insulin resistance and impaired glucose tolerance. Obese Zucker rats (fa/fa) were given 1 mg/kg of clenbuterol by oral intubation daily for 5 wk. Controls received an equivalent volume of water according to the same schedule. At the end of the treatment, rats were catheterized for euglycemic-hyperinsulinemic (15 mU insulin. kg(-1). min(-1)) clamping. Clenbuterol did not change body weight compared with the control group but caused a redistribution of body weight: leg muscle weights increased, and abdominal fat weight decreased. The glucose infusion rate needed to maintain euglycemia and the rate of glucose disappearance were greater in the clenbuterol-treated rats. Furthermore, plasma insulin levels were decreased, and the rate of glucose uptake into hindlimb muscles and abdominal fat was increased in the clenbuterol-treated rats. This increased rate of glucose uptake was accompanied by a parallel increase in the rate of glycogen synthesis. The increase in muscle glucose uptake could not be ascribed to an increase in the glucose transport protein GLUT-4 in clenbuterol-treated rats. We conclude that chronic clenbuterol treatment reduces the insulin resistance of the obese Zucker rat by increasing insulin-stimulated muscle and adipose tissue glucose uptake. The improvements noted may be related to the repartitioning of body weight between tissues.

  6. Association between Lipid Ratios and Insulin Resistance in a Chinese Population

    PubMed Central

    Zhang, Liying; Chen, Shanying; Deng, Aiwen; Liu, Xinyu; Liang, Yan; Shao, Xiaofei; Sun, Mingxia; Zou, Hequn

    2015-01-01

    Aim To explore the association of lipid ratios and triglyceride (TG) with insulin resistance (IR) in a Chinese population. We also provide the clinical utility of lipid ratios to identify men and women with IR. Methods This cross-sectional study included 614 men and 1055 women without diabetes. Insulin resistance was defined by homeostatic model assessment of IR > 2.69. Lipid ratios included the TG/ high density lipoprotein cholesterol (HDL-C), the total cholesterol (TC)/HDL-C and the low density lipoprotein cholesterol (LDL-C)/HDL –C. Logistic regression models and accurate estimates of the area under the receiver operating characteristic (AUROC) curves were obtained. Results In normal-weight men, none of lipid ratios nor TG was associated with IR. In overweight/obese men, normal-weight women and overweight/obese women, the TG/HDL-C, the TC/HDL-C and TG were significantly associated with IR, and the associations were independent of waist circumference. All of the AUROCs for the TG/HDL-C and TG were > 0.7. The AUROCs for TC/HDL-C ratio were 0.69–0.77. The optimal cut-offs for TG/HDL-C were 1.51 in men and 0.84 in women. The optimal cut-offs for TG were 1.78 mmol/L in men and 1.49 mmol/L in women, respectively. In men, the optimal cut-off for LDL-C/HDL-C is 3.80. In women, the optimal cut-off for LDL-C/HDL-C is 3.82. Conclusion The TG/HDL-C, the TC/HDL-C and TG are associated with IR in overweight/obese men, normal-weight and overweight/obese women. The LDL-C/HDL-C is only associated with IR in normal-weight women. The TG/HDL-C and TG might be used as surrogate markers for assessing IR. PMID:25635876

  7. Insulin resistance in the liver: Deficiency or excess of insulin?

    PubMed Central

    Bazotte, Roberto B; Silva, Lorena G; Schiavon, Fabiana PM

    2014-01-01

    In insulin-resistant states (obesity, pre-diabetes, and type 2 diabetes), hepatic production of glucose and lipid synthesis are heightened in concert, implying that insulin deficiency and insulin excess coexists in this setting. The fact that insulin may be inadequate or excessive at any one point in differing organs and tissues has many biologic ramifications. In this context the concept of metabolic compartmentalization in the liver is offered herein as one perspective of this paradox. In particular, we focus on the hypothesis that insulin resistance accentuates differences in periportal and perivenous hepatocytes, namely periportal glucose production and perivenous lipid synthesis. Subsequently, excessive production of glucose and accumulation of lipids could be expected in the livers of patients with obesity and insulin resistance. Overall, in this review, we provide our integrative perspective regarding how excessive production of glucose in periportal hepatocytes and accumulation of lipids in perivenous hepatocytes interact in insulin resistant states. PMID:25486190

  8. Food fried in extra-virgin olive oil improves postprandial insulin response in obese, insulin-resistant women.

    PubMed

    Farnetti, Sara; Malandrino, Noemi; Luciani, Davide; Gasbarrini, Giovanni; Capristo, Esmeralda

    2011-03-01

    The benefits of low glycemic load (GL) diets on clinical outcome in several metabolic and cardiovascular diseases have extensively been demonstrated. The GL of a meal can be affected by modulating the bioavailability of carbohydrates or by changing food preparation. We investigated the effect on plasma glucose and insulin response in lean and obese women of adding raw or fried extra-virgin olive oil to a carbohydrate-containing meal. After an overnight fast, 12 obese insulin-resistant women (body mass index [BMI], 32.8 ± 2.2 kg/m(2)) and five lean subjects (BMI, 22.2 ± 1.2 kg/m(2)) were randomly assigned to receive two different meals (designated A and B). Meal A was composed of 60 g of pasta made from wheat flour and 150 g of grilled courgettes with 25 g of uncooked oil. Meal B included 15 g of oil in the 150 g of deep-fried courgettes and 10 g of oil in the 60 g of stir-fried pasta. Both meals included 150 g of apple. Blood samples were collected at baseline and every 30 minutes over a 3-hour post-meal period and were tested for levels of glucose, insulin, C-peptide, and triglycerides. The area under the curve (AUC) values were calculated. In obese women the AUCs for C-peptide were significantly higher after meal A than after meal B at 120 minutes (W [Wilcoxon sign rank test] = 27.5, P = .0020), 150 minutes (W = 26.5, P = .0039), and 180 minutes (W = 26.5, P = .0039). No differences were found in lean subjects. This study demonstrated that in obese, insulin-resistant women, food fried in extra-virgin olive oil significantly reduced both insulin and C-peptide responses after a meal.

  9. Cellular and Molecular Players in Adipose Tissue Inflammation in the Development of Obesity-induced Insulin Resistance

    PubMed Central

    Lee, Byung-Cheol; Lee, Jongsoon

    2013-01-01

    There is increasing evidence showing that inflammation is an important pathogenic mediator of the development of obesity-induced insulin resistance. It is now generally accepted that tissue-resident immune cells play a major role in the regulation of this obesity-induced inflammation. The roles that adipose tissue (AT)-resident immune cells play have been particularly extensively studied. AT contains most types of immune cells and obesity increases their numbers and activation levels, particularly in AT macrophages (ATMs). Other pro-inflammatory cells found in AT include neutrophils, Th1 CD4 T cells, CD8 T cells, B cells, DCs, and mast cells. However, AT also contains anti-inflammatory cells that counter the pro-inflammatory immune cells that are responsible for the obesity-induced inflammation in this tissue. These anti-inflammatory cells include regulatory CD4 T cells (Tregs), Th2 CD4 T cells, and eosinophils. Hence, AT inflammation is shaped by the regulation of pro- and anti-inflammatory immune cell homeostasis, and obesity skews this balance towards a more pro-inflammatory status. Recent genetic studies revealed several molecules that participate in the development of obesity-induced inflammation and insulin resistance. In this review, the cellular and molecular players that participate in the regulation of obesity-induced inflammation and insulin resistance are discussed, with particular attention being placed on the roles of the cellular players in these pathogeneses. PMID:23707515

  10. Complement Factor H Is Expressed in Adipose Tissue in Association With Insulin Resistance

    PubMed Central

    Moreno-Navarrete, José María; Martínez-Barricarte, Rubén; Catalán, Victoria; Sabater, Mònica; Gómez-Ambrosi, Javier; Ortega, Francisco José; Ricart, Wifredo; Blüher, Mathias; Frühbeck, Gema; Rodríguez de Cordoba, Santiago; Fernández-Real, José Manuel

    2010-01-01

    OBJECTIVE Activation of the alternative pathway of the complement system, in which factor H (fH; complement fH [CFH]) is a key regulatory component, has been suggested as a link between obesity and metabolic disorders. Our objective was to study the associations between circulating and adipose tissue gene expressions of CFH and complement factor B (fB; CFB) with obesity and insulin resistance. RESEARCH DESIGN AND METHODS Circulating fH and fB were determined by enzyme-linked immunosorbent assay in 398 subjects. CFH and CFB gene expressions were evaluated in 76 adipose tissue samples, in isolated adipocytes, and in stromovascular cells (SVC) (n = 13). The effects of weight loss and rosiglitazone were investigated in independent cohorts. RESULTS Both circulating fH and fB were associated positively with BMI, waist circumference, triglycerides, and inflammatory parameters and negatively with insulin sensitivity and HDL cholesterol. For the first time, CFH gene expression was detected in human adipose tissue (significantly increased in subcutaneous compared with omental fat). CFH gene expression in omental fat was significantly associated with insulin resistance. In contrast, CFB gene expression was significantly increased in omental fat but also in association with fasting glucose and triglycerides. The SVC fraction was responsible for these differences, although isolated adipocytes also expressed fB and fH at low levels. Both weight loss and rosiglitazone led to significantly decreased circulating fB and fH levels. CONCLUSIONS Increased circulating fH and fB concentrations in subjects with altered glucose tolerance could reflect increased SVC-induced activation of the alternative pathway of complement in omental adipose tissue linked to insulin resistance and metabolic disturbances. PMID:19833879

  11. Complement factor H is expressed in adipose tissue in association with insulin resistance.

    PubMed

    Moreno-Navarrete, José María; Martínez-Barricarte, Rubén; Catalán, Victoria; Sabater, Mònica; Gómez-Ambrosi, Javier; Ortega, Francisco José; Ricart, Wifredo; Blüher, Mathias; Frühbeck, Gema; Rodríguez de Cordoba, Santiago; Fernández-Real, José Manuel

    2010-01-01

    Activation of the alternative pathway of the complement system, in which factor H (fH; complement fH [CFH]) is a key regulatory component, has been suggested as a link between obesity and metabolic disorders. Our objective was to study the associations between circulating and adipose tissue gene expressions of CFH and complement factor B (fB; CFB) with obesity and insulin resistance. Circulating fH and fB were determined by enzyme-linked immunosorbent assay in 398 subjects. CFH and CFB gene expressions were evaluated in 76 adipose tissue samples, in isolated adipocytes, and in stromovascular cells (SVC) (n = 13). The effects of weight loss and rosiglitazone were investigated in independent cohorts. Both circulating fH and fB were associated positively with BMI, waist circumference, triglycerides, and inflammatory parameters and negatively with insulin sensitivity and HDL cholesterol. For the first time, CFH gene expression was detected in human adipose tissue (significantly increased in subcutaneous compared with omental fat). CFH gene expression in omental fat was significantly associated with insulin resistance. In contrast, CFB gene expression was significantly increased in omental fat but also in association with fasting glucose and triglycerides. The SVC fraction was responsible for these differences, although isolated adipocytes also expressed fB and fH at low levels. Both weight loss and rosiglitazone led to significantly decreased circulating fB and fH levels. Increased circulating fH and fB concentrations in subjects with altered glucose tolerance could reflect increased SVC-induced activation of the alternative pathway of complement in omental adipose tissue linked to insulin resistance and metabolic disturbances.

  12. Evaluating the association of APOA2 polymorphism with insulin resistance in adolescents.

    PubMed

    Zaki, Moushira Erfan; Amr, Khalda Sayed; Abdel-Hamid, Mohamed

    2014-12-01

    265T>C SNP in the APOA-II gene promoter may be associated with obesity risk and insulin resistance (IR). This study aims to analyze the association between the APOA2 - 265T>C SNP and risk for obesity and IR in adolescents. The study was conducted on 500 adolescents. They were 240 obese and 260 non-obese individuals, aged 16-21 years old. Their mean age was 18.25 ± 2.54 years. Variables examined body weight, height, waist circumference (WC), systolic and diastolic blood pressure (BP), body fat percentage (BF%), and abdominal visceral fat layer. Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was used as a biomarker for IR. BF% was assessed by body composition analyzer and abdominal visceral fat thickness was determined by ultrasonography. The APOA2 - 265T>C polymorphism genotype was analyzed by PCR amplification of a 273-bp fragment. Genotype frequencies were in Hardy-Weinberg equilibrium. The frequency of the mutant C allele was significantly higher in obese cases than non-obese cases. After multivariate adjustment, waist, BF%, visceral adipose layer and HOMA-IR were significantly higher in homozygous allele CC carriers than TT + TC carriers. Homozygous individuals for the CC allele had statistically higher values of energy intake, total fat (g/day) and saturated fat (SATFAT) than carriers of the T allele. Homozygous individuals for the C allele had higher obesity risk than carriers of the T allele and had elevated levels of visceral adipose tissue. Moreover, the present study shows that the CC polymorphism is associated with the development of IR [OR 1.89 (1.35-2.91), P = .012] and remains significant after adjusting for gender, age and body mass index.

  13. Evaluating the association of APOA2 polymorphism with insulin resistance in adolescents

    PubMed Central

    Zaki, Moushira Erfan; Amr, Khalda Sayed; Abdel-Hamid, Mohamed

    2014-01-01

    Background 265T>C SNP in the APOA-II gene promoter may be associated with obesity risk and insulin resistance (IR). This study aims to analyze the association between the APOA2 − 265T>C SNP and risk for obesity and IR in adolescents. Material and methods The study was conducted on 500 adolescents. They were 240 obese and 260 non-obese individuals, aged 16–21 years old. Their mean age was 18.25 ± 2.54 years. Variables examined body weight, height, waist circumference (WC), systolic and diastolic blood pressure (BP), body fat percentage (BF%), and abdominal visceral fat layer. Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was used as a biomarker for IR. BF% was assessed by body composition analyzer and abdominal visceral fat thickness was determined by ultrasonography. The APOA2 − 265T>C polymorphism genotype was analyzed by PCR amplification of a 273-bp fragment. Results Genotype frequencies were in Hardy–Weinberg equilibrium. The frequency of the mutant C allele was significantly higher in obese cases than non-obese cases. After multivariate adjustment, waist, BF%, visceral adipose layer and HOMA-IR were significantly higher in homozygous allele CC carriers than TT + TC carriers. Homozygous individuals for the CC allele had statistically higher values of energy intake, total fat (g/day) and saturated fat (SATFAT) than carriers of the T allele. Conclusions Homozygous individuals for the C allele had higher obesity risk than carriers of the T allele and had elevated levels of visceral adipose tissue. Moreover, the present study shows that the CC polymorphism is associated with the development of IR [OR 1.89 (1.35–2.91), P = .012] and remains significant after adjusting for gender, age and body mass index. PMID:25606421

  14. IGF-1 and Insulin Resistance Are Major Determinants of Common Carotid Artery Thickness in Morbidly Obese Young Patients.

    PubMed

    Sirbu, Anca; Nicolae, Horia; Martin, Sorina; Barbu, Carmen; Copaescu, Catalin; Florea, Suzana; Panea, Cristina; Fica, Simona

    2016-03-01

    We assessed the relationship between insulin resistance, serum insulin-like growth factor 1 (IGF-1) levels, and common carotid intima-media thickness (CC-IMT) in morbidly obese young patients. A total of 249 patients (aged 37.9 ± 9.8 years, body mass index [BMI] 45.6 ± 8.3 kg/m(2)) were evaluated (metabolic tests, serum IGF-1 measurements, homeostasis model assessment-insulin resistance [HOMA-IR], and ultrasonographically assessed CC-IMT) in a research program for bariatric surgery candidates. After adjusting for age, gender, BMI, systolic blood pressure, uric acid, antihypertensive and lipid-lowering treatment, metabolic syndrome, and metabolic class, both HOMA-IR and IGF-1 z-score were significantly associated with CC-IMT. These results were confirmed in logistic regression analysis, in which age (β = 1.11, P = .001), gender (β = 3.19, P = .001), HOMA-IR (β = 1.221, P = .005), and IGF-1 z-score (β = 1.734, P = .009) were the only independent determinants of abnormal CC-IMT, presumably modulating the effect of the other risk factors included in the regression. Area under the receiver-operating characteristic curve for the model was 0.841 (confidence interval: 0.776-0.907; P < .001). In conclusion, in morbidly obese young adults, insulin resistance and IGF-1 z-score are significantly associated with CC-IMT, independent of other major cardiovascular risk factors. © The Author(s) 2015.

  15. Circulating ApoJ is closely associated with insulin resistance in human subjects.

    PubMed

    Seo, Ji A; Kang, Min-Cheol; Ciaraldi, Theodore P; Kim, Sang Soo; Park, Kyong Soo; Choe, Charles; Hwang, Won Min; Lim, Dong Mee; Farr, Olivia; Mantzoros, Christos; Henry, Robert R; Kim, Young-Bum

    2018-01-01

    Insulin resistance is a major risk factor for type 2 diabetes. ApolipoproteinJ (ApoJ) has been implicated in altered pathophysiologic states including cardiovascular and Alzheimer's disease. However, the function of ApoJ in regulation of glucose homeostasis remains unclear. This study sought to determine whether serum ApoJ levels are associated with insulin resistance in human subjects and if they change after interventions that improve insulin sensitivity. Serum ApoJ levels and insulin resistance status were assessed in nondiabetic (ND) and type 2 diabetic (T2D) subjects. The impacts of rosiglitazone or metformin therapy on serum ApoJ levels and glucose disposal rate (GDR) during a hyperinsulinemic/euglycemic clamp were evaluated in a separate cohort of T2D subjects. Total ApoJ protein or that associated with the HDL and LDL fractions was measured by immunoblotting or ELISA. Fasting serum ApoJ levels were greatly elevated in T2D subjects (ND vs T2D; 100±8.3 vs. 150.6±8.5AU, P<0.0001). Circulating ApoJ levels strongly correlated with fasting glucose, fasting insulin, HOMA-IR, and BMI. ApoJ levels were significantly and independently associated with HOMA-IR, even after adjustment for age, sex, and BMI. Rosiglitazone treatment in T2D subjects resulted in a reduction in serum ApoJ levels (before vs. after treatment; 100±13.9 vs. 77±15.2AU, P=0.015), whereas metformin had no effect on ApoJ levels. The change in ApoJ levels during treatment was inversely associated with the change in GDR. Interestingly, ApoJ content in the LDL fraction was inversely associated with HOMA-IR. Serum ApoJ levels are closely correlated with the magnitude of insulin resistance regardless of obesity, and decrease along with improvement of insulin resistance in response only to rosiglitazone in type 2 diabetes. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Uncoupling of Obesity from Insulin Resistance Through a Targeted Mutation in aP2, the Adipocyte Fatty Acid Binding Protein

    NASA Astrophysics Data System (ADS)

    Hotamisligil, Gokhan S.; Johnson, Randall S.; Distel, Robert J.; Ellis, Ramsey; Papaioannou, Virginia E.; Spiegelman, Bruce M.

    1996-11-01

    Fatty acid binding proteins (FABPs) are small cytoplasmic proteins that are expressed in a highly tissue-specific manner and bind to fatty acids such as oleic and retinoic acid. Mice with a null mutation in aP2, the gene encoding the adipocyte FABP, were developmentally and metabolically normal. The aP2-deficient mice developed dietary obesity but, unlike control mice, they did not develop insulin resistance or diabetes. Also unlike their obese wild-type counterparts, obese aP2-/- animals failed to express in adipose tissue tumor necrosis factor-α (TNF-α), a molecule implicated in obesity-related insulin resistance. These results indicate that aP2 is central to the pathway that links obesity to insulin resistance, possibly by linking fatty acid metabolism to expression of TNF-α.

  17. Adolescent Obesity and Insulin Resistance: Roles of Ectopic Fat Accumulation and Adipose Inflammation.

    PubMed

    Caprio, Sonia; Perry, Rachel; Kursawe, Romy

    2017-05-01

    As a consequence of the global rise in the prevalence of adolescent obesity, an unprecedented phenomenon of type 2 diabetes has emerged in pediatrics. At the heart of the development of type 2 diabetes lies a key metabolic derangement: insulin resistance (IR). Despite the widespread occurrence of IR affecting an unmeasurable number of youths worldwide, its pathogenesis remains elusive. IR in obese youth is a complex phenomenon that defies explanation by a single pathway. In this review we first describe recent data on the prevalence, severity, and racial/ethnic differences in pediatric obesity. We follow by elucidating the initiating events associated with the onset of IR, and describe a distinct "endophenotype" in obese adolescents characterized by a thin superficial layer of abdominal subcutaneous adipose tissue, increased visceral adipose tissue, marked IR, dyslipidemia, and fatty liver. Further, we provide evidence for the cellular and molecular mechanisms associated with this peculiar endophenotype and its relations to IR in the obese adolescent. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

  18. Contribution of the lean body mass to insulin resistance in postmenopausal women with visceral obesity: a Monet study.

    PubMed

    Brochu, Martin; Mathieu, Marie-Eve; Karelis, Antony D; Doucet, Eric; Lavoie, Marie-Eve; Garrel, Dominique; Rabasa-Lhoret, Rémi

    2008-05-01

    Some insulin-resistant obese postmenopausal (PM) women are characterized by an android body fat distribution type and higher levels of lean body mass (LBM) compared to insulin-sensitive obese PM women. This study investigates the independent contribution of LBM to the detrimental effect of visceral fat (VF) levels on the metabolic profile. One hundred and three PM women (age: 58.0+/-4.9 years) were studied and categorized in four groups on the basis of their VF (higher vs. lower) and lean BMI (LBMI=LBM (kg)/height (m2); higher vs. lower). Measures included: fasting lipids, glucose homeostasis (by euglycemic/hyperinsulinemic clamp technique and 2-h oral glucose tolerance test (OGTT)), C-reactive protein (CRP) levels, fat distribution (by computed tomography (CT) scan), and body composition (by dual-energy X-ray absorptiometry). Women in the higher VF/higher LBMI group had lower glucose disposal and higher plasma insulin levels compared to the other groups. They also had higher plasma CRP levels than the women in the lower VF/lower LBMI group. VF was independently associated with insulin levels, measures of glucose disposal, and CRP levels (P<0.05). LBMI was also independently associated with insulin levels, glucose disposal, and CRP levels (P<0.05). Finally, significant interactions were observed between LBMI and VF levels for insulin levels during the OGTT and measures of glucose disposal (P<0.05). In conclusion, VF and LBMI are both independently associated with alterations in glucose homeostasis and CRP levels. The contribution of VF to insulin resistance seems to be exacerbated by increased LBM in PM women.

  19. Short stature, abdominal obesity, insulin resistance and alterations in lipid profile in very low-income women living in Maceió, north-eastern Brazil.

    PubMed

    Florêncio, Telma T; Ferreira, Haroldo S; Cavalcante, Jairo C; Stux, Gabriela R; Sawaya, Ana L

    2007-04-01

    To test the hypothesis that short stature is associated with abdominal obesity, insulin resistance and lipid profile changes. Anthropometric data were collected from 237 women (18-60 years old), residents of a shantytown in Maceió. Biochemical profiles of 60 individuals drawn from this population were determined. Total and low-density lipoprotein (LDL) cholesterol levels and insulin resistance rose with increasing waist : hip circumference ratio, particularly in women. Short, overweight individuals exhibited larger biochemical alterations than overweight individuals of average stature. Short stature, when associated with overweight, is a risk factor for increased insulin resistance and alterations in lipid profile.

  20. Jejunal gluconeogenesis associated with insulin resistance level and its evolution after Roux-en-Y gastric bypass.

    PubMed

    Gutierrez-Repiso, Carolina; Garcia-Serrano, Sara; Moreno-Ruiz, Francisco J; Alcain-Martinez, Guillermo; Rodriguez-Pacheco, Francisca; Garcia-Fuentes, Eduardo

    2017-04-01

    Intestinal gluconeogenesis (GNG) may play an important role in glucose homeostasis, but there is little information about the condition in humans. To study the relationship between intestinal GNG and insulin resistance, its association with the evolution of morbidly obese patients after bariatric surgery, and the effect of insulin and or leptin. Regional university hospital, Malaga (Spain). Jejunal mRNA expression of genes involved in GNG was analyzed in 3 groups of morbidly obese patients who underwent Roux-en-Y gastric bypass: with low insulin resistance (MO-low-IR), with high insulin resistance (MO-high-IR), and with type 2 diabetes treated with metformin (MO-metf-T2D). Also, intestinal epithelial cells (IEC) from MO-low-IR were incubated with different doses of insulin and or leptin. In MO-high-IR, glutaminase, phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6 Pase), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 α), and sterol regulatory element-binding proteins 1 c (SREBP-1 c) expressions were significantly higher than in MO-low-IR. In MO-metf-T2 D, only PEPCK was significantly lower than in MO-high-IR. In IEC, an incubation with a high glucose and insulin dose produced an increase of PEPCK and SREBP-1 c, and a decrease of glutaminase, fructose 1,6-bisphosphatase (FBPase), and PGC-1 α expression. At high doses of leptin, G6 Pase and FBPase were significantly increased. The improvement of insulin resistance 3 months after bariatric surgery was positively associated with high G6 Pase and FBPase expression. mRNA expression of genes involved in GNG is increased in the jejunum of MO-high-IR, and regulated by insulin and or leptin. High mRNA expression of genes involved in GNG is associated with a better evolution of insulin resistance after bariatric surgery. Copyright © 2016 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

  1. Fat-Specific DsbA-L Overexpression Promotes Adiponectin Multimerization and Protects Mice From Diet-Induced Obesity and Insulin Resistance

    PubMed Central

    Liu, Meilian; Xiang, Ruihua; Wilk, Sarah Ann; Zhang, Ning; Sloane, Lauren B.; Azarnoush, Kian; Zhou, Lijun; Chen, Hongzhi; Xiang, Guangda; Walter, Christi A.; Austad, Steven N.; Musi, Nicolas; DeFronzo, Ralph A.; Asmis, Reto; Scherer, Philipp E.; Dong, Lily Q.; Liu, Feng

    2012-01-01

    The antidiabetic and antiatherosclerotic effects of adiponectin make it a desirable drug target for the treatment of metabolic and cardiovascular diseases. However, the adiponectin-based drug development approach turns out to be difficult due to extremely high serum levels of this adipokine. On the other hand, a significant correlation between adiponectin multimerization and its insulin-sensitizing effects has been demonstrated, suggesting a promising alternative therapeutic strategy. Here we show that transgenic mice overexpressing disulfide bond A oxidoreductase-like protein in fat (fDsbA-L) exhibited increased levels of total and the high-molecular-weight form of adiponectin compared with wild-type (WT) littermates. The fDsbA-L mice also displayed resistance to diet-induced obesity, insulin resistance, and hepatic steatosis compared with WT control mice. The protective effects of DsbA-L overexpression on diet-induced insulin resistance, but not increased body weight and fat cell size, were significantly decreased in adiponectin-deficient fDsbA-L mice (fDsbA-L/Ad−/−). In addition, the fDsbA-L/Ad−/− mice displayed greater activity and energy expenditure compared with adiponectin knockout mice under a high-fat diet. Taken together, our results demonstrate that DsbA-L protects mice from diet-induced obesity and insulin resistance through adiponectin-dependent and independent mechanisms. In addition, upregulation of DsbA-L could be an effective therapeutic approach for the treatment of obesity and its associated metabolic disorders. PMID:22807031

  2. Socioeconomic status is positively associated with measures of adiposity and insulin resistance, but inversely associated with dyslipidaemia in Colombian children

    PubMed Central

    Buitrago-Lopez, Adriana; van den Hooven, Edith H; Rueda-Clausen, Christian F; Serrano, Norma; Ruiz, Alvaro J; Pereira, Mark A; Mueller, Noel T

    2015-01-01

    Background Low socioeconomic status (SES) has been associated with higher risk of cardiometabolic diseases in developed societies, but investigation of SES and cardiometabolic risk in children in less economically developed populations is sparse. We aimed to examine associations among SES and cardiometabolic risk factors in Colombian children. Methods We used data from a population-based study of 1282 children aged 6–10 years from Bucaramanga, Colombia. SES was classified according to household wealth, living conditions and access to public utilities. Anthropometric and biochemical parameters were measured at a clinic visit. Cardiometabolic risk factors were analysed continuously using linear regression and as binary outcomes—according to established paediatric cut points—using logistic regression to calculate OR and 95% CIs. Results Mean age of the children was 8.4 (SD 1.4) and 51.1% of the sample were boys. Odds of overweight/obesity, abdominal obesity and insulin resistance were greater among higher SES. Compared with the lowest SES stratum, children in the highest SES had higher odds of overweight/obesity (OR=3.25, 95% CI 1.89 to 5.57), abdominal obesity (OR=2.74, 95% CI 1.41 to 5.31) and insulin resistance (OR=2.60, 95% CI 1.81 to 3.71). In contrast, children in the highest SES had lower odds of hypertriglyceridaemia (triglycerides ≥90th centile; OR=0.28, 95% CI 0.14 to 0.54) and low (≤10th centile) high-density lipoprotein (HDL) cholesterol (OR=0.35, 95% CI 0.15 to 0.78). Conclusions In Colombian children, SES is directly associated with obesity and insulin resistance, but inversely associated with dyslipidaemia (hypertriglyceridaemia and low HDL cholesterol). Our findings highlight the need to analyse cardiometabolic risk factors separately in children and to carefully consider a population's level of economic development when studying their social determinants of cardiometabolic disease. PMID:25691273

  3. The Apparent Relation between Plasma 25-Hydroxyvitamin D and Insulin Resistance Is Largely Attributable to Central Adiposity in Overweight and Obese Adults12

    PubMed Central

    Wright, Christian S; Weinheimer-Haus, Eileen M; Fleet, James C; Peacock, Munro; Campbell, Wayne W

    2015-01-01

    Background: Research indicates that plasma 25-hydroxyvitamin D [25(OH)D] is associated with insulin resistance, but whether regional adiposity confounds this association is unclear. Objective: This study assessed the potential influence of adiposity and its anatomical distribution on the relation between plasma 25(OH)D and insulin resistance. Methods: A secondary analysis of data from middle-aged overweight and obese healthy adults [n = 336: 213 women and 123 men; mean ± SD (range); age: 48 ± 8 y (35–65 y); body mass index (BMI; in kg/m2): 30.3 ± 2.7 (26–35)] from West Lafayette, Indiana (40.4°N), were used for this cross-sectional analysis. Multiple linear regression analyses that controlled for multiple covariates were used as the primary statistical model. Results: Of all participants, 8.6% and 20.5% displayed moderate [20.1–37.5 nmol/L plasma 25(OH)D] to mild (37.6–49.9 nmol/L) vitamin D insufficiency, respectively. A regression analysis controlling for age, sex, race, plasma parathyroid hormone concentration, season of year, and supplement use showed that 25(OH)D was negatively associated with fasting insulin (P = 0.021). Additional regression analyses showed that total and central adiposity but not peripheral adiposity predicted low plasma 25(OH)D [total fat mass index (FMI): P = 0.018; android FMI: P = 0.052; gynoid FMI: P = 0.15; appendicular FMI: P = 0.07) and insulin resistance (homeostasis model assessment of insulin resistance: total and android FMI, P <0.0001; gynoid FMI, P = 0.94; appendicular FMI, P = 0.86). The associations of total and central adiposity with insulin resistance remained significant after adjusting for plasma 25(OH)D. However, adjusting for central adiposity but not other anatomical measures of fat distribution eliminated the association between plasma 25(OH)D and insulin resistance. Conclusion: Central adiposity drives the association between plasma 25(OH)D and insulin resistance in overweight and obese adults. The trial

  4. PEDF-induced alteration of metabolism leading to insulin resistance.

    PubMed

    Carnagarin, Revathy; Dharmarajan, Arunasalam M; Dass, Crispin R

    2015-02-05

    Pigment epithelium-derived factor (PEDF) is an anti-angiogenic, immunomodulatory, and neurotrophic serine protease inhibitor protein. PEDF is evolving as a novel metabolic regulatory protein that plays a causal role in insulin resistance. Insulin resistance is the central pathogenesis of metabolic disorders such as obesity, type 2 diabetes mellitus, polycystic ovarian disease, and metabolic syndrome, and PEDF is associated with them. The current evidence suggests that PEDF administration to animals induces insulin resistance, whereas neutralisation improves insulin sensitivity. Inflammation, lipolytic free fatty acid mobilisation, and mitochondrial dysfunction are the proposed mechanism of PEDF-mediated insulin resistance. This review summarises the probable mechanisms adopted by PEDF to induce insulin resistance, and identifies PEDF as a potential therapeutic target in ameliorating insulin resistance. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  5. The fruit of Acanthopanax senticosus (Rupr. et Maxim.) Harms improves insulin resistance and hepatic lipid accumulation by modulation of liver adenosine monophosphate-activated protein kinase activity and lipogenic gene expression in high-fat diet-fed obese mice.

    PubMed

    Saito, Tetsuo; Nishida, Miyako; Saito, Masafumi; Tanabe, Akari; Eitsuka, Takahiro; Yuan, Shi-Hua; Ikekawa, Nobuo; Nishida, Hiroshi

    2016-10-01

    Obesity-associated insulin resistance is a major risk factor for most metabolic diseases, including dyslipidemia and type 2 diabetes. Acanthopanax senticosus (Rupr. et Maxim.) Harms (Goka) root has been used in traditional Chinese medicine for treatment of diabetes and other conditions; however, little is known about the effects of Goka fruit (GF). Goka fruit is rich in anthocyanin, which has beneficial effects on obesity and insulin resistance via activation of adenosine monophosphate-activated protein kinase (AMPK). We hypothesized that GF can improve obesity-associated insulin resistance. The aim of the present study was to investigate whether GF improves insulin resistance in high-fat diet (HFD)-induced obese mice. High-fat diet mice treated with GF (500 and 1000 mg/kg) for 12 weeks showed an improved glucose tolerance and insulin sensitivity, as well as reduced plasma insulin and liver lipid accumulation. Moreover, GF administration to HFD mice resulted in down-regulation of fatty acid synthase expression and up-regulation of cholesterol 7-alpha-hydroxylase expression in the liver. Notably, AMPK phosphorylation in the liver increased after GF administration. In summary, GF supplementation improved obesity-associated insulin resistance and hepatic lipid accumulation through modulation of AMPK activity and lipid metabolism-associated gene expression. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Adipose-specific deletion of Kif5b exacerbates obesity and insulin resistance in a mouse model of diet-induced obesity.

    PubMed

    Cui, Ju; Pang, Jing; Lin, Ya-Jun; Gong, Huan; Wang, Zhen-He; Li, Yun-Xuan; Li, Jin; Wang, Zai; Jiang, Ping; Dai, Da-Peng; Li, Jian; Cai, Jian-Ping; Huang, Jian-Dong; Zhang, Tie-Mei

    2017-06-01

    Recent studies have shown that KIF5B (conventional kinesin heavy chain) mediates glucose transporter type 4 translocation and adiponectin secretion in 3T3-L1 adipocytes, suggesting an involvement of KIF5B in the homeostasis of metabolism. However, the in vivo physiologic function of KIF5B in adipose tissue remains to be determined. In this study, adipose-specific Kif5b knockout (F-K5bKO) mice were generated using the Cre-LoxP strategy. F-K5bKO mice had similar body weights to controls fed on a standard chow diet. However, F-K5bKO mice had hyperlipidemia and significant glucose intolerance and insulin resistance. Deletion of Kif5b aggravated the deleterious impact of a high-fat diet (HFD) on body weight gain, hepatosteatosis, glucose tolerance, and systematic insulin sensitivity. These changes were accompanied by impaired insulin signaling, decreased secretion of adiponectin, and increased serum levels of leptin and proinflammatory adipokines. F-K5bKO mice fed on an HFD exhibited lower energy expenditure and thermogenic dysfunction as a result of whitening of brown adipose due to decreased mitochondria biogenesis and down-regulation of key thermogenic gene expression. In conclusion, selective deletion of Kif5b in adipose tissue exacerbates HFD-induced obesity and its associated metabolic disorders, partly through a decrease in energy expenditure, dysregulation of adipokine secretion, and insulin signaling.-Cui, J., Pang, J., Lin, Y.-J., Gong, H., Wang, Z.-H., Li, Y.-X., Li, J., Wang, Z., Jiang, P., Dai, D.-P., Li, J., Cai, J.-P., Huang, J.-D., Zhang, T.-M. Adipose-specific deletion of Kif5b exacerbates obesity and insulin resistance in a mouse model of diet-induced obesity. © FASEB.

  7. Insulin resistance in the control of body fat distribution: a new hypothesis.

    PubMed

    Ali, A T; Ferris, W F; Naran, N H; Crowther, N J

    2011-02-01

    Obesity causes insulin resistance, which is a prime etiological factor for type 2 diabetes, dyslipidemia, and cardiovascular disease. However, insulin resistance may be a normal physiological response to obesity that limits further fat deposition and which only has pathological effects at high levels. The current hypothesis suggests that in obesity the initial deposition of triglycerides occurs in subcutaneous adipose tissue and as this increases in size insulin resistance will rise and limit further subcutaneous lipid accumulation. Triglycerides will then be diverted to the visceral fat depot as well as to ectopic sites. This leads to a substantial rise in insulin resistance and the prevalence of its associated disorders. Evidence supporting this hypothesis includes studies showing that in lean subjects the prime determinant of insulin resistance is BMI, that is, subcutaneous fat whilst in overweight and obese subjects it is waist circumference and visceral adiposity. It has also been shown that the metabolic syndrome suddenly increases in prevalence at high levels of insulin resistance and we suggest that this is due to the diversion of lipids from the subcutaneous to the visceral depot. This system may have functioned in our evolutionary past to limit excessive adiposity by causing lipid deposition to occur at a site that has maximal effects on insulin resistance but involves minimal weight gain. © Georg Thieme Verlag KG Stuttgart · New York.

  8. Age-related inflammation and insulin resistance: a review of their intricate interdependency.

    PubMed

    Park, Min Hi; Kim, Dae Hyun; Lee, Eun Kyeong; Kim, Nam Deuk; Im, Dong Soon; Lee, Jaewon; Yu, Byung Pal; Chung, Hae Young

    2014-12-01

    Chronic inflammation is a major risk factor underlying aging and the associated diseases of aging; of particular interest is insulin resistance during aging. Chronic inflammation impairs normal lipid accumulation, adipose tissue function, mitochondrial function, and causes endoplasmic reticulum (ER) stress, which lead to insulin resistance. However, some studies show that insulin resistance itself amplifies chronic inflammation. The activity of the insulin-dependent Akt signaling pathway is highlighted because of its decrease in insulin-sensitive organs, like liver and muscle, which may underlie insulin resistance and hyperinsulinemia, and its increased levels in non-metabolic organs, such as kidney and aorta. In that the prevalence of obesity has increased substantially for all age groups in recent years, our review summarizes the data showing the involvement of chronic inflammation in obesity-induced insulin resistance, which perpetuates reciprocal interactions between the chronic inflammatory process and increased adiposity, thereby accelerating the aging process.

  9. The efficacy and tolerability of azilsartan in obese insulin-resistant mice with left ventricular pressure overload.

    PubMed

    Tarikuz Zaman, A K M; McLean, Danielle L; Sobel, Burton E

    2013-10-01

    Angiotensin II receptor blockers (ARBs) are used widely for the treatment of heart failure. However, their use in obese and insulin-resistant patients remains controversial. To clarify their potential efficacy in these conditions, we administered azilsartan medoxomil (azilsartan), a prodrug of an angiotensin II receptor blocker to mice fed a high-fat diet (HFD) with left ventricular (LV) pressure overload (aortic banding). LV fibrosis (hydroxyproline), cardiac plasminogen activator inhibitor-1 (PAI-1; a marker of profibrosis), and creatine kinase (a marker of myocardial viability and energetics) were assessed. LV wall thickness and cardiac function were assessed echocardiographically. Mice given a HFD were obese and insulin resistant. Their LV hypertrophy was accompanied by greater LV PAI-1 and reduced LV creatine kinase compared with normal diet controls. Drug treatment reduced LV wall thickness, hypertrophy, and PAI-1 and increased cardiac output after aortic banding compared with results in HFD vehicle controls. Thus, azilsartan exerted favorable biological effects on the hearts of obese insulin-resistant mice subjected to LV pressure overload consistent with its potential utility in patients with analogous conditions.

  10. Targeted metabolomic analysis reveals the association between the postprandial change in palmitic acid, branched-chain amino acids and insulin resistance in young obese subjects.

    PubMed

    Liu, Liyan; Feng, Rennan; Guo, Fuchuan; Li, Ying; Jiao, Jundong; Sun, Changhao

    2015-04-01

    Obesity is the result of a positive energy balance and often leads to difficulties in maintaining normal postprandial metabolism. The changes in postprandial metabolites after an oral glucose tolerance test (OGTT) in young obese Chinese men are unclear. In this work, the aim is to investigate the complex metabolic alterations in obesity provoked by an OGTT using targeted metabolomics. We used gas chromatography-mass spectrometry and ultra high performance liquid chromatography-triple quadrupole mass spectrometry to analyze serum fatty acids, amino acids and biogenic amines profiles from 15 control and 15 obese subjects at 0, 30, 60, 90 and 120 min during an OGTT. Metabolite profiles from 30 obese subjects as independent samples were detected in order to validate the change of metabolites. There were the decreased levels of fatty acid, amino acids and biogenic amines after OGTT in obesity. At 120 min, percent change of 20 metabolites in obesity has statistical significance when comparing with the controls. The obese parameters was positively associated with changes in arginine and histidine (P<0.05) and the postprandial change in palmitic acid (PA), branched-chain amino acids (BCAAs) and phenylalanine between 1 and 120 min were positively associated with fasting insulin and HOMA-IR (all P<0.05) in the obese group. The postprandial metabolite of PA and BCAAs may play important role in the development and onset of insulin resistance in obesity. Our findings offer new insights in the complex physiological regulation of the metabolism during an OGTT in obesity. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  11. Correlation of P-wave dispersion with insulin sensitivity in obese adolescents.

    PubMed

    Sert, Ahmet; Aslan, Eyup; Buyukınan, Muammer; Pirgon, Ozgur

    2017-03-01

    P-wave dispersion is a new and simple electrocardiographic marker that has been reported to be associated with inhomogeneous and discontinuous propagation of sinus impulses. In the present study, we evaluated P-wave dispersion in obese adolescents and investigated the relationship between P-wave dispersion, cardiovascular risk factors, and echocardiographic parameters. We carried out a case-control study comparing 150 obese adolescents and 50 healthy controls. Maximum and minimum P-wave durations were measured using a 12-lead surface electrocardiogram, and P-wave dispersion was calculated as the difference between these two measures. Echocardiographic examination was also performed for each subject. Multivariate linear regression analysis with stepwise variable selection was used to evaluate parameters associated with increased P-wave dispersion in obese subjects. Maximum P-wave duration and P-wave dispersion were significantly higher in obese adolescents than control subjects (143±19 ms versus 117±20 ms and 49±15 ms versus 29±9 ms, p<0.0001 for both). P-wave dispersion was positively correlated with body mass index, waist and hip circumferences, systolic and diastolic blood pressures, total cholesterol, serum levels of low-density lipoprotein cholesterol, triglycerides, glucose, and insulin, homoeostasis model assessment for insulin resistance score, left ventricular mass, and left atrial dimension. P-wave dispersion was negatively correlated with high-density lipoprotein cholesterol levels. By multiple stepwise regression analysis, left atrial dimension (β: 0.252, p=0.008) and homoeostasis model assessment for insulin resistance (β: 0.205; p=0.009) were independently associated with increased P-wave dispersion in obese adolescents. Insulin resistance is a significant, independent predictor of P-wave dispersion in obese adolescents.

  12. Insulin Sensitivity Determines Effects of Insulin and Meal Ingestion on Systemic Vascular Resistance in Healthy Subjects.

    PubMed

    Woerdeman, Jorn; Meijer, Rick I; Eringa, Etto C; Hoekstra, Trynke; Smulders, Yvo M; Serné, Erik H

    2016-01-01

    In addition to insulin's metabolic actions, insulin can dilate arterioles which increase blood flow to metabolically active tissues. This effect is blunted in insulin-resistant subjects. Insulin's effect on SVR, determined by resistance arterioles, has, however, rarely been examined directly. We determined the effects of both hyperinsulinemia and a mixed meal on SVR and its relationship with insulin sensitivity. Thirty-seven lean and obese women underwent a hyperinsulinemic-euglycemic clamp, and 24 obese volunteers underwent a mixed-meal test. SVR was assessed using CPP before and during hyperinsulinemia as well as before and 60 and 120 minutes after a meal. SVR decreased significantly during hyperinsulinemia (-13%; p < 0.001) and after the meal (-11%; p < 0.001). Insulin decreased SVR more strongly in insulin-sensitive individuals (standardized β: -0.44; p = 0.01). In addition, SVR at 60 minutes after meal ingestion was inversely related to the Matsuda index (β: -0.39; p = 0.04) and the change in postprandial SVR was directly related to postprandial glycemia (β: 0.53; p < 0.01). Hyperinsulinemia and meal ingestion decrease SVR, which is directly associated with metabolic insulin resistance. This suggests that resistance to insulin-induced vasodilatation contributes to regulation of vascular resistance. © 2015 John Wiley & Sons Ltd.

  13. Familial and individual predictors of obesity and insulin resistance in urban Hispanic children

    PubMed Central

    Santiago-Torres, Margarita; Cui, Yuchen; Adams, Alexandra K.; Allen, David B.; Carrel, Aaron L.; Guo, Jessica Y.; Delgado-Rendon, Angelica; LaRowe, Tara L.; Schoeller, Dale A.

    2015-01-01

    Background High intake of sugar-sweetened beverages (SSB) has been suggested to contribute to the pediatric obesity epidemic, however, how the home food environment influence children’s intake of SSB among Hispanic families is still poorly understood. Objectives To evaluate the relationships between the home food environment and Hispanic children’s diet in relation to weight status and insulin resistance (IR). Methods A food frequency questionnaire was administered to 187 Hispanic children (ages 10 to 14 years), and anthropometrics were measured. IR was estimated from fasting insulin and glucose levels using the homeostasis model assessment of insulin resistance (HOMAIR). Parents reported on family demographics and the home food environment. A structural equation modeling approach was applied to examine the hypothesized relationships among variables. Results The prevalence of childhood overweight and obesity was 52.8% and it was positively associated with HOMAIR (β=0.687, P <.0001). Children’s SSB consumption was positively associated with children’s BMI z-score (β=0.151, P <0.05) and subsequently to HOMAIR. Children’s SSB consumption was predicted by home availability (β=0.191) and parental intake of SSB (β=0.419) (P <0.05). The model fit indices [X2 = 45.821 (d.f. = 30, P > 0.01 and < 0.05), X2/d.f. = 1.53, RMSEA = 0.053 (90% C.I. = 0.016, 0.082), CFI = 0.904] suggested a satisfactory goodness-of-fit. Conclusions The home food environment and parental diet seem to play an important role in the children’s access to and intake of SSB, which in turn predicted children’s weight status. PMID:25728238

  14. Association of insulin resistance with breast, ovarian, endometrial and cervical cancers in non-diabetic women

    PubMed Central

    Sun, Wanwan; Lu, Jieli; Wu, Shengli; Bi, Yufang; Mu, Yiming; Zhao, Jiajun; Liu, Chao; Chen, Lulu; Shi, Lixin; Li, Qiang; Yang, Tao; Yan, Li; Wan, Qin; Liu, Yan; Wang, Guixia; Luo, Zuojie; Tang, Xulei; Chen, Gang; Huo, Yanan; Gao, Zhengnan; Su, Qing; Ye, Zhen; Wang, Youmin; Qin, Guijun; Deng, Huacong; Yu, Xuefeng; Shen, Feixia; Chen, Li; Zhao, Liebin; Wang, Tiange; Sun, Jichao; Xu, Min; Xu, Yu; Chen, Yuhong; Dai, Meng; Zhang, Jie; Zhang, Di; Lai, Shenghan; Li, Donghui; Ning, Guang; Wang, Weiqing

    2016-01-01

    Hyperinsulinemia and insulin resistance were reported to play a crucial role in diabetes-cancer relationship. This study aimed to explore the associations between insulin resistance and several female cancers in a non-diabetic population. This cross-sectional study was conducted in 121,230 middle-aged and elderly non-diabetic women. Cancer diagnosis was self-reported and further validated by medical records. Insulin resistance was defined as homeostasis model assessment of insulin resistance (HOMA-IR) ≥ 2.50. The prevalence of both premenopausal and postmenopausal breast cancer, postmenopausal ovarian cancer and premenopausal endometrial cancer were higher in insulin-resistant participants than in insulin-sensitive participants (premenopausal breast cancer, 0.45 vs 0.28%; postmenopausal breast cancer, 0.86 vs 0.63%; postmenopausal ovarian cancer, 0.17 vs 0.09%; premenopausal endometrial cancer, 0.43 vs 0.25%, respectively, all P < 0.05). Individuals with insulin resistance had higher odds ratio (OR) of breast cancer, both premenopausal and postmenopausal (OR 1.98, 95% confidence interval (CI) 1.19-3.32; OR 1.29, 95% CI 1.01-1.63), postmenopausal ovarian cancer (OR 2.17, 95% CI 1.10-3.40) as well as total endometrial cancer (OR 1.47, 95% CI 1.02-2.12). Subgroup analysis revealed that the possitive association between insulin resistance and risk of prevalent breast cancer was observed in popualtion with younger age, overweight or obesity, higher education and impaired glucose tolerance (IGR). No relationships were observed for the risk of prevalent cervical cancers with insulin resistance. Non-diabetic women with insulin resistance had higher risk of prevalent breast, ovarian and endomatrial cancer, which suggests special attentions to these female cancer screening and prevention. PMID:27822422

  15. WNIN/GR-Ob - an insulin-resistant obese rat model from inbred WNIN strain.

    PubMed

    Harishankar, N; Vajreswari, A; Giridharan, N V

    2011-09-01

    WNIN/GR-Ob is a mutant obese rat strain with impaired glucose tolerance (IGT) developed at the National Institute of Nutrition (NIN), Hyderabad, India, from the existing 80 year old Wistar rat (WNIN) stock colony. The data presented here pertain to its obese nature along with IGT trait as evidenced by physical, physiological and biochemical parameters. The study also explains its existence, in three phenotypes: homozygous lean (+/+), heterozygous carrier (+/-) and homozygous obese (-/-). Thirty animals (15 males and 15 females) from each phenotype (+/+, +/-, -/-) and 24 lean and obese (6 males and 6 females) rats were taken for growth and food intake studies respectively. Twelve adult rats from each phenotype were taken for body composition measurement by total body electrical conductivity (TOBEC); 12 rats of both genders from each phenotype at different ages were taken for clinical chemistry parameters. Physiological indices of insulin resistance were calculated according to the homeostasis model assessment for insulin resistance (HOMA-IR) and also by studying U¹⁴C 2-deoxy glucose uptake (2DG). WNINGR-Ob mutants had high growth, hyperphagia, polydipsia, polyurea, glycosuria, and significantly lower lean body mass, higher fat mass as compared with carrier and lean rats. These mutants, at 50 days of age displayed abnormal response to glucose load (IGT), hyperinsulinaemia, hypertriglyceridaemia, hypercholesterolaemia and hyperleptinaemia. Basal and insulin-stimulated glucose uptakes by diaphragm were significantly decreased in obese rats as compared with lean rats. Obese rats of the designated WNIN/GR-Ob strain showed obesity with IGT, as adjudged by physical, physiological and biochemical indices. These indices varied among the three phenotypes, being lowest in lean, highest in obese and intermediate in carrier phenotypes thereby suggesting that obesity is inherited as autosomal incomplete dominant trait in this strain. This mutant obese rat model is easy to

  16. Association of glycosylated hemoglobin (HbA1c) levels with Iinsulin resistance in obese children.

    PubMed

    Onal, Zehra Esra; Atasayan, Vildan; Gürbüz, Tamay; Hepkaya, Evrim; Nuhoğlu, Cağatay

    2014-09-01

    We investigated the relationship between insulin resistance reflected by homeostasis model assessment (HOMA-IR) index and serum HbA1c levels of obese children. This study included 70 obese and 60 normal weight healthy children between the ages of 3 and 15. Anthropometric measures and biochemical tests (fasting glucose, fasting insulin, HbA1c) were performed on all subjects. Plasma glucose levels were measured by the glucose oxidase method. Plasma insulin concentrations were measured by radioimmunoassay (RIA). HOMA-IR index was used to estimate insulin resistance. A cut-off HOMA-IR level of ≥2.5 was accepted. The HbA1c analysis was performed using high-pressure liquid chromatography. The statistical analysis was performed using SPSS 5. Student's unpaired t-test and the Mann-Whitney U test were used to determine statistical significance. Gender distribution did not reveal significant difference among the obese (F: 48.6%, M: 51.4%) and the non-obese (F: 46.7%, M: 53.3%) groups. The mean age value was significantly higher in the obese group (10.09 ± 3.09) (p > 0.005) than the non-obese group (8.31 ± 3.14) (p < 0.05). The mean value of body mass index (BMI) was 25.55 ± 4.3 in the obese group and 16.63 ± 2.3 in the non-obese group. The mean HOMA-IR values of obese group (2.84 ± 1.77) was significantly higher than the non-obese group (1.50 ± 0.95) (p < 0.005). Insulin resistance was significantly higher in the obese group. Subjects with HOMA-IR ≥2.5 levels in the obese group had significantly higher HbA1c values than those with HOMA-IR <2.5 levels. High HbA1c levels in obese children can be used as a screening tool to detect insulin sensitivity and resistance at an early stage.

  17. [Insulin resistance--a physiopathological condition with numerous sequelae: non-insulin-dependent diabetes mellitus (NIDDM), android obesity, essential hypertension, dyslipidemia and atherosclerosis].

    PubMed

    Pedersen, O

    1992-05-11

    Recent research has demonstrated that reduced insulin-stimulated glucose metabolism in skeletal muscle (insulin resistance) and hyperinsulinism are common features in widespread diseases such as essential hypertension, android obesity, non-insulin dependent diabetes mellitus, dyslipidemia (in the form of raised serum triglyceride and reduced serum high-density lipoprotein (HDL) cholesterol) and arteriosclerosis. Simultaneously, investigations in a comprehensive group of healthy middle-aged men have revealed insulin resistance in one fourth. On the basis of these observations, a working hypothesis is suggested which postulates that genetic abnormalities in one or more of the candidate genes in the modes of action of insulin occur in a great proportion of the population. These may result in insulin resistance (primary genetic insulin resistance). Primary insulin resistance may be potentiated by a series of circumstances such as ageing, high-fat diet, lack of physical activity, hormonal and metabolic abnormalities or drugs (secondary insulin resistance). As a consequence of the reduced effect of insulin on muscle tissue, compensatory hyperinsulinism develops. Depending on the remaining vulnerability of the individual the hyperinsulinism is presumed to result in development of one or more phenotypes. For example if the beta-cells of the pancreas are unable to secrete sufficient insulin to compensate the insulin resistance on account of genetic defects, glucose intolerance will develop. In a similar manner, hyperinsulinism in insulin-resistant individuals who are predisposed to essential hypertension is presumed to reveal genetic defects in the blood pressure regulating mechanisms and thus contribute to development of the disease.(ABSTRACT TRUNCATED AT 250 WORDS)

  18. JNK Activation of BIM Promotes Hepatic Oxidative Stress, Steatosis, and Insulin Resistance in Obesity.

    PubMed

    Litwak, Sara A; Pang, Lokman; Galic, Sandra; Igoillo-Esteve, Mariana; Stanley, William J; Turatsinze, Jean-Valery; Loh, Kim; Thomas, Helen E; Sharma, Arpeeta; Trepo, Eric; Moreno, Christophe; Gough, Daniel J; Eizirik, Decio L; de Haan, Judy B; Gurzov, Esteban N

    2017-12-01

    The members of the BCL-2 family are crucial regulators of the mitochondrial pathway of apoptosis in normal physiology and disease. Besides their role in cell death, BCL-2 proteins have been implicated in the regulation of mitochondrial oxidative phosphorylation and cellular metabolism. It remains unclear, however, whether these proteins have a physiological role in glucose homeostasis and metabolism in vivo. In this study, we report that fat accumulation in the liver increases c-Jun N-terminal kinase-dependent BCL-2 interacting mediator of cell death (BIM) expression in hepatocytes. To determine the consequences of hepatic BIM deficiency in diet-induced obesity, we generated liver-specific BIM-knockout (BLKO) mice. BLKO mice had lower hepatic lipid content, increased insulin signaling, and improved global glucose metabolism. Consistent with these findings, lipogenic and lipid uptake genes were downregulated and lipid oxidation enhanced in obese BLKO mice. Mechanistically, BIM deficiency improved mitochondrial function and decreased oxidative stress and oxidation of protein tyrosine phosphatases, and ameliorated activation of peroxisome proliferator-activated receptor γ/sterol regulatory element-binding protein 1/CD36 in hepatocytes from high fat-fed mice. Importantly, short-term knockdown of BIM rescued obese mice from insulin resistance, evidenced by reduced fat accumulation and improved insulin sensitivity. Our data indicate that BIM is an important regulator of liver dysfunction in obesity and a novel therapeutic target for restoring hepatocyte function. © 2017 by the American Diabetes Association.

  19. Cellular and molecular players in adipose tissue inflammation in the development of obesity-induced insulin resistance.

    PubMed

    Lee, Byung-Cheol; Lee, Jongsoon

    2014-03-01

    There is increasing evidence showing that inflammation is an important pathogenic mediator of the development of obesity-induced insulin resistance. It is now generally accepted that tissue-resident immune cells play a major role in the regulation of this obesity-induced inflammation. The roles that adipose tissue (AT)-resident immune cells play have been particularly extensively studied. AT contains most types of immune cells and obesity increases their numbers and activation levels, particularly in AT macrophages (ATMs). Other pro-inflammatory cells found in AT include neutrophils, Th1 CD4 T cells, CD8 T cells, B cells, DCs, and mast cells. However, AT also contains anti-inflammatory cells that counter the pro-inflammatory immune cells that are responsible for the obesity-induced inflammation in this tissue. These anti-inflammatory cells include regulatory CD4 T cells (Tregs), Th2 CD4 T cells, and eosinophils. Hence, AT inflammation is shaped by the regulation of pro- and anti-inflammatory immune cell homeostasis, and obesity skews this balance towards a more pro-inflammatory status. Recent genetic studies revealed several molecules that participate in the development of obesity-induced inflammation and insulin resistance. In this review, the cellular and molecular players that participate in the regulation of obesity-induced inflammation and insulin resistance are discussed, with particular attention being placed on the roles of the cellular players in these pathogeneses. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease. Copyright © 2013 Elsevier B.V. All rights reserved.

  20. Associations Between Insulin Resistance, Free Fatty Acids, and Oocyte Quality in Polycystic Ovary Syndrome During In Vitro Fertilization

    PubMed Central

    Niu, Zhihong; Lin, Nan; Gu, Ruihuan; Sun, Yijuan

    2014-01-01

    Context: Both polycystic ovary syndrome (PCOS) and obesity are associated with specific reproductive health complications, including lower oocyte quality and clinical pregnancy rates in assisted conception cycles, which may be a result of metabolism-induced changes in the oocyte through the microenvironment of follicular fluid. Free fatty acids (FFAs) are important biomedical indicators of abnormal lipid metabolism and have pronounced effects on cells, leading to changes in metabolism, cell growth, and differentiation Objective: Our objective was to determine the effect of FFA metabolism in plasma and follicular fluid on oocyte quality in the women with PCOS undergoing in vitro fertilization. Design and Setting: Ninety-three women undergoing in vitro fertilization treatment, including 55 with PCOS and 38 age-matched controls, were recruited. PCOS patients were divided into obese and nonobese subgroups on the basis of their body mass index. Main Outcome Measures: Embryo quality was morphologically assessed, and serum sex hormone and insulin levels were measured. FFAs in plasma and follicular fluid were measured using gas chromatography-mass spectrometry. Results: PCOS was found to be associated with significantly higher LH/FSH, total T, free androgen index (FAI), and lower SHBG levels, independent of obesity(P < .05). Obese women with PCOS had a significantly higher total T level, FAI, fasting insulin, insulin resistance index as determined by homeostasis model assessment for insulin resistance, and lower SHBG levels than the nonobese women with PCOS (P < .05). The embryo fragmentation score was significantly positively correlated with the oleic acid concentration in all PCOS patients (r = 0.22, P = .04, for nonobese patients and r = 0.25, P = .03, for obese patients). Conclusions: Our findings clearly demonstrated that PCOS is associated with significantly higher FAI and insulin resistance levels and decreased plasma SHBG levels, independent of body mass index

  1. Molecular Mechanisms of Chromium in Alleviating Insulin Resistance

    PubMed Central

    Hua, Yinan; Clark, Suzanne; Ren, Jun; Sreejayan, Nair

    2011-01-01

    Type 2 diabetes is often associated with obesity, dyslipidemia, and cardiovascular anomalies and is a major health problem approaching global epidemic proportions. Insulin resistance, a prediabetic condition, precedes the onset of frank type 2 diabetes and offers potential avenues for early intervention to treat the disease. Although lifestyle modifications and exercise can reduce the incidence of diabetes, compliance has proved to be difficult, warranting pharmacological interventions. However, most of the currently available drugs that improve insulin sensitivity have adverse effects. Therefore, attractive strategies to alleviate insulin resistance include dietary supplements. One such supplement is chromium, which has been shown reduce insulin resistance in some, but not all, studies. Furthermore, the molecular mechanisms of chromium in alleviating insulin resistance remain elusive. This review examines emerging reports on the effect of chromium, as well as molecular and cellular mechanisms by which chromium may provide beneficial effects in alleviating insulin resistance. PMID:22423897

  2. Current role of the NLRP3 inflammasome on obesity and insulin resistance: A systematic review.

    PubMed

    Rheinheimer, Jakeline; de Souza, Bianca M; Cardoso, Natali S; Bauer, Andrea C; Crispim, Daisy

    2017-09-01

    NLRP3 inflammasome activation seems to be a culprit behind the chronic inflammation characteristic of obesity and insulin resistance (IR). Nutrient excess generates danger-associated molecules that activate NLRP3 inflammasome-caspase 1, leading to maturation of IL-1β and IL-18, which are proinflammatory cytokines released by immune cells infiltrating the adipose tissue (AT) from obese subjects. Although several studies have reported an association of the NLRP3 inflammasome with obesity and/or IR; contradictory results were also reported by other studies. Therefore, we conducted a systematic review to summarize results of studies that evaluated the association of the NLRP3 with obesity and IR. Nineteen studies were included in the review. These studies focused on NLRP3 expression/polymorphism analyses in AT. Overall, human studies indicate that obesity and IR are associated with increased NLRP3 expression in AT. Studies in obese mice corroborate this association. Moreover, high fat diet (HFD) increases Nlrp3 expression in murine AT while calorie-restricted diet decreases its expression. Hence, Nlrp3 blockade in mice protects against HFD-induced obesity and IR. NLRP3 rs10754558 polymorphism is associated with risk for T2DM in Chinese Han populations. In conclusion, available studies strongly points for an association between NLRP3 inflammasome and obesity/IR. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Endoplasmic reticulum stress regulates inflammation and insulin resistance in skeletal muscle from pregnant women.

    PubMed

    Liong, Stella; Lappas, Martha

    2016-04-15

    Sterile inflammation and infection are key mediators of inflammation and peripheral insulin resistance associated with gestational diabetes mellitus (GDM). Studies have shown endoplasmic reticulum (ER) stress to induce inflammation and insulin resistance associated with obesity and type 2 diabetes, however is paucity of studies investigating the effects of ER stress in skeletal muscle on inflammation and insulin resistance associated with GDM. ER stress proteins IRE1α, GRP78 and XBP-1s were upregulated in skeletal muscle of obese pregnant women, whereas IRE1α was increased in GDM women. Suppression of ER stress, using ER stress inhibitor tauroursodeoxycholic acid (TUDCA) or siRNA knockdown of IRE1α and GRP78, significantly downregulated LPS-, poly(I:C)- or IL-1β-induced production of IL-6, IL-8, IL-1β and MCP-1. Furthermore, LPS-, poly(I:C)- or TNF-α-induced insulin resistance was improved following suppression of ER stress, by increasing insulin-stimulated phosphorylation of IR-β, IRS-1, GLUT-4 expression and glucose uptake. In summary, our inducible obesity and GDM-like models suggests that the development of GDM may be involved in activating ER stress-induced inflammation and insulin resistance in human skeletal muscle. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  4. Fasting serum insulin and the homeostasis model of insulin resistance (HOMA-IR) in the monitoring of lifestyle interventions in obese persons.

    PubMed

    Vogeser, Michael; König, Daniel; Frey, Ingrid; Predel, Hans-Georg; Parhofer, Klaus Georg; Berg, Aloys

    2007-09-01

    Lifestyle changes with increased physical activity and balanced energy intake are recognized as the principal interventions in obesity and insulin resistance. Only few prospective studies, however, have so far addressed the potential role of routine biochemical markers of insulin sensitivity in the monitoring of respective interventions. Fasting insulin and glucose was measured in 33 obese individuals undergoing a lifestyle modification program (MOBILIS) at baseline and after 1 year. The HOMA-IR index (homeostasis model of insulin resistance) was calculated as [fasting serum glucose*fasting serum insulin/22.5], with lower values indicating a higher degree of insulin sensitivity. While the median body mass index (BMI) and waist circumference decreased by 10% and 11%, respectively, the HOMA-IR index decreased in an over-proportional manner by 45% within 1 year (BMI baseline, median 35.7, interquartile range (IQR) 33.7-37.7; after 1 year, median 32.2, IQR 29.6-35.1. HOMA-IR baseline, median 2.9, IQR 1.5-4.6; after 1 year 1.6, IQR 0.9-2.7). In contrast to HOMA-IR and fasting serum insulin, no significant changes in fasting serum glucose were observed. Baseline and post-intervention HOMA-IR showed a high degree of inter-individual variation with eight individuals maintaining high HOMA-IR values despite weight loss after 1 year of intervention. Individual changes in the carbohydrate metabolism achieved by a lifestyle intervention program were displayed by fasting serum insulin concentrations and the HOMA-IR but not by fasting glucose measurement alone. Therefore, assessment of the HOMA-IR may help to individualize lifestyle interventions in obesity and to objectify improvements in insulin sensitivity after therapeutic lifestyle changes.

  5. Compensatory hyperinsulinemia in high-fat diet-induced obese mice is associated with enhanced insulin translation in islets

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kanno, Ayumi, E-mail: akanno@med.kobe-u.ac.jp; Asahara, Shun-ichiro, E-mail: asahara@med.kobe-u.ac.jp; Masuda, Katsuhisa, E-mail: katsuhisa.m.0707@gmail.com

    A high-fat diet (HF) is associated with obesity, insulin resistance, and hyperglycemia. Animal studies have shown compensatory mechanisms in pancreatic β-cells after high fat load, such as increased pancreatic β-cell mass, enhanced insulin secretion, and exocytosis. However, the effects of high fat intake on insulin synthesis are obscure. Here, we investigated whether insulin synthesis was altered in correlation with an HF diet, for the purpose of obtaining further understanding of the compensatory mechanisms in pancreatic β-cells. Mice fed an HF diet are obese, insulin resistant, hyperinsulinemic, and glucose intolerant. In islets of mice fed an HF diet, more storage ofmore » insulin was identified. We analyzed insulin translation in mouse islets, as well as in INS-1 cells, using non-radioisotope chemicals. We found that insulin translational levels were significantly increased in islets of mice fed an HF diet to meet systemic demand, without altering its transcriptional levels. Our data showed that not only increased pancreatic β-cell mass and insulin secretion but also elevated insulin translation is the major compensatory mechanism of pancreatic β-cells. - Highlights: • More stored insulin was recognized in islets of mice fed a high-fat diet. • Insulin translation was not enhanced by fatty acids, but by insulin demand. • Insulin transcription was not altered in islets of mice fed a high-fat diet. • Insulin translation was markedly enhanced in islets of mice fed a high-fat diet. • Non-radioisotope chemicals were used to measure insulin translation in mouse islets.« less

  6. Multiorgan insulin sensitivity in lean and obese subjects.

    PubMed

    Conte, Caterina; Fabbrini, Elisa; Kars, Marleen; Mittendorfer, Bettina; Patterson, Bruce W; Klein, Samuel

    2012-06-01

    To provide a comprehensive assessment of multiorgan insulin sensitivity in lean and obese subjects with normal glucose tolerance. The hyperinsulinemic-euglycemic clamp procedure with stable isotopically labeled tracer infusions was performed in 40 obese (BMI 36.2 ± 0.6 kg/m(2), mean ± SEM) and 26 lean (22.5 ± 0.3 kg/m(2)) subjects with normal glucose tolerance. Insulin was infused at different rates to achieve low, medium, and high physiological plasma concentrations. In obese subjects, palmitate and glucose R(a) in plasma decreased with increasing plasma insulin concentrations. The decrease in endogenous glucose R(a) was greater during low-, medium-, and high-dose insulin infusions (69 ± 2, 74 ± 2, and 90 ± 2%) than the suppression of palmitate R(a) (52 ± 4, 68 ± 1, and 79 ± 1%). Insulin-mediated increase in glucose disposal ranged from 24 ± 5% at low to 253 ± 19% at high physiological insulin concentrations. The suppression of palmitate R(a) and glucose R(a) were greater in lean than obese subjects during low-dose insulin infusion but were the same in both groups during high-dose insulin infusion, whereas stimulation of glucose R(d) was greater in lean than obese subjects across the entire physiological range of plasma insulin. Endogenous glucose production and adipose tissue lipolytic rate are both very sensitive to small increases in circulating insulin, whereas stimulation of muscle glucose uptake is minimal until high physiological plasma insulin concentrations are reached. Hyperinsulinemia within the normal physiological range can compensate for both liver and adipose tissue insulin resistance, but not skeletal muscle insulin resistance, in obese people who have normal glucose tolerance.

  7. Pro-inflammatory adipocytokines, oxidative stress, insulin, Zn and Cu: Interrelations with obesity in Egyptian non-diabetic obese children and adolescents.

    PubMed

    Habib, Salem A; Saad, Entsar A; Elsharkawy, Ashraf A; Attia, Zeinab R

    2015-09-01

    To investigate the inter-relationships between adipocytokines, oxidative stress, insulin, Zn and Cu and obesity among Egyptian obese non-diabetic children and adolescents. 72 obese children and adolescents of both sexes (5-17 years) were recruited for the study. 40 healthy normal non-obese persons of matched ages and sexes were used as control group. Lipid profile, tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and leptin levels were measured. Malondialdehyde (MDA) and reduced glutathione (GSH) concentrations and superoxide dismutase (SOD) activity were estimated. Micronutrients (Zn and Cu) concentrations in addition to insulin and fasting blood sugar (FBS) levels were also evaluated. Estimation of insulin resistance (homeostatic model assessment (HOMA-IR)) was derived from FBS measurements. Significant elevations (P<0.001) in TNF-α, IL-6, leptin, MDA, Cu and FBS levels and significant decreases (P<0.001) in GSH, Zn levels and SOD activity were detected among obese individuals as compared with control group. Insulin and triglyceride levels were significantly increased in obese male children and HDL-cholesterol level was increased significantly in obese adolescent females compared to controls. However, total cholesterol and LDL-cholesterol levels were significantly high in all obese cases as compared with controls. Insulin resistance was detected in 100% of the patients. We concluded that obesity with pro-inflammatory adipocytokines and hypozincemia together by many mechanisms participate in excessive oxidative stress and are highly associated with inflammation and the development of obesity-related complications. Obesity represents a critical risk factor for development of insulin resistance status. Copyright © 2015 Medical University of Bialystok. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  8. Insulin sensitivity deteriorates after short-term lifestyle intervention in the insulin sensitive phenotype of obesity.

    PubMed

    Gilardini, Luisa; Vallone, Luciana; Cottafava, Raffaella; Redaelli, Gabriella; Croci, Marina; Conti, Antonio; Pasqualinotto, Lucia; Invitti, Cecilia

    2012-01-01

    To investigate the effects of a 3-month lifestyle intervention on insulin sensitivity and its related cardiometabolic factors in obese patients. Anthropometry, body composition, oral glucose tolerance test, lipids, alanine aminotransferase, insulin sensitivity (insulinogenic index (ISI), homeostasis model assessment, β-cell performance (disposition index)) were evaluated in 263 obese women and 93 obese men before and after 3 months of hypocaloric low fat/high protein diet associated with physical activity 30 min/day. Patients were divided into 3 groups according to the intervention-induced ISI changes: group 1 (decrease), group 2 (stability) and group 3 (increase). Insulin sensitivity and the disposition index were significantly higher before the intervention in group 1 than in group 3. BMI, waist circumference, and fat mass significantly decreased in groups 1 and 3 in both sexes. β-cell performance decreased in group 1 and increased in group 3. Metabolic variables improved in group 3, whereas glucose levels increased in women of group 1. The post-intervention insulin sensitivity was lower in group 1 than in group 3. Lifestyle intervention induces changes in insulin sensitivity and metabolic factors that depend on the pre-intervention degree of insulin sensitivity. Weight loss leads to metabolic benefits in insulin-resistant, obese patients, whereas it may paradoxically worsen the metabolic conditions in the insulin-sensitive phenotype of obesity. Copyright © 2012 S. Karger GmbH, Freiburg.

  9. Association of obesity risk SNPs in PCSK1 with insulin sensitivity and proinsulin conversion.

    PubMed

    Heni, Martin; Haupt, Axel; Schäfer, Silke A; Ketterer, Caroline; Thamer, Claus; Machicao, Fausto; Stefan, Norbert; Staiger, Harald; Häring, Hans-Ulrich; Fritsche, Andreas

    2010-06-09

    Prohormone convertase 1 is involved in maturation of peptides. Rare mutations in gene PCSK1, encoding this enzyme, cause childhood obesity and abnormal glucose homeostasis with elevated proinsulin concentrations. Common single nucleotide polymorphisms (SNPs) within this gene, rs6232 and rs6235, are associated with obesity. We studied whether these SNPs influence the prediabetic traits insulin resistance, beta-cell dysfunction, or glucose intolerance. We genotyped 1498 German subjects for SNPs rs6232 and rs6235 within PCSK1. The subjects were metabolically characterized by oral glucose tolerance test with glucose, insulin, proinsulin, and C-peptide measurements. A subgroup of 512 subjects underwent a hyperinsulinemic-euglycemic clamp. The minor allele frequencies were 25.8% for SNP rs6235 and 6.0% for rs6232. After adjustment for sex and age, we found no association of SNPs rs6235 and rs6232 with BMI or other weight-related traits (all p >or= 0.07). Both minor alleles, adjusted for sex, age, BMI and insulin sensitivity were associated with elevated AUCproinsulin and AUCproinsulin/AUCinsulin (rs6235: p(additive) model Insulin secretion was not affected by the variants (different secretion parameters, all p >or= 0.08). The minor allele of SNP rs6232 was additionally associated with 15% higher OGTT-derived and 19% higher clamp-derived insulin sensitivity (pdom associated with parameters of glucose metabolism. Like rare mutations in PCSK1, the more common variants tested determine glucose-stimulated proinsulin conversion, but not insulin secretion. In addition, rs6232, encoding the amino acid exchange N221D, influences insulin sensitivity and glucose homeostasis.

  10. Long-term treatment with metformin in obese, insulin-resistant adolescents: results of a randomized double-blinded placebo-controlled trial

    PubMed Central

    van der Aa, M P; Elst, M A J; van de Garde, E M W; van Mil, E G A H; Knibbe, C A J; van der Vorst, M M J

    2016-01-01

    Background: As adolescents with obesity and insulin resistance may be refractory to lifestyle intervention therapy alone, additional off-label metformin therapy is often used. In this study, the long-term efficacy and safety of metformin versus placebo in adolescents with obesity and insulin resistance is studied. Methods: In a randomized placebo-controlled double-blinded trial, 62 adolescents with obesity aged 10–16 years old with insulin resistance received 2000 mg of metformin or placebo daily and physical training twice weekly over 18 months. Primary end points were change in body mass index (BMI) and insulin resistance measured by the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR). Secondary end points were safety and tolerability of metformin. Other end points were body fat percentage and HbA1c. Results: Forty-two participants completed the 18-month study (66% girls, median age 13 (12–15) years, BMI 30.0 (28.3 to 35.0) kg m−2 and HOMA-IR 4.08 (2.40 to 5.88)). Median ΔBMI was +0.2 (−2.9 to 1.3) kg m−2 (metformin) versus +1.2 (−0.3 to 2.4) kg m−2 (placebo) (P=0.015). No significant difference was observed for HOMA-IR. No serious adverse events were reported. Median change in fat percentage was −3.1 (−4.8 to 0.3) versus −0.8 (−3.2 to 1.6)% (P=0.150), in fat mass −0.2 (−5.2 to 2.1) versus +2.0 (1.2–6.4) kg (P=0.007), in fat-free mass +2.0 (−0.1 to 4.0) versus +4.5 (1.3 to 11.6) kg (P=0.047) and in ΔHbA1c +1.0 (−1.0 to 2.3) versus +3.0 (0.0 to 5.0) mmol mol−1 (P=0.020) (metformin versus placebo). Conclusions: Long-term treatment with metformin in adolescents with obesity and insulin resistance results in stabilization of BMI and improved body composition compared with placebo. Therefore, metformin may be useful as an additional therapy in combination with lifestyle intervention in adolescents with obesity and insulin resistance. PMID:27571249

  11. Long-term treatment with metformin in obese, insulin-resistant adolescents: results of a randomized double-blinded placebo-controlled trial.

    PubMed

    van der Aa, M P; Elst, M A J; van de Garde, E M W; van Mil, E G A H; Knibbe, C A J; van der Vorst, M M J

    2016-08-29

    As adolescents with obesity and insulin resistance may be refractory to lifestyle intervention therapy alone, additional off-label metformin therapy is often used. In this study, the long-term efficacy and safety of metformin versus placebo in adolescents with obesity and insulin resistance is studied. In a randomized placebo-controlled double-blinded trial, 62 adolescents with obesity aged 10-16 years old with insulin resistance received 2000 mg of metformin or placebo daily and physical training twice weekly over 18 months. Primary end points were change in body mass index (BMI) and insulin resistance measured by the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR). Secondary end points were safety and tolerability of metformin. Other end points were body fat percentage and HbA1c. Forty-two participants completed the 18-month study (66% girls, median age 13 (12-15) years, BMI 30.0 (28.3 to 35.0) kg m(-2) and HOMA-IR 4.08 (2.40 to 5.88)). Median ΔBMI was +0.2 (-2.9 to 1.3) kg m(-2) (metformin) versus +1.2 (-0.3 to 2.4) kg m(-2) (placebo) (P=0.015). No significant difference was observed for HOMA-IR. No serious adverse events were reported. Median change in fat percentage was -3.1 (-4.8 to 0.3) versus -0.8 (-3.2 to 1.6)% (P=0.150), in fat mass -0.2 (-5.2 to 2.1) versus +2.0 (1.2-6.4) kg (P=0.007), in fat-free mass +2.0 (-0.1 to 4.0) versus +4.5 (1.3 to 11.6) kg (P=0.047) and in ΔHbA1c +1.0 (-1.0 to 2.3) versus +3.0 (0.0 to 5.0) mmol mol(-1) (P=0.020) (metformin versus placebo). Long-term treatment with metformin in adolescents with obesity and insulin resistance results in stabilization of BMI and improved body composition compared with placebo. Therefore, metformin may be useful as an additional therapy in combination with lifestyle intervention in adolescents with obesity and insulin resistance.

  12. Skeletal Muscle Triglycerides, Diacylglycerols, and Ceramides in Insulin Resistance

    PubMed Central

    Amati, Francesca; Dubé, John J.; Alvarez-Carnero, Elvis; Edreira, Martin M.; Chomentowski, Peter; Coen, Paul M.; Switzer, Galen E.; Bickel, Perry E.; Stefanovic-Racic, Maja; Toledo, Frederico G.S.; Goodpaster, Bret H.

    2011-01-01

    OBJECTIVE Chronic exercise and obesity both increase intramyocellular triglycerides (IMTGs) despite having opposing effects on insulin sensitivity. We hypothesized that chronically exercise-trained muscle would be characterized by lower skeletal muscle diacylglycerols (DAGs) and ceramides despite higher IMTGs and would account for its higher insulin sensitivity. We also hypothesized that the expression of key skeletal muscle proteins involved in lipid droplet hydrolysis, DAG formation, and fatty-acid partitioning and oxidation would be associated with the lipotoxic phenotype. RESEARCH DESIGN AND METHODS A total of 14 normal-weight, endurance-trained athletes (NWA group) and 7 normal-weight sedentary (NWS group) and 21 obese sedentary (OBS group) volunteers were studied. Insulin sensitivity was assessed by glucose clamps. IMTGs, DAGs, ceramides, and protein expression were measured in muscle biopsies. RESULTS DAG content in the NWA group was approximately twofold higher than in the OBS group and ~50% higher than in the NWS group, corresponding to higher insulin sensitivity. While certain DAG moieties clearly were associated with better insulin sensitivity, other species were not. Ceramide content was higher in insulin-resistant obese muscle. The expression of OXPAT/perilipin-5, adipose triglyceride lipase, and stearoyl-CoA desaturase protein was higher in the NWA group, corresponding to a higher mitochondrial content, proportion of type 1 myocytes, IMTGs, DAGs, and insulin sensitivity. CONCLUSIONS Total myocellular DAGs were markedly higher in highly trained athletes, corresponding with higher insulin sensitivity, and suggest a more complex role for DAGs in insulin action. Our data also provide additional evidence in humans linking ceramides to insulin resistance. Finally, this study provides novel evidence supporting a role for specific skeletal muscle proteins involved in intramyocellular lipids, mitochondrial oxidative capacity, and insulin resistance. PMID

  13. Importance of Lean Muscle Maintenance to Improve Insulin Resistance by Body Weight Reduction in Female Patients with Obesity.

    PubMed

    Fukushima, Yaeko; Kurose, Satoshi; Shinno, Hiromi; Cao Thu, Ha; Takao, Nana; Tsutsumi, Hiromi; Kimura, Yutaka

    2016-04-01

    It has recently been suggested that skeletal muscle has an important role in insulin resistance in obesity, in addition to exercise tolerance and the fat index. The aim of this study was to identify body composition factors that contribute to improvement of insulin resistance in female patients with obesity who reduce body weight. We studied 92 female obese patients (age 40.9±10.4 years, body mass index 33.2±4.6 kg/m²) who reduced body weight by ≥5% after an intervention program including diet, exercise therapy, and cognitive behavioral therapy. Before and after the intervention, body composition was evaluated by dual-energy X-ray absorptiometry to examine changes in skeletal muscle mass. Homeostasis model assessment of insulin resistance (HOMA-IR) was measured as an index of insulin resistance. Cardiopulmonary exercise was also performed by all patients. There were significant improvements in body weight (-10.3%±4.5%), exercise tolerance (anaerobic threshold oxygen uptake 9.1%±18.4%, peak oxygen uptake 11.0%±14.2%), and HOMA-IR (-20.2%±38.3%). Regarding body composition, there were significant decreases in total body fat (-19.3%±9.6%), total fat-free mass (-2.7%±4.3%), and % body fat (-10.1%±7.5%), whereas % skeletal muscle significantly increased (8.9%±7.2%). In stepwise multiple linear regression analysis with change in HOMA-IR as the dependent variable, the change in % skeletal muscle was identified as an independent predictor (β=-0.280, R²=0.068, P<0.01). Improvement of insulin resistance in female obese patients requires maintenance of skeletal muscle mass.

  14. Adipose tissue NAD+ biology in obesity and insulin resistance: From mechanism to therapy.

    PubMed

    Yamaguchi, Shintaro; Yoshino, Jun

    2017-05-01

    Nicotinamide adenine dinucleotide (NAD + ) biosynthetic pathway, mediated by nicotinamide phosphoribosyltransferase (NAMPT), a key NAD + biosynthetic enzyme, plays a pivotal role in controlling many biological processes, such as metabolism, circadian rhythm, inflammation, and aging. Over the past decade, NAMPT-mediated NAD + biosynthesis, together with its key downstream mediator, namely the NAD + -dependent protein deacetylase SIRT1, has been demonstrated to regulate glucose and lipid metabolism in a tissue-dependent manner. These discoveries have provided novel mechanistic and therapeutic insights into obesity and its metabolic complications, such as insulin resistance, an important risk factor for developing type 2 diabetes and cardiovascular disease. This review will focus on the importance of adipose tissue NAMPT-mediated NAD + biosynthesis and SIRT1 in the pathophysiology of obesity and insulin resistance. We will also critically explore translational and clinical aspects of adipose tissue NAD + biology. © 2017 WILEY Periodicals, Inc.

  15. Socioeconomic status is positively associated with measures of adiposity and insulin resistance, but inversely associated with dyslipidaemia in Colombian children.

    PubMed

    Buitrago-Lopez, Adriana; van den Hooven, Edith H; Rueda-Clausen, Christian F; Serrano, Norma; Ruiz, Alvaro J; Pereira, Mark A; Mueller, Noel T

    2015-06-01

    Low socioeconomic status (SES) has been associated with higher risk of cardiometabolic diseases in developed societies, but investigation of SES and cardiometabolic risk in children in less economically developed populations is sparse. We aimed to examine associations among SES and cardiometabolic risk factors in Colombian children. We used data from a population-based study of 1282 children aged 6-10 years from Bucaramanga, Colombia. SES was classified according to household wealth, living conditions and access to public utilities. Anthropometric and biochemical parameters were measured at a clinic visit. Cardiometabolic risk factors were analysed continuously using linear regression and as binary outcomes-according to established paediatric cut points-using logistic regression to calculate OR and 95% CIs. Mean age of the children was 8.4 (SD 1.4) and 51.1% of the sample were boys. Odds of overweight/obesity, abdominal obesity and insulin resistance were greater among higher SES. Compared with the lowest SES stratum, children in the highest SES had higher odds of overweight/obesity (OR=3.25, 95% CI 1.89 to 5.57), abdominal obesity (OR=2.74, 95% CI 1.41 to 5.31) and insulin resistance (OR=2.60, 95% CI 1.81 to 3.71). In contrast, children in the highest SES had lower odds of hypertriglyceridaemia (triglycerides ≥90th centile; OR=0.28, 95% CI 0.14 to 0.54) and low (≤10th centile) high-density lipoprotein (HDL) cholesterol (OR=0.35, 95% CI 0.15 to 0.78). In Colombian children, SES is directly associated with obesity and insulin resistance, but inversely associated with dyslipidaemia (hypertriglyceridaemia and low HDL cholesterol). Our findings highlight the need to analyse cardiometabolic risk factors separately in children and to carefully consider a population's level of economic development when studying their social determinants of cardiometabolic disease. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a

  16. Clinical impact of insulin resistance syndrome in cardiovascular diseases and its therapeutic approach.

    PubMed

    Harano, Y; Suzuki, M; Shinozaki, K; Hara, Y; Ryomoto, K; Kanazawa, A; Nishioheda, Y; Tsushima, M

    1996-06-01

    In subjects with coronary artery diseases (obstructive and vasospastic angina pectoris (AP)) who have no diabetes, hypertension, obesity and physical inactivity, insulin sensitivity was significantly reduced with compensated hyperinsulinemia on OGTT. Insulin resistance significantly correlated with coronary atherosclerosis score. In vasospastic AP (VAP), those who fulfilled more than 3 risk factors out of 5 (hyperinsulinemia, obesity, glucose intolerance, hypertension, dyslipidemia) consist of 70 and 40% for smokers and nonsmokers respectively. Insulin resistance syndrome who fulfilled all the criteria was 9-10% for VAP. In atherothrombotic brain infarction (ATTI) with the same exclusion criteria, the similar insulin resistance and hyperinsulinemia have been observed, but not in embolic (cardiac origin) or lacunar infarction. In ATTI, high TG and apo B with low HDL-chol were noted in blood. In essential hypertension without diabetes and obesity, hyperinsulinemia was noted in 25-35% and insulin resistance in 56-88%. Reduction of blood pressure with alpha blocker (bunazosin), ACE inhibitor (cilazapril), long-acting Ca++ blocker (amlodipine) significantly improved lowered insulin sensitivity. Insulin resistance rather than hyperinsulinemia is more closely associated with blood pressure. Cardiovascular diseases (vasospastic and obstructive AP, brain cortical artery diseases) are prone to develop diabetes because of insulin resistance and also promote the generation of cumulative risk factors resulting in a vicious cycle. Efforts to alleviate insulin resistance is crucial for the primary and secondary prevention of cardiovascular diseases.

  17. Adipokines and Hepatic Insulin Resistance

    PubMed Central

    Hassan, Waseem

    2013-01-01

    Obesity is a major risk factor for insulin resistance and type 2 diabetes. Adipose tissue is now considered to be an active endocrine organ that secretes various adipokines such as adiponectin, leptin, resistin, tumour necrosis factor-α, and interleukin-6. Recent studies have shown that these factors might provide a molecular link between increased adiposity and impaired insulin sensitivity. Since hepatic insulin resistance plays the key role in the whole body insulin resistance, clarification of the regulatory processes about hepatic insulin resistance by adipokines in rodents and human would seem essential in order to understand the mechanism of type 2 diabetes and for developing novel therapeutic strategies to treat it. PMID:23762871

  18. Polycystic ovary syndrome and anti-Müllerian hormone: role of insulin resistance, androgens, obesity and gonadotrophins.

    PubMed

    Cassar, Samantha; Teede, Helena J; Moran, Lisa J; Joham, Anju E; Harrison, Cheryce L; Strauss, Boyd J; Stepto, Nigel K

    2014-12-01

    Polycystic ovary syndrome (PCOS) is a complex endocrine disorder associated with insulin resistance, hyperandrogenism, obesity, altered gonadotrophin release and anovulatory infertility. Anti-Müllerian hormone (AMH) has been proposed as a marker of ovarian function and fertility. Across a cohort of lean and overweight women with and without PCOS, we investigated the association of AMH with insulin resistance and body composition using gold standard measures. A secondary aim was to examine whether AMH was useful to determine PCOS status. Cross-sectional study. A total of 22 lean and 21 overweight women with PCOS and 19 lean and 16 overweight non-PCOS healthy controls were recruited. PCOS was diagnosed based on the Rotterdam criteria. Euglycaemic-hyperinsulinaemic clamp for assessing insulin resistance, dual energy X-ray absorptiometry and computed tomography for assessing adiposity, and blood sampling for the assessment of androgens, gonadotrophins and AMH. Anti-Müllerian hormone levels were increased in women with PCOS (P <0·001) regardless of adiposity, with this increase associated with testosterone (P <0·001) rather than insulin resistance (P = 0·79), adiposity (P = 0·98) or gonadotrophins. In assessing the ability of AMH to predict PCOS, a value of 30 pmol/l or higher indicated 79% of women with PCOS were correctly identified as having the condition. Anti-Müllerian hormone appears primarily related to androgen status suggesting a direct and predominant role of androgens in the pathophysiology of reproductive dysfunction in PCOS. As AMH reflects PCOS status, it may also be useful in PCOS diagnosis. © 2014 John Wiley & Sons Ltd.

  19. Metabolism and insulin signaling in common metabolic disorders and inherited insulin resistance.

    PubMed

    Højlund, Kurt

    2014-07-01

    Type 2 diabetes, obesity and polycystic ovary syndrome (PCOS) are common metabolic disorders which are observed with increasing prevalences, and which are caused by a complex interplay between genetic and environmental factors, including increased calorie intake and physical inactivity. These metabolic disorders are all characterized by reduced plasma adiponectin and insulin resistance in peripheral tissues. Quantitatively skeletal muscle is the major site of insulin resistance. Both low plasma adiponectin and insulin resistance contribute to an increased risk of type 2 diabetes and cardiovascular disease. In several studies, we have investigated insulin action on glucose and lipid metabolism, and at the molecular level, insulin signaling to glucose transport and glycogen synthesis in skeletal muscle from healthy individuals and in obesity, PCOS and type 2 diabetes. Moreover, we have described a novel syndrome characterized by postprandial hyperinsulinemic hypoglycemia and insulin resistance. This syndrome is caused by a mutation in the tyrosine kinase domain of the insulin receptor gene (INSR). We have studied individuals with this mutation as a model of inherited insulin resistance. Type 2 diabetes, obesity and PCOS are characterized by pronounced defects in the insulin-stimulated glucose uptake, in particular glycogen synthesis and to a lesser extent glucose oxidation, and the ability of insulin to suppress lipid oxidation. In inherited insulin resistance, however, only insulin action on glucose uptake and glycogen synthesis is impaired. This suggests that the defects in glucose and lipid oxidation in the common metabolic disorders are secondary to other factors. In young women with PCOS, the degree of insulin resistance was similar to that seen in middle-aged patients with type 2 diabetes. This supports the hypothesis of an unique pathogenesis of insulin resistance in PCOS. Insulin in physiological concentrations stimulates glucose uptake in human skeletal

  20. Dissociation between APOC3 variants, hepatic triglyceride content and insulin resistance.

    PubMed

    Kozlitina, Julia; Boerwinkle, Eric; Cohen, Jonathan C; Hobbs, Helen H

    2011-02-01

    Nonalcoholic fatty liver disease (NAFLD) is an escalating health problem that is frequently associated with obesity and insulin resistance. The mechanistic relationship between NAFLD, obesity, and insulin resistance is not well understood. A nonsynonymous variant in patatin-like phospholipase domain containing 3 (rs738409, I148M) has been reproducibly associated with increased hepatic triglyceride content (HTGC) but has not been associated with either the body mass index (BMI) or indices of insulin resistance. Conversely, two sequence variants in apolipoprotein C3 (APOC3) that have been linked to hypertriglyceridemia (rs2854117 C > T and rs2854116 T > C) have recently been reported to be associated with both hepatic fat content and insulin resistance. Here we genotyped two APOC3 variants in 1228 African Americans, 843 European Americans and 426 Hispanics from a multiethnic population based study, the Dallas Heart Study and test for association with HTGC and homeostatic model of insulin resistance (HOMA-IR). We also examined the relationship between these two variants and HOMA-IR in the Atherosclerosis Risk in Communities (ARIC) study. No significant difference in hepatic fat content was found between carriers and noncarriers in the Dallas Heart Study. Neither APOC3 variant was associated with HOMA-IR in the Dallas Heart Study; this lack of association was confirmed in the ARIC study, even after the analysis was restricted to lean (BMI < 25 kg/m(2) ) individuals (n = 4399). Our data do not support a causal relationship between these two variants in APOC3 and either HTGC or insulin resistance in middle-aged men and women. Copyright © 2010 American Association for the Study of Liver Diseases.

  1. Convergence in insulin resistance between very severely obese and lean women at the end of pregnancy.

    PubMed

    Forbes, Shareen; Barr, Sarah M; Reynolds, Rebecca M; Semple, Scott; Gray, Calum; Andrew, Ruth; Denison, Fiona C; Walker, Brian R; Norman, Jane E

    2015-11-01

    Disrupted intermediary metabolism may contribute to the adverse pregnancy outcomes in women with very severe obesity. Our aim was to study metabolism in such pregnancies. We recruited a longitudinal cohort of very severely obese (n = 190) and lean (n = 118) glucose-tolerant women for anthropometric and metabolic measurements at early, mid and late gestation and postpartum. In case-control studies of very severely obese and lean women we measured glucose and glycerol turnover during low- and high-dose hyperinsulinaemic-euglycaemic clamps (HEC) at early and late pregnancy and in non-pregnant women (each n = 6-9) and body fat distribution by MRI in late pregnancy (n = 10/group). Although greater glucose, insulin, NEFA and insulin resistance (HOMA-IR), and greater weight and % fat mass (FM) was observed in very severely obese vs lean participants, the degree of worsening was attenuated in the very severely obese individuals with advancing gestation, with no difference in triacylglycerol (TG) concentrations between very severely obese and lean women at term. Enhanced glycerol production was observed in early pregnancy only in very severely obese individuals, with similar intrahepatic FM in very severely obese vs lean women by late gestation. Offspring from obese mothers were heavier (p = 0.04). Pregnancies complicated by obesity demonstrate attenuation in weight gain and insulin resistance compared with pregnancies in lean women. Increased glycerol production is confined to obese women in early pregnancy and obese and lean individuals have similar intrahepatic FM by term. When targeting maternal metabolism to treat adverse pregnancy outcomes, therapeutic intervention may be most effective applied early in pregnancy.

  2. Effect of fat loss on arterial elasticity in obese adolescents with clinical insulin resistance: RESIST study.

    PubMed

    Ho, Mandy; Gow, Megan; Baur, Louise A; Benitez-Aguirre, Paul Z; Tam, Charmaine S; Donaghue, Kim C; Craig, Maria E; Cowell, Chris T; Garnett, Sarah P

    2014-10-01

    Reduced arterial elasticity contributes to an obesity-related increase in cardiovascular risk in adults. To evaluate the effect of fat loss on arterial elasticity in obese adolescents at risk of type 2 diabetes. A secondary data analysis of the RESIST study was performed in two hospitals in Sydney, Australia. The study included 56 subjects (ages, 10 to 17 y; 25 males) with prediabetes and/or clinical features of insulin resistance. A 12-month lifestyle plus metformin intervention. Arterial elasticity and systemic vascular resistance were measured using radial tonometry pulse contour analysis, percentage body fat (%BF) was measured by dual-energy x-ray absorptiometry, and insulin sensitivity index was derived from an oral glucose tolerance test and lipids. Adolescents (n = 31) with decreased %BF (mean change [range], -4.4% [-18.3 to -0.01%]) after the intervention had significant increases in the mean large arterial elasticity index (mean change [95%CI], 5.1 [1.9 to 8.2] mL/mm Hg * 10; P = .003) and insulin sensitivity index (0.5 [0.1 to 0.9]; P = .010) and a decrease in systemic vascular resistance (-82 [-129 to -35] dyne * s * cm(-5); P = .001). There were no significant changes in these parameters in adolescents who increased their %BF. Nor was there any significant change in the mean small arterial elasticity index in either group. Long-term follow-up of these adolescents is warranted to assess whether the observed changes in vascular elasticity will lead to a clinical benefit including reduced cardiovascular morbidity and mortality.

  3. Defective Insulin Signalling, Mediated by Inflammation, Connects Obesity to Alzheimer Disease; Relevant Pharmacological Therapies and Preventive Dietary Interventions.

    PubMed

    Rodriguez-Casado, Arantxa; Toledano-Díaz, Adolfo; Toledano, Adolfo

    2017-01-01

    Recent evidence suggests that obesity, besides being a risk factor for cardiovascular events, also increases the risk of Alzheimer's disease. Insulin resistance is common in all cases of obesity and appears to be the linkage between both diseases. Obesity, often associated with excessive fat and sugar intake, represents a preclinical stage toward insulin resistance during which nutrition intervention is likely to have maximum effect. In this way, healthy lifestyles lifetime to prevent obesity-related modifiable risk factors such as inflammation, oxidative stress and metabolic disorders could be simultaneously beneficial for preserving cognition and controlling the Alzheimer's disease. This review relates extensive research literature on facts linking nutrients and dietary patterns to obesity and Alzheimer's disease. In addition briefly presents molecular mechanisms involved in obesity- induced insulin resistance and the contribution of peripheral inflammatory and defective insulin signalling pathways, as well as ectopic lipids accumulation to Alzheimer's development through brain inflammation, neuronal insulin resistance, and cognitive dysfunction seen in Alzheimer's disease. The work relates current and emerging pharmacological and non-pharmacological therapies for the management of obesity, insulin resistance and Alzheimer's considering them as disorders with common molecular features. The findings of this review validate the importance of some nutritional interventions as possible approach to prevent or delay simultaneously progression of Alzheimer's disease and obesity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  4. Lean muscle mass in classic or ovulatory PCOS: association with central obesity and insulin resistance.

    PubMed

    Mario, F M; do Amarante, F; Toscani, M K; Spritzer, P M

    2012-10-01

    This age-matched case-control study assessed total and segmental lean muscle mass in classic or ovulatory polycystic ovary syndrome (PCOS) patients and investigated whether lean mass is associated with hormone and metabolic features. Participants underwent anthropometric and clinical evaluation. Habitual physical activity was assessed with a digital pedometer, and body composition by dual-energy X-ray absorptiometry. Laboratory measurements included total cholesterol, cholesterol fractions, triglycerides, glucose, total serum testosterone, serum insulin, estradiol, luteinizing hormone, and SHBG. Energy intake was calculated using a food frequency questionnaire. Classic PCOS patients had higher body mass index (BMI), waist circumference, testosterone and lipid accumulation product values than ovulatory PCOS and controls. Energy consumption, homeostasis model assessment index, SHBG, free androgen index and triglycerides, total and trunk lean mass were higher only in classic PCOS women vs. controls. Arm, leg, trunk, total or limb lean masses were not correlated with hormone levels in any of the groups. However, in PCOS women lipid accumulation product was positively correlated with total (r=0.56, p=0.001), trunk (r=0.59, p=0.001), arm (r=0.54, p=0.001), leg (r=0.44, p=0.03) and limb (r=0.48, p=0.001) lean masses. BMI was positively correlated with all lean mass segments and independently associated with total lean mass. Lipid accumulation product and BMI were independently associated with trunk lean mass variation. The increase in lean mass in classic PCOS appears to be associated with insulin resistance and central obesity rather than with energy intake, physical activity or androgens. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.

  5. Association of peripheral total and differential leukocyte counts with obesity-related complications in young adults.

    PubMed

    Yoshimura, Aya; Ohnishi, Shunsuke; Orito, Chieko; Kawahara, Yukako; Takasaki, Hiroyo; Takeda, Hiroshi; Sakamoto, Naoya; Hashino, Satoshi

    2015-01-01

    Obesity has been demonstrated to be associated with elevated leukocytes in adults and children. This study assessed the associations between peripheral total and differential leukocyte counts and obesity-related complications in young adults. 12 obese (median age 21.5 (range 19-28) years, median BMI 35.7 (range 32.0-44.9) kg/m(2)) and 11 normal (median age 23 (range 18-27) years, median BMI 19.5 (range 18.1-21.7) kg/m(2)) adults were enrolled. Complete blood count and serum levels of liver enzymes, fasting blood glucose, insulin and lipids were measured, and the homeostasis model assessment of insulin resistance was calculated. Fat mass was calculated using a bioimpedance analysis device, and ultrasonography was performed to measure fat thickness and to detect fatty change of the liver. Total leukocyte and monocyte counts were significantly increased in obese young adults. Total leukocyte count was associated with liver enzyme levels, insulin resistance as well as visceral and subcutaneous fat thickness. Neutrophil count was associated with insulin resistance. Lymphocyte count was associated with serum liver enzymes, insulin resistance, and dyslipidemia. Monocyte count was associated with serum liver enzyme, insulin resistance, visceral and subcutaneous fat thickness, body fat mass, and percentage body fat. The results of this study suggest that chronic low-grade systemic inflammation is associated with obesity-related complications such as nonalcoholic fatty liver disease, insulin resistance, and dyslipidemia in young adults. © 2015 S. Karger GmbH, Freiburg.

  6. Dependence of Cardiac Systolic Function on Elevated Fatty Acid Availability in Obese, Insulin-Resistant Rats.

    PubMed

    Smith, Wayne; Norton, Gavin R; Woodiwiss, Angela J; Lochner, Amanda; du Toit, Eugene F

    2016-07-01

    Clinical data advocating an adverse effect of obesity on left ventricular (LV) systolic function independent of comorbidities is controversial. We hypothesized that in obesity with prediabetic insulin resistance, circulating fatty acids (FAs) become a valuable fuel source in the maintenance of normal systolic function. Male Wistar rats were fed a high caloric diet for 32 weeks to induce obesity. Myocardial LV systolic function was assessed using echocardiography and isolated heart preparations. Aortic output was reduced in obese rat hearts over a range of filling pressures (for example: 15 cmH2O, obese: 32.6 ± 1.2 ml/min vs control: 46.2 ± 0.9 ml/min, P < .05) when perfused with glucose alone. Similarly, the slope of the LV end-systolic pressure-volume relationship decreased, and there was a right shift in the LV end-systolic stress-strain relationship as determined in Langendorff perfused, isovolumic rat heart preparations in the presence of isoproterenol (10(-8)M) (LV systolic stress-strain relationship and a reduced load-independent intrinsic systolic myocardial function, obese: 791 ± 62 g/cm(2) vs control: 1186 ± 74 g/cm(2), P < .01). The addition of insulin to the perfusion buffer improved aortic output, whereas the addition of FAs completely normalized aortic output. LV function was maintained in obese animals in vivo during an inotropic challenge. Elevated circulating FA levels may be important to maintain myocardial systolic function in the initial stages of obesity and insulin resistance. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Dissociation Between APOC3 Variants, Hepatic Triglyceride Content and Insulin Resistance

    PubMed Central

    Kozlitina, Julia; Boerwinkle, Eric; Cohen, Jonathan C; Hobbs, Helen H

    2011-01-01

    Nonalcoholic fatty liver disease (NAFLD) is an escalating health problem that is frequently associated with obesity and insulin resistance. The mechanistic relationship between NAFLD, obesity, and insulin resistance is not well understood. A nonsynonymous variant in patatin-like phospholipase domain containing 3 (rs738409, I148M) has been reproducibly associated with increased hepatic triglyceride content (HTGC) but has not been associated with either the body mass index (BMI) or indices of insulin resistance. Conversely, two sequence variants in apolipoprotein C3 (APOC3) that have been linked to hypertriglyceridemia (rs2854117 C > T and rs2854116 T > C) have recently been reported to be associated with both hepatic fat content and insulin resistance. Here we genotyped two APOC3 variants in 1228 African Americans, 843 European Americans and 426 Hispanics from a multiethnic population based study, the Dallas Heart Study and test for association with HTGC and homeostatic model of insulin resistance (HOMA-IR). We also examined the relationship between these two variants and HOMA-IR in the Atherosclerosis Risk in Communities (ARIC) study. No significant difference in hepatic fat content was found between carriers and noncarriers in the Dallas Heart Study. Neither APOC3 variant was associated with HOMA-IR in the Dallas Heart Study; this lack of association was confirmed in the ARIC study, even after the analysis was restricted to lean (BMI < 25 kg/m2) individuals (n = 4399). Conclusion: Our data do not support a causal relationship between these two variants in APOC3 and either HTGC or insulin resistance in middle-aged men and women. (Hepatology 2011;53:467-474) PMID:21274868

  8. Diet-genotype interactions in the development of the obese, insulin-resistant phenotype of C57BL/6J mice lacking melanocortin-3 or -4 receptors.

    PubMed

    Sutton, Gregory M; Trevaskis, James L; Hulver, Matthew W; McMillan, Ryan P; Markward, Nathan J; Babin, M Josephine; Meyer, Emily A; Butler, Andrew A

    2006-05-01

    Loss of brain melanocortin receptors (Mc3rKO and Mc4rKO) causes increased adiposity and exacerbates diet-induced obesity (DIO). Little is known about how Mc3r or Mc4r genotype, diet, and obesity affect insulin sensitivity. Insulin resistance, assessed by insulin and glucose tolerance tests, Ser(307) phosphorylation of insulin receptor substrate 1, and activation of protein kinase B, was examined in control and DIO wild-type (WT), Mc3rKO and Mc4rKO C57BL/6J mice. Mc4rKO mice were hyperphagic and had increased metabolic efficiency (weight gain per kilojoule consumed) relative to WT; both parameters increased further on high-fat diet. Obesity of Mc3rKO was more dependent on fat intake, involving increased metabolic efficiency. Fat mass of DIO Mc3rKO and Mc4rKO was similar, although Mc4rKO gained weight more rapidly. Mc4rKO develop hepatic insulin resistance and severe hepatic steatosis with obesity, independent of diet. DIO caused further deterioration of insulin action in Mc4rKO of either sex and, in male Mc3rKO, compared with controls, associated with increased fasting insulin, severe glucose intolerance, and reduced insulin signaling in muscle and adipose tissue. DIO female Mc3rKO exhibited very modest perturbations in glucose metabolism and insulin sensitivity. Consistent with previous data suggesting impaired fat oxidation, both Mc3rKO and Mc4rKO had reduced muscle oxidative metabolism, a risk factor for weight gain and insulin resistance. Energy expenditure was, however, increased in Mc4rKO compared with Mc3rKO and controls, perhaps due to hyperphagia and metabolic costs associated with rapid growth. In summary, DIO affects insulin sensitivity more severely in Mc4rKO compared with Mc3rKO, perhaps due to a more positive energy balance.

  9. Cafeteria diet induces obesity and insulin resistance associated with oxidative stress but not with inflammation: improvement by dietary supplementation with a melon superoxide dismutase.

    PubMed

    Carillon, Julie; Romain, Cindy; Bardy, Guillaume; Fouret, Gilles; Feillet-Coudray, Christine; Gaillet, Sylvie; Lacan, Dominique; Cristol, Jean-Paul; Rouanet, Jean-Max

    2013-12-01

    Oxidative stress is involved in obesity. However, dietary antioxidants could prevent oxidative stress-induced damage. We have previously shown the preventive effects of a melon superoxide dismutase (SODB) on oxidative stress. However, the mechanism of action of SODB is still unknown. Here, we evaluated the effects of a 1-month curative supplementation with SODB on the liver of obese hamsters. Golden Syrian hamsters received either a standard diet or a cafeteria diet composed of high-fat, high-sugar, and high-salt supermarket products, for 15 weeks. This diet resulted in insulin resistance and in increased oxidative stress in the liver. However, inflammatory markers (IL-6, TNF-α, and NF-κB) were not enhanced and no liver steatosis was detected, although these are usually described in obesity-induced insulin resistance models. After the 1-month supplementation with SODB, body weight and insulin resistance induced by the cafeteria diet were reduced and hepatic oxidative stress was corrected. This could be due to the increased expression of the liver antioxidant defense proteins (manganese and copper/zinc superoxide dismutase, catalase, and glutathione peroxidase). Even though no inflammation was detected in the obese hamsters, inflammatory markers were decreased after SODB supplementation, probably through the reduction of oxidative stress. These findings suggest for the first time that SODB could exert its antioxidant properties by inducing the endogenous antioxidant defense. The mechanisms underlying this induction need to be further investigated. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. Role of microRNAs on adipogenesis, chronic low-grade inflammation, and insulin resistance in obesity.

    PubMed

    Cruz, Kyria Jayanne Clímaco; de Oliveira, Ana Raquel Soares; Morais, Jennifer Beatriz Silva; Severo, Juliana Soares; Marreiro PhD, Dilina do Nascimento

    2017-03-01

    The aim of this review was to convey updated information on the role of microRNAs in adipogenesis, chronic low-grade inflammation, and insulin resistance in obesity. Obesity is a chronic disease characterized by the presence of metabolic disorders (e.g., low-grade chronic inflammation), which contributes to the manifestation of insulin resistance. Diverse molecular mechanisms have been implicated in the development of these disorders, and microRNAs stand out as a contributing factor. They are a class of noncoding RNAs that regulate the expression of genes by inducing cleavage of mRNAs or via inhibition of protein translation. It is important to point out that obese individuals show alterations in the expression of microRNAs favoring manifestation of the metabolic disorders present in these patients, and these alterations may be reversed by the loss of weight. Therefore, microRNAs may be regarded as potential biomarkers of obesity-related disorders. Further studies on this topic may advance the understanding of the molecular basis of obesity, including the participation of microRNAs in the pathogenesis of this disease. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Dietary carbohydrate intake, insulin resistance and gastro-oesophageal reflux disease: a pilot study in European- and African-American obese women.

    PubMed

    Pointer, S D; Rickstrew, J; Slaughter, J C; Vaezi, M F; Silver, H J

    2016-11-01

    Although obesity rates are higher in African-American than European-American women, gastro-oesophageal reflux disease (GERD) and its comorbidities are more prevalent in European-American women. A common denominator for increased adiposity, and consequent insulin resistance, is excess dietary macronutrient intake - which may promote greater prevalence and severity of GERD in women. To investigate whether GERD is more robustly associated with dietary carbohydrate intake, particularly dietary simple carbohydrate intake, and insulin resistance in European-American women. About 144 obese women were assessed at baseline and 16 weeks after consuming a high-fat/low-carbohydrate diet. GERD diagnosis and medication usage was confirmed in medical records with symptoms and medications assessed weekly. About 33.3% (N = 33) of European-American and 20.0% (N = 9) of African-American women had GERD at baseline. Total carbohydrate (r = 0.34, P < 0.001), sugars (r = 0.30, P = 0.005), glycaemic load (r = 0.34, P = 0.001) and HOMA IR (r = 0.30, P = 0.004) were associated with GERD, but only in European-American women. In response to high-fat/low-carbohydrate diet, reduced intake of sugars was associated with reduced insulin resistance. By the end of diet week 10, all GERD symptoms and medication usage had resolved in all women. GERD symptoms and medication usage was more prevalent in European-American women, for whom the relationships between dietary carbohydrate intake, insulin resistance and GERD were most significant. Nevertheless, high-fat/low-carbohydrate diet benefited all women with regard to reducing GERD symptoms and frequency of medication use. © 2016 John Wiley & Sons Ltd.

  12. Blunted suppression of acyl-ghrelin in response to fructose ingestion in obese adolescents: the role of insulin resistance.

    PubMed

    Van Name, Michelle; Giannini, Cosimo; Santoro, Nicola; Jastreboff, Ania M; Kubat, Jessica; Li, Fangyong; Kursawe, Romy; Savoye, Mary; Duran, Elvira; Dziura, James; Sinha, Rajita; Sherwin, Robert S; Cline, Gary; Caprio, Sonia

    2015-03-01

    Fructose consumption has risen alongside obesity and diabetes. Gut hormones involved in hunger and satiety (ghrelin and PYY) may respond differently to fructose compared with glucose ingestion. This study evaluated the effects of glucose and fructose ingestion on ghrelin and PYY in lean and obese adolescents with differing insulin sensitivity. Adolescents were divided into lean (n = 14), obese insulin sensitive (n = 12) (OIS), and obese insulin resistant (n = 15) (OIR). In a double-blind, cross-over design, subjects drank 75 g of glucose or fructose in random order, serum was obtained every 10 minutes for 60 minutes. Baseline acyl-ghrelin was highest in lean and lowest in OIR (P = 0.02). After glucose ingestion, acyl-ghrelin decreased similarly in lean and OIS but was lower in OIR (vs. lean, P = 0.03). Suppression differences were more pronounced after fructose (lean vs. OIS, P = 0.008, lean vs. OIR, P < 0.001). OIS became significantly hungrier after fructose (P = 0.015). PYY was not significantly different at baseline, varied minimally after glucose, and rose after fructose. Compared with lean, OIS adolescents have impaired acyl-ghrelin responses to fructose but not glucose, whereas OIR adolescents have blunted responses to both. Diminished suppression of acyl-ghrelin in childhood obesity, particularly if accompanied by insulin resistance, may promote hunger and overeating. © 2015 The Obesity Society.

  13. Leptin Rapidly Improves Glucose Homeostasis in Obese Mice by Increasing Hypothalamic Insulin Sensitivity

    PubMed Central

    Koch, Christiane; Augustine, Rachael A.; Steger, Juliane; Ganjam, Goutham K.; Benzler, Jonas; Pracht, Corinna; Lowe, Chrishanthi; Schwartz, Michael W.; Shepherd, Peter R.; Anderson, Greg M.; Grattan, David R.; Tups, Alexander

    2013-01-01

    Obesity is associated with resistance to the actions of both leptin and insulin via mechanisms that remain incompletely understood. To investigate whether leptin resistance per se contributes to insulin resistance and impaired glucose homeostasis, we investigated the effect of acute leptin administration on glucose homeostasis in normal as well as leptin- or leptin receptor-deficient mice. In hyperglycemic, leptin-deficient Lepob/ob mice, leptin acutely and potently improved glucose metabolism, before any change of body fat mass, via a mechanism involving the p110α and β isoforms of phosphatidylinositol-3-kinase (PI3K). Unlike insulin, however, the anti-diabetic effect of leptin occurred independently of phospho-AKT, a major downstream target of PI3K, and instead involved enhanced sensitivity of the hypothalamus to insulin action upstream of PI3K, through modulation of IRS1 (insulin receptor substrate 1) phosphorylation. These data suggest that leptin resistance, as occurs in obesity, reduces the hypothalamic response to insulin and thereby impairs peripheral glucose homeostasis, contributing to the development of type 2 diabetes. PMID:21123564

  14. Leptin rapidly improves glucose homeostasis in obese mice by increasing hypothalamic insulin sensitivity.

    PubMed

    Koch, Christiane; Augustine, Rachael A; Steger, Juliane; Ganjam, Goutham K; Benzler, Jonas; Pracht, Corinna; Lowe, Chrishanthi; Schwartz, Michael W; Shepherd, Peter R; Anderson, Greg M; Grattan, David R; Tups, Alexander

    2010-12-01

    Obesity is associated with resistance to the actions of both leptin and insulin via mechanisms that remain incompletely understood. To investigate whether leptin resistance per se contributes to insulin resistance and impaired glucose homeostasis, we investigated the effect of acute leptin administration on glucose homeostasis in normal as well as leptin- or leptin receptor-deficient mice. In hyperglycemic, leptin-deficient Lep(ob/ob) mice, leptin acutely and potently improved glucose metabolism, before any change of body fat mass, via a mechanism involving the p110α and β isoforms of phosphatidylinositol-3-kinase (PI3K). Unlike insulin, however, the anti-diabetic effect of leptin occurred independently of phospho-AKT, a major downstream target of PI3K, and instead involved enhanced sensitivity of the hypothalamus to insulin action upstream of PI3K, through modulation of IRS1 (insulin receptor substrate 1) phosphorylation. These data suggest that leptin resistance, as occurs in obesity, reduces the hypothalamic response to insulin and thereby impairs peripheral glucose homeostasis, contributing to the development of type 2 diabetes.

  15. Insulin resistance and polycystic ovary syndrome.

    PubMed

    Galluzzo, Aldo; Amato, Marco Calogero; Giordano, Carla

    2008-09-01

    Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in humans, affecting approximately 7-8% of women of reproductive age. Despite the criteria adopted, PCOS is considered to be a predominantly hyperandrogenetic syndrome and the evaluation of metabolic parameters and insulin sensitivity is not mandatory. Most women with PCOS also exhibit features of the metabolic syndrome, including insulin resistance, obesity and dyslipidaemia. While the association with type 2 diabetes is well established, whether the incidence of cardiovascular disease is increased in women with PCOS remains unclear. Acknowledging the strong impact of insulin-resistance in the genesis of PCOS could be helpful not only to make the diagnosis more robust, but also for conferring better cardiovascular risk prevention. Several current studies support a strong recommendation that women with PCOS should undergo comprehensive evaluation for the metabolic syndrome and recognized cardiovascular risk factors, and receive appropriate treatment as needed. Lifestyle modifications remain the first-line therapy for all obese women with PCOS. However, many of these women do not lose weight easily. Insulin-sensitizing drugs are discussed as a promising and unique therapeutic option for the chronic treatment of PCOS.

  16. Association between insulin resistance and risk of complications in children and adolescents with type 1 diabetes.

    PubMed

    Krochik, Andrea G; Botto, Marianela; Bravo, Mónica; Hepner, Mirta; Frontroth, Juan P; Miranda, Miguel; Mazza, Carmen

    2015-01-01

    It has been hypothesized that insulin resistance may be involved in the development of type 1 diabetes complications and early diagnosis would be important for their prevention. Our aim was to study insulin resistance in our population of children with type 1 diabetes and to identify associated early risk factors for micro- and macrovascular complications. A descriptive, cross-sectional study was conducted including 150 children with type 1 diabetes. Anthropometric, bioelectric impedance, carotid Doppler ultrasonography, electromyography, and conduction velocity studies were performed. Baseline plasma glucose, lipid profile, uric acid, plasma thyrotropin, glycosylated hemoglobin A1C, and microalbuminuria were assessed. More insulin-resistant patients were defined as those having an estimated glucose disposal rate (eGDR) value below the first quartile. Clinically manifest microvascular complications were not found in any of the patients. More insulin-resistant patients had a greater sub scapular fold thickness, a higher incidence of obesity (12% vs. 1.7% p 0.007), higher fructosamine levels (496 vs. 403 p<0.00019, and a higher incidence of altered lipid metabolism (70% vs. 39% p 0.0007). In the subgroup of patients with lower eGDR there were more children with lipid disorders, obesity, and worse diabetic control, which, if not corrected, may lead to development of micro- and macrovascular complications. Copyright © 2014 Diabetes India. Published by Elsevier Ltd. All rights reserved.

  17. Central arterial stiffness and diastolic dysfunction are associated with insulin resistance and abdominal obesity in young women but polycystic ovary syndrome does not confer additional risk.

    PubMed

    Rees, E; Coulson, R; Dunstan, F; Evans, W D; Blundell, H L; Luzio, S D; Dunseath, G; Halcox, J P; Fraser, A G; Rees, D A

    2014-09-01

    Are arterial stiffness, carotid intima-media thickness and diastolic dysfunction increased in young women with polycystic ovary syndrome (PCOS) independently of the effects of obesity? Insulin resistance and central obesity are associated with subclinical cardiovascular dysfunction in young women, but a diagnosis of PCOS does not appear to confer additional risk at this age. Some studies have shown that young women with PCOS may have increased measures of cardiovascular risk, including arterial stiffness, carotid intima-media thickness and myocardial dysfunction. However, it is difficult to establish how much of this risk is due to PCOS per se and how much is due to obesity and insulin resistance, which are common in PCOS and themselves associated with greater vascular risk. This cross-sectional study comprised 84 women with PCOS and 95 healthy volunteers, aged 16-45 years. The study was conducted in a university hospital. Subjects underwent a comprehensive assessment of body composition (including computed tomography (CT) assessment of visceral fat; VF), measurements of arterial stiffness (aortic pulse wave velocity; aPWV), common carotid intima-media thickness (ccIMT), diastolic function (longitudinal tissue velocity; e':a') and endocrinological measures. A sample size of 80 in each group gave 80% power for detecting a difference of 0.45 m/s in aPWV or a difference of 0.25 in e':a'. After adjustment for age and body mass index (BMI), PCOS subjects had a greater insulin response (insulin area under the curve-IAUC) following glucose challenge (adjusted difference [AD] 35 900 pmol min/l, P < 0.001) and higher testosterone (AD 0.57 nmol/l, P < 0.001) and high molecular weight adiponectin than controls (AD 3.01 µg/ml, P = 0.02), but no significant differences in aPWV (AD -0.13 m/s, P = 0.33), ccIMT (AD -0.01 mm, P = 0.13), or e':a' (AD -0.01, P = 0.86) were observed. After adjustment for age, height and central pulse pressure, e':a' and aPWV were associated with log

  18. Quality of diet is associated with insulin resistance in the Cree (Eeyouch) indigenous population of northern Québec.

    PubMed

    Johnson-Down, L; Labonte, M E; Martin, I D; Tsuji, L J S; Nieboer, E; Dewailly, E; Egeland, G; Lucas, M

    2015-01-01

    Indigenous people worldwide have a greater disease burden than their non-aboriginal counterparts with health challenges that include increased obesity and higher prevalence of diabetes. We investigate the relationships of dietary patterns with nutritional biomarkers, selected environmental contaminants and measures of insulin resistance in the Cree (Eeyouch) of northern Québec Canada. The cross-sectional 'Nituuchischaayihitaau Aschii: A Multi-Community Environment-and-Health Study in Eeyou Istchee' recruited 835 adult participants (≥18 y) from 7 communities in the James Bay region of northern Québec. The three dietary patterns identified by principal component analysis (PCA) were: inland and coastal patterns with loadings on traditional foods, and a junk food pattern with high-fat and high-sugar foods. We investigated dietary patterns scores (in quantiles) in relation with nutritional biomarkers, environmental contaminants, anthropometry, blood pressure, fasting plasma glucose and insulin, and insulin resistance. Homeostatic model assessment (HOMA-IR) was used as surrogate markers of insulin resistance. ANCOVA ascertained relationships between dietary patterns relationship and outcomes. Greater scores for the traditional patterns were associated with higher levels of n-3 fatty acids, mercury and polychlorinated biphenyls (PCBs) (P trend <0.001). Higher scores for the junk food pattern were associated with lower levels of PCBs and Vitamin D, but higher fasting plasma insulin and HOMA-IR. Our results suggest that poor diet quality accompanied greater insulin resistance. Impacts of diet quality on insulin resistance, as a sign of metabolism perturbation, deserve more attention in this indigenous population with high rates of obesity and diabetes. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. Nutritional Approaches for Managing Obesity-Associated Metabolic Diseases

    PubMed Central

    Botchlett, Rachel; Woo, Shih-Lung; Liu, Mengyang; Pei, Ya; Guo, Xin; Li, Honggui; Wu, Chaodong

    2017-01-01

    Obesity is an ongoing pandemic and serves as a causal factor of a wide spectrum of metabolic diseases including diabetes, fatty liver disease, and cardiovascular disease. Much evidence has demonstrated that nutrient overload/overnutrition initiates or exacerbates inflammatory responses in tissues/organs involved in the regulation of systemic metabolic homeostasis. This obesity-associated inflammation is usually at a low-grade and viewed as metabolic inflammation. When it exists continuously, inflammation inappropriately alters metabolic pathways and impairs insulin signaling cascades in peripheral tissues/organs such as adipose tissue, the liver and skeletal muscle, resulting in local fat deposition and insulin resistance and systemic metabolic dysregulation. In addition, inflammatory mediators, e.g., proinflammatory cytokines, and excessive nutrients, e.g., glucose and fatty acids, act together to aggravate local insulin resistance and form a vicious cycle to further disturb local metabolic pathways and exacerbate systemic metabolic dysregulation. Owing to the critical role of nutrient metabolism in the control of the initiation and progression of inflammation and insulin resistance, nutritional approaches have been implicated as effective tools for managing obesity and obesity-associated metabolic diseases. Based on the mounting evidence generated from both basic and clinical research, nutritional approaches are commonly used for suppressing inflammation, improving insulin sensitivity, and/or decreasing fat deposition. Consequently, the combined effects are responsible for improvement of systemic insulin sensitivity and metabolic homeostasis. PMID:28400405

  20. Consumption of added sugars from liquid but not solid sources predicts impaired glucose homeostasis and insulin resistance among youth at risk of obesity.

    PubMed

    Wang, Jiawei; Light, Kelly; Henderson, Mélanie; O'Loughlin, Jennifer; Mathieu, Marie-Eve; Paradis, Gilles; Gray-Donald, Katherine

    2014-01-01

    Little is known about longitudinal associations between added sugar consumption (solid and liquid sources) and glucose-insulin homeostasis among youth. Caucasian children (8-10 y) with at least one obese biological parent were recruited in the QUébec Adipose and Lifestyle InvesTigation in Youth (QUALITY) cohort (n = 630) and followed-up 2 y later (n = 564). Added sugars were assessed by 3 24-h dietary recalls at baseline. Two-year changes were examined in multivariate linear regression models, adjusting for baseline level, age, sex, Tanner stage, energy intake, fat mass (dual-energy X-ray absorptiometry), and physical activity (7 d accelerometer). Added sugar intake in either liquid or solid sources was not related to changes in adiposity measures (fat mass, body mass index, or waist circumference). However, a higher consumption (10 g/d) of added sugars from liquid sources was associated with 0.04 mmol/L higher fasting glucose, 2.3 pmol/L higher fasting insulin, 0.1 unit higher homeostasis model assessment of insulin resistance (HOMA-IR), and 0.4 unit lower Matsuda-insulin sensitivity index (Matsuda-ISI) in all participants (P < 0.01). No associations were observed with consumption of added sugars from solid sources. Overweight/obese children at baseline had greater increases in adiposity indicators, fasting insulin, and HOMA-IR and decreases in Matsuda-ISI during those 2 y than normal-weight children. Consumption of added sugars from liquid or solid sources was not associated with changes in adiposity, but liquid added sugars were a risk factor for the development of impaired glucose homeostasis and insulin resistance over 2 y among youth at risk of obesity.

  1. Cellular Insulin Resistance Disrupts Leptin-Mediated Control of Neuronal Signaling and Transcription

    PubMed Central

    Nazarians-Armavil, Anaies; Menchella, Jonathan A.

    2013-01-01

    Central resistance to the actions of insulin and leptin is associated with the onset of obesity and type 2 diabetes mellitus, whereas leptin and insulin signaling is essential for both glucose and energy homeostasis. Although it is known that leptin resistance can lead to attenuated insulin signaling, whether insulin resistance can lead to or exacerbate leptin resistance is unknown. To investigate the molecular events underlying crosstalk between these signaling pathways, immortalized hypothalamic neuronal models, rHypoE-19 and mHypoA-2/10, were used. Prolonged insulin exposure was used to induce cellular insulin resistance, and thereafter leptin-mediated regulation of signal transduction and gene expression was assessed. Leptin directly repressed agouti-related peptide mRNA levels but induced urocortin-2, insulin receptor substrate (IRS)-1, IRS2, and IR transcription, through leptin-mediated phosphatidylinositol 3-kinase/Akt activation. Neuronal insulin resistance, as assessed by attenuated Akt phosphorylation, blocked leptin-mediated signal transduction and agouti-related peptide, urocortin-2, IRS1, IRS2, and insulin receptor synthesis. Insulin resistance caused a substantial decrease in insulin receptor protein levels, forkhead box protein 1 phosphorylation, and an increase in suppressor of cytokine signaling 3 protein levels. Cellular insulin resistance may cause or exacerbate neuronal leptin resistance and, by extension, obesity. It is essential to unravel the effects of neuronal insulin resistance given that both peripheral, as well as the less widely studied central insulin resistance, may contribute to the development of metabolic, reproductive, and cardiovascular disorders. This study provides improved understanding of the complex cellular crosstalk between insulin-leptin signal transduction that is disrupted during neuronal insulin resistance. PMID:23579487

  2. Dietary intervention, but not losartan, completely reverses non-alcoholic steatohepatitis in obese and insulin resistant mice.

    PubMed

    Verbeek, Jef; Spincemaille, Pieter; Vanhorebeek, Ilse; Van den Berghe, Greet; Vander Elst, Ingrid; Windmolders, Petra; van Pelt, Jos; van der Merwe, Schalk; Bedossa, Pierre; Nevens, Frederik; Cammue, Bruno; Thevissen, Karin; Cassiman, David

    2017-02-23

    Dietary intervention is the cornerstone of non-alcoholic steatohepatitis (NASH) treatment. However, histological evidence of its efficacy is limited and its impact on hepatic pathways involved in NASH is underreported. The efficacy of the angiotensin receptor type 1 blocker losartan is controversial because of varying results in a few animal and human studies. We evaluated the effect of dietary intervention versus losartan on NASH and associated systemic metabolic features in a representative mouse model. Male C57BL/6 J mice with high fat-high sucrose diet (HF-HSD) induced NASH, obesity, insulin resistance and hypercholesterolemia were subjected to dietary intervention (switch from HF-HSD to normal chow diet (NCD)) (n = 9), continuation HF-HSD together with losartan (30 mg/kg/day) (n = 9) or continuation HF-HSD only (n = 9) for 8 weeks. 9 mice received NCD during the entire experiment (20 weeks). We assessed the systemic metabolic effects and performed a detailed hepatic histological and molecular profiling. A P-value of < 0.05, using the group with continuation of HF-HSD only as control, was considered as statistically significant. Dietary intervention normalized obesity, insulin resistance, and hypercholesterolemia (for all P < 0.001), and remarkably, completely reversed all histological features of pre-existent NASH (for all P < 0.001), including fibrosis measured by quantification of collagen proportional area (P < 0.01). At the hepatic molecular level, dietary intervention targeted fibrogenesis with a normalization of collagen type I alpha 1, transforming growth factor β1, tissue inhibitor of metalloproteinase 1 mRNA levels (for all P < 0.01), lipid metabolism with a normalization of fatty acid translocase/CD36, fatty acid transport protein 5, fatty acid synthase mRNA levels (P < 0.05) and markers related to mitochondrial function with a normalization of hepatic ATP content (P < 0.05) together with sirtuin1 and

  3. [Some peculiarities in the manifestation of oxidative stress and current status of antioxidant system in adolescents of different age groups with obesity, complicated by insulin resistance and without it].

    PubMed

    Kuleshova, D K; Davydov, V V

    2014-01-01

    The study has shown that neuroendocrine obesity in adolescents is associated with the formation of oxidative stress which is more pronounced in early than in late puberty. Obesity with concomitant insulin resistance increases manifestations of oxidative stress accompanied by a compensatory increase in the activity of catabolic enzymes and reduced capacity of the defense antioxidant system in late puberty. These alterations may be caused by age-related changes in hormonal secretion under conditions of insulin resistance in late puberty.

  4. Preserved insulin sensitivity predicts metabolically healthy obese phenotype in children and adolescents.

    PubMed

    Vukovic, Rade; Milenkovic, Tatjana; Mitrovic, Katarina; Todorovic, Sladjana; Plavsic, Ljiljana; Vukovic, Ana; Zdravkovic, Dragan

    2015-12-01

    Available data on metabolically healthy obese (MHO) phenotype in children suggest that gender, puberty, waist circumference, insulin sensitivity, and other laboratory predictors have a role in distinguishing these children from metabolically unhealthy obese (MUO) youth. The goal of this study was to identify predictors of MHO phenotype and to analyze glucose and insulin metabolism during oral glucose tolerance test (OGTT) in MHO children. OGTT was performed in 244 obese children and adolescents aged 4.6-18.9 years. Subjects were classified as MHO in case of no fulfilled criterion of metabolic syndrome except anthropometry or as MUO (≥2 fulfilled criteria). Among the subjects, 21.7 % had MHO phenotype, and they were more likely to be female, younger, and in earlier stages of pubertal development, with lower degree of abdominal obesity. Insulin resistance was the only independent laboratory predictor of MUO phenotype (OR 1.59, CI 1.13-2.25), with 82 % sensitivity and 60 % specificity for diagnosing MUO using HOMA-IR cutoff point of ≥2.85. Although no significant differences were observed in glucose regulation, MUO children had higher insulin demand throughout OGTT, with 1.53 times higher total insulin secretion. Further research is needed to investigate the possibility of targeted treatment of insulin resistance to minimize pubertal cross-over to MUO in obese children. • Substantial proportion of the obese youth (21-68 %) displays a metabolically healthy (MHO) phenotype. • Gender, puberty, waist circumference, insulin sensitivity, and lower levels of uric acid and transaminases have a possible role in distinguishing MHO from metabolically unhealthy obese (MUO) children. • Insulin resistance was found to be the only significant laboratory predictor of MUO when adjusted for gender, puberty, and the degree of abdominal obesity. • Besides basal insulin resistance, MUO children were found to have a significantly higher insulin secretion throughout OGTT in

  5. Genetic variation in exon 17 of INSR is associated with insulin resistance and hyperandrogenemia among lean Indian women with polycystic ovary syndrome.

    PubMed

    Mukherjee, Srabani; Shaikh, Nuzhat; Khavale, Sushma; Shinde, Gayatri; Meherji, Pervin; Shah, Nalini; Maitra, Anurupa

    2009-05-01

    Polycystic ovary syndrome (PCOS) is a multigenic disorder, and insulin resistance is one of its hallmark features. Polymorphisms in exon 17 of insulin receptor (INSR) gene are reported to be associated with PCOS. We investigated this association in Indian women and its putative relationship with PCOS associated traits, which has not been explored so far. In this case control study, the polymorphisms were investigated by direct sequencing in 180 women with PCOS and 144 age matched controls. Clinical, anthropometric, biochemical, and hormonal parameters were also estimated. The silent C/T polymorphism at His1058 in exon 17 of INSR was found to be present in our study population. The polymorphic genotype (CT+TT) was significantly associated with PCOS in lean women (chi(2)=8.493, df=1, P=0.004). It showed association with higher fasting insulin levels (P=0.02), homeostasis model assessment of insulin resistance (P=0.005), free androgen index (P=0.03), and lower quantitative insulin sensitivity check index (P=0.004) in lean PCOS women. No other novel or known polymorphism was identified in exon 17 in this cohort. The study shows significant association of C/T polymorphism at His1058 of INSR with PCOS in the lean rather than obese Indian women. Its association with indices of insulin resistance and hyperandrogenemia is also seen in the same group. The findings strengthen the concept that pathogenesis of PCOS is different in lean and obese women.

  6. SGLT2-inhibitor and DPP-4 inhibitor improve brain function via attenuating mitochondrial dysfunction, insulin resistance, inflammation, and apoptosis in HFD-induced obese rats.

    PubMed

    Sa-Nguanmoo, Piangkwan; Tanajak, Pongpan; Kerdphoo, Sasiwan; Jaiwongkam, Thidarat; Pratchayasakul, Wasana; Chattipakorn, Nipon; Chattipakorn, Siriporn C

    2017-10-15

    Dipeptidyl peptidase-4 inhibitor (vildagliptin) has been shown to exert beneficial effects on insulin sensitivity and neuroprotection in obese-insulin resistance. Recent studies demonstrated the neuroprotection of the sodium-glucose co-transporter 2 inhibitor (dapagliflozin) in diabetes. However, the comparative effects of both drugs and a combination of two drugs on metabolic dysfunction and brain dysfunction impaired by the obese-insulin resistance have never been investigated. Forty male Wistar rats were divided into two groups, and received either a normal-diet (ND, n=8) or a high-fat diet (HFD, n=32) for 16weeks. At week 13, the HFD-fed rats were divided into four subgroups (n=8/subgroup) to receive either a vehicle, vildagliptin (3mg/kg/day) dapagliflozin (1mg/kg/day) or combined drugs for four weeks. ND rats were given a vehicle for four weeks. Metabolic parameters and brain function were investigated. The results demonstrated that HFD rats developed obese-insulin resistance and cognitive decline. Dapagliflozin had greater efficacy on improved peripheral insulin sensitivity and reduced weight gain than vildagliptin. Single therapy resulted in equally improved brain mitochondrial function, insulin signaling, apoptosis and prevented cognitive decline. However, only dapagliflozin improved hippocampal synaptic plasticity. A combination of the drugs had greater efficacy in improving brain insulin sensitivity and reducing brain oxidative stress than the single drug therapy. These findings suggested that dapagliflozin and vildagliptin equally prevented cognitive decline in the obese-insulin resistance, possibly through some similar mechanisms. Dapagliflozin had greater efficacy than vildagliptin for preserving synaptic plasticity, thus combined drugs could be the best therapeutic approach for neuroprotection in the obese-insulin resistance. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Common genetic variation in the SERPINF1 locus determines overall adiposity, obesity-related insulin resistance, and circulating leptin levels.

    PubMed

    Böhm, Anja; Ordelheide, Anna-Maria; Machann, Jürgen; Heni, Martin; Ketterer, Caroline; Machicao, Fausto; Schick, Fritz; Stefan, Norbert; Fritsche, Andreas; Häring, Hans-Ulrich; Staiger, Harald

    2012-01-01

    Pigment epithelium-derived factor (PEDF) belongs to the serpin family of peptidase inhibitors (serpin F1) and is among the most abundant glycoproteins secreted by adipocytes. In vitro and mouse in vivo data revealed PEDF as a candidate mediator of obesity-induced insulin resistance. Therefore, we assessed whether common genetic variation within the SERPINF1 locus contributes to adipose tissue-related prediabetic phenotypes in humans. A population of 1,974 White European individuals at increased risk for type 2 diabetes was characterized by an oral glucose tolerance test with glucose and insulin measurements (1,409 leptin measurements) and genotyped for five tagging SNPs covering 100% of common genetic variation (minor allele frequency ≥ 0.05) in the SERPINF1 locus. In addition, a subgroup of 486 subjects underwent a hyperinsulinaemic-euglycaemic clamp and a subgroup of 340 magnetic resonance imaging (MRI) and spectroscopy (MRS). After adjustment for gender and age and Bonferroni correction for the number of SNPs tested, SNP rs12603825 revealed significant association with MRI-derived total adipose tissue mass (p = 0.0094) and fasting leptin concentrations (p = 0.0035) as well as nominal associations with bioelectrical impedance-derived percentage of body fat (p = 0.0182) and clamp-derived insulin sensitivity (p = 0.0251). The association with insulin sensitivity was completely abolished by additional adjustment for body fat (p = 0.8). Moreover, the fat mass-increasing allele of SNP rs12603825 was significantly associated with elevated fasting PEDF concentrations (p = 0.0436), and the PEDF levels were robustly and positively associated with all body fat parameters measured and with fasting leptin concentrations (p<0.0001, all). In humans at increased risk for type 2 diabetes, a functional common genetic variant in the gene locus encoding PEDF contributes to overall body adiposity, obesity-related insulin resistance, and circulating leptin

  8. Partial Reversal of Obesity-Induced Insulin Resistance Owing to Anti-Inflammatory Immunomodulatory Potential of Flaxseed Oil.

    PubMed

    Bashir, Samina; Ali, Shakir; Khan, Farah

    2015-01-01

    The present study was designed to assess the potential of supplementation of diet with Flaxseed (Linum usitatissimum, L.) oil (FXO), on obesity-related inflammation and reversal of obesity-induced insulin resistance. Swiss Albino mice, C57bl/6 mice and co-culture of 3T3-L1 adipocytes - RAW 264.7 macrophages to mimick obese adipose tissue environment were used for the study. Oral gavage of FXO at concentrations of 4, 8 or 16 mg/kg body weight (bwt) for 4 weeks or high-fat diet (HFD, 60% energy as fat) supplemented with dietary FXO (4, 8 or 16 mg/kg bwt) was given to the mice. FXO was characterised using gas chromatography - mass spectrometry. FXO supplemented HFD-fed mice (4 mg/kg bwt exhibited reduced adiposity index, serum glucose levels and triglycerides (8 and 16 mg/kg bwt) and improvement in insulin sensitisation (4, 8 and 16 mg/kg bwt) when compared with HFD mice. The co-culture showed a dose-dependent shift in cytokines towards anti-inflammatory (IL-4) state, with a decrease in pro-inflammatory TNF-α (p < 0.05). For immunomodulatory studies a dose-dependent increase (p < 0.05) was observed in antigen-specific levels of Th2 (IL-4) cytokine, serum anti-ova IgG1 and IgE levels. Suppression in anti-ova IgG2a, IgG2b, and IgG3 and antigen-specific Th1 cytokines like TNF-α and IFN-γ significantly (p < 0.05) was observed at 16 mg/kg bwt dosage. The results indicate that FXO exhibits an anti-inflammatory immunomodulatory potential and may partially relieve symptoms of obesity-associated insulin resistance.

  9. Relationship between inflammation, insulin resistance and type 2 diabetes: 'cause or effect'?

    PubMed

    Greenfield, Jerry R; Campbell, Lesley V

    2006-05-01

    Inflammation has been implicated as an important aetiological factor in the development of both insulin resistance and type 2 diabetes mellitus. This conclusion is predominantly drawn from studies demonstrating associations between elevated (but 'normal range') levels of circulating acute phase inflammatory markers, typified by C-reactive protein (CRP), and indices of insulin resistance and the development of type 2 diabetes. There is debate as to whether these associations are independent of body fatness or, rather, an epiphenomenon of obesity, particularly central obesity, a strong predictor of insulin resistance and type 2 diabetes and an important source of inflammatory cytokines, such as interleukin-6. Some of this controversy and the inability to draw definitive conclusions from these studies relate to the fact that most studies measure body fat and its distribution indirectly using anthropometric estimates, such as Body Mass Index and waist circumference, rather than directly by dual-energy X-ray absorptiometry, computed tomography or magnetic resonance imaging. Furthermore, use of the term inflammation may be inappropriate when describing mild elevations of CRP in the 'normal range' in the absence of the other changes that characterise classical inflammatory diseases, such as a reduction in levels (or evidence of consumption) of complement proteins. Debate as to whether obesity mediates the association between circulating levels of inflammatory markers and insulin resistance can be resolved by well-designed studies using body fat measured by gold-standard methods. In this review, we present evidence to support the suggestion that body fat is the primary determinant of circulating inflammatory marker levels in the basal state and that marginally elevated levels of circulating interleukin-6 and CRP in obesity are a consequence rather than a cause of insulin resistance. The importance of genetic influences in determining both body fatness and circulating CRP

  10. Association of obesity risk SNPs in PCSK1 with insulin sensitivity and proinsulin conversion

    PubMed Central

    2010-01-01

    Background Prohormone convertase 1 is involved in maturation of peptides. Rare mutations in gene PCSK1, encoding this enzyme, cause childhood obesity and abnormal glucose homeostasis with elevated proinsulin concentrations. Common single nucleotide polymorphisms (SNPs) within this gene, rs6232 and rs6235, are associated with obesity. We studied whether these SNPs influence the prediabetic traits insulin resistance, β-cell dysfunction, or glucose intolerance. Methods We genotyped 1498 German subjects for SNPs rs6232 and rs6235 within PCSK1. The subjects were metabolically characterized by oral glucose tolerance test with glucose, insulin, proinsulin, and C-peptide measurements. A subgroup of 512 subjects underwent a hyperinsulinemic-euglycemic clamp. Results The minor allele frequencies were 25.8% for SNP rs6235 and 6.0% for rs6232. After adjustment for sex and age, we found no association of SNPs rs6235 and rs6232 with BMI or other weight-related traits (all p ≥ 0.07). Both minor alleles, adjusted for sex, age, BMI and insulin sensitivity were associated with elevated AUCproinsulin and AUCproinsulin/AUCinsulin (rs6235: padditive model ≤ 0.009, effect sizes 8/8%, rs6232: pdominant model ≤ 0.01, effect sizes 10/21%). Insulin secretion was not affected by the variants (different secretion parameters, all p ≥ 0.08). The minor allele of SNP rs6232 was additionally associated with 15% higher OGTT-derived and 19% higher clamp-derived insulin sensitivity (pdom ≤ 0.0047), 4.5% lower HOMAIR (pdom = 0.02) and 3.5% lower 120-min glucose (pdom = 0.0003) independently of BMI and proinsulin conversion. SNP rs6235 was not associated with parameters of glucose metabolism. Conclusions Like rare mutations in PCSK1, the more common variants tested determine glucose-stimulated proinsulin conversion, but not insulin secretion. In addition, rs6232, encoding the amino acid exchange N221D, influences insulin sensitivity and glucose homeostasis. PMID:20534142

  11. Suppression of Adaptive Immune Cell Activation Does Not Alter Innate Immune Adipose Inflammation or Insulin Resistance in Obesity.

    PubMed

    Subramanian, Manikandan; Ozcan, Lale; Ghorpade, Devram Sampat; Ferrante, Anthony W; Tabas, Ira

    2015-01-01

    Obesity-induced inflammation in visceral adipose tissue (VAT) is a major contributor to insulin resistance and type 2 diabetes. Whereas innate immune cells, notably macrophages, contribute to visceral adipose tissue (VAT) inflammation and insulin resistance, the role of adaptive immunity is less well defined. To address this critical gap, we used a model in which endogenous activation of T cells was suppressed in obese mice by blocking MyD88-mediated maturation of CD11c+ antigen-presenting cells. VAT CD11c+ cells from Cd11cCre+Myd88fl/fl vs. control Myd88fl/fl mice were defective in activating T cells in vitro, and VAT T and B cell activation was markedly reduced in Cd11cCre+Myd88fl/fl obese mice. However, neither macrophage-mediated VAT inflammation nor systemic inflammation were altered in Cd11cCre+Myd88fl/fl mice, thereby enabling a focused analysis on adaptive immunity. Unexpectedly, fasting blood glucose, plasma insulin, and the glucose response to glucose and insulin were completely unaltered in Cd11cCre+Myd88fl/fl vs. control obese mice. Thus, CD11c+ cells activate VAT T and B cells in obese mice, but suppression of this process does not have a discernible effect on macrophage-mediated VAT inflammation or systemic glucose homeostasis.

  12. Blunted Suppression of Acyl-Ghrelin in Response to Fructose Ingestion in Obese Adolescents: the Role of Insulin Resistance

    PubMed Central

    Van Name, Michelle; Giannini, Cosimo; Santoro, Nicola; Jastreboff, Ania; Kubat, Jessica; Li, Fangyong; Kursawe, Romy; Savoye, Mary; Duran, Elvira; Dziura, James; Sinha, Rajita; Sherwin, Robert; Cline, Gary; Caprio, Sonia

    2015-01-01

    Objective Fructose consumption has risen alongside obesity and diabetes. Gut hormones involved in hunger and satiety (ghrelin and PYY) may respond differently to fructose compared to glucose ingestion. We evaluated the effects of glucose and fructose ingestion on ghrelin and PYY in lean and obese adolescents with differing insulin sensitivity. Methods Adolescents were divided into lean (n=14), obese insulin sensitive (n=12) (OIS), and obese insulin resistant (n=15) (OIR). In a double-blind, cross-over design, subjects drank 75g of glucose or fructose in random order, serum was obtained every 10 minutes for 60 minutes. Results Baseline acyl-ghrelin was highest in lean and lowest in OIR (p=0.02). After glucose ingestion acyl-ghrelin decreased similarly in lean and OIS, but appeared lower in OIR (vs lean p=0.03). Suppression differences were more pronounced after fructose (lean vs. OIS p=0.008, lean vs. OIR p<0.001). OIS became significantly hungrier after fructose (p=0.015). PYY was not significantly different at baseline, varied minimally after glucose, and rose after fructose. Conclusion Compared to lean, OIS adolescents have impaired acyl-ghrelin responses to fructose but not glucose, whereas OIR adolescents have blunted responses to both. Diminished suppression of acyl-ghrelin in childhood obesity, particularly if accompanied by insulin resistance, may promote hunger and overeating. PMID:25645909

  13. Intensive lifestyle intervention including high-intensity interval training program improves insulin resistance and fasting plasma glucose in obese patients.

    PubMed

    Marquis-Gravel, Guillaume; Hayami, Douglas; Juneau, Martin; Nigam, Anil; Guilbeault, Valérie; Latour, Élise; Gayda, Mathieu

    2015-01-01

    To analyze the effects of a long-term intensive lifestyle intervention including high-intensity interval training (HIIT) and Mediterranean diet (MedD) counseling on glycemic control parameters, insulin resistance and β-cell function in obese subjects. The glycemic control parameters (fasting plasma glucose, glycated hemoglobin), insulin resistance, and β-cell function of 72 obese subjects (54 women; mean age = 53 ± 9 years) were assessed at baseline and upon completion of a 9-month intensive lifestyle intervention program conducted at the cardiovascular prevention and rehabilitation center of the Montreal Heart Institute, from 2009 to 2012. The program included 2-3 weekly supervised exercise training sessions (HIIT and resistance exercise), combined to MedD counseling. Fasting plasma glucose (FPG) (mmol/L) (before: 5.5 ± 0.9; after: 5.2 ± 0.6; P < 0.0001), fasting insulin (pmol/L) (before: 98 ± 57; after: 82 ± 43; P = 0.003), and insulin resistance, as assessed by the HOMA-IR score (before: 3.6 ± 2.5; after: 2.8 ± 1.6; P = 0.0008) significantly improved, but not HbA1c (%) (before: 5.72 ± 0.55; after: 5.69 ± 0.39; P = 0.448), nor β-cell function (HOMA-β, %) (before: 149 ± 78; after: 144 ± 75; P = 0.58). Following a 9-month intensive lifestyle intervention combining HIIT and MedD counseling, obese subjects experienced significant improvements of FPG and insulin resistance. This is the first study to expose the effects of a long-term program combining HIIT and MedD on glycemic control parameters among obese subjects.

  14. C1q/TNF-related protein 6 (CTRP6) links obesity to adipose tissue inflammation and insulin resistance.

    PubMed

    Lei, Xia; Seldin, Marcus M; Little, Hannah C; Choy, Nicholas; Klonisch, Thomas; Wong, G William

    2017-09-08

    Obesity is associated with chronic low-grade inflammation, and metabolic regulators linking obesity to inflammation have therefore received much attention. Secreted C1q/TNF-related proteins (CTRPs) are one such group of regulators that regulate glucose and fat metabolism in peripheral tissues and modulate inflammation in adipose tissue. We have previously shown that expression of CTRP6 is up-regulated in leptin-deficient mice and, conversely, down-regulated by the anti-diabetic drug rosiglitazone. Here, we provide evidence for a novel role of CTRP6 in modulating both inflammation and insulin sensitivity. We found that in obese and diabetic humans and mouse models, CTRP6 expression was markedly up-regulated in adipose tissue and that stromal vascular cells, such as macrophages, are a major CTRP6 source. Overexpressing mouse or human CTRP6 impaired glucose disposal in peripheral tissues in response to glucose and insulin challenge in wild-type mice. Conversely, Ctrp6 gene deletion improved insulin action and increased metabolic rate and energy expenditure in diet-induced obese mice. Mechanistically, CTRP6 regulates local inflammation and glucose metabolism by targeting macrophages and adipocytes, respectively. In cultured macrophages, recombinant CTRP6 dose-dependently up-regulated the expression and production of TNF-α. Conversely, CTRP6 deficiency reduced circulating inflammatory cytokines and pro-inflammatory macrophages in adipose tissue. CTRP6-overexpressing mice or CTRP6-treated adipocytes had reduced insulin-stimulated Akt phosphorylation and glucose uptake. In contrast, loss of CTRP6 enhanced insulin-stimulated Akt activation in adipose tissue. Together, these results establish CTRP6 as a novel metabolic/immune regulator linking obesity to adipose tissue inflammation and insulin resistance. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  15. Smad3 deficiency protects mice from obesity-induced podocyte injury that precedes insulin resistance.

    PubMed

    Sun, Yu B Y; Qu, Xinli; Howard, Victor; Dai, Lie; Jiang, Xiaoyun; Ren, Yi; Fu, Ping; Puelles, Victor G; Nikolic-Paterson, David J; Caruana, Georgina; Bertram, John F; Sleeman, Mark W; Li, Jinhua

    2015-08-01

    Signaling by TGF-β/Smad3 plays a key role in renal fibrosis. As obesity is one of the major risk factors of chronic and end-stage renal disease, we studied the role of Smad3 signaling in the pathogenesis of obesity-related renal disease. After switching to a high fat diet, the onset of Smad3 C-terminal phosphorylation, increase in albuminuria, and the early stages of peripheral and renal insulin resistance occurred at 1 day, and 4 and 8 weeks, respectively, in C57BL/6 mice. The loss of synaptopodin, a functional marker of podocytes, and phosphorylation of the Smad3 linker region (T179 and S213) appeared after 4 weeks of the high fat diet. This suggests a temporal pattern of Smad3 signaling activation leading to kidney injury and subsequent insulin resistance in the development of obesity-related renal disease. In vivo, Smad3 knockout attenuated the high fat diet-induced proteinuria, renal fibrosis, overall podocyte injury, and mitochondrial dysfunction in podocytes. In vitro palmitate caused a rapid activation of Smad3 in 30 min, loss of synaptopodin in 2 days, and impaired insulin signaling in 3 days in isolated mouse podocytes. Blockade of either Smad3 phosphorylation by SIS3 (a Smad3 inhibitor) or T179 phosphorylation by flavopiridol (a CDK9 inhibitor) prevented the palmitate-induced loss of synaptopodin and mitochondrial function in podocytes. Thus, Smad3 signaling plays essential roles in obesity-related renal disease and may be a novel therapeutic target.

  16. Effect of two different hypocaloric diets in transaminases and insulin resistance in nonalcoholic fatty liver disease and obese patients.

    PubMed

    de Luis, D A; Aller, R; Izaola, O; Gonzalez Sagrado, M; Conde, R

    2010-01-01

    The aim of our study was to examine the changes in hypertransaminasemia after weight reduction in obese patients with and without NAFLD and the relation with insulin resistance. A population of 162 obese patients was randomly allocated to two groups: a) diet I (low fat) and b) diet II (low carbohydrate), dieting along 3 months. Patients were classified as group I (n=112) when serum ALT activity was normal or group II (NAFLD, n=30) when serum ALT activity was (>or=43 UI/L). In control group with diet I, BMI, weight, fat mass, waist to hip ratio, waist circumference, systolic pressure, total cholesterol, LDL cholesterol, HOMA and insulin levels decreased. In NAFLD group with diet I improved the same parameters and glucose, triglycerides, ALT, AST, gamaglutamine transferase levels, too. In control group with diet II, BMI, weight, fat mass, waist to hip ratio, waist circumference, systolic pressure, total cholesterol, LDL cholesterol, HOMA and insulin levels decreased. In NAFLD group with diet II improved the same parameters and glucose, triglycerides, ALT and gamaglutamine transferase levels, without statistical changes in AST. We showed that weight reduction secondary to two hypocaloric diets was associated with improvement in hipertransaminasemia and insulin resistance in NAFLD patients.

  17. Dietary Anthocyanins and Insulin Resistance: When Food Becomes a Medicine.

    PubMed

    Belwal, Tarun; Nabavi, Seyed Fazel; Nabavi, Seyed Mohammad; Habtemariam, Solomon

    2017-10-12

    Insulin resistance is an abnormal physiological state that occurs when insulin from pancreatic β-cells is unable to trigger a signal transduction pathway in target organs such as the liver, muscles and adipose tissues. The loss of insulin sensitivity is generally associated with persistent hyperglycemia (diabetes), hyperinsulinemia, fatty acids and/or lipid dysregulation which are often prevalent under obesity conditions. Hence, insulin sensitizers are one class of drugs currently employed to treat diabetes and associated metabolic disorders. A number of natural products that act through multiple mechanisms have also been identified to enhance insulin sensitivity in target organs. One group of such compounds that gained interest in recent years are the dietary anthocyanins. Data from their in vitro, in vivo and clinical studies are scrutinized in this communication to show their potential health benefit through ameliorating insulin resistance. Specific mechanism of action ranging from targeting specific signal transduction receptors/enzymes to the general antioxidant and anti-inflammatory mechanisms of insulin resistance are presented.

  18. Associations of Insulin Resistance and Adiponectin With Mortality in Women With Breast Cancer

    PubMed Central

    Duggan, Catherine; Irwin, Melinda L.; Xiao, Liren; Henderson, Katherine D.; Smith, Ashley Wilder; Baumgartner, Richard N.; Baumgartner, Kathy B.; Bernstein, Leslie; Ballard-Barbash, Rachel; McTiernan, Anne

    2011-01-01

    Purpose Overweight or obese breast cancer patients have a worse prognosis compared with normal-weight patients. This may be attributed to hyperinsulinemia and dysregulation of adipokine levels associated with overweight and obesity. Here, we evaluate whether low levels of adiponectin and a greater level of insulin resistance are associated with breast cancer mortality and all-cause mortality. Patients and Methods We measured glucose, insulin, and adiponectin levels in fasting serum samples from 527 women enrolled in the Health, Eating, Activity, and Lifestyle (HEAL) Study, a multiethnic, prospective cohort study of women diagnosed with stage I-IIIA breast cancer. We evaluated the association between adiponectin and insulin and glucose levels (expressed as the Homeostatic Model Assessment [HOMA] score) represented as continuous measures and median split categories, along with breast cancer mortality and all-cause mortality, using Cox proportional hazards models. Results Increasing HOMA scores were associated with reduced breast cancer survival (hazard ratio [HR], 1.12; 95% CI, 1.05 to 1.20) and reduced all-cause survival (HR, 1.09; 95% CI, 1.02 to 1.15) after adjustment for possible confounders. Higher levels of adiponectin (above the median: 15.5 μg/mL) were associated with longer breast cancer survival (HR, 0.39; 95% CI, 0.15 to 0.95) after adjustment for covariates. A continuous measure of adiponectin was not associated with either breast cancer–specific or all-cause mortality. Conclusion Elevated HOMA scores and low levels of adiponectin, both associated with obesity, were associated with increased breast cancer mortality. To the best of our knowledge, this is the first demonstration of the association between low levels of adiponectin and increased breast cancer mortality in breast cancer survivors. PMID:21115858

  19. Oral vitamin D supplementation has a lower bioavailability and reduces hypersecretion of parathyroid hormone and insulin resistance in obese Chinese males.

    PubMed

    Zhou, Ji-Chang; Zhu, Yu-Mei; Chen, Zheng; Mo, Jun-Luan; Xie, Feng-Zhu; Wen, Ying-Hong; Guo, Ping; Peng, Ji; Xu, Jian; Wang, Jun; Liu, Xiao-Li

    2015-08-01

    To examine the vitamin D status, SNP of the vitamin D receptor gene (VDR) and the effects of vitamin D supplementation on parathyroid hormone and insulin secretion in adult males with obesity or normal weight in a subtropical Chinese city. An intervention trial. Shenzhen City, Guangdong Province, China. From a cross-sectional survey conducted from June to July, eighty-two normal-weight and ninety-nine obese males (18-69 years) were screened to analyse their vitamin D status and for five SNP of VDR. From these individuals, in the same season of a different year, obese and normal-weight male volunteers (twenty-one per group) were included for an intervention trial with oral vitamin D supplementation at 1250 µg/week for 8 weeks. For the survey, there was no significant difference (P>0·05) in baseline circulating 25-hydroxyvitamin D concentrations or in the percentages of participants in different categories of vitamin D status between the two groups. The VDR SNP, rs3782905, was significantly associated with obesity (P=0·043), but none of the examined SNP were correlated with serum 25-hydroxyvitamin D when adjusted for age, BMI and study group. After vitamin D supplementation, serum 25-hydroxyvitamin D concentration, hypersecretions of parathyroid hormone and insulin, and insulin resistance in the obese were changed beneficially (P<0·05); however, the increase in serum 25-hydroxyvitamin D was less than that of the normal-weight men. For obese and normal-weight men of subtropical China, the summer baseline vitamin D status was similar. However, oral vitamin D supplementation revealed a decreased bioavailability of vitamin D in obese men and ameliorated their hypersecretion of parathyroid hormone and insulin resistance.

  20. Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations

    PubMed Central

    Huang-Doran, Isabel; Tomlinson, Patsy; Payne, Felicity; Gast, Alexandra; Sleigh, Alison; Bottomley, William; Harris, Julie; Daly, Allan; Rocha, Nuno; Rudge, Simon; Clark, Jonathan; Kwok, Albert; Romeo, Stefano; McCann, Emma; Müksch, Barbara; Dattani, Mehul; Zucchini, Stefano; Wakelam, Michael; Foukas, Lazaros C.; Savage, David B.; Murphy, Rinki; O’Rahilly, Stephen; Semple, Robert K.

    2016-01-01

    Obesity-related insulin resistance is associated with fatty liver, dyslipidemia, and low plasma adiponectin. Insulin resistance due to insulin receptor (INSR) dysfunction is associated with none of these, but when due to dysfunction of the downstream kinase AKT2 phenocopies obesity-related insulin resistance. We report 5 patients with SHORT syndrome and C-terminal mutations in PIK3R1, encoding the p85α/p55α/p50α subunits of PI3K, which act between INSR and AKT in insulin signaling. Four of 5 patients had extreme insulin resistance without dyslipidemia or hepatic steatosis. In 3 of these 4, plasma adiponectin was preserved, as in insulin receptor dysfunction. The fourth patient and her healthy mother had low plasma adiponectin associated with a potentially novel mutation, p.Asp231Ala, in adiponectin itself. Cells studied from one patient with the p.Tyr657X PIK3R1 mutation expressed abundant truncated PIK3R1 products and showed severely reduced insulin-stimulated association of mutant but not WT p85α with IRS1, but normal downstream signaling. In 3T3-L1 preadipocytes, mutant p85α overexpression attenuated insulin-induced AKT phosphorylation and adipocyte differentiation. Thus, PIK3R1 C-terminal mutations impair insulin signaling only in some cellular contexts and produce a subphenotype of insulin resistance resembling INSR dysfunction but unlike AKT2 dysfunction, implicating PI3K in the pathogenesis of key components of the metabolic syndrome. PMID:27766312

  1. [Metabolic profile in obese patients with obstructive sleep apnea. A comparison between patients with insulin resistance and with insulin sensitivity].

    PubMed

    Dumitrache-Rujinski, Stefan; Dinu, Ioana; Călcăianu, George; Erhan, Ionela; Cocieru, Alexandru; Zaharia, Dragoş; Toma, Claudia Lucia; Bogdan, Miron Alexandru

    2014-01-01

    Obstructive sleep apnea syndrome (OSAS) may induce metabolic abnormalities through intermittent hypoxemia and simpathetic activation. It is difficult to demonstrate an independent role of OSAS in the occurrence of metabolic abnormalities, as obesity represents an important risk factor for both OSAS and metabolic abnormalities. to assess the relations between insulin resistance (IR), insulin sensitivity (IS), OSAS severity and nocturnal oxyhaemoglobin levels in obese, nondiabetic patients with daytime sleepiness. We evaluated 99 consecutive, obese, nondiabetic patients (fasting glycemia < 126 mg/dL, no hypoglycemic or hypolipemiant medication) diagnosed with OSAS (AHI > 5/hour and daytime sleepiness) by an ambulatory six channel cardio-respiratory polygraphy. Hight, weight serum triglycerides (TG), high density lipoprotein-cholesterol (HDL-C) levels were evaluated. Correlations between Apneea Hypopnea Index (AHI), Oxygen Desaturation Index (ODI), average and lowest oxyhaemoglobin saturation (SaO), body mass index (BMI) and insulin resistance or sensitivity were assesed. IR was defined as a TG/ HDL-Cratio > 3, and insulin sensitivity (IS) as a TG/HDL-C ratio < 2. 64 patients (out of 99) had lR and 18 IS. In the IR group (44 men and 20 women), the mean age was 52 +/- 10.6 years, mean BMI: 38.54 +/- 6.67 Kg/m2 (30-60), TG/HDL-C:5, 27 +/- 2.03 (3.02-11.1), mean AHI: 49.65 +/- 25.55/hour (7-110), mean ODI: 4769 +/- 24.95/hour (4-98), mean average SaO2 89.42 +/- 4.6 and mean lowest SaO2 68.4% +/- 13.8% (32-88%). 48 patients had severe, 7 moderate and 9 mild OSAS. In the IS group (10 men and 8 women), the mean age was 58.4 +/- 8.2years, mean BMI: 35.4 +/- 4.29 Kg/m2 (30-46), TG/ HDL-C: 1.64 +/- 0.29 (1.13-1.95), mean AHI: 45.8 +/- 30.3/hour (9-131), mean ODI: 39.9 +/- 32.2/hour (2-133), mean average SaO2 90.8 +/- 8.2 (81-95) and mean lowest SaO2: 74% +/- 10.8% (52-87%). 12 patients had severe, 3 moderate and 3 mild OSAS. Insulin sensitivity positively correlated with mean

  2. Medical implications of obesity in horses--lessons for human obesity.

    PubMed

    Johnson, Philip J; Wiedmeyer, Charles E; Messer, Nat T; Ganjam, Venkataseshu K

    2009-01-01

    There is growing recognition that obesity is common and represents a significant detriment to the health of companion animals in a manner similar to that by which it is affecting the human population. As is the case for other species, obesity appears to promote insulin resistance in horses and it is through this pathophysiological process that many of the adverse medical consequences of obesity are being characterized. Equine medical conditions that have been described in the context of obesity and insulin resistance differ from those in humans. Chronic human conditions that have been attributed to obesity and insulin resistance, such as atherosclerosis and diabetes mellitus, are rarely described in obese horses. Significant current interest is centered on the recognition that insulin resistance plays a role in the pathogenesis of laminitis, a potentially severe and debilitating cause of lameness in the equine species. Other equine medical conditions that are more likely in obese, insulin-resistant individuals include hyperlipemia (hepatic lipidosis) and developmental orthopedic disease (osteochondrosis). Pituitary pars intermedia dysfunction (equine Cushing's syndrome) represents another common endocrinopathic condition of older horses associated with insulin resistance. This review presents an introductory overview of the present understanding of obesity and insulin resistance and how these conditions may be associated with disease conditions in horses. © Diabetes Technology Society

  3. Medical Implications of Obesity in Horses—Lessons for Human Obesity

    PubMed Central

    Johnson, Philip J.; Wiedmeyer, Charles E.; Messer, Nat T.; Ganjam, Venkataseshu K.

    2009-01-01

    There is growing recognition that obesity is common and represents a significant detriment to the health of companion animals in a manner similar to that by which it is affecting the human population. As is the case for other species, obesity appears to promote insulin resistance in horses and it is through this pathophysiological process that many of the adverse medical consequences of obesity are being characterized. Equine medical conditions that have been described in the context of obesity and insulin resistance differ from those in humans. Chronic human conditions that have been attributed to obesity and insulin resistance, such as atherosclerosis and diabetes mellitus, are rarely described in obese horses. Significant current interest is centered on the recognition that insulin resistance plays a role in the pathogenesis of laminitis, a potentially severe and debilitating cause of lameness in the equine species. Other equine medical conditions that are more likely in obese, insulin-resistant individuals include hyperlipemia (hepatic lipidosis) and developmental orthopedic disease (osteochondrosis). Pituitary pars intermedia dysfunction (equine Cushing's syndrome) represents another common endocrinopathic condition of older horses associated with insulin resistance. This review presents an introductory overview of the present understanding of obesity and insulin resistance and how these conditions may be associated with disease conditions in horses. PMID:20046661

  4. Increased plasma FGF21 level as an early biomarker for insulin resistance and metabolic disturbance in obese insulin-resistant rats.

    PubMed

    Tanajak, Pongpan; Pongkan, Wanpitak; Chattipakorn, Siriporn C; Chattipakorn, Nipon

    2018-05-01

    Propose: To investigate the temporal relationship between plasma fibroblast growth factor 21 levels, insulin resistance, metabolic dysfunction and cardiac fibroblast growth factor 21 resistance in long-term high-fat diet-induced obese rats. In total, 36 male Wistar rats were fed with either a normal diet or high-fat diet for 12 weeks. Blood was collected from the tail tip, and plasma was used to determine metabolic profiles and fibroblast growth factor 21 levels. Rats were sacrificed at weeks 4, 8 and 12, and the hearts were rapidly removed for the determination of cardiac fibroblast growth factor 21 signalling pathways. Body weight and plasma fibroblast growth factor 21 levels were increased after 4 weeks of consumption of a high-fat diet. At weeks 8 and 12, high-fat diet rats had significantly increased body weight and plasma fibroblast growth factor 21 levels, together with increased plasma insulin, HOMA index, area under the curve of glucose, plasma total cholesterol, plasma low-density lipoprotein cholesterol, serum malondialdehyde and cardiac malondialdehyde levels. However, plasma high-density lipoprotein cholesterol levels and cardiac fibroblast growth factor 21 signalling proteins (p-FGFR1 Tyr 154 , p-ERK1/2 Thr 202 /Tyr 204 and p-Akt Ser 473 ) were decreased, compared with normal diet rats. These findings suggest that plasma fibroblast growth factor 21 levels could be an early predictive biomarker prior to the development of insulin resistance, metabolic disturbance and cardiac fibroblast growth factor 21 resistance.

  5. The transcriptional coactivators p/CIP and SRC-1 control insulin resistance through IRS1 in obesity models.

    PubMed

    Wang, Zhiyong; Shah, O Jameel; Hunter, Tony

    2012-01-01

    Three p160 family members, p/CIP, SRC1, and TIF2, have been identified as transcriptional coactivators for nuclear hormone receptors and other transcription factors in vitro. In a previous study, we reported initial characterization of the obesity-resistant phenotypes of p/CIP and SRC-1 double knockout (DKO) mice, which exhibit increased energy expenditure, and suggested that nuclear hormone receptor target genes were involved in these phenotypes. In this study, we demonstrate that p/CIP and SRC1 control insulin signaling in a cell-autonomous manner both in vitro and in vivo. Genetic deletion of p/CIP and SRC-1 increases glucose uptake and enhances insulin sensitivity in both regular chow- and high fat diet-fed DKO mice despite increased food intake. Interestingly, we discover that loss of p/CIP and SRC-1 results in resistance to age-related obesity and glucose intolerance. We show that expression levels of a key insulin signaling component, insulin receptor substrate 1 (IRS1), are significantly increased in two cell lines representing fat and muscle lineages with p/CIP and SRC-1 deletions and in white adipose tissue and skeletal muscle of DKO mice; this may account for increased glucose metabolism and insulin sensitivity. This is the first evidence that the p160 coactivators control insulin signaling and glucose metabolism through IRS1. Therefore, our studies indicate that p/CIP and SRC-1 are potential therapeutic targets not only for obesity but also for diabetes.

  6. The Transcriptional Coactivators p/CIP and SRC-1 Control Insulin Resistance through IRS1 in Obesity Models

    PubMed Central

    Wang, Zhiyong; Shah, O. Jameel; Hunter, Tony

    2012-01-01

    Three p160 family members, p/CIP, SRC1, and TIF2, have been identified as transcriptional coactivators for nuclear hormone receptors and other transcription factors in vitro. In a previous study, we reported initial characterization of the obesity-resistant phenotypes of p/CIP and SRC-1 double knockout (DKO) mice, which exhibit increased energy expenditure, and suggested that nuclear hormone receptor target genes were involved in these phenotypes. In this study, we demonstrate that p/CIP and SRC1 control insulin signaling in a cell-autonomous manner both in vitro and in vivo. Genetic deletion of p/CIP and SRC-1 increases glucose uptake and enhances insulin sensitivity in both regular chow- and high fat diet-fed DKO mice despite increased food intake. Interestingly, we discover that loss of p/CIP and SRC-1 results in resistance to age-related obesity and glucose intolerance. We show that expression levels of a key insulin signaling component, insulin receptor substrate 1 (IRS1), are significantly increased in two cell lines representing fat and muscle lineages with p/CIP and SRC-1 deletions and in white adipose tissue and skeletal muscle of DKO mice; this may account for increased glucose metabolism and insulin sensitivity. This is the first evidence that the p160 coactivators control insulin signaling and glucose metabolism through IRS1. Therefore, our studies indicate that p/CIP and SRC-1 are potential therapeutic targets not only for obesity but also for diabetes. PMID:22859932

  7. Loss of ABHD15 Impairs the Anti-lipolytic Action of Insulin by Altering PDE3B Stability and Contributes to Insulin Resistance.

    PubMed

    Xia, Wenmin; Pessentheiner, Ariane R; Hofer, Dina C; Amor, Melina; Schreiber, Renate; Schoiswohl, Gabriele; Eichmann, Thomas O; Walenta, Evelyn; Itariu, Bianca; Prager, Gerhard; Hackl, Hubert; Stulnig, Thomas; Kratky, Dagmar; Rülicke, Thomas; Bogner-Strauss, Juliane G

    2018-05-15

    Elevated circulating fatty acids (FAs) contribute to obesity-associated metabolic complications, but the mechanisms by which insulin suppresses lipolysis are poorly understood. We show that α/β-hydrolase domain-containing 15 (ABHD15) is required for the anti-lipolytic action of insulin in white adipose tissue (WAT). Neither insulin nor glucose treatments can suppress FA mobilization in global and conditional Abhd15-knockout (KO) mice. Accordingly, insulin signaling is impaired in Abhd15-KO adipocytes, as indicated by reduced AKT phosphorylation, glucose uptake, and de novo lipogenesis. In vitro data reveal that ABHD15 associates with and stabilizes phosphodiesterase 3B (PDE3B). Accordingly, PDE3B expression is decreased in the WAT of Abhd15-KO mice, mechanistically explaining increased protein kinase A (PKA) activity, hormone-sensitive lipase (HSL) phosphorylation, and undiminished FA release upon insulin signaling. Ultimately, Abhd15-KO mice develop insulin resistance. Notably, ABHD15 expression is decreased in humans with obesity and diabetes compared to humans with obesity and normal glucose tolerance, identifying ABHD15 as a potential therapeutic target to mitigate insulin resistance. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  8. Thinking about brain insulin resistance.

    PubMed

    Al Haj Ahmad, Reem M; Al-Domi, Hayder A

    2018-05-06

    Dementia and type 2 diabetes mellitus (T2DM) are two of the epidemics of our time; in which insulin resistance (IR) is playing the central role. Epidemiological studies found that different types of dementia development may be promoted by the presence of T2DM. We aimed in this review to highlight the role of insulin and the IR in the brain as a pathophysiological factor of dementia development and also to expand our understanding of T2DM as a mediator of IR in the brain and to review the possible mechanisms of action that may explain the association. A critical review of the relevant published English articles up to 2018, using PubMed, Google Scholar, Science Direct, ADI, and WHO database was carried out. Keywords were included insulin resistance, T3DM, T2DM, dementia, brain insulin resistance were used. The rapidly increased prevalence of dementia concurrently with T2DM and obesity need urgent action to illustrate guidelines for prevention, modifying, and treatment based on mechanistic studies. Copyright © 2018 Diabetes India. Published by Elsevier Ltd. All rights reserved.

  9. Polycystic ovary syndrome, insulin resistance, and obesity: navigating the pathophysiologic labyrinth.

    PubMed

    Rojas, Joselyn; Chávez, Mervin; Olivar, Luis; Rojas, Milagros; Morillo, Jessenia; Mejías, José; Calvo, María; Bermúdez, Valmore

    2014-01-01

    Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine-metabolic disorder that implies various severe consequences to female health, including alarming rates of infertility. Although its exact etiology remains elusive, it is known to feature several hormonal disturbances, including hyperandrogenemia, insulin resistance (IR), and hyperinsulinemia. Insulin appears to disrupt all components of the hypothalamus-hypophysis-ovary axis, and ovarian tissue insulin resistance results in impaired metabolic signaling but intact mitogenic and steroidogenic activity, favoring hyperandrogenemia, which appears to be the main culprit of the clinical picture in PCOS. In turn, androgens may lead back to IR by increasing levels of free fatty acids and modifying muscle tissue composition and functionality, perpetuating this IR-hyperinsulinemia-hyperandrogenemia cycle. Nonobese women with PCOS showcase several differential features, with unique biochemical and hormonal profiles. Nevertheless, lean and obese patients have chronic inflammation mediating the long term cardiometabolic complications and comorbidities observed in women with PCOS, including dyslipidemia, metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. Given these severe implications, it is important to thoroughly understand the pathophysiologic interconnections underlying PCOS, in order to provide superior therapeutic strategies and warrant improved quality of life to women with this syndrome.

  10. Polycystic Ovary Syndrome, Insulin Resistance, and Obesity: Navigating the Pathophysiologic Labyrinth

    PubMed Central

    Rojas, Joselyn; Chávez, Mervin; Olivar, Luis; Rojas, Milagros; Morillo, Jessenia; Mejías, José; Calvo, María; Bermúdez, Valmore

    2014-01-01

    Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine-metabolic disorder that implies various severe consequences to female health, including alarming rates of infertility. Although its exact etiology remains elusive, it is known to feature several hormonal disturbances, including hyperandrogenemia, insulin resistance (IR), and hyperinsulinemia. Insulin appears to disrupt all components of the hypothalamus-hypophysis-ovary axis, and ovarian tissue insulin resistance results in impaired metabolic signaling but intact mitogenic and steroidogenic activity, favoring hyperandrogenemia, which appears to be the main culprit of the clinical picture in PCOS. In turn, androgens may lead back to IR by increasing levels of free fatty acids and modifying muscle tissue composition and functionality, perpetuating this IR-hyperinsulinemia-hyperandrogenemia cycle. Nonobese women with PCOS showcase several differential features, with unique biochemical and hormonal profiles. Nevertheless, lean and obese patients have chronic inflammation mediating the long term cardiometabolic complications and comorbidities observed in women with PCOS, including dyslipidemia, metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. Given these severe implications, it is important to thoroughly understand the pathophysiologic interconnections underlying PCOS, in order to provide superior therapeutic strategies and warrant improved quality of life to women with this syndrome. PMID:25763405

  11. Endocrine and metabolic effects of consuming fructose- and glucose-sweetened beverages with meals in obese men and women: influence of insulin resistance on plasma triglyceride responses.

    PubMed

    Teff, Karen L; Grudziak, Joanne; Townsend, Raymond R; Dunn, Tamara N; Grant, Ryan W; Adams, Sean H; Keim, Nancy L; Cummings, Bethany P; Stanhope, Kimber L; Havel, Peter J

    2009-05-01

    Compared with glucose-sweetened beverages, consumption of fructose-sweetened beverages with meals elevates postprandial plasma triglycerides and lowers 24-h insulin and leptin profiles in normal-weight women. The effects of fructose, compared with glucose, ingestion on metabolic profiles in obese subjects has not been studied. The objective of the study was to compare the effects of fructose- and glucose-sweetened beverages consumed with meals on hormones and metabolic substrates in obese subjects. The study had a within-subject design conducted in the clinical and translational research center. Participants included 17 obese men (n = 9) and women (n = 8), with a body mass index greater than 30 kg/m(2). Subjects were studied under two conditions involving ingestion of mixed nutrient meals with either glucose-sweetened beverages or fructose-sweetened beverages. The beverages provided 30% of total kilocalories. Blood samples were collected over 24 h. Area under the curve (24 h AUC) for glucose, lactate, insulin, leptin, ghrelin, uric acid, triglycerides (TGs), and free fatty acids was measured. Compared with glucose-sweetened beverages, fructose consumption was associated with lower AUCs for insulin (1052.6 +/- 135.1 vs. 549.2 +/- 79.7 muU/ml per 23 h, P < 0.001) and leptin (151.9 +/- 22.7 vs. 107.0 +/- 15.0 ng/ml per 24 h, P < 0.03) and increased AUC for TG (242.3 +/- 96.8 vs. 704.3 +/- 124.4 mg/dl per 24 h, P < 0.0001). Insulin-resistant subjects exhibited larger 24-h TG profiles (P < 0.03). In obese subjects, consumption of fructose-sweetened beverages with meals was associated with less insulin secretion, blunted diurnal leptin profiles, and increased postprandial TG concentrations compared with glucose consumption. Increases of TGs were augmented in obese subjects with insulin resistance, suggesting that fructose consumption may exacerbate an already adverse metabolic profile present in many obese subjects.

  12. Endocrinology and Adolescence: aerobic exercise reduces insulin resistance markers in obese youth: a meta-analysis of randomized controlled trials.

    PubMed

    García-Hermoso, Antonio; Saavedra, Jose M; Escalante, Yolanda; Sánchez-López, Mairena; Martínez-Vizcaíno, Vicente

    2014-10-01

    The purpose of this meta-analysis was to examine the evidence for the effectiveness of aerobic exercise interventions on reducing insulin resistance markers in obese children and/or adolescents. A secondary outcome was change in percentage of body fat. A computerized search was made from seven databases: CINAHL, Cochrane Central Register of Controlled Trials, EMBASE, ERIC, MEDLINE, PsycINFO, and Science Citation Index. The analysis was restricted to randomized controlled trials that examined the effect of aerobic exercise on insulin resistance markers in obese youth. Two independent reviewers screened studies and extracted data. Effect sizes (ES) and 95% confidence interval (CI) were calculated, and the heterogeneity of the studies was estimated using Cochran's Q-statistic. Nine studies were selected for meta-analysis as they fulfilled the inclusion criteria (n=367). Aerobic exercise interventions resulted in decreases in fasting glucose (ES=-0.39; low heterogeneity) and insulin (ES=-0.40; low heterogeneity) and in percentage of body fat (ES=-0.35; low heterogeneity). These improvements were specifically accentuated in adolescents (only in fasting insulin), or through programs lasting more than 12 weeks, three sessions per week, and over 60 min of aerobic exercise per session. This meta-analysis provides insights into the effectiveness of aerobic exercise interventions on insulin resistance markers in the obese youth population. © 2014 European Society of Endocrinology.

  13. A Prospective Observational Study of Obesity, Body Composition, and Insulin Resistance in 18 Women With Bipolar Disorder and 17 Matched Control Subjects

    PubMed Central

    Fleet-Michaliszyn, Sara B.; Soreca, Isabella; Otto, Amy D.; Jakicic, John M.; Fagiolini, Andrea; Kupfer, David J.; Goodpaster, Bret H.

    2012-01-01

    Objective Patients with bipolar disorder are at increased risk for diabetes and cardiovascular diseases, possibly because of more severe insulin resistance. The primary purpose of this study was to determine whether insulin resistance is characteristic of bipolar disorder. Method The Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was performed in 18 women with DSM-IV bipolar I disorder, and results were compared to those of 17 matched controls. Other risk factors were compared, including blood pressure, blood lipids, and abdominal obesity by computed tomography (CT). Additionally, substrate utilization was measured by indirect calorimetry, and free-living energy expenditure was estimated using wearable activity monitors. All data were collected between February 2006 and December 2007. Results Patients with bipolar disorder were no more insulin resistant than controls after accounting for generalized obesity (mean ± SEM HOMA-IR = 2.7 ± 0.7 vs. 2.5 ± 0.7, for patients and controls, respectively; p = .79). Although blood lipid profiles were generally similar in patients and controls, obese patients had higher blood pressure than controls. Obese patients had more mean ± SEM total abdominal fat (718.1 ± 35.1 cm2 vs. 607.4 ± 33.6 cm2: p = .04), and tended (p = .06) to have more visceral abdominal fat. Patients oxidized 13% less fat during resting conditions, although their resting metabolic rate was similar to that of controls. Conclusion Women with bipolar I disorder were no more insulin resistant than matched controls after accounting for their level of obesity. However, they were more hypertensive, had higher amounts of abdominal obesity, and had reduced rates of fat oxidation. Therefore, women with bipolar I disorder may be at a heightened risk for future weight gain and concomitant risk for diabetes and cardiovascular disease. PMID:19026257

  14. [Insulin resistance in the pathogenesis of polycystic ovarian disease (PCOD)].

    PubMed

    Jakowicki, J

    1994-10-01

    In polycystic ovarian disease there is a strong association between hyperinsulinemia and hyperandrogenism but not with obesity alone. The magnitude of peripheral insulin resistance is similar to that seen in non-insulin-dependent diabetes mellitus. Mild hyperinsulinemia in PCOD patients is not impair the carbohydrate metabolism. The elimination of the cause of hyperandrogenism by bilateral oophorectomy, long-acting Gn-RH agonist or antiandrogen cyproterone acetate did not improve the associated insulin resistance. In opposition to insulin resistance in the tissues responsible for metabolism of carbohydrate, the ovary remains sensitive to the effects of pancreatic hormone. Presumably this mechanism involved the interaction with IGF-I receptors to stimulate thecal and stromal androgen production. Insulin may sensitize the stroma to the stimulatory effect of LH. In the mechanism of follicular arrest take part increased level of binding proteins for IGF-I, mainly IGFBP 2, -4 and 5 inhibit FSH and IGF-I action.

  15. White blood cells levels and PCOS: direct and indirect relationship with obesity and insulin resistance, but not with hyperandogenemia.

    PubMed

    Papalou, Olga; Livadas, Sarantis; Karachalios, Athanasios; Tolia, Nikoleta; Kokkoris, Panayiotis; Tripolitakis, Konstantinos; Diamanti-Kandarakis, Evanthia

    2015-01-01

    To study white blood cells count (WBC) in women suffering from PCOS and compare these results with age and BMI-matched healthy women. The specific aim of this study was to assess the possible correlations of WBC with the major components of PCOS, obesity, insulin resistance and hyperandrogenism. Anthropometrical, metabolic and hormonal data were analyzed from 203 women with PCOS (NIH criteria) and 76 age-matched controls. In the total population studied (N=279), WBC was significantly higher (P=0.003) in the PCOS group compared with age-matched healthy women and was positively correlated with BMI (r=0.461, p<0.001), total testosterone (r= 0.210, p<0.001), insulin (r=0.271, p<0.001), triglycerides (r=0.285, p<0.001), HOMA score (r=0.206, p=0.001), FAI (r=0.329, p<0.001) and negatively correlated with SHBG (r=-0.300, p<0.001) and HDL (r=-0.222, p<0.001). Due to the fact that WHR was only available in the group of PCOS women, the role of central adiposity is assessed only in this group. Multiple regression analysis in the PCOS group, including WHR, revealed BMI, SHBG and TGL as the main predicting factors of WBC. Multinomial logistic regression analysis was also conducted and overweight/obesity was the sole independent risk factor for elevated WBC (higher tertile) (OR:0.907 CI:0.85-0.96, p=0.002). After dividing the sample based on BMI in the lean subgroups, WBC did not differ significantly between PCOS and controls, while multiple regression analysis indicated SHBG as the main predicting factor of WBC. Finally, we picked out the group of overweight/obese (BMI ≥25 kg/m2) women with PCOS and conducted another classification based on HOMA score (HOMA-IR≤2: insulin-sensitive women, HOMA-IR>2: insulin-resistant women) in the group of overweight and obese women with PCOS separately. In overweight women with PCOS, WBC, although higher in the group of insulin-resistant, did not differ significantly between the two groups, while in the subcategory of overweight women WBC

  16. The role of production of adipsin and leptin in the development of insulin resistance in patients with abdominal obesity.

    PubMed

    Vasilenko, M A; Kirienkova, E V; Skuratovskaia, D A; Zatolokin, P A; Mironyuk, N I; Litvinova, L S

    2017-07-01

    We investigated the tissue-specific features of the production of adipokines (leptin and adipsin) by adipose tissue in obese patients depending on the degree of obesity and the state of carbohydrate metabolism. An increase in the content of adipsin and leptin in the blood plasma was found. In patients with varying degrees of obesity with and without type 2 diabetes mellitus (DM 2), we determined the level of tissue-specific expression of LEP and CFD genes encoding leptin and adipsin, respectively. The contribution of different adipose tissue depots to the blood plasma level of adipsin and leptin in obese patients with and without DM 2 was established. The disturbance of reciprocal relationships between adipsin and leptin in obesity is associated with the development of insulin resistance.

  17. Relationship of oxidative stress in skeletal muscle with obesity and obesity-associated hyperinsulinemia in horses.

    PubMed

    Banse, Heidi E; Frank, Nicholas; Kwong, Grace P S; McFarlane, Dianne

    2015-10-01

    In horses, hyperinsulinemia and insulin resistance (insulin dysregulation) are associated with the development of laminitis. Although obesity is associated with insulin dysregulation, the mechanism of obesity-associated insulin dysregulation remains to be established. We hypothesized that oxidative stress in skeletal muscle is associated with obesity-associated hyperinsulinemia in horses. Thirty-five light breed horses with body condition scores (BCS) of 3/9 to 9/9 were studied, including 7 obese, normoinsulinemic (BCS ≥ 7, resting serum insulin < 30 μIU/mL) and 6 obese, hyperinsulinemic (resting serum insulin ≥ 30 μIU/mL) horses. Markers of oxidative stress (oxidative damage, mitochondrial function, and antioxidant capacity) were evaluated in skeletal muscle biopsies. A Spearman's rank correlation coefficient was used to determine relationships between markers of oxidative stress and BCS. Furthermore, to assess the role of oxidative stress in obesity-related hyperinsulinemia, markers of antioxidant capacity and oxidative damage were compared among lean, normoinsulinemic (L-NI); obese, normoinsulinemic (O-NI); and obese, hyperinsulinemic (O-HI) horses. Increasing BCS was associated with an increase in gene expression of a mitochondrial protein responsible for mitochondrial biogenesis (estrogen-related receptor alpha, ERRα) and with increased antioxidant enzyme total superoxide dismutase (TotSOD) activity. When groups (L-NI, O-NI, and O-HI) were compared, TotSOD activity was increased and protein carbonyls, a marker of oxidative damage, decreased in the O-HI compared to the L-NI horses. These findings suggest that a protective antioxidant response occurred in the muscle of obese animals and that obesity-associated oxidative damage in skeletal muscle is not central to the pathogenesis of equine hyperinsulinemia.

  18. ALOX5AP Overexpression in Adipose Tissue Leads to LXA4 Production and Protection Against Diet-Induced Obesity and Insulin Resistance.

    PubMed

    Elias, Ivet; Ferré, Tura; Vilà, Laia; Muñoz, Sergio; Casellas, Alba; Garcia, Miquel; Molas, Maria; Agudo, Judith; Roca, Carles; Ruberte, Jesús; Bosch, Fatima; Franckhauser, Sylvie

    2016-08-01

    Eicosanoids, such as leukotriene B4 (LTB4) and lipoxin A4 (LXA4), may play a key role during obesity. While LTB4 is involved in adipose tissue inflammation and insulin resistance, LXA4 may exert anti-inflammatory effects and alleviate hepatic steatosis. Both lipid mediators derive from the same pathway, in which arachidonate 5-lipoxygenase (ALOX5) and its partner, arachidonate 5-lipoxygenase-activating protein (ALOX5AP), are involved. ALOX5 and ALOX5AP expression is increased in humans and rodents with obesity and insulin resistance. We found that transgenic mice overexpressing ALOX5AP in adipose tissue had higher LXA4 rather than higher LTB4 levels, were leaner, and showed increased energy expenditure, partly due to browning of white adipose tissue (WAT). Upregulation of hepatic LXR and Cyp7a1 led to higher bile acid synthesis, which may have contributed to increased thermogenesis. In addition, transgenic mice were protected against diet-induced obesity, insulin resistance, and inflammation. Finally, treatment of C57BL/6J mice with LXA4, which showed browning of WAT, strongly suggests that LXA4 is responsible for the transgenic mice phenotype. Thus, our data support that LXA4 may hold great potential for the future development of therapeutic strategies for obesity and related diseases. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  19. Mitochondrial dysfunction and insulin resistance from the outside in: extracellular matrix, the cytoskeleton, and mitochondria

    PubMed Central

    Coletta, Dawn K.

    2011-01-01

    Insulin resistance in skeletal muscle is a prominent feature of obesity and type 2 diabetes. The association between mitochondrial changes and insulin resistance is well known. More recently, there is growing evidence of a relationship between inflammation, extracellular remodeling, and insulin resistance. The intent of this review is to propose a potentially novel mechanism for the development of insulin resistance, focusing on the underappreciated connections among inflammation, extracellular remodeling, cytoskeletal interactions, mitochondrial function, and insulin resistance in human skeletal muscle. Several sources of inflammation, including expansion of adipose tissue resulting in increased lipolysis and alterations in pro- and anti-inflammatory cytokines, contribute to the insulin resistance observed in obesity and type 2 diabetes. In the experimental model of lipid oversupply, an inflammatory response in skeletal muscle leads to altered expression extracellular matrix-related genes as well as nuclear encoded mitochondrial genes. A similar pattern also is observed in “naturally” occurring insulin resistance in muscle of obese nondiabetic individuals and patients with type 2 diabetes mellitus. More recently, alterations in proteins (including α-actinin-2, desmin, proteasomes, and chaperones) involved in muscle structure and function have been observed in insulin-resistant muscle. Some of these cytoskeletal proteins are mechanosignal transducers that allow muscle fibers to sense contractile activity and respond appropriately. The ensuing alterations in expression of genes coding for mitochondrial proteins and cytoskeletal proteins may contribute to the mitochondrial changes observed in insulin-resistant muscle. These changes in turn may lead to a reduction in fat oxidation and an increase in intramyocellular lipid, which contributes to the defects in insulin signaling in insulin resistance. PMID:21862724

  20. CREG1 heterozygous mice are susceptible to high fat diet-induced obesity and insulin resistance.

    PubMed

    Tian, Xiaoxiang; Yan, Chenghui; Liu, Meili; Zhang, Quanyu; Liu, Dan; Liu, Yanxia; Li, Shaohua; Han, Yaling

    2017-01-01

    Cellular repressor of E1A-stimulated genes 1 (CREG1) is a small glycoprotein whose physiological function is unknown. In cell culture studies, CREG1 promotes cellular differentiation and maturation. To elucidate its physiological functions, we deleted the Creg1 gene in mice and found that loss of CREG1 leads to early embryonic death, suggesting that it is essential for early development. In the analysis of Creg1 heterozygous mice, we unexpectedly observed that they developed obesity as they get older. In this study, we further studied this phenotype by feeding wild type (WT) and Creg1 heterozygote (Creg1+/-) mice a high fat diet (HFD) for 16 weeks. Our data showed that Creg1+/- mice exhibited a more prominent obesity phenotype with no change in food intake compared with WT controls when challenged with HFD. Creg1 haploinsufficiency also exacerbated HFD-induced liver steatosis, dyslipidemia and insulin resistance. In addition, HFD markedly increased pro-inflammatory cytokines in plasma and epididymal adipose tissue in Creg1+/- mice as compared with WT controls. The activation level of NF-κB, a major regulator of inflammatory response, in epididymal adipose tissue was also elevated in parallel with the cytokines in Creg1+/- mice. These pro-inflammatory responses elicited by CREG1 reduction were confirmed in 3T3-L1-derived adipocytes with CREG1 depletion by siRNA transfection. Given that adipose tissue inflammation has been shown to play a key role in obesity-induced insulin resistance and metabolic syndrome, our results suggest that Creg1 haploinsufficiency confers increased susceptibility of adipose tissue to inflammation, leading to aggravated obesity and insulin resistance when challenged with HFD. This study uncovered a novel function of CREG1 in metabolic disorders.

  1. The PPARα/γ dual agonist chiglitazar improves insulin resistance and dyslipidemia in MSG obese rats

    PubMed Central

    Li, Ping-Ping; Shan, Song; Chen, Yue-Teng; Ning, Zhi-Qiang; Sun, Su-Juan; Liu, Quan; Lu, Xian-Ping; Xie, Ming-Zhi; Shen, Zhu-Fang

    2006-01-01

    The aim of this study was to investigate the capacity of chiglitazar to improve insulin resistance and dyslipidemia in monosodium L-glutamate (MSG) obese rats and to determine whether its lipid-lowering effect is mediated through its activation of PPARα. Chiglitazar is a PPARα/γ dual agonist. The compound improved impaired insulin and glucose tolerance; decreased plasma insulin level and increased the insulin sensitivity index and decreased HOMA index. Euglycemic hyperinsulinemic clamp studies showed chiglitazar increased the glucose infusion rate in MSG obese rats. Chiglitazar inhibited alanine gluconeogenesis, lowered the hepatic glycogen level in MSG obese rats. Like rosiglitazone, chiglitazar promoted the differentiation of adipocytes and decreased the maximal diameter of adipocytes. In addition, chiglitazar decreased the fibrosis and lipid accumulation in the islets and increased the size of islets. Chiglitazar reduced plasma triglyceride, total cholesterol (TCHO), nonesterified fatty acids (NEFA) and low density lipoprotein-cholesterol levels; lowered hepatic triglyceride and TCHO contents; decreased muscular NEFA level. Unlike rosiglitazone, chiglitazar showed significant increase of mRNA expression of PPARα, CPT1, BIFEZ, ACO and CYP4A10 in the liver of MSG obese rats. These data suggest that PPARα/γ coagonist, such as chiglitazar, affect lipid homeostasis with different mechanisms from rosiglitazone, chiglitazar may have better effects on lipid homeostasis in diabetic patients than selective PPARγ agonists. PMID:16751799

  2. [The insulin resistance syndrome and fibrinolysis disorders].

    PubMed

    Okapcová, J; Hrnciar, J

    1997-06-01

    The high atherogenic potential of the insulin resistance syndrome can be only partly explained by the association of "classical" risk factors of atherosclerosis which are considered part of it, i.e. impaired carbohydrate tolerance/diabetes mellitus type II, dyslipidaemia, hypertension and obesity. Impaired fibrinolysis due to excessive production of the plasminogen activator inhibitor-1 (PAI-1) are further risk factors which participate in the process of atherogenesis from the beginning of formation of the atheromatous plaque to the thrombotic occlusion of the vascular lumen. The authors present a group of 25 patients with different grades of glucose resistance, evaluated by theinsulin response to a glucose load. The insulin resistant group (n = 15) differed significantly from the non-resistant one (n = 10) as regards body weight and the central type of obesity (< 0.01 and 0.001 resp.) insulin level on fasting and after a load (< 0.0001 and 0.001 resp.), triglyceride levels (< 0.01), the incidence of diabetes or impaired carbohydrate tolerance (66.7 vs. 20%) and hypertension (53.3 vs. 20%), but also as regards the PAI-1 activity (.0001). As regards blood sugar levels, total and HDL cholesterol the groups did not differ. The authors investigated also the relationship between PAI-1 activity and different components of the insulin resistance syndrome in the whole group. The closest correlation was found between the PAI-1 activity and the general insulinaemic response to a glucose load (< 0.001) and between PAI-1 and triglycerides (< 0.001). Based on the presented results it may be stated that hypofibnrinolysis as a result of excessive production of PAI.1 is part of the insulin resistance syndrome and potentiates its high atherogenic risk.

  3. Effects of vildagliptin versus sitagliptin, on cardiac function, heart rate variability and mitochondrial function in obese insulin-resistant rats

    PubMed Central

    Apaijai, Nattayaporn; Pintana, Hiranya; Chattipakorn, Siriporn C; Chattipakorn, Nipon

    2013-01-01

    Background and Purpose Long-term high-fat diet (HFD) consumption has been shown to cause insulin resistance, which is characterized by hyperinsulinaemia with metabolic inflexibility. Insulin resistance is associated with cardiac sympathovagal imbalance, cardiac dysfunction and cardiac mitochondrial dysfunction. Dipeptidyl peptidase-4 (DPP-4) inhibitors, vildagliptin and sitagliptin, are oral anti-diabetic drugs often prescribed in patients with cardiovascular disease. Therefore, in this study, we sought to determine the effects of vildagliptin and sitagliptin in a murine model of insulin resistance. Experimental Approach Male Wistar rats weighing 180–200 g, were fed either a normal diet (20% energy from fat) or a HFD (59% energy from fat) for 12 weeks. These rats were then divided into three subgroups to receive vildagliptin (3 mg·kg−1·day−1), sitagliptin (30 mg·kg−1·day−1) or vehicle for another 21 days. Metabolic parameters, oxidative stress, heart rate variability (HRV), cardiac function and cardiac mitochondrial function were determined. Key Results Rats that received HFD developed insulin resistance characterized by increased body weight, plasma insulin, total cholesterol and oxidative stress levels along with a decreased high-density lipoprotein (HDL) level. Moreover, cardiac dysfunction, depressed HRV, cardiac mitochondrial dysfunction and cardiac mitochondrial morphology changes were observed in HFD rats. Both vildagliptin and sitagliptin decreased plasma insulin, total cholesterol and oxidative stress as well as increased HDL level. Furthermore, vildagliptin and sitagliptin attenuated cardiac dysfunction, prevented cardiac mitochondrial dysfunction and completely restored HRV. Conclusions and Implications Both vildagliptin and sitagliptin share similar efficacy in cardioprotection in obese insulin-resistant rats. PMID:23488656

  4. Associations of maternal BMI and insulin resistance with the maternal metabolome and newborn outcomes.

    PubMed

    Sandler, Victoria; Reisetter, Anna C; Bain, James R; Muehlbauer, Michael J; Nodzenski, Michael; Stevens, Robert D; Ilkayeva, Olga; Lowe, Lynn P; Metzger, Boyd E; Newgard, Christopher B; Scholtens, Denise M; Lowe, William L

    2017-03-01

    Maternal obesity increases the risk for large-for-gestational-age birth and excess newborn adiposity, which are associated with adverse long-term metabolic outcomes in offspring, probably due to effects mediated through the intrauterine environment. We aimed to characterise the maternal metabolic milieu associated with maternal BMI and its relationship to newborn birthweight and adiposity. Fasting and 1 h serum samples were collected from 400 European-ancestry mothers in the Hyperglycaemia and Adverse Pregnancy Outcome Study who underwent an OGTT at ∼28 weeks gestation and whose offspring had anthropometric measurements at birth. Metabolomics assays were performed using biochemical analyses of conventional clinical metabolites, targeted MS-based measurement of amino acids and acylcarnitines and non-targeted GC/MS. Per-metabolite analyses demonstrated broad associations with maternal BMI at fasting and 1 h for lipids, amino acids and their metabolites together with carbohydrates and organic acids. Similar metabolite classes were associated with insulin resistance with unique associations including branched-chain amino acids. Pathway analyses indicated overlapping and unique associations with maternal BMI and insulin resistance. Network analyses demonstrated collective associations of maternal metabolite subnetworks with maternal BMI and newborn size and adiposity, including communities of acylcarnitines, lipids and related metabolites, and carbohydrates and organic acids. Random forest analyses demonstrated contribution of lipids and lipid-related metabolites to the association of maternal BMI with newborn outcomes. Higher maternal BMI and insulin resistance are associated with broad-based changes in maternal metabolites, with lipids and lipid-related metabolites accounting, in part, for the association of maternal BMI with newborn size at birth.

  5. Epicardial adipose tissue is associated with visceral fat, metabolic syndrome, and insulin resistance in menopausal women.

    PubMed

    Fernández Muñoz, María J; Basurto Acevedo, Lourdes; Córdova Pérez, Nydia; Vázquez Martínez, Ana Laura; Tepach Gutiérrez, Nayive; Vega García, Sara; Rocha Cruz, Alberto; Díaz Martínez, Alma; Saucedo García, Renata; Zárate Treviño, Arturo; González Escudero, Eduardo Alberto; Degollado Córdova, José Antonio

    2014-06-01

    Epicardial adipose tissue has been associated with several obesity-related parameters and with insulin resistance. Echocardiographic assessment of this tissue is an easy and reliable marker of cardiometabolic risk. However, there are insufficient studies on the relationship between epicardial fat and insulin resistance during the postmenopausal period, when cardiovascular risk increases in women. The objective of this study was to examine the association between epicardial adipose tissue and visceral adipose tissue, waist circumference, body mass index, and insulin resistance in postmenopausal women. A cross sectional study was conducted in 34 postmenopausal women with and without metabolic syndrome. All participants underwent a transthoracic echocardiogram and body composition analysis. A positive correlation was observed between epicardial fat and visceral adipose tissue, body mass index, and waist circumference. The values of these correlations of epicardial fat thickness overlying the aorta-right ventricle were r = 0.505 (P < .003), r = 0.545 (P < .001), and r = 0.515 (P < .003), respectively. Epicardial adipose tissue was higher in postmenopausal women with metabolic syndrome than in those without this syndrome (mean [standard deviation], 544.2 [122.9] vs 363.6 [162.3] mm(2); P = .03). Epicardial fat thickness measured by echocardiography was associated with visceral adipose tissue and other obesity parameters. Epicardial adipose tissue was higher in postmenopausal women with metabolic syndrome. Therefore, echocardiographic assessment of epicardial fat may be a simple and reliable marker of cardiovascular risk in postmenopausal women. Copyright © 2013 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.

  6. Poor Sleep Quality is Associated with Insulin Resistance in Postmenopausal Women With and Without Metabolic Syndrome.

    PubMed

    Kline, Christopher E; Hall, Martica H; Buysse, Daniel J; Earnest, Conrad P; Church, Timothy S

    2018-05-01

    Poor sleep quality has previously been shown to be related to insulin resistance in apparently healthy adults. However, it is unclear whether an association between sleep quality and insulin resistance exists among adults with metabolic syndrome (MetS). Participants included 347 overweight/obese postmenopausal women without type 2 diabetes (age: 57.5 ± 6.5 years; body mass index [BMI]: 31.7 ± 3.7 kg/m 2 ; 54% with MetS). Sleep quality was assessed with the six-item Medical Outcomes Study Sleep Scale; values were categorized into quartiles. Insulin resistance was calculated from fasting glucose and insulin with the homeostasis model assessment of insulin resistance (HOMA2-IR) method. Analysis of covariance models were used to examine the association between sleep quality and HOMA2-IR after accounting for MetS and covariates (e.g., BMI, cardiorespiratory fitness, and energy intake). Women with the worst sleep quality had significantly higher HOMA2-IR values than women in all other quartiles (P ≤ 0.05 for each), and women with MetS had significantly higher HOMA2-IR values than women without MetS (P < 0.0001), but the relationship between sleep quality and HOMA2-IR did not differ between those with or without MetS (P = 0.26). Women with MetS in the worst quartile of sleep quality had higher HOMA2-IR values than all other women (P < 0.02). Taking >30 min to fall asleep, frequent restless sleep, and frequent daytime drowsiness were each related to higher HOMA2-IR values (each P < 0.04). Sleep quality is an important correlate of insulin resistance in postmenopausal women with and without MetS. Intervention studies are needed to determine whether improving sleep improves insulin resistance in populations at elevated cardiometabolic risk.

  7. Skeletal muscle respiratory uncoupling prevents diet-induced obesity and insulin resistance in mice.

    PubMed

    Li, B; Nolte, L A; Ju, J S; Han, D H; Coleman, T; Holloszy, J O; Semenkovich, C F

    2000-10-01

    To determine whether uncoupling respiration from oxidative phosphorylation in skeletal muscle is a suitable treatment for obesity and type 2 diabetes, we generated transgenic mice expressing the mitochondrial uncoupling protein (Ucp) in skeletal muscle. Skeletal muscle oxygen consumption was 98% higher in Ucp-L mice (with low expression) and 246% higher in Ucp-H mice (with high expression) than in wild-type mice. Ucp mice fed a chow diet had the same food intake as wild-type mice, but weighed less and had lower levels of glucose and triglycerides and better glucose tolerance than did control mice. Ucp-L mice were resistant to obesity induced by two different high-fat diets. Ucp-L mice fed a high-fat diet had less adiposity, lower levels of glucose, insulin and cholesterol, and an increased metabolic rate at rest and with exercise. They were also more responsive to insulin, and had enhanced glucose transport in skeletal muscle in the setting of increased muscle triglyceride content. These data suggest that manipulating respiratory uncoupling in muscle is a viable treatment for obesity and its metabolic sequelae.

  8. Evaluation of beta-cell sensitivity to glucose and first-phase insulin secretion in obese dogs.

    PubMed

    Verkest, Kurt R; Fleeman, Linda M; Rand, Jacquie S; Morton, John M

    2011-03-01

    To compare beta-cell sensitivity to glucose, first-phase insulin secretion, and glucose tolerance between dogs with naturally occurring obesity of > 2 years' duration and lean dogs. 17 client-owned obese or lean dogs. Frequently sampled IV glucose tolerance tests were performed with minimal model analysis on 6 obese dogs and matched controls. Glucagon stimulation tests were performed on 5 obese dogs and matched controls. Obese dogs were half as sensitive to the effects of insulin as lean dogs. Plasma glucose concentrations after food withholding did not differ significantly between groups; plasma insulin concentrations were 3 to 4 times as great in obese as in lean dogs. Obese dogs had plasma insulin concentrations twice those of lean dogs after administration of glucose and 4 times as great after administration of glucagon. First-phase insulin secretion was greater in obese dogs. Obese dogs compensated for obesity-induced insulin resistance by secreting more insulin. First-phase insulin secretion and beta-cell glucose sensitivity were not lost despite years of obesity-induced insulin resistance and compensatory hyperinsulinemia. These findings help explain why dogs, unlike cats and humans, have not been documented to develop type 2 diabetes mellitus.

  9. Central obesity, type 2 diabetes and insulin: exploring a pathway full of thorns

    PubMed Central

    Papakyriakou, Panagiotis; Panagiotou, Themistoklis N.

    2015-01-01

    The prevalence of type 2 diabetes (T2D) is rapidly increasing. This is strongly related to the contemporary lifestyle changes that have resulted in increased rates of overweight individuals and obesity. Central (intra-abdominal) obesity is observed in the majority of patients with T2D. It is associated with insulin resistance, mainly at the level of skeletal muscle, adipose tissue and liver. The discovery of macrophage infiltration in the abdominal adipose tissue and the unbalanced production of adipocyte cytokines (adipokines) was an essential step towards novel research perspectives for a better understanding of the molecular mechanisms governing the development of insulin resistance. Furthermore, in an obese state, the increased cellular uptake of non-esterified fatty acids is exacerbated without any subsequent β-oxidation. This in turn contributes to the accumulation of intermediate lipid metabolites that cause defects in the insulin signaling pathway. This paper examines the possible cellular mechanisms that connect central obesity with defects in the insulin pathway. It discusses the discrepancies observed from studies organized in cell cultures, animal models and humans. Finally, it emphasizes the need for therapeutic strategies in order to achieve weight reduction in overweight and obese patients with T2D. PMID:26170839

  10. Inverse Relationship of the CMKLR1 Relative Expression and Chemerin Serum Levels in Obesity with Dysmetabolic Phenotype and Insulin Resistance

    PubMed Central

    Corona-Meraz, Fernanda-Isadora; Navarro-Hernández, Rosa-Elena; Ruíz-Quezada, Sandra-Luz; Madrigal-Ruíz, Perla-Monserrat; Castro-Albarrán, Jorge; Chavarría-Ávila, Efraín; Guzmán-Ornelas, Milton-Omar; Gómez-Bañuelos, Eduardo; Petri, Marcelo-Herón; Ramírez-Cedano, Joel-Isidro; Aguilar-Aldrete, María-Elena; Ríos-Ibarra, Clara; Vázquez-Del Mercado, Mónica

    2016-01-01

    Background. In obesity there is a subclinical chronic low-grade inflammatory response where insulin resistance (IR) may develop. Chemerin is secreted in white adipose tissue and promotes low-grade inflammatory process, where it expressed CMKLR1 receptor. The role of chemerin and CMKLR1 in inflammatory process secondary to obesity is not defined yet. Methods. Cross-sectional study with 134 individuals classified as with and without obesity by body mass index (BMI) and IR. Body fat storage measurements and metabolic and inflammatory markers were measured by routine methods. Soluble chemerin and basal levels of insulin by ELISA and relative expression of CMKLR1 were evaluated with qPCR and 2−ΔΔCT method. Results. Differences (P < 0.05) were observed between obesity and lean individuals in body fat storage measurements and metabolic-inflammatory markers. Both CMKLR1 expression and chemerin levels were increased in obesity without IR. Soluble chemerin levels correlate with adiposity and metabolic markers (r = 8.8% to 38.5%), P < 0.05. Conclusion. The increment of CMKLR1 expression was associated with insulin production. Increased serum levels of chemerin in obesity were observed, favoring a dysmetabolic response. The results observed in this study suggest that both chemerin and CMKLR1 have opposite expression in the context of low-grade inflammatory response manifested in the development of IR. PMID:27239101

  11. Globular adiponectin ameliorates metabolic insulin resistance via AMPK-mediated restoration of microvascular insulin responses

    PubMed Central

    Zhao, Lina; Fu, Zhuo; Wu, Jing; Aylor, Kevin W; Barrett, Eugene J; Cao, Wenhong; Liu, Zhenqi

    2015-01-01

    Abstract Hypoadiponectinaemia is closely associated with endothelial dysfunction and insulin resistance, and microvasculature plays a critical role in the regulation of insulin action in muscle. Here we tested whether adiponectin replenishment could improve metabolic insulin sensitivity in male rats fed a high-fat diet (HFD) via the modulation of microvascular insulin responses. Male Sprague–Dawley rats were fed either a HFD or low-fat diet (LFD) for 4 weeks. Small resistance artery myograph changes in tension, muscle microvascular recruitment and metabolic response to insulin were determined. Compared with rats fed a LFD, HFD feeding abolished the vasodilatory actions of globular adiponectin (gAd) and insulin on pre-constricted distal saphenous arteries. Pretreatment with gAd improved insulin responses in arterioles isolated from HFD rats, which was blocked by AMP-activated protein kinase (AMPK) inhibition. Similarly, HFD abolished microvascular responses to either gAd or insulin and decreased insulin-stimulated glucose disposal by ∼60%. However, supplementing gAd fully rescued insulin’s microvascular action and significantly improved the metabolic responses to insulin in HFD male rats and these actions were abolished by inhibition of either AMPK or nitric oxide production. We conclude that HFD induces vascular adiponectin and insulin resistance but gAd administration can restore vascular insulin responses and improve insulin’s metabolic action via an AMPK- and nitric oxide-dependent mechanism in male rats. Key points Adiponectin is an adipokine with anti-inflammatory and anti-diabetic properties. Hypoadiponectinaemia is closely associated with endothelial dysfunction and insulin resistance in obesity and diabetes. Insulin resistance is present in muscle microvasculature and this may contribute to decreased insulin delivery to, and action in, muscle. In this study we examined whether adiponectin ameliorates metabolic insulin resistance by affecting muscle

  12. Shrimp oil extracted from the shrimp processing waste reduces the development of insulin resistance and metabolic phenotypes in diet-induced obese rats.

    PubMed

    Nair, Sandhya; Gagnon, Jacques; Pelletier, Claude; Tchoukanova, Nadia; Zhang, Junzeng; Ewart, H Stephen; Ewart, K Vanya; Jiao, Guangling; Wang, Yanwen

    2017-08-01

    Diet-induced obesity, insulin resistance, impaired glucose tolerance, chronic inflammation, and oxidative stress represent the main features of type 2 diabetes mellitus. The present study was conducted to examine the efficacy and mechanisms of shrimp oil on glucose homeostasis in obese rats. Male CD rats fed a high-fat diet (52 kcal% fat) and 20% fructose drinking water were divided into 4 groups and treated with the dietary replacement of 0%, 10%, 15%, or 20% of lard with shrimp oil for 10 weeks. Age-matched rats fed a low-fat diet (10 kcal% fat) were used as the normal control. Rats on the high-fat diet showed impaired (p < 0.05) glucose tolerance and insulin resistance compared with rats fed the low-fat diet. Shrimp oil improved (p < 0.05) oral glucose tolerance, insulin response, and homeostatic model assessment-estimated insulin resistance index; decreased serum insulin, leptin, hemoglobin A1c, and free fatty acids; and increased adiponectin. Shrimp oil also increased (p < 0.05) antioxidant capacity and reduced oxidative stress and chronic inflammation. The results demonstrated that shrimp oil dose-dependently improved glycemic control in obese rats through multiple mechanisms.

  13. Detecting insulin resistance in polycystic ovary syndrome: purposes and pitfalls.

    PubMed

    Legro, Richard S; Castracane, V Daniel; Kauffman, Robert P

    2004-02-01

    Approximately 50% to 70% of all women with polycystic ovary syndrome (PCOS) have some degree of insulin resistance, and this hormone insensitivity probably contributes to the hyperandrogenism that is responsible for the signs and symptoms of PCOS. Although uncertainty exists, early detection and treatment of insulin resistance in this population could ultimately reduce the incidence or severity of diabetes mellitus, dyslipidemia, hypertension, and cardiovascular disease. Even if that proves to be the case, there are still several problems with our current approach to insulin sensitivity assessment in PCOS, including the apparent lack of consensus on what defines PCOS and "normal" insulin sensitivity, ethnic and genetic variability, the presence of other factors contributing to insulin resistance such as obesity, stress, and aging, and concern about whether simplified models of insulin sensitivity have the precision to predict treatment needs, responses, and future morbidity. Although the hyperinsulinemic-euglycemic clamp technique is the gold standard for measuring insulin sensitivity, it is too expensive, time-consuming, and labor-intensive to be of practical use in an office setting. Homeostatic measurements (fasting glucose/insulin ratio or homeostatic model assessment [HOMA] value) and minimal model tests (particularly the oral glucose tolerance test [OGTT]) represent the easiest office-based assessments of insulin resistance in the PCOS patient. The OGTT is probably the best simple, office-based method to assess women with PCOS because it provides information about both insulin resistance and glucose intolerance. The diagnosis of glucose intolerance holds greater prognostic and treatment implications. All obese women with PCOS should be screened for the presence of insulin resistance by looking for other stigmata of the insulin resistance syndrome such as hypertension, dyslipidemia, central obesity, and glucose intolerance.

  14. Mechanism of insulin resistance in normal pregnancy.

    PubMed

    Hodson, K; Man, C Dalla; Smith, F E; Thelwall, P E; Cobelli, C; Robson, S C; Taylor, R

    2013-08-01

    Normal pregnancy is associated with insulin resistance although the mechanism is not understood. Increased intramyocellular lipid is closely associated with the insulin resistance of type 2 diabetes and obesity, and the aim of this study was to determine whether this was so for the physiological insulin resistance of pregnancy. Eleven primiparous healthy pregnant women (age: 27-39 years, body mass index 24.0±3.1 kg/m2) and no personal or family history of diabetes underwent magnetic resonance studies to quantify intramyocellular lipid, plasma lipid fractions, and insulin sensitivity. The meal-related insulin sensitivity index was considerably lower in pregnancy (45.6±9.9 vs. 193.0±26.1; 10(-4) dl/kg/min per pmol/l, p=0.0002). Fasting plasma triglyceride levels were elevated 3-fold during pregnancy (2.3±0.2 vs. 0.8±0.1 mmol/l, p<0.01) and the low-density density lipoprotein fraction, responsible for fatty acid delivery to muscle and other tissues, was 6-fold elevated (0.75±0.43 vs. 0.12±0.09 mmol/l; p=0.001). However, mean intramyocellular lipid concentrations of the soleus muscle were not different during pregnancy (20.0±2.3 vs. 19.1±3.2 mmol/l, p=0.64). The pregnancy effect on muscle insulin resistance is distinct from that underlying type 2 diabetes. © Georg Thieme Verlag KG Stuttgart · New York.

  15. Effects of diet composition on weight loss, metabolic factors and biomarkers in a 1-year weight loss intervention in obese women examined by baseline insulin resistance status

    PubMed Central

    Rock, Cheryl L.; Flatt, Shirley W.; Pakiz, Bilge; Quintana, Elizabeth L.; Heath, Dennis D.; Rana, Brinda K.; Natarajan, Loki

    2018-01-01

    Background Obesity is a risk factor for postmenopausal breast cancer incidence and pre- and postmenopausal breast cancer mortality, which may be explained by several metabolic and hormonal factors (sex hormones, insulin resistance, and inflammation) that are biologically related. Differential effects of dietary composition on weight loss and these metabolic factors may occur in insulin-sensitive vs. insulin-resistant obese women. Objective To examine the effect of diet composition on weight loss and metabolic, hormonal and inflammatory factors in overweight/obese women stratified by insulin resistance status in a 1-year weight loss intervention. Methods and Results Nondiabetic women who were overweight/obese (n = 245) were randomly assigned to a lower fat (20% energy), higher carbohydrate (65% energy) diet; a lower carbohydrate (45% energy), higher fat (35% energy) diet; or a walnut-rich (18% energy), higher fat (35% energy), lower carbohydrate (45% energy) diet. All groups lost weight at follow-up (P < 0.0001), with mean (SEM) percent loss of 9.2 (1.1)% in lower fat, 6.5 (0.9)% in lower carbohydrate, and 8.2 (1.0)% in walnut-rich groups at 12 months. The diet × time × insulin resistance status interaction was not statistically significant in the model for overall weight loss, although insulin sensitive women at 12 months lost more weight in the lower fat vs. lower carbohydrate group (7.5 kg vs 4.3 kg, P = 0.06), and in the walnut-rich vs. lower carbohydrate group (8.1 kg vs 4.3 kg, P = 0.04). Sex hormone binding globulin increased within each group except in the lower carbohydrate group at 12 months (P < 0.01). C-reactive protein and interleukin-6 decreased at follow-up in all groups (P < 0.01). Conclusions Findings provide some support for differential effects of diet composition on weight loss depending on insulin resistance status. Prescribing walnuts is associated with weight loss comparable to a standard lower fat diet in a behavioral weight loss

  16. Effects of diet composition on weight loss, metabolic factors and biomarkers in a 1-year weight loss intervention in obese women examined by baseline insulin resistance status.

    PubMed

    Rock, Cheryl L; Flatt, Shirley W; Pakiz, Bilge; Quintana, Elizabeth L; Heath, Dennis D; Rana, Brinda K; Natarajan, Loki

    2016-11-01

    Obesity is a risk factor for postmenopausal breast cancer incidence and premenopausal and postmenopausal breast cancer mortality, which may be explained by several metabolic and hormonal factors (sex hormones, insulin resistance, and inflammation) that are biologically related. Differential effects of dietary composition on weight loss and these metabolic factors may occur in insulin-sensitive vs. insulin-resistant obese women. To examine the effect of diet composition on weight loss and metabolic, hormonal and inflammatory factors in overweight/obese women stratified by insulin resistance status in a 1-year weight loss intervention. Nondiabetic women who were overweight/obese (n=245) were randomly assigned to a lower fat (20% energy), higher carbohydrate (65% energy) diet; a lower carbohydrate (45% energy), higher fat (35% energy) diet; or a walnut-rich (18% energy), higher fat (35% energy), lower carbohydrate (45% energy) diet. All groups lost weight at follow-up (P<0.0001), with mean (SEM) percent loss of 9.2(1.1)% in lower fat, 6.5(0.9)% in lower carbohydrate, and 8.2(1.0)% in walnut-rich groups at 12months. The diet×time×insulin resistance status interaction was not statistically significant in the model for overall weight loss, although insulin sensitive women at 12months lost more weight in the lower fat vs. lower carbohydrate group (7.5kg vs. 4.3kg, P=0.06), and in the walnut-rich vs. lower carbohydrate group (8.1kg vs. 4.3kg, P=0.04). Sex hormone binding globulin increased within each group except in the lower carbohydrate group at 12months (P<0.01). C-reactive protein and interleukin-6 decreased at follow-up in all groups (P<0.01). Findings provide some support for differential effects of diet composition on weight loss depending on insulin resistance status. Prescribing walnuts is associated with weight loss comparable to a standard lower fat diet in a behavioral weight loss intervention. Weight loss itself may be the most critical factor for reducing

  17. Chronic apelin treatment improves hepatic lipid metabolism in obese and insulin-resistant mice by an indirect mechanism.

    PubMed

    Bertrand, Chantal; Pradère, Jean-Philippe; Geoffre, Nancy; Deleruyelle, Simon; Masri, Bernard; Personnaz, Jean; Le Gonidec, Sophie; Batut, Aurélie; Louche, Katie; Moro, Cédric; Valet, Philippe; Castan-Laurell, Isabelle

    2018-04-01

    Apelin treatment has been shown to improve insulin sensitivity in insulin resistant mice by acting in skeletal muscles. However, the effects of systemic apelin on the hepatic energy metabolism have not been addressed. We thus aimed to determine the effect of chronic apelin treatment on the hepatic lipid metabolism in insulin resistant mice. The apelin receptor (APJ) expression was also studied in this context since its regulation has only been reported in severe liver pathologies. Mice were fed a high-fat diet (HFD) in order to become obese and insulin resistant compared to chow fed mice (CD). HFD mice then received a daily intraperitoneal injection of apelin (0.1 µmol/kg) or PBS during 28 days. Triglycerides content and the expression of different lipogenesis-related genes were significantly decreased in the liver of HFD apelin-treated compared to PBS-treated mice. Moreover, at this stage of insulin resistance, the beta-oxidation was increased in liver homogenates of HFD PBS-treated mice compared to CD mice and reduced in HFD apelin-treated mice. Finally, APJ expression was not up-regulated in the liver of insulin resistant mice. In isolated hepatocytes from chow and HFD fed mice, apelin did not induce significant effect. Altogether, these results suggest that systemic apelin treatment decreases steatosis in insulin resistant mice without directly targeting hepatocytes.

  18. Body adiposity but not insulin resistance is associated with -675 4G/5G polymorphism in the PAI-1 gene in a sample of Mexican children.

    PubMed

    de la Cruz-Mosso, Ulises; Muñoz-Valle, José Francisco; Salgado-Bernabé, Aralia Berenice; Castro-Alarcón, Natividad; Salgado-Goytia, Lorenzo; Sánchez-Corona, José; Flores-Martínez, Silvia Esperanza; Parra-Rojas, Isela

    2013-01-01

    To assess whether the -675 4G/5G polymorphism in the plasminogen activator inhibitor-1 gene is associated with obesity and insulin resistance in Mexican children. A cross-sectional study was performed in 174 children, 89 with normal-weight and 85 with obesity, aged from 6 to 13 years. All children were from state of Guerrero, and recruited from three primary schools in the city of Chilpancingo, state of Guerrero, Mexico. Insulin levels were determined by immunoenzymatic assay. The homeostasis model assessment was used to determine insulin resistance. The -675 4G/5G polymorphism in PAI-1 gene was analyzed by polymerase chain reaction-restriction fragment length polymorphism. The prevalence of insulin resistance in the obese group was higher (49.41%) than in the normal-weight group (16.85%). The 4G/5G PAI-1 polymorphism was found in Hardy Weinberg equilibrium. The 4G/5G genotype contributed to a significant increase in waist-hip ratio (β=0.02, p=0.006), waist circumference (β=4.42, p=0.009), and subscapular skinfold thickness (β=1.79, p=0.04); however, it was not related with insulin resistance. The -675 4G/5G genotype of PAI-1 gene was associated with increase of body adiposity in Mexican children. Copyright © 2013 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

  19. Branched-chain amino acids in metabolic signalling and insulin resistance

    PubMed Central

    Lynch, Christopher J.; Adams, Sean H.

    2015-01-01

    Branched-chain amino acids (BCAAs) are important nutrient signals that have direct and indirect effects. Frequently, BCAAs have been reported to mediate antiobesity effects, especially in rodent models. However, circulating levels of BCAAs tend to be increased in individuals with obesity and are associated with worse metabolic health and future insulin resistance or type 2 diabetes mellitus (T2DM). A hypothesized mechanism linking increased levels of BCAAs and T2DM involves leucine-mediated activation of the mammalian target of rapamycin complex 1 (mTORC1), which results in uncoupling of insulin signalling at an early stage. A BCAA dysmetabolism model proposes that the accumulation of mitotoxic metabolites (and not BCAAs per se) promotes β-cell mitochondrial dysfunction, stress signalling and apoptosis associated with T2DM. Alternatively, insulin resistance might promote aminoacidaemia by increasing the protein degradation that insulin normally suppresses, and/or by eliciting an impairment of efficient BCAA oxidative metabolism in some tissues. Whether and how impaired BCAA metabolism might occur in obesity is discussed in this Review. Research on the role of individual and model-dependent differences in BCAA metabolism is needed, as several genes (BCKDHA, PPM1K, IVD and KLF15) have been designated as candidate genes for obesity and/or T2DM in humans, and distinct phenotypes of tissue-specific branched chain ketoacid dehydrogenase complex activity have been detected in animal models of obesity and T2DM. PMID:25287287

  20. Branched-chain amino acids in metabolic signalling and insulin resistance.

    PubMed

    Lynch, Christopher J; Adams, Sean H

    2014-12-01

    Branched-chain amino acids (BCAAs) are important nutrient signals that have direct and indirect effects. Frequently, BCAAs have been reported to mediate antiobesity effects, especially in rodent models. However, circulating levels of BCAAs tend to be increased in individuals with obesity and are associated with worse metabolic health and future insulin resistance or type 2 diabetes mellitus (T2DM). A hypothesized mechanism linking increased levels of BCAAs and T2DM involves leucine-mediated activation of the mammalian target of rapamycin complex 1 (mTORC1), which results in uncoupling of insulin signalling at an early stage. A BCAA dysmetabolism model proposes that the accumulation of mitotoxic metabolites (and not BCAAs per se) promotes β-cell mitochondrial dysfunction, stress signalling and apoptosis associated with T2DM. Alternatively, insulin resistance might promote aminoacidaemia by increasing the protein degradation that insulin normally suppresses, and/or by eliciting an impairment of efficient BCAA oxidative metabolism in some tissues. Whether and how impaired BCAA metabolism might occur in obesity is discussed in this Review. Research on the role of individual and model-dependent differences in BCAA metabolism is needed, as several genes (BCKDHA, PPM1K, IVD and KLF15) have been designated as candidate genes for obesity and/or T2DM in humans, and distinct phenotypes of tissue-specific branched chain ketoacid dehydrogenase complex activity have been detected in animal models of obesity and T2DM.

  1. Free fatty acid-induced hepatic insulin resistance is attenuated following lifestyle intervention in obese individuals with impaired glucose tolerance.

    PubMed

    Haus, Jacob M; Solomon, Thomas P J; Marchetti, Christine M; Edmison, John M; González, Frank; Kirwan, John P

    2010-01-01

    The objective of the study was to examine the effects of an exercise/diet lifestyle intervention on free fatty acid (FFA)-induced hepatic insulin resistance in obese humans. Obese men and women (n = 23) with impaired glucose tolerance were randomly assigned to either exercise training with a eucaloric (EU; approximately 1800 kcal; n = 11) or hypocaloric (HYPO; approximately 1300 kcal; n = 12) diet for 12 wk. Hepatic glucose production (HGP; milligrams per kilogram fat-free mass(-1) per minute(-1)) and hepatic insulin resistance were determined using a two-stage sequential hyperinsulinemic (40 mU/m(2) . min(-1)) euglycemic (5.0 mm) clamp with [3-(3)H]glucose. Measures were obtained at basal, during insulin infusion (INS; 120 min), and insulin plus intralipid/heparin infusion (INS/FFA; 300 min). At baseline, basal HGP was similar between groups; hyperinsulinemia alone did not completely suppress HGP, whereas INS/FFA exhibited less suppression than INS (EU, 4.6 +/- 0.8, 2.0 +/- 0.5, and 2.6 +/- 0.4; HYPO, 3.8 +/- 0.5, 1.2 +/- 0.3, and 2.3 +/- 0.4, respectively). After the intervention the HYPO group lost more body weight (P < 0.05) and fat mass (P < 0.05). However, both lifestyle interventions reduced hepatic insulin resistance during basal (P = 0.005) and INS (P = 0.001) conditions, and insulin-mediated suppression of HGP during INS was equally improved in both groups (EU: -42 +/- 22%; HYPO: -50 +/- 20%, before vs. after, P = 0.02). In contrast, the ability of insulin to overcome FFA-induced hepatic insulin resistance and HGP was improved only in the HYPO group (EU: -15 +/- 24% vs. HYPO: -58 +/- 19%, P = 0.02). Both lifestyle interventions are effective in reducing hepatic insulin resistance under basal and hyperinsulinemic conditions. However, the reversal of FFA-induced hepatic insulin resistance is best achieved with a combined exercise/caloric-restriction intervention.

  2. Free Fatty Acid-Induced Hepatic Insulin Resistance is Attenuated Following Lifestyle Intervention in Obese Individuals with Impaired Glucose Tolerance

    PubMed Central

    Haus, Jacob M.; Solomon, Thomas P. J.; Marchetti, Christine M.; Edmison, John M.; González, Frank; Kirwan, John P.

    2010-01-01

    Objective: The objective of the study was to examine the effects of an exercise/diet lifestyle intervention on free fatty acid (FFA)-induced hepatic insulin resistance in obese humans. Research Design and Methods: Obese men and women (n = 23) with impaired glucose tolerance were randomly assigned to either exercise training with a eucaloric (EU; ∼1800 kcal; n = 11) or hypocaloric (HYPO; ∼1300 kcal; n = 12) diet for 12 wk. Hepatic glucose production (HGP; milligrams per kilogram fat-free mass−1 per minute−1) and hepatic insulin resistance were determined using a two-stage sequential hyperinsulinemic (40 mU/m2 · min−1) euglycemic (5.0 mm) clamp with [3-3H]glucose. Measures were obtained at basal, during insulin infusion (INS; 120 min), and insulin plus intralipid/heparin infusion (INS/FFA; 300 min). Results: At baseline, basal HGP was similar between groups; hyperinsulinemia alone did not completely suppress HGP, whereas INS/FFA exhibited less suppression than INS (EU, 4.6 ± 0.8, 2.0 ± 0.5, and 2.6 ± 0.4; HYPO, 3.8 ± 0.5, 1.2 ± 0.3, and 2.3 ± 0.4, respectively). After the intervention the HYPO group lost more body weight (P < 0.05) and fat mass (P < 0.05). However, both lifestyle interventions reduced hepatic insulin resistance during basal (P = 0.005) and INS (P = 0.001) conditions, and insulin-mediated suppression of HGP during INS was equally improved in both groups (EU: −42 ± 22%; HYPO: −50 ± 20%, before vs. after, P = 0.02). In contrast, the ability of insulin to overcome FFA-induced hepatic insulin resistance and HGP was improved only in the HYPO group (EU: −15 ± 24% vs. HYPO: −58 ± 19%, P = 0.02). Conclusions: Both lifestyle interventions are effective in reducing hepatic insulin resistance under basal and hyperinsulinemic conditions. However, the reversal of FFA-induced hepatic insulin resistance is best achieved with a combined exercise/caloric-restriction intervention. PMID:19906790

  3. Serum LBP Is Associated with Insulin Resistance in Women with PCOS.

    PubMed

    Zhu, Qibo; Zhou, Huang; Zhang, Aipin; Gao, Rufei; Yang, Shumin; Zhao, Changhong; Wang, Yue; Hu, Jinbo; Goswami, Richa; Gong, Lilin; Li, Qifu

    2016-01-01

    Lipopolysaccharide-binding protein (LBP) is closely associated with many metabolic disorders. However, no study has been done to explore the relationship between LBP and polycystic ovary syndrome (PCOS). The objective of this study was to investigate whether the serum LBP level is elevated and associated with insulin resistance (IR) in PCOS. In this cross-sectional study, 117 PCOS patients and 121 age-matched controls were recruited. Hyperinsulinemic-euglycemic clamp was performed with an expression of M value for insulin sensitivity. Fasting serum samples were collected to detect LBP, lipids, insulin, sex hormones and high sensitive C reactive protein (hs-CRP). Pearson's correlation and multiple linear regression was used to analyze the associations between M value and LBP level. The study was performed in a clinical research center. Compared with controls, PCOS subjects had a significantly higher LBP concentration (33.03±14.59 vs. 24.35±10.31 μg/ml, p<0.001), and lower M value (8.21±3.06 vs. 12.31±1.72 mg/min/kg, p<0.001). Both in lean and overweight/obese individuals, serum LBP level was higher in PCOS subjects than that in controls. M value was negatively correlated with body mass index (BMI), fasting serum insulin, triglycerides, low-density lipoprotein cholesterol (LDL-c), free testosterone, high sensitive C reactive protein (hs-CRP) and LBP, whereas positively correlated with high-density lipoprotein cholesterol (HDL-c) and sex hormone binding globulin (SHBG). Serum LBP level was associated with M value after adjusting for BMI, fasting serum insulin, SHBG, as well as hs-CRP. Serum LBP level significantly is elevated in PCOS, and is independently associated with IR in PCOS.

  4. Dietary Aloe Improves Insulin Sensitivity via the Suppression of Obesity-induced Inflammation in Obese Mice.

    PubMed

    Shin, Eunju; Shim, Kyu-Suk; Kong, Hyunseok; Lee, Sungwon; Shin, Seulmee; Kwon, Jeunghak; Jo, Tae Hyung; Park, Young-In; Lee, Chong-Kil; Kim, Kyungjae

    2011-02-01

    Insulin resistance is an integral feature of metabolic syndromes, including obesity, hyperglycemia, and hyperlipidemia. In this study, we evaluated whether the aloe component could reduce obesity-induced inflammation and the occurrence of metabolic disorders such as blood glucose and insulin resistance. Male C57BL/6 obese mice fed a high-fat diet for 54 days received a supplement of aloe formula (PAG, ALS, Aloe QDM, and Aloe QDM complex) or pioglitazone (PGZ) and were compared with unsupplemented controls (high-fat diet; HFD) or mice fed a regular diet (RD). RT-PCR and western blot analysis were used to quantify the expression of obesity-induced inflammation. Aloe QDM lowered fasting blood glucose and plasma insulin compared with HFD. Obesity-induced inflammatory cytokine (IL-1β, -6, -12, TNF-α) and chemokine (CX3CL1, CCL5) mRNA and protein were decreased markedly, as was macrophage infiltration and hepatic triglycerides by Aloe QDM. At the same time, Aloe QDM decreased the mRNA and protein of PPARγ/LXRα and 11β-HSD1 both in the liver and WAT. Dietary aloe formula reduces obesity-induced glucose tolerance not only by suppressing inflammatory responses but also by inducing anti-inflammatory cytokines in the WAT and liver, both of which are important peripheral tissues affecting insulin resistance. The effect of Aloe QDM complex in the WAT and liver are related to its dual action on PPARγ and 11β-HSD1 expression and its use as a nutritional intervention against T2D and obesity-related inflammation is suggested.

  5. Impact of exercise training without caloric restriction on inflammation, insulin resistance and visceral fat mass in obese adolescents.

    PubMed

    Mendelson, M; Michallet, A-S; Monneret, D; Perrin, C; Estève, F; Lombard, P R; Faure, P; Lévy, P; Favre-Juvin, A; Pépin, J-L; Wuyam, B; Flore, P

    2015-08-01

    Exercise training has been shown to improve cardiometabolic health in obese adolescents. Evaluate the impact of a 12-week exercise-training programme (without caloric restriction) on obese adolescents' cardiometabolic and vascular risk profiles. We measured systemic markers of oxidation, inflammation, metabolic variables and endothelial function in 20 obese adolescents (OB) (age: 14.5 ± 1.5 years; body mass index: 34.0 ± 4.7 kg m(-2) ) and 20 age- and gender-matched normal-weight adolescents (NW). Body composition was assessed by magnetic resonance imagery. Peak aerobic capacity and maximal fat oxidation were evaluated during specific incremental exercise tests. OB participated in a 12-week exercise-training programme. OB presented lower peak aerobic capacity (24.2 ± 5.9 vs. 39.8 ± 8.3 mL kg(-1)  min(-1) , P < 0.05) and maximal fat oxidation compared with NW (P < 0.05). OB displayed greater F2t-Isoprostanes (20.5 ± 6.7 vs. 13.4 ± 4.2 ng mmol(-1) creatinine), Interleukin-1 receptor antagonist (IL-1Ra) (1794.8 ± 532.2 vs. 835.1 ± 1027.4 pg mL(-1) ), Tumor Necrosis Factor-α (TNF-α) (2.1 ± 1.2 vs. 1.5 ± 1.0 pg mL(-1) ), Soluble Tumor Necrosis Factor-α Type II Receptor (sTNFαRII), leptin, insulin, homeostasis model assessment of insulin resistance, version 2 (HOMA2-IR), high-sensitive C-reactive protein, triglycerides and lower adiponectin and high-density lipoprotein cholesterol (all P < 0.05). After exercise training, despite lack of weight loss, VO2peak (mL.kg(-1) .min(-1) ) and maximal fat oxidation increased (P < 0.05). IL-1Ra and IFN-gamma-inducible protein 10 (IP-10) decreased (P < 0.05). Insulin and HOMA2-IR decreased (14.8 ± 1.5 vs. 10.2 ± 4.2 μUI mL(-1) and 1.9 ± 0.8 vs. 1.3 ± 0.6, respectively, P < 0.05). Change in visceral fat mass was inversely associated with change in maximal fat oxidation (r = -0.54; P = 0.024). The

  6. Insulin sensitivity and metabolic flexibility following exercise training among different obese insulin-resistant phenotypes.

    PubMed

    Malin, Steven K; Haus, Jacob M; Solomon, Thomas P J; Blaszczak, Alecia; Kashyap, Sangeeta R; Kirwan, John P

    2013-11-15

    Impaired fasting glucose (IFG) blunts the reversal of impaired glucose tolerance (IGT) after exercise training. Metabolic inflexibility has been implicated in the etiology of insulin resistance; however, the efficacy of exercise on peripheral and hepatic insulin sensitivity or substrate utilization in adults with IFG, IGT, or IFG + IGT is unknown. Twenty-four older (66.7 ± 0.8 yr) obese (34.2 ± 0.9 kg/m(2)) adults were categorized as IFG (n = 8), IGT (n = 8), or IFG + IGT (n = 8) according to a 75-g oral glucose tolerance test (OGTT). Subjects underwent 12-wk of exercise (60 min/day for 5 days/wk at ∼85% HRmax) and were instructed to maintain a eucaloric diet. A euglycemic hyperinsulinemic clamp (40 mU·m(2)·min(-1)) with [6,6-(2)H]glucose was used to determine peripheral and hepatic insulin sensitivity. Nonoxidative glucose disposal and metabolic flexibility [insulin-stimulated respiratory quotient (RQ) minus fasting RQ] were also assessed. Glucose incremental area under the curve (iAUCOGTT) was calculated from the OGTT. Exercise increased clamp-derived peripheral and hepatic insulin sensitivity more in adults with IFG or IGT alone than with IFG + IGT (P < 0.05). Exercise reduced glucose iAUCOGTT in IGT only (P < 0.05), and the decrease in glucose iAUCOGTT was inversely correlated with the increase in peripheral but not hepatic insulin sensitivity (P < 0.01). Increased clamp-derived peripheral insulin sensitivity was also correlated with enhanced metabolic flexibility, reduced fasting RQ, and higher nonoxidative glucose disposal (P < 0.05). Adults with IFG + IGT had smaller gains in clamp-derived peripheral insulin sensitivity and metabolic flexibility, which was related to blunted improvements in postprandial glucose. Additional work is required to assess the molecular mechanism(s) by which chronic hyperglycemia modifies insulin sensitivity following exercise training.

  7. Changes in whole-body fat distribution, intrahepatic lipids, and insulin resistance of obese adolescents during a low-level lifestyle intervention.

    PubMed

    Springer, Fabian; Ballweg, Verena; Schweizer, Roland; Schick, Fritz; Ranke, Michael B; Binder, Gerhard; Ehehalt, Stefan

    2015-12-01

    The aim of this study was to analyze changes in adipose tissue (AT) distribution, intrahepatic lipids (IHL), and insulin resistance (IR) among a group of obese adolescents undergoing a 7-months low-level lifestyle intervention. Thirty-nine obese Caucasian adolescents (mean age 13.9 years, body mass index standard deviation score (BMI-SDSLMS) 2.14) were included. AT and IHL were determined by T1-weighted magnetic resonance (MR) imaging and single-voxel MR spectroscopy; IR was estimated using the homeostatic model assessment (HOMA-IR). The lifestyle intervention led to a reduction of both BMI-SDSLMS (boys 2.27 to 2.17; girls 2.00 to 1.82) and HOMA-IR (boys 6.1 to 4.4 (p = 0.008); girls 6.2 to 4.7 (p = 0.030)). IHL dropped in both genders (boys 7.5 to 4.3 %; girls 4.6 to 3.4 %) positively correlating with HOMA-IR (boys r = 0.52; girls r = 0.68), while in contrast visceral AT did not change significantly. Although the lifestyle intervention only slightly reduced BMI-SDSLMS, insulin sensitivity improved in both genders and came along with a marked reduction of IHL. This suggests that IHL might play the dominant role regarding insulin resistance in the youth, especially if compared to other AT compartments such as visceral AT. • MR imaging/spectroscopy can be used to evaluate body fat distribution and intrahepatic lipids in the youth. • The strength of associations between body fat compartments and insulin resistance is under scientific debate. • The study emphasizes that even a low-level lifestyle intervention has a beneficial effect. • The study suggests that intrahepatic lipids are an important factor in the development of insulin resistance.

  8. (n-3) Fatty Acids Alleviate Adipose Tissue Inflammation and Insulin Resistance: Mechanistic Insights12

    PubMed Central

    Kalupahana, Nishan S.; Claycombe, Kate J.; Moustaid-Moussa, Naima

    2011-01-01

    Obesity is associated with the metabolic syndrome, a significant risk factor for developing type 2 diabetes and cardiovascular diseases. Chronic low-grade inflammation occurring in the adipose tissue of obese individuals is causally linked to the pathogenesis of insulin resistance and the metabolic syndrome. Although the exact trigger of this inflammatory process is unknown, adipose tissue hypoxia, endoplasmic reticular stress, and saturated fatty acid–mediated activation of innate immune processes have been identified as important processes in these disorders. Furthermore, macrophages and T lymphocytes have important roles in orchestrating this immune process. Although energy restriction leading to weight loss is the primary dietary intervention to reverse these obesity-associated metabolic disorders, other interventions targeted at alleviating adipose tissue inflammation have not been explored in detail. In this regard, (n-3) PUFA of marine origin both prevent and reverse high-fat-diet–induced adipose tissue inflammation and insulin resistance in rodents. We provide an update on the pathogenesis of adipose tissue inflammation and insulin resistance in obesity and discuss potential mechanisms by which (n-3) PUFA prevent and reverse these changes and the implications in human health. PMID:22332072

  9. The origins and drivers of insulin resistance.

    PubMed

    Johnson, Andrew M F; Olefsky, Jerrold M

    2013-02-14

    Obesity-induced insulin resistance is the major determinant of metabolic syndrome, which precedes the development of type 2 diabetes mellitus and is thus the driving force behind the emerging diabetes epidemic. The precise causes of insulin resistance are varied, and the relative importance of each is a matter of ongoing research. Here, we offer a Perspective on the heterogeneous etiology of insulin resistance, focusing in particular on the role of inflammation, lipid metabolism, and the gastrointestinal microbiota. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. Prediction of future risk of insulin resistance and metabolic syndrome based on Korean boy's metabolite profiling.

    PubMed

    Lee, AeJin; Jang, Han Byul; Ra, Moonjin; Choi, Youngshim; Lee, Hye-Ja; Park, Ju Yeon; Kang, Jae Heon; Park, Kyung-Hee; Park, Sang Ick; Song, Jihyun

    2015-01-01

    Childhood obesity is strongly related to future insulin resistance and metabolic syndrome. Thus, identifying early biomarkers of obesity-related diseases based on metabolic profiling is useful to control future metabolic disorders. We compared metabolic profiles between obese and normal-weight children and investigated specific biomarkers of future insulin resistance and metabolic syndrome. In all, 186 plasma metabolites were analysed at baseline and after 2 years in 109 Korean boys (age 10.5±0.4 years) from the Korean Child Obesity Cohort Study using the AbsoluteIDQ™ p180 Kit. We observed that levels of 41 metabolites at baseline and 40 metabolites at follow-up were significantly altered in obese children (p<0.05). Obese children showed significantly higher levels of branched-chain amino acids (BCAAs) and several acylcarnitines and lower levels of acyl-alkyl phosphatidylcholines. Also, baseline BCAAs were significantly positively correlated with both homeostasis model assessment for insulin resistance (HOMA-IR) and continuous metabolic risk score at the 2-year follow-up. In logistic regression analyses with adjustments for degree of obesity at baseline, baseline BCAA concentration, greater than the median value, was identified as a predictor of future risk of insulin resistance and metabolic syndrome. High BCAA concentration could be "early" biomarkers for predicting future metabolic diseases. Copyright © 2014 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

  11. Sodium butyrate epigenetically modulates high-fat diet-induced skeletal muscle mitochondrial adaptation, obesity and insulin resistance through nucleosome positioning

    PubMed Central

    Henagan, Tara M; Stefanska, Barbara; Fang, Zhide; Navard, Alexandra M; Ye, Jianping; Lenard, Natalie R; Devarshi, Prasad P

    2015-01-01

    Background and Purpose Sodium butyrate (NaB), an epigenetic modifier, is effective in promoting insulin sensitivity. The specific genomic loci and mechanisms underlying epigenetically induced obesity and insulin resistance and the targets of NaB are not fully understood. Experimental Approach The anti-diabetic and anti-obesity effects of NaB treatment were measured by comparing phenotypes and physiologies of C57BL/6J mice fed a low-fat diet (LF), high-fat diet (HF) or high-fat diet plus NaB (HF + NaB) for 10 weeks. We determined a possible mechanism of NaB action through induction of beneficial skeletal muscle mitochondrial adaptations and applied microccocal nuclease digestion with sequencing (MNase-seq) to assess whole genome differences in nucleosome occupancy or positioning and to identify associated epigenetic targets of NaB. Key Results NaB prevented HF diet-induced increases in body weight and adiposity without altering food intake or energy expenditure, improved insulin sensitivity as measured by glucose and insulin tolerance tests, and decreased respiratory exchange ratio. In skeletal muscle, NaB increased the percentage of type 1 fibres, improved acylcarnitine profiles as measured by metabolomics and produced a chromatin structure, determined by MNase-seq, similar to that seen in LF. Targeted analysis of representative nuclear-encoded mitochondrial genes showed specific repositioning of the −1 nucleosome in association with altered gene expression. Conclusions and Implications NaB treatment may be an effective pharmacological approach for type 2 diabetes and obesity by inducing −1 nucleosome repositioning within nuclear-encoded mitochondrial genes, causing skeletal muscle mitochondrial adaptations that result in more complete β-oxidation and a lean, insulin sensitive phenotype. PMID:25559882

  12. INS VNTR is not associated with childhood obesity in 1,023 families: a family-based study.

    PubMed

    Bouatia-Naji, Nabila; De Graeve, Franck; Brönner, Günter; Lecoeur, Cécile; Vatin, Vincent; Durand, Emmanuelle; Lichtner, Peter; Nguyen, Thuy T; Heude, Barbara; Weill, Jacques; Lévy-Marchal, Claire; Hebebrand, Johannes; Froguel, Philippe; Meyre, David

    2008-06-01

    Previous studies have described genetic associations of the insulin gene variable number tandem repeat (INS VNTR) variant with childhood obesity and associated phenotypes. We aimed to assess the contribution of INS VNTR genotypes to childhood obesity and variance of insulin resistance, insulin secretion, and birth weight using family-based design. Participants were either French or German whites. We used transmission disequilibrium tests (TDTs) for assessing binary traits and quantitative pedigree disequilibrium tests for assessing continuous traits. In contrast to previous findings, we did not observe any familial association with childhood obesity (T = 50%, P = 0.77) in the 1,023 families tested. In French obese children, INS VNTR did not associate with fasting insulin levels (P = 0.23) and class I allele showed only borderline association with increased insulin secretion index at 30 min (P = 0.03). INS VNTR did not associate with birth weight in obese children (P = 0.98) and TDT analyses in 350 French families with history of low birth weight (LBW) showed no association with this condition (P = 0.92). In summary, our study, the largest performed so far, does not support the previously reported associations between INS VNTR and childhood obesity, insulin resistance, or birth weight, and does not suggest any major role for this variant in modulating these traits.

  13. Insulin resistance influences weight loss in non-obese women who followed a home-based exercise program and slight caloric restriction.

    PubMed

    Mediano, Mauro Felippe Felix; Sichieri, Rosely

    2011-06-01

    This study aimed to evaluate the influence of insulin resistance status on weight changes in non-obese women who followed a home-based exercise program and slight caloric restriction over a period of 12 months. Middle-aged (25-45 year), non-obese (body mass index of 23-29.9 kg/m(2)) women were randomly assigned to control (CG) or home-based exercise group (HB). The HB group received a booklet explaining the physical exercises to be practiced at home at least three times per week (40 min/session). Both groups were required to follow a small energy restriction of 100-300 calories per day. For the analysis, women were stratified in two groups according to baseline insulin sensitivity: NIR (non-insulin resistant; n = 121) and IR (insulin resistant; n = 64). Women classified as IR at baseline had greater weight loss after 12 months of follow-up (-1.6 kg vs. -1.1 kg; p = 0.01), and HB exercise helped to reduce weight only among NIR women (-1.5 vs. -0.7; p = 0.04); no differences were observed between intervention groups for IR women (-1.5 vs. -1.7; p = 0.24). There were no differences between IR and NIR groups for lipid profile after adjustment for weight changes. Insulin resistance facilitated weight loss, and home-based exercise promoted greater weight loss only in non-insulin resistance women. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  14. Serum levels of fractalkine are associated with markers of insulin resistance in gestational diabetes.

    PubMed

    Ebert, T; Hindricks, J; Kralisch, S; Lossner, U; Jessnitzer, B; Richter, J; Blüher, M; Stumvoll, M; Fasshauer, M

    2014-08-01

    Fractalkine has recently been introduced as an adipokine that improves glucose tolerance. Regulation of fractalkine in gestational diabetes, as well as its association with markers of obesity, glucose and lipid metabolism, inflammation and renal function, has not been elucidated. Circulating fractalkine was quantified by enzyme-linked immunosorbent assay in 74 women with gestational diabetes and 74 healthy, pregnant control subjects matched for age, BMI, and gestational age. Median (interquartile range) levels of fractalkine were not significantly different between the two groups [gestational diabetes: 2.24 (2.16) μg/l; control: 2.45 (1.38) μg/l] (P = 0.461). In multivariate linear regression analysis, fractalkine remained independently associated with homeostasis model assessment of insulin resistance (β = -0.253, P = 0.002) and the proinflammatory adipokine progranulin (β = 0.218, P = 0.007). Circulating fractalkine is not different between women with gestational diabetes and control subjects, but the adipokine is independently associated with markers of insulin resistance and proinflammatory progranulin in pregnancy. © 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.

  15. Insulin resistance is associated with depression risk in polycystic ovary syndrome.

    PubMed

    Greenwood, Eleni A; Pasch, Lauri A; Cedars, Marcelle I; Legro, Richard S; Eisenberg, Esther; Huddleston, Heather G

    2018-06-13

    To test the hypothesis that insulin resistance is associated with depression risk in polycystic ovary syndrome (PCOS). Secondary analysis of data from a multicenter randomized trial. Multicenter university-based clinical practices. Seven hundred thirty-eight women with PCOS by modified Rotterdam criteria seeking pregnancy enrolled in a randomized clinical trial comparing clomiphene citrate versus letrozole. The Primary Care Evaluation of Mental Disorders Patient Health Questionnaire was self-administered to identify depression using a validated algorithm at enrollment. Demographic and anthropometric data were collected, and serum assays were performed. Insulin resistance was estimated using the homeostatic model of insulin resistance (HOMA-IR), with a cutoff of >2.2 considered abnormal. Demographic, endocrine, and metabolic parameters associated with depression. In a univariate logistic regression analysis, elevated HOMA-IR was associated with 2.3-fold increased odds of depression (odds ratio [OR] = 2.32; 95% confidence interval [CI], 1.28-4.21). This association remained significant after controlling for age and body mass index (adjusted OR [aOR] = 2.23; 95% CI, 1.11-4.46) and in a model including additional potential confounders (aOR = 2.03; 95% CI, 1.00-4.16). Insulin resistance has a strong and independent association with depression in PCOS and may serve as a physiologic mediator. Our findings corroborate a growing body of evidence linking insulin resistance to depressed mood. The association between insulin resistance and depressed mood warrants further investigation to elucidate mechanisms and identify potential therapeutic targets. Copyright © 2018 American Society for Reproductive Medicine. All rights reserved.

  16. Insulin resistance is associated with the aggressiveness of pancreatic ductal carcinoma.

    PubMed

    Dugnani, Erica; Balzano, Gianpaolo; Pasquale, Valentina; Scavini, Marina; Aleotti, Francesca; Liberati, Daniela; Di Terlizzi, Gaetano; Gandolfi, Alessandra; Petrella, Giovanna; Reni, Michele; Doglioni, Claudio; Bosi, Emanuele; Falconi, Massimo; Piemonti, Lorenzo

    2016-12-01

    To study whether insulin resistance accelerates the development and/or the progression of pancreatic adenocarcinoma (PDAC), we hypothesized that patients with insulin resistance, compared with those without insulin resistance, show: (1) a younger age and more advanced PDAC stage at diagnosis and (2) a shorter disease-free and overall survival after PDAC diagnosis. Prospective observational study of patients admitted to a referral center for pancreatic disease. Insulin resistance was defined as a HOMA-IR value greater than the 66th percentile value of the patients included in this study. Survival was estimated according to Kaplan-Meier and by Cox regression. Of 296 patients with PDAC, 99 (33 %) met criteria for being classified as insulin resistant at diagnosis. Median follow-up time after diagnosis was 5.27 ± 0.23 years. Patients with insulin resistance received a diagnosis of PDAC at a similar age compared to patients without insulin resistance (67.1 ± 9 vs. 66.8 ± 10 years, p = 0.68), but were more likely to have a cancer stage ≥3 (23.2 vs. 14.2 %, p = 0.053) and a residual disease after surgery (R1 56.4 vs. 38 %; p = 0.007). The median overall survival was 1.3 ± 0.14 and 1.79 ± 0.11 years for the patients with and without insulin resistance, respectively (p = 0.016). Results did not change when patients with diabetes at PDAC diagnosis were excluded from the analysis. Multivariate analysis showed that insulin resistance was independently associated with overall survival. Insulin resistance is associated with the aggressiveness of PDAC.

  17. Adipocytokines, neuropeptide Y and insulin resistance in overweight women with gynoid and android type of adipose tissue distribution.

    PubMed

    Orbetzova, Maria M; Koleva, Daniela I; Mitkov, Mitko D; Atanassova, Iliana B; Nikolova, Julia G; Atanassova, Pepa K; Genchev, Gencho D

    2012-01-01

    The AIM of the study was to compare the levels of certain adipose tissue hormones in women with the two main morphological types of obesity - android and gynoid obesity. The study included 2 groups of age- and weight-matched women with android (n = 32) and gynoid (n = 27) type of obesity, and a group of age-matched healthy women (n = 24) with normal weight and body constitution. Leptin, resistin, tumour necrosis factor alpha (TNFalpha), neuropeptide Y (NPY), glucose and insulin were measured. HOMA index was calculated. Leptin levels in the women with gynoid obesity did not differ significantly from those in the controls and the women with android obesity. The controls had significantly lower leptin levels compared with the android obesity women. NPY was significantly higher in the control women compared to the women with android obesity and did not differ significantly between the two groups of obese women. TNFalpha levels in all groups were very similar. Resistin did not show significant differences between all groups but tended to have the lowest levels in the controls. In the women with android obesity, insulin was significantly higher than that in the women with gynoid obesity and the controls. Insulin resistance was found in the women with android obesity only. Basal insulin and HOMA index in the women with gynoid obesity did not differ significantly from the values in the control group. The results from this study contribute to understanding the association of adipose tissue hormones and insulin resistance in obesity. When adipose tissue is predominantly distributed in the abdominal area at similar amount and percentage of body fats, leptin production is higher and insulin resistance develops. In the gynoid type of adipose tissue predisposition, overt insulin resistance is not found, leptin levels does not differ significantly from those in the control group.

  18. Plasma sterol evidence for decreased absorption and increased synthesis of cholesterol in insulin resistance and obesity.

    PubMed

    Paramsothy, Pathmaja; Knopp, Robert H; Kahn, Steven E; Retzlaff, Barbara M; Fish, Brian; Ma, Lina; Ostlund, Richard E

    2011-11-01

    The rise in LDL with egg feeding in lean insulin-sensitive (LIS) participants is 2- and 3-fold greater than in lean insulin-resistant (LIR) and obese insulin-resistant (OIR) participants, respectively. We determined whether differences in cholesterol absorption, synthesis, or both could be responsible for these differences by measuring plasma sterols as indexes of cholesterol absorption and endogenous synthesis. Plasma sterols were measured by gas chromatography-mass spectrometry in a random subset of 34 LIS, 37 LIR, and 37 OIR participants defined by the insulin sensitivity index (S(I)) and by BMI criteria selected from a parent group of 197 participants. Cholestanol and plant sterols provide a measure of cholesterol absorption, and lathosterol provides a measure of cholesterol synthesis. The mean (±SD) ratio of plasma total absorption biomarker sterols to cholesterol was 4.48 ± 1.74 in LIS, 3.25 ± 1.06 in LIR, and 2.82 ± 1.08 in OIR participants. After adjustment for age and sex, the relations of the absorption sterol-cholesterol ratios were as follows: LIS > OIR (P < 0.001), LIS > LIR (P < 0.001), and LIR > OIR (P = 0.11). Lathosterol-cholesterol ratios were 0.71 ± 0.32 in the LIS participants, 0.95 ± 0.47 in the LIR participants, and 1.29 ± 0.55 in the OIR participants. After adjustment for age and sex, the relations of lathosterol-cholesterol ratios were as follows: LIS < OIR (P < 0.001), LIS < LIR (P = 0.03), and LIR < OIR (P = 0.002). Total sterol concentrations were positively associated with S(I) and negatively associated with obesity, whereas lathosterol correlations were the opposite. Cholesterol absorption was highest in the LIS participants, whereas cholesterol synthesis was highest in the LIR and OIR participants. Therapeutic diets for hyperlipidemia should emphasize low-cholesterol diets in LIS persons and weight loss to improve S(I) and to decrease cholesterol overproduction in LIR and OIR persons.

  19. Increased abundance of insulin/insulin-like growth factor-I hybrid receptors in skeletal muscle of obese subjects is correlated with in vivo insulin sensitivity.

    PubMed

    Federici, M; Porzio, O; Lauro, D; Borboni, P; Giovannone, B; Zucaro, L; Hribal, M L; Sesti, G

    1998-08-01

    We reported that in noninsulin-dependent diabetes melitus (NIDDM) patients expression of insulin/insulin-like growth factor I (IGF-I) hybrid receptors is increased in insulin target tissues. Whether this is a defect associated with NIDDM or represents a generalized abnormality associated with insulin resistant states is still unsettled. To address this, we applied a microwell-based immunoassay to measure abundance of insulin receptors, type 1 IGF receptors, and hybrid receptors in muscle of eight normal and eight obese subjects. Maximal insulin binding to insulin receptors was lower in obese than in control subjects (B/T = 1.8 +/- 0.20 and 2.6 +/- 0.30; P < 0.03, respectively) and was negatively correlated with insulinemia (r = -0.60; P < 0.01). Maximal IGF-I binding to type 1 IGF receptors was higher in obese than in controls (B/T = 1.9 +/- 0.20 and 0.86 +/- 0.10; P < 0.0001, respectively) and was negatively correlated with plasma IGF-I levels (r = -0.69; P < 0.003). Hybrid receptor abundance was higher in obese than in normal subjects (B/T = 1.21 +/- 0.14 and 0.44 +/- 0.06; P < 0.0003, respectively) and was negatively correlated with insulin binding (r = -0.60; P < 0.01) and positively correlated with IGF-I binding (r = 0.92; P < 0.0001). Increased abundance of hybrids was correlated with insulinemia (r = 0.70; P < 0.002) and body mass index (r = 0.71; P < 0.0019), whereas it was negatively correlated with in vivo insulin sensitivity measured by ITT (r = -0.67; P < 0.016). These results indicate that downregulation of insulin receptors or upregulation of type 1 IGF receptors because of changes in plasma insulin and IGF-I levels may result in modifications in hybrid receptor abundance.

  20. Young overweight and obese women with lower circulating osteocalcin concentrations exhibit higher insulin resistance and concentrations of C-reactive protein.

    PubMed

    Lucey, Alice J; Paschos, Georgios K; Thorsdottir, Inga; Martínéz, J Alfredo; Cashman, Kevin D; Kiely, Máireád

    2013-01-01

    The role of the skeleton in the regulation of energy metabolism in humans is not clear. This study investigates the hypothesis that biomarkers of bone turnover are associated with indices of glucose homeostasis and systemic inflammation in young adults. A cross-sectional study investigating the relationships between biomarkers of bone turnover (serum total and uncarboxylated osteocalcin, bone-specific alkaline phosphatase, C-telopeptide of type I collagen, urinary N-telopeptide of type I collagen) and glucose metabolism (fasting plasma glucose [FPG], insulin, insulin resistance [homeostatic model assessment of insulin resistance]), systemic inflammation (high-sensitivity C-reactive protein [hsCRP] and interleukin-6), adipokines (leptin and adiponectin), and body composition was conducted in 268 young, nondiabetic overweight and obese adults aged 20 to 40 years (116 men, 152 women; body mass index, 27.5-32.5 kg/m(2)). Data on diet, physical activity, serum 25-hydroxyvitamin D, and parathyroid hormone were also collected. In women, there was a stepwise increase in lean body mass (P < .05) and a decrease in serum hsCRP (P < .001) across tertiles of total osteocalcin. Multiple linear regression analysis showed significant inverse associations between total osteocalcin and FPG (β = -0.350; P = .016; 95% confidence interval [CI], -0.35 to -0.04), insulin (β = -0.455; P = .002; 95% CI, -1.9 to -0.46), and homeostatic model assessment of insulin resistance (β = -0.508; P = .001; 95% CI, -10.93 to -3.17) in women with total osteocalcin concentrations below the group median. Men in the lowest tertile of uncarboxylated osteocalcin had twice the concentration of hsCRP than did other men (P = .05). In this sample, women with less lean body mass had lower circulating total osteocalcin concentrations and exhibited higher FPG, insulin resistance, and hsCRP compared with their similarly sized counterparts, suggesting that associations between osteocalcin and systemic

  1. Insulin resistance in prepubertal obese children correlates with sex-dependent early onset metabolomic alterations.

    PubMed

    Mastrangelo, A; Martos-Moreno, G Á; García, A; Barrios, V; Rupérez, F J; Chowen, J A; Barbas, C; Argente, J

    2016-10-01

    Insulin resistance (IR) is usually the first metabolic alteration diagnosed in obese children and the key risk factor for development of comorbidities. The factors determining whether or not IR develops as a result of excess body mass index (BMI) are still not completely understood. This study aimed to elucidate the mechanisms underpinning the predisposition toward hyperinsulinemia-related complications in obese children by using a metabolomic strategy that allows a profound interpretation of metabolic profiles potentially affected by IR. Serum from 60 prepubertal obese children (30 girls/30 boys, 50% IR and 50% non-IR in each group, but with similar BMIs) were analyzed by using liquid chromatography-mass spectrometry, gas chromatography-mass spectrometry and capillary electrophoresis-mass spectrometry following an untargeted metabolomics approach. Validation was then performed on a group of 100 additional children with the same characteristics. When obese children with and without IR were compared, 47 metabolites out of 818 compounds (P<0.05) obtained after data pre-processing were found to be significantly different. Bile acids exhibit the greatest changes (that is, approximately a 90% increase in IR). The majority of metabolites differing between groups were lysophospholipids (15) and amino acids (17), indicating inflammation and central carbon metabolism as the most altered processes in impaired insulin signaling. Multivariate analysis (OPLS-DA models) showed subtle differences between groups that were magnified when females were analyzed alone. Inflammation and central carbon metabolism, together with the contribution of the gut microbiota, are the most altered processes in obese children with impaired insulin signaling in a sex-specific fashion despite their prepubertal status.

  2. Lack of effect of a moderate hypocaloric diet on visfatin levels in morbid obese patients: relationship with insulin resistance.

    PubMed

    De Luis, D A; Gonzalez Sagrado, M; Conde, R; Aller, R; Izaola, O; Castro, M J; Romero, E

    2010-12-01

    The insulin-mimetic adipocytokine visfatin has been related to obesity. The aim of this study was to examine whether weight loss could change visfatin concentrations in morbidly obese patients and its relationship with insulin resistance. This was an interventional study analyzing a population of 41 morbidly obese patients. A biochemical analysis was realized before and after 2 months on a hypocaloric diet. After weight loss (average 4.41%), BMI, weight, fat mass, fat free mass, waist circumference, systolic blood pressure, serum glucose, total cholesterol, insulin and HOMA decreased. The serum concentrations of visfatin did not decrease (43.5 + 30.8 vs. 47.1 + 38.1 ng/ml). In the multivariate analysis visfatin concentrations as a dependent variable, only C reactive protein remained as an independent predictor in the model before diet, with an increase of 1.82 ng/ml (CI 95%: 0.02 - 3.61) basal visfatin concentrations with each increase of 1 mg/dl of CRP. Only HOMA remained as an independent predictor in the model after diet, with an increase of 11.4 ng/ml (CI 95%: 1.76 - 21.11) posttreatment visfatin concentrations with each increase of 1 unit HOMA. Weight reduction after a 2 months on a hypocaloric diet is not associated with a significant change in circulating visfatin in morbidly obese patients.

  3. Decaffeinated Green Coffee Bean Extract Attenuates Diet-Induced Obesity and Insulin Resistance in Mice

    PubMed Central

    Song, Su Jin; Choi, Sena; Park, Taesun

    2014-01-01

    This study investigated whether decaffeinated green coffee bean extract prevents obesity and improves insulin resistance and elucidated its mechanism of action. Male C57BL/6N mice (N = 48) were divided into six dietary groups: chow diet, HFD, HFD-supplemented with 0.1%, 0.3%, and 0.9% decaffeinated green coffee bean extract, and 0.15% 5-caffeoylquinic acid. Based on the reduction in HFD-induced body weight gain and increments in plasma lipids, glucose, and insulin levels, the minimum effective dose of green coffee bean extract appears to be 0.3%. Green coffee bean extract resulted in downregulation of genes involved in WNT10b- and galanin-mediated adipogenesis and TLR4-mediated proinflammatory pathway and stimulation of GLUT4 translocation to the plasma membrane in white adipose tissue. Taken together, decaffeinated green coffee bean extract appeared to reverse HFD-induced fat accumulation and insulin resistance by downregulating the genes involved in adipogenesis and inflammation in visceral adipose tissue. PMID:24817902

  4. Circulating leptin and adiponectin are associated with insulin resistance in healthy postmenopausal women with hot flashes.

    PubMed

    Huang, Wan-Yu; Chang, Chia-Chu; Chen, Dar-Ren; Kor, Chew-Teng; Chen, Ting-Yu; Wu, Hung-Ming

    2017-01-01

    Hot flashes have been postulated to be linked to the development of metabolic disorders. This study aimed to evaluate the relationship between hot flashes, adipocyte-derived hormones, and insulin resistance in healthy, non-obese postmenopausal women. In this cross-sectional study, a total of 151 women aged 45-60 years were stratified into one of three groups according to hot-flash status over the past three months: never experienced hot flashes (Group N), mild-to-moderate hot flashes (Group M), and severe hot flashes (Group S). Variables measured in this study included clinical parameters, hot flash experience, fasting levels of circulating glucose, lipid profiles, plasma insulin, and adipocyte-derived hormones. Multiple linear regression analysis was used to evaluate the associations of hot flashes with adipocyte-derived hormones, and with insulin resistance. The study was performed in a hospital medical center. The mean (standard deviation) of body-mass index was 22.8(2.7) for Group N, 22.6(2.6) for Group M, and 23.5(2.4) for Group S, respectively. Women in Group S displayed statistically significantly higher levels of leptin, fasting glucose, and insulin, and lower levels of adiponectin than those in Groups M and N. Multivariate linear regression analysis revealed that hot-flash severity was significantly associated with higher leptin levels, lower adiponectin levels, and higher leptin-to-adiponectin ratio. Univariate linear regression analysis revealed that hot-flash severity was strongly associated with a higher HOMA-IR index (% difference, 58.03%; 95% confidence interval, 31.00-90.64; p < 0.001). The association between hot flashes and HOMA-IR index was attenuated after adjusting for leptin or adiponectin and was no longer significant after simultaneously adjusting for leptin and adiponectin. The present study provides evidence that hot flashes are associated with insulin resistance in postmenopausal women. It further suggests that hot flash association with

  5. Circulating leptin and adiponectin are associated with insulin resistance in healthy postmenopausal women with hot flashes

    PubMed Central

    Huang, Wan-Yu; Chang, Chia-Chu; Chen, Dar-Ren; Kor, Chew-Teng; Chen, Ting-Yu; Wu, Hung-Ming

    2017-01-01

    Introduction Hot flashes have been postulated to be linked to the development of metabolic disorders. This study aimed to evaluate the relationship between hot flashes, adipocyte-derived hormones, and insulin resistance in healthy, non-obese postmenopausal women. Participants and design In this cross-sectional study, a total of 151 women aged 45–60 years were stratified into one of three groups according to hot-flash status over the past three months: never experienced hot flashes (Group N), mild-to-moderate hot flashes (Group M), and severe hot flashes (Group S). Variables measured in this study included clinical parameters, hot flash experience, fasting levels of circulating glucose, lipid profiles, plasma insulin, and adipocyte-derived hormones. Multiple linear regression analysis was used to evaluate the associations of hot flashes with adipocyte-derived hormones, and with insulin resistance. Settings The study was performed in a hospital medical center. Results The mean (standard deviation) of body-mass index was 22.8(2.7) for Group N, 22.6(2.6) for Group M, and 23.5(2.4) for Group S, respectively. Women in Group S displayed statistically significantly higher levels of leptin, fasting glucose, and insulin, and lower levels of adiponectin than those in Groups M and N. Multivariate linear regression analysis revealed that hot-flash severity was significantly associated with higher leptin levels, lower adiponectin levels, and higher leptin-to-adiponectin ratio. Univariate linear regression analysis revealed that hot-flash severity was strongly associated with a higher HOMA-IR index (% difference, 58.03%; 95% confidence interval, 31.00–90.64; p < 0.001). The association between hot flashes and HOMA-IR index was attenuated after adjusting for leptin or adiponectin and was no longer significant after simultaneously adjusting for leptin and adiponectin. Conclusion The present study provides evidence that hot flashes are associated with insulin resistance in

  6. Structural equation modeling of the associations between the home environment and obesity-related cardiovascular fitness and insulin resistance among Hispanic children.

    PubMed

    Santiago-Torres, Margarita; Cui, Yuchen; Adams, Alexandra K; Allen, David B; Carrel, Aaron L; Guo, Jessica Y; LaRowe, Tara L; Schoeller, Dale A

    2016-06-01

    Hispanic children are disproportionally affected by obesity-related risk of metabolic disease. We used the structural equation modeling to examine the associations between specific diet and physical activity (PA) behaviors at home and Hispanic children's metabolic health. A total of 187 Hispanic children and their parents from an urban community in Wisconsin participated in the study. Exposure variables included, children's daily intake of sugar-sweetened beverages (SSB) and PA; home availability of SSB and PA areas/equipment; and parents' intake of SSB and PA, assessed through self-administered questionnaires. Outcome variables for children's metabolic health included, measured anthropometrics; cardiovascular fitness assessed using the Progressive Aerobic Cardiovascular Endurance Run (PACER); and insulin resistance determined with the homeostasis model assessment of insulin resistance (HOMAIR). We found that children's daily intake of SSB was positively associated with BMI z-score, which in turn, was positively associated with HOMAIR (P < 0.05). Specific diet behaviors at home associated with children's intake of SSB, included home availability of SSB, which mediated the association between parents' and children's intake of SSB (P < 0.05). Children's PA was positively associated with PACER z-score, which in turn, was inversely associated with HOMAIR (P < 0.05). Specific PA behaviors at home associated with children's PA, included home availability of PA areas/equipment, which mediated the association between parents' and children's PA (P < 0.05). The structural equation model indices suggested a satisfactory model fit (Chi-square, X(2) = 53.1, comparative fix index = 0.92, root-mean-squared error associated = 0.04). The findings confirm the need for interventions at the family level that promotes healthier home environments by targeting poor diet and low levels of PA in all family members. Published by Elsevier Ltd.

  7. Insulin resistance determined by Homeostasis Model Assessment (HOMA) and associations with metabolic syndrome among Chinese children and teenagers

    PubMed Central

    2013-01-01

    Objective The aim of this study is to assess the association between the degree of insulin resistance and the different components of the metabolic syndrome among Chinese children and adolescents. Moreover, to determine the cut-off values for homeostasis model assessment of insulin resistance (HOMA-IR) at MS risk. Methods 3203 Chinese children aged 6 to 18 years were recruited. Anthropometric and biochemical parameters were measured. Metabolic syndrome (MS) was identified by a modified Adult Treatment Panel III (ATP III) definition. HOMA-IR index was calculated and the normal reference ranges were defined from the healthy participants. Receiver operating characteristic (ROC) analysis was used to find the optimal cutoff of HOMA-IR for diagnosis of MS. Results With the increase of insulin resistance (quintile of HOMA-IR value), the ORs of suffering MS or its related components were significantly increased. Participants in the highest quintile of HOMA-IR were about 60 times more likely to be classified with metabolic syndrome than those in the lowest quintile group. Similarly, the mean values of insulin and HOMA-IR increased with the number of MS components. The present HOMA-IR cutoff point corresponding to the 95th percentile of our healthy reference children was 3.0 for whole participants, 2.6 for children in prepubertal stage and 3.2 in pubertal period, respectively. The optimal point for diagnosis of MS was 2.3 in total participants, 1.7 in prepubertal children and 2.6 in pubertal adolescents, respectively, by ROC curve, which yielded high sensitivity and moderate specificity for a screening test. According to HOMA-IR > 3.0, the prevalence of insulin resistance in obese or MS children were 44.3% and 61.6% respectively. Conclusions Our data indicates insulin resistance is common among Chinese obese children and adolescents, and is strongly related to MS risk, therefore requiring consideration early in life. As a reliable measure of insulin resistance and

  8. Insulin resistance determined by Homeostasis Model Assessment (HOMA) and associations with metabolic syndrome among Chinese children and teenagers.

    PubMed

    Yin, Jinhua; Li, Ming; Xu, Lu; Wang, Ying; Cheng, Hong; Zhao, Xiaoyuan; Mi, Jie

    2013-11-15

    The aim of this study is to assess the association between the degree of insulin resistance and the different components of the metabolic syndrome among Chinese children and adolescents. Moreover, to determine the cut-off values for homeostasis model assessment of insulin resistance (HOMA-IR) at MS risk. 3203 Chinese children aged 6 to 18 years were recruited. Anthropometric and biochemical parameters were measured. Metabolic syndrome (MS) was identified by a modified Adult Treatment Panel III (ATP III) definition. HOMA-IR index was calculated and the normal reference ranges were defined from the healthy participants. Receiver operating characteristic (ROC) analysis was used to find the optimal cutoff of HOMA-IR for diagnosis of MS. With the increase of insulin resistance (quintile of HOMA-IR value), the ORs of suffering MS or its related components were significantly increased. Participants in the highest quintile of HOMA-IR were about 60 times more likely to be classified with metabolic syndrome than those in the lowest quintile group. Similarly, the mean values of insulin and HOMA-IR increased with the number of MS components. The present HOMA-IR cutoff point corresponding to the 95th percentile of our healthy reference children was 3.0 for whole participants, 2.6 for children in prepubertal stage and 3.2 in pubertal period, respectively. The optimal point for diagnosis of MS was 2.3 in total participants, 1.7 in prepubertal children and 2.6 in pubertal adolescents, respectively, by ROC curve, which yielded high sensitivity and moderate specificity for a screening test. According to HOMA-IR > 3.0, the prevalence of insulin resistance in obese or MS children were 44.3% and 61.6% respectively. Our data indicates insulin resistance is common among Chinese obese children and adolescents, and is strongly related to MS risk, therefore requiring consideration early in life. As a reliable measure of insulin resistance and assessment of MS risk, the optimal HOMA-IR cut

  9. (n-3) Fatty acids alleviate adipose tissue inflammation and insulin resistance: Mechanistic insights

    USDA-ARS?s Scientific Manuscript database

    Obesity is associated with the metabolic syndrome, a significant risk factor for developing type-2 diabetes and cardiovascular diseases. A chronic low-grade inflammation occurring in the adipose tissue of obese individuals is causally linked to the pathogenesis of insulin resistance and the metaboli...

  10. An investigation of the associations among sleep duration and quality, body mass index and insulin resistance in newly diagnosed type 2 diabetes mellitus patients.

    PubMed

    Arora, Teresa; Chen, Mimi Z; Omar, Omar M; Cooper, Ashley R; Andrews, Rob C; Taheri, Shahrad

    2016-02-01

    To examine direct and indirect associations of sleep duration and quality with insulin resistance, considering body mass index (BMI) as a potential mediator in newly diagnosed type 2 diabetes mellitus patients. Cross-sectional data from patients enrolled in the Early Activity in Diabetes study. We studied 522 newly diagnosed type 2 diabetes mellitus patients, 65.9% male, mean age 63.5 ± 10.1 years. Of the total sample 53% had a BMI of ⩾30 kg/m(2). Participants completed a 7-day sleep diary and sleep questionnaire. Average sleep duration (minutes), average nap duration (minutes) and average number of night awakenings were derived. Objective measures of height and body weight were obtained for the BMI calculation (kg/m(2)). Insulin resistance was obtained using the homeostatic model assessment - insulin resistance (HOMA2-IR) standardized technique. Average number of night awakenings was positively correlated with BMI (r= 0.22, p < 0.001) and negatively associated with logged HOMA2-IR (r= -0.16, p = 0.04). Path analysis demonstrated night awakenings were directly associated with BMI and indirectly associated with insulin resistance, whilst considering BMI as a potential mediator (p < 0.05). Sleep duration was not associated with BMI or insulin resistance (p > 0.05). Sleep quality, not sleep duration, plays an important role in insulin resistance in newly diagnosed type 2 diabetes mellitus patients. BMI may mediate the relationship between indicators of sleep quality and insulin resistance. There is a need to examine the impact of improving sleep quality on obesity and insulin resistance in patients with type 2 diabetes mellitus.

  11. Compliance with behavioral guidelines for diet, physical activity and sedentary behaviors is related to insulin resistance among overweight and obese youth.

    PubMed

    Huang, Jeannie S; Gottschalk, Michael; Norman, Gregory J; Calfas, Karen J; Sallis, James F; Patrick, Kevin

    2011-02-01

    Overweight and obesity are established risk factors for insulin resistance in youth. A number of behavioral recommendations have been publicized with the goal of improving glycemic control. However, there is limited information about whether meeting these behavioral recommendations actually reduces insulin resistance. 92 youths 11 - 16 years with BMI ≥ 85% underwent oral glucose tolerance testing. HOMA-IR and AUCInsulin/AUCGlucose were calculated as measures of insulin resistance. Dietary and physical activity (PA) measures were performed. Assessments included whether or not participants met recommended levels of diet, PA and sedentary behaviors.62% youths met criteria for insulin resistance. 82% (75/92) met at least one behavioral recommendation. Participants who met ≥ 1 dietary, sedentary, or PA recommendations had significantly reduced insulin resistance as compared with youth who did not. This relationship remained significant in multivariate modeling of insulin resistance adjusting for age, sex, and BMI. Even relatively minor behavior change may reduce insulin resistance in youth at risk for diabetes. Our findings support the relevance of current behavioral interventions for glycemic control. Clinical Trials #NCT00412165.

  12. Insulin resistance and its association with catch-up growth in Chinese children born small for gestational age.

    PubMed

    Liu, Chunhua; Wu, Baiyan; Lin, Niyang; Fang, Xiaoyi

    2017-01-01

    To assess insulin resistance and β-cell function from birth to age 4 years and to examine their associations with catch-up growth (CUG) in Chinese small-for-gestational-age (SGA) children. Weight and height were measured yearly from birth to age 4 years, and transformed into age- and gender-adjusted SD scores. Fasting serum insulin and glucose were measured, and fasting insulin resistance and β-cell function were estimated using the homeostasis model assessment (HOMA). The mean HOMA-IR of the SGA group was significantly lower than that of the appropriate-for-gestational-age (AGA) group at ages 2 and 3 years old, and the mean HOMA% of the SGA group was significantly lower than that of the AGA group at age 4 years old. At 4 years of age, HOMA for insulin resistance was positively correlated with the height gain and SD of height gain between 0 and 5 months, and HOMA% was positively correlated with the weight gain and SD of weight gain between 6 and 12 months in SGA children. SGA children with CUG show a greater propensity to develop insulin resistance than AGA children between ages 2 and 4 years old. HOMA parameters are related to CUG in the first year of life. © 2016 The Obesity Society.

  13. Dietary Aloe Improves Insulin Sensitivity via the Suppression of Obesity-induced Inflammation in Obese Mice

    PubMed Central

    Shin, Eunju; Shim, Kyu-Suk; Kong, Hyunseok; Lee, Sungwon; Shin, Seulmee; Kwon, Jeunghak; Jo, Tae Hyung; Park, Young-In; Lee, Chong-Kil

    2011-01-01

    Background Insulin resistance is an integral feature of metabolic syndromes, including obesity, hyperglycemia, and hyperlipidemia. In this study, we evaluated whether the aloe component could reduce obesity-induced inflammation and the occurrence of metabolic disorders such as blood glucose and insulin resistance. Methods Male C57BL/6 obese mice fed a high-fat diet for 54 days received a supplement of aloe formula (PAG, ALS, Aloe QDM, and Aloe QDM complex) or pioglitazone (PGZ) and were compared with unsupplemented controls (high-fat diet; HFD) or mice fed a regular diet (RD). RT-PCR and western blot analysis were used to quantify the expression of obesity-induced inflammation. Results Aloe QDM lowered fasting blood glucose and plasma insulin compared with HFD. Obesity-induced inflammatory cytokine (IL-1β, -6, -12, TNF-α) and chemokine (CX3CL1, CCL5) mRNA and protein were decreased markedly, as was macrophage infiltration and hepatic triglycerides by Aloe QDM. At the same time, Aloe QDM decreased the mRNA and protein of PPARγ/LXRα and 11β-HSD1 both in the liver and WAT. Conclusion Dietary aloe formula reduces obesity-induced glucose tolerance not only by suppressing inflammatory responses but also by inducing anti-inflammatory cytokines in the WAT and liver, both of which are important peripheral tissues affecting insulin resistance. The effect of Aloe QDM complex in the WAT and liver are related to its dual action on PPARγ and 11β-HSD1 expression and its use as a nutritional intervention against T2D and obesity-related inflammation is suggested. PMID:21494375

  14. Weight loss after bariatric surgery reverses insulin-induced increases in brain glucose metabolism of the morbidly obese.

    PubMed

    Tuulari, Jetro J; Karlsson, Henry K; Hirvonen, Jussi; Hannukainen, Jarna C; Bucci, Marco; Helmiö, Mika; Ovaska, Jari; Soinio, Minna; Salminen, Paulina; Savisto, Nina; Nummenmaa, Lauri; Nuutila, Pirjo

    2013-08-01

    Obesity and insulin resistance are associated with altered brain glucose metabolism. Here, we studied brain glucose metabolism in 22 morbidly obese patients before and 6 months after bariatric surgery. Seven healthy subjects served as control subjects. Brain glucose metabolism was measured twice per imaging session: with and without insulin stimulation (hyperinsulinemic-euglycemic clamp) using [18F]fluorodeoxyglucose scanning. We found that during fasting, brain glucose metabolism was not different between groups. However, the hyperinsulinemic clamp increased brain glucose metabolism in a widespread manner in the obese but not control subjects, and brain glucose metabolism was significantly higher during clamp in obese than in control subjects. After follow-up, 6 months postoperatively, the increase in glucose metabolism was no longer observed, and this attenuation was coupled with improved peripheral insulin sensitivity after weight loss. We conclude that obesity is associated with increased insulin-stimulated glucose metabolism in the brain and that this abnormality can be reversed by bariatric surgery.

  15. Adipocyte-myocyte crosstalk in skeletal muscle insulin resistance; is there a role for thyroid hormone?

    PubMed

    Havekes, Bas; Sauerwein, Hans P

    2010-11-01

    To review original research studies and reviews that present data on adipocyte-myocyte crosstalk in the development of skeletal muscle insulin resistance with a specific focus on thyroid hormone. Adipose tissue communicates with skeletal muscle not only through free fatty acids but also through secretion of various products called adipokines. Adipokines came out as governors of insulin sensitivity and are deregulated in obesity. In addition to well known leptin, adiponectin, interleukin-6 and tumor necrosis factor-alpha, newer adipokines like retinol-binding protein 4 have been associated with insulin resistance. There is mounting evidence that not only adipose tissue but also skeletal muscle produces and secretes biologically active proteins or 'myokines' that facilitate metabolic crosstalk between organ systems. In recent years, increased expression of myostatin, a secreted anabolic inhibitor of muscle growth and development, has been associated with obesity and insulin resistance. Both hypothyroidism and hyperthyroidism affect insulin sensitivity in multiple ways that might overlap adipocyte-myocyte crosstalk. Recent studies have provided new insights in effects of processing of the parent hormone T4 to the active T3 at the level of the skeletal muscle. Adipocyte-myocyte crosstalk is an important modulator in the development of skeletal muscle insulin resistance. Thyroid disorders are very common and may have detrimental effects on skeletal muscle insulin resistance, potentially by interacting with adipocyte-myocyte crosstalk.

  16. Low skeletal muscle mass is associated with insulin resistance, diabetes, and metabolic syndrome in the Korean population: the Korea National Health and Nutrition Examination Survey (KNHANES) 2009-2010.

    PubMed

    Moon, Seong-Su

    2014-01-01

    Sarcopenia is an emerging risk factor for metabolic disorders. No study of the association of sarcopenia with insulin resistance, diabetes, and metabolic syndrome (MS) according to age group and obesity status in the general population has been reported. We investigated these associations in the Korean population. Participants included 4558 males and 5874 females, who were ≥20 years of age or older from the fourth and fifth Korea National Health and Nutritional Examination Surveys of the Korean population (2009 and 2010). Age was categorized according to three groups (20-39, 40-59, and ≥ 60 years). Obesity was defined according to body mass index. Sarcopenia was defined as the appendicular skeletal muscle mass (ASM) divided by weight (Wt) (%) of > 2SD below the sex-specific mean for young adults. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. After adjustment for confounding variables, sarcopenia showed a significant association with HOMA-IR in the non-obese group (P<0.001). Sarcopenia was found to be a risk factor for diabetes in the non-obese group (OR, 2.140; 95% CI, 1.549-2.956; P<0.001). Sarcopenia also showed an association with MS in the non-obese group (OR, 2.209; 95% CI, 1.679-2.906; P<0.001), but not in the obese-group. However, these results were not relevant to young age group. In conclusion, sarcopenia showed an association with insulin resistance, diabetes, and MS, in the non-obese population. Sarcopenia may be an early predictor for diabetes and MS susceptibility in the non-obese population, particularly in elderly people.

  17. Insulin resistance and improvements in signal transduction.

    PubMed

    Musi, Nicolas; Goodyear, Laurie J

    2006-02-01

    Type 2 diabetes and obesity are common metabolic disorders characterized by resistance to the actions of insulin to stimulate skeletal muscle glucose disposal. Insulin-resistant muscle has defects at several steps of the insulin-signaling pathway, including decreases in insulin-stimulated insulin receptor and insulin receptor substrate-1 tyrosine phosphorylation, and phosphatidylinositol 3-kinase (PI 3-kinase) activation. One approach to increase muscle glucose disposal is to reverse/improve these insulin-signaling defects. Weight loss and thiazolidinediones (TZDs) improve glucose disposal, in part, by increasing insulin-stimulated insulin receptor and IRS-1 tyrosine phosphorylation and PI 3-kinase activity. In contrast, physical training and metformin improve whole-body glucose disposal but have minimal effects on proximal insulin-signaling steps. A novel approach to reverse insulin resistance involves inhibition of the stress-activated protein kinase Jun N-terminal kinase (JNK) and the protein tyrosine phosphatases (PTPs). A different strategy to increase muscle glucose disposal is by stimulating insulin-independent glucose transport. AMP-activated protein kinase (AMPK) is an enzyme that works as a fuel gauge and becomes activated in situations of energy consumption, such as muscle contraction. Several studies have shown that pharmacologic activation of AMPK increases glucose transport in muscle, independent of the actions of insulin. AMPK activation is also involved in the mechanism of action of metformin and adiponectin. Moreover, in the hypothalamus, AMPK regulates appetite and body weight. The effect of AMPK to stimulate muscle glucose disposal and to control appetite makes it an important pharmacologic target for the treatment of type 2 diabetes and obesity.

  18. Gene expression of leptin, resistin, and adiponectin in the white adipose tissue of obese patients with non-alcoholic fatty liver disease and insulin resistance.

    PubMed

    Baranova, Ancha; Gowder, Shobha J; Schlauch, Karen; Elariny, Hazem; Collantes, Rochelle; Afendy, Arian; Ong, Janus P; Goodman, Zachary; Chandhoke, Vikas; Younossi, Zobair M

    2006-09-01

    Adipose tissue is an active endocrine organ that secretes a variety of metabolically important substances including adipokines. These factors affect insulin sensitivity and may represent a link between obesity, insulin resistance, type 2 diabetes (DM), and nonalcoholic fatty liver disease (NAFLD). This study uses real-time polymerase chain reaction (PCR) quantification of mRNAs encoding adiponectin, leptin, and resistin on snap-frozen samples of intra-abdominal adipose tissue of morbidly obese patients undergoing bariatric surgery. Morbidly obese patients undergoing bariatric surgery were studied. Patients were classified into two groups: Group A (with insulin resistance) (N=11; glucose 149.84 +/- 40.56 mg/dL; serum insulin 8.28 +/- 3.52 microU/mL), and Group B (without insulin resistance) (N=10; glucose 102.2 +/- 8.43 mg/dL; serum insulin 3.431 +/- 1.162 microU/mL). Adiponectin mRNA in intra-abdominal adipose tissue and serum adiponectin levels were significantly lower in Group A compared to Group B patients (P<0.016 and P<0.03, respectively). Although serum resistin was higher in Group A than in Group B patients (P<0.005), resistin gene expression was not different between the two groups. Finally, for leptin, neither serum level nor gene expression was different between the two groups. Serum adiponectin level was the only predictor of nonalcoholic steatohepatitis (NASH) in this study (P=0.024). Obese patients with insulin resistance have decreased serum adiponectin and increased serum resistin. Additionally, adiponectin gene expression is also decreased in the adipose tissue of these patients. This low level of adiponectin expression may predispose patients to the progressive form of NAFLD or NASH.

  19. Sleep Duration and Media Time Have a Major Impact on Insulin Resistance and Metabolic Risk Factors in Obese Children and Adolescents.

    PubMed

    Sayin, Fatma Kubra; Buyukinan, Muammer

    2016-08-01

    Lifestyle factors sleep duration and media time during childhood differ between countries. This study examined whether sleep duration and media time affect metabolic risk factors insulin resistance (IR), blood lipid profile, and liver enzymes, and whether there is a relationship between sleep time and media time in Turkish obese children and adolescents. Subjects included 108 obese children and adolescents (aged 10-15 years) whose lifestyle factors were assessed using a survey containing questions about sleep durations, television viewing, media use, and demographic factors. Metabolic risk factors were compared among groups categorized according to sleep and media duration. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and triglyceride (TG) levels and homeostasis model assessment of insulin resistance (HOMA-IR) values were higher in subjects who spent >5 hours/day on media. Children 10-13 years old who slept <9 hours/day were more likely to have higher insulin and HOMA-IR (p < 0.05) levels and lower high-density lipoprotein cholesterol (HDL-C) levels compared with subjects who slept 9-10 hours/day and >10 hours/day. Correlation analysis revealed a negative relationship between sleep time and media time (r = -0.471, p = 0.000). Short sleep duration was associated with IR and an elevated plasma lipoprotein profile in children and adolescents. Our results suggest that insufficient sleep and excessive media exposure may contribute to metabolic risk in the context of obesity, and therefore, working to improve sleep duration and limit media time could help reduce metabolic risk in obese children and adolescents.

  20. Early and progressive insulin resistance in young, non-obese cancer survivors treated with hematopoietic stem cell transplantation.

    PubMed

    Bizzarri, Carla; Pinto, Rita M; Ciccone, Sara; Brescia, Letizia P; Locatelli, Franco; Cappa, Marco

    2015-09-01

    It is unclear whether there is a causative relationship between the development of metabolic syndrome (MS) and increased risk of early cardiovascular morbidity in patients receiving hematopoietic stem cell transplantation (HSCT) during childhood. Early identification of risk factors associated with insulin resistance, MS, and abnormal glucose tolerance during childhood or adolescence in these patients could represent a useful tool for preventing cardiovascular disorders. In a single-center, prospective, descriptive, cross-sectional study, we studied 45 survivors of hematological malignancies (age: 13.9 ± 4.8 years) treated with HSCT before the age of 18 years and 90 matched healthy controls. We collected clinical, imaging, and laboratory data including oral glucose tolerance test (OGTT). 7/45 patients (15.6%) showed abnormal glucose tolerance at OGTT, 1/45 (2.2%) was obese, and none fulfilled the criteria for MS. A waist/height ratio >0.5 was associated with patients with abnormal glucose tolerance (85.7% of cases), compared to patients with normal glucose tolerance (42.1%) and controls (23.3%). In patients with abnormal glucose tolerance, use of total body irradiation (TBI) as conditioning regimen was more common, and time elapsed from HSCT was longer. Patients treated with HSCT may develop insulin resistance early after transplantation. They do not show overt obesity, but have redistribution of fat tissue with central fat accumulation. The main factors associated with increased metabolic risk are TBI and time from HSCT. Evaluation of MS and glucose tolerance should be part of hormonal follow-up, which should be routinely proposed to these patients. © 2015 Wiley Periodicals, Inc.

  1. Resistance training enhances insulin suppression of endogenous glucose production in elderly women.

    PubMed

    Honka, Miikka-Juhani; Bucci, Marco; Andersson, Jonathan; Huovinen, Ville; Guzzardi, Maria Angela; Sandboge, Samuel; Savisto, Nina; Salonen, Minna K; Badeau, Robert M; Parkkola, Riitta; Kullberg, Joel; Iozzo, Patricia; Eriksson, Johan G; Nuutila, Pirjo

    2016-03-15

    An altered prenatal environment during maternal obesity predisposes offspring to insulin resistance, obesity, and their consequent comorbidities, type 2 diabetes and cardiovascular disease. Telomere shortening and frailty are additional risk factors for these conditions. The aim of this study was to evaluate the effects of resistance training on hepatic metabolism and ectopic fat accumulation. Thirty-five frail elderly women, whose mothers' body mass index (BMI) was known, participated in a 4-mo resistance training program. Endogenous glucose production (EGP) and hepatic and visceral fat glucose uptake were measured during euglycemic hyperinsulinemia with [(18)F]fluorodeoxyglucose and positron emission tomography. Ectopic fat was measured using magnetic resonance spectroscopy and imaging. We found that the training intervention reduced EGP during insulin stimulation [from 5.4 (interquartile range 3.0, 7.0) to 3.9 (-0.4, 6.1) μmol·kg body wt(-1)·min(-1), P = 0.042] in the whole study group. Importantly, the reduction was higher among those whose EGP was more insulin resistant at baseline (higher than the median) [-5.6 (7.1) vs. 0.1 (5.4) μmol·kg body wt(-1)·min(-1), P = 0.015]. Furthermore, the decrease in EGP was associated with telomere elongation (r = -0.620, P = 0.001). The resistance training intervention did not change either hepatic or visceral fat glucose uptake or the amounts of ectopic fat. Maternal obesity did not influence the studied measures. In conclusion, resistance training improves suppression of EGP in elderly women. The finding of improved insulin sensitivity of EGP with associated telomere lengthening implies that elderly women can reduce their risk for type 2 diabetes and cardiovascular disease with resistance training. Copyright © 2016 the American Physiological Society.

  2. Association of Serum Ferritin Levels with Metabolic Syndrome and Insulin Resistance.

    PubMed

    Padwal, Meghana K; Murshid, Mohsin; Nirmale, Prachee; Melinkeri, R R

    2015-09-01

    The impact of CVDs and Type II DM is increasing over the last decade. It has been estimated that by 2025 their incidence will double. Ferritin is one of the key proteins regulating iron homeostasis and is a widely available clinical biomarker of iron status. Some studies suggest that prevalence of atherosclerosis and insulin resistance increases significantly with increasing serum ferritin. Metabolic syndrome is known to be associated with increased risk of atherosclerosis as well as insulin resistance. The present study was designed to explore the association of serum ferritin levels with metabolic syndrome and insulin resistance. The present study was prospective, cross sectional. The study protocol was approved by IEC. The study group consisted of 90 participants (50 cases of metabolic syndrome and 40 age and sex matched controls). Diagnosis of metabolic syndrome was done as per NCEP ATP III criteria. Estimation of serum Ferritin and Insulin was done by Chemiluminescence Immunoassay (CLIA) while Glucose by Glucose Oxidase and Peroxidase (GOD-POD) method. Insulin Resistance was calculated by HOMA IR score. Data obtained was statistically analysed by using student t-test. We found statistically significant rise in the levels of serum ferritin (p=<0.001), glucose (p=<0.001), insulin (p=<0.001) and HOMA IR score (p=<0.0001) in cases of metabolic syndrome as compared with controls. High serum ferritin levels though within normal range are significantly associated with both metabolic syndrome and insulin resistance.

  3. Effects of exercise and lifestyle modification on fitness, insulin resistance, skeletal muscle oxidative phosphorylation and intramyocellular lipid content in obese children and adolescents.

    PubMed

    McCormack, S E; McCarthy, M A; Harrington, S G; Farilla, L; Hrovat, M I; Systrom, D M; Thomas, B J; Torriani, M; McInnis, K; Grinspoon, S K; Fleischman, A

    2014-08-01

    Obesity is associated with poor fitness and adverse metabolic consequences in children. To investigate how exercise and lifestyle modification may improve fitness and insulin sensitivity in this population. Randomized controlled trial, 21 obese (body mass index ≥ 95% percentile) subjects, ages 10 to 17 years. Subjects were given standardized healthful lifestyle advice for 8 weeks. In addition, they were randomized to an in-home supervised exercise intervention (n = 10) or control group (n = 11). Fasting laboratory studies (insulin, glucose, lipid profile) and assessments of fitness, body composition, skeletal muscle oxidative phosphorylation and intramyocellular lipid content (IMCL), were performed at baseline and study completion. Subjects were 13.0 ± 1.9 (standard deviation) years old, 72% female and 44% non-white. Exercise improved fitness (P = 0.03) and power (P = 0.01), and increased IMCL (P = 0.02). HOMA-IR decreased among all subjects in response to lifestyle modification advice (P = 0.01), regardless of exercise training assignment. In univariate analysis in all subjects, change in cardiovascular fitness was associated with change in HOMA-IR. In exploratory analyses, increased IMCL was associated with greater resting energy expenditure (r = 0.78, P = 0.005) and a decrease in fasting respiratory quotient (r = -0.70, P = 0.02) (n = 11). Change in fitness was found to be related to change in insulin resistance in response to lifestyle modification and exercise in obese children. IMCL increased with exercise in these obese children, which may reflect greater muscle lipid oxidative capacity. © 2013 The Authors. Pediatric Obesity © 2013 International Association for the Study of Obesity.

  4. Effect of obesity and insulin resistance on myocardial substrate metabolism and efficiency in young women.

    PubMed

    Peterson, Linda R; Herrero, Pilar; Schechtman, Kenneth B; Racette, Susan B; Waggoner, Alan D; Kisrieva-Ware, Zulia; Dence, Carmen; Klein, Samuel; Marsala, JoAnn; Meyer, Timothy; Gropler, Robert J

    2004-05-11

    Obesity is a risk factor for impaired cardiac performance, particularly in women. Animal studies suggest that alterations in myocardial fatty acid metabolism and efficiency in obesity can cause decreased cardiac performance. In the present study, we tested the hypothesis that myocardial fatty acid metabolism and efficiency are abnormal in obese women. We studied 31 young women (body mass index [BMI] 19 to 52 kg/m2); 19 were obese (BMI >30 kg/m2). Myocardial oxygen consumption (MVO2) and fatty acid uptake (MFAUp), utilization (MFAU), and oxidation (MFAO) were quantified by positron emission tomography. Cardiac work was measured by echocardiography, and efficiency was calculated as work/MVO2. BMI correlated with MVO2 (r=0.58, P=0.0006), MFAUp (r=0.42, P<0.05), and efficiency (r=-0.40, P<0.05). Insulin resistance, quantified by the glucose area under the curve (AUC) during an oral glucose tolerance test, correlated with MFAUp (r=0.55, P<0.005), MFAU (r=0.62, P<0.001), and MFAO (r=0.58, P<0.005). A multivariate, stepwise regression analysis showed that BMI was the only independent predictor of MVO2 and efficiency (P=0.0005 and P<0.05, respectively). Glucose AUC was the only independent predictor of MFAUp, MFAU, and MFAO (P<0.05, <0.005, and <0.005, respectively). In young women, obesity is a significant predictor of increased MVO2 and decreased efficiency, and insulin resistance is a robust predictor of MFAUp, MFAU, and MFAO. This increase in fatty acid metabolism and decrease in efficiency is concordant with observations made in experimental models of obesity. These metabolic changes may play a role in the pathogenesis of decreased cardiac performance in obese women.

  5. Chromium supplementation in non-obese non-diabetic subjects is associated with a decline in insulin sensitivity

    PubMed Central

    2012-01-01

    Background The use of chromium supplements is widespread for the prevention and treatment of diabetes mellitus but there are conflicting reports on efficacy, possibly reflecting discrepant effects across different populations. In the present studies, we test the hypothesis that chromium supplementation raises serum chromium levels and correspondingly improves insulin sensitivity. Methods A double blind placebo-controlled randomized trial was conducted on 31 non-obese, normoglycemic subjects. After baseline studies, the subjects were randomized to placebo or chromium picolinate 500 μg twice a day. The primary endpoint was change in insulin sensitivity as measured by euglycemic hyperinsulinemic clamp. Pre-specified secondary endpoints included fasting lipids, blood pressure, weight, body composition measured by DXA scan. Results After 16 weeks of chromium picolinate therapy there was no significant change in insulin sensitivity between groups (p=0.83). There was, however, a strong association between serum chromium and change in insulin resistance (β = -0.83, p=0.01), where subjects with the highest serum chromium had a worsening of insulin sensitivity. This effect could not be explained by changes in physiological parameters such as body weight, truncal fat and serum lipids with chromium therapy. Conclusions Chromium therapy did not improve insulin sensitivity in non-obese normoglycemic individuals. Further, subjects who have high serum chromium levels paradoxically had a decline in insulin sensitivity. Caution therefore should be exercised in recommending the use of this supplement. Trial registration The study was registered on the NIH registry (clinicaltrials.gov) and the identifier is NCT00846248 PMID:23194380

  6. Common PCSK1 haplotypes are associated with obesity in the Chinese population.

    PubMed

    Chang, Yi-Cheng; Chiu, Yen-Feng; Shih, Kuang-Chung; Lin, Ming-Wei; Sheu, Wayne Huey-Herng; Donlon, Timothy; Curb, Jess David; Jou, Yuh-Shan; Chang, Tien-Jyun; Li, Hung-Yuan; Chuang, Lee-Ming

    2010-07-01

    Prohormone convertase subtilisin/kexin type 1 (PCSK1) genetic polymorphisms have recently been associated with obesity in European populations. This study aimed to examine whether common PCSK1 genetic variation is associated with obesity and related metabolic phenotypes in the Chinese population. We genotyped nine common tag single-nucleotide polymorphisms (tagSNP) of the PCSK1 gene in 1,094 subjects of Chinese origin from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family study. One SNP in the PCSK1 gene (rs155971) were nominally associated with risk of obesity in the SAPPHIRe cohort (P = 0.01). A common protective haplotype was associated with reduced risk of obesity (23.79% vs. 32.89%, P = 0.01) and smaller waist circumference (81.71 +/- 10.22 vs. 84.75 +/- 10.48 cm, P = 0.02). Another common haplotype was significantly associated with increased risk of obesity (37.07% vs. 23.84%, P = 0.005). The global P value for haplotype association with obesity was 0.02. We also identified a suggestive association of another PCSK1 SNP (rs3811951) with fasting glucose, fasting insulin, homeostasis model assessment of insulin resistance (HOMA(IR)), triglycerides, and high-density lipoprotein cholesterol (P = 0.05, 0.003, 0.001, 0.04, and 0.04, respectively). These data indicate common PCSK1 genetic variants are associated with obesity in the Chinese population.

  7. Obesity and Its Metabolic Complications: The Role of Adipokines and the Relationship between Obesity, Inflammation, Insulin Resistance, Dyslipidemia and Nonalcoholic Fatty Liver Disease

    PubMed Central

    Jung, Un Ju; Choi, Myung-Sook

    2014-01-01

    Accumulating evidence indicates that obesity is closely associated with an increased risk of metabolic diseases such as insulin resistance, type 2 diabetes, dyslipidemia and nonalcoholic fatty liver disease. Obesity results from an imbalance between food intake and energy expenditure, which leads to an excessive accumulation of adipose tissue. Adipose tissue is now recognized not only as a main site of storage of excess energy derived from food intake but also as an endocrine organ. The expansion of adipose tissue produces a number of bioactive substances, known as adipocytokines or adipokines, which trigger chronic low-grade inflammation and interact with a range of processes in many different organs. Although the precise mechanisms are still unclear, dysregulated production or secretion of these adipokines caused by excess adipose tissue and adipose tissue dysfunction can contribute to the development of obesity-related metabolic diseases. In this review, we focus on the role of several adipokines associated with obesity and the potential impact on obesity-related metabolic diseases. Multiple lines evidence provides valuable insights into the roles of adipokines in the development of obesity and its metabolic complications. Further research is still required to fully understand the mechanisms underlying the metabolic actions of a few newly identified adipokines. PMID:24733068

  8. Population-based cross-sectional study on insulin resistance and insulin-secretory capacity in Japanese school children.

    PubMed

    Nishimura, Rimei; Sano, Hironari; Onda, Yoshiko; Tsujino, Daisuke; Ando, Kiyotaka; Ebara, Futoshi; Matsudaira, Toru; Ishikawa, Shinichiro; Sakamoto, Takuya; Tajima, Naoko; Utsunomiya, Kazunori

    2017-09-01

    Little information is available regarding the status of insulin resistance (IR) and insulin deficiency (ID), as well as their relationship with obesity in children using the homeostasis model assessment (HOMA) in a population-based setting. The study included a total of 445 ninth-grade children participating in health check-up programs implemented in Tsunan Town, Niigata, Japan (boys/girls, 252/193 [participation rates: 98.1/95.5%]). HOMA of insulin resistance ≥2.5 was defined as IR, and HOMA of β-cell function <40 defined as ID. The medians (25-75th percentiles) of HOMA of insulin resistance, HOMA of β-cell function, Disposition Index and body mass index in boys were 1.2 (0.8-1.7), 64 (44-93), 52 (43-64) and 19.2 (18.0-20.7) kg/m 2 , respectively, vs 1.5 (1.0-2.0), 86 (63-120), 60 (50-74) and 20.4 (18.9-22.0) kg/m 2 , respectively, in girls. The HOMA of insulin resistance, HOMA of β-cell function and Disposition Index values were significantly higher in the girls (P = 0.002, P < 0.001 and P < 0.001, respectively). Those with IR accounted for a significantly higher proportion of girls than boys (15.5/8.7%; P = 0.027); those with obesity accounted for 9.9/10.7% (boys/girls); and those with IR and obesity accounted for 2.4/4.7%. Those with ID accounted for a significantly higher proportion of boys than girls (20.6/8.8%; P = 0.001), whereas those with ID and obesity accounted for a very small proportion of either group (0.4/0.5%). The presence of IR was higher among the girls. In contrast, ID was more frequent among the boys. The infrequent presence of ID among children might support the presence of non-obese type 2 diabetes adults in Japan. © 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

  9. Herbal Formula HT048 Attenuates Diet-Induced Obesity by Improving Hepatic Lipid Metabolism and Insulin Resistance in Obese Rats.

    PubMed

    Lee, Yoon Hee; Jin, Bora; Lee, Sung Hyun; Song, MiKyung; Bae, HyeonHui; Min, Byung Jae; Park, Juyeon; Lee, Donghun; Kim, Hocheol

    2016-10-25

    It is well established that obesity causes a variety of chronic diseases such as cardiovascular diseases and diabetes. Despite the diligent scientific efforts to find effective ways to lower the level of obesity, the size of obese population grows continuously around the world. Here we present the results that show feeding diet containing HT048, a mixture of the extracts of Crataegus pinnatifida leaves and Citrus unshiu peel, two of the well-known traditional herbal medicines in Eastern Asia, decreases obesity in rats. We fed rats with five different diets for 10 weeks: chow diet (STD), high-fat diet (HFD), high-fat diet with 0.04% orlistat, a drug to treat obesity (HFD + Orlistat), high-fat diet with 0.2% HT048 ( w / w ; HFD + 0.2% HT048), and high-fat diet with 0.6% HT048 ( w / w ; HFD + 0.6% HT048). It was found that both body and total white adipose tissue weight of HT048 groups significantly decreased compared to those of the HFD group. Moreover, HT048 decreased serum insulin levels in HFD-fed obese rats. At the molecular level, HT048 supplementation downregulated genes involved in lipogenesis, gluconeogenesis, and adipogenesis, while the expression level of β-oxidation genes was increased. Supplementation-drug interactions are not likely as HFD and HT048-containing diet did not significantly induce genes encoding CYPs. Collectively, this study suggests that HT048 taken as dietary supplement helps to decrease obesity and insulin resistance in HFD-fed obese rats.

  10. Lower Circulating B12 Is Associated with Higher Obesity and Insulin Resistance during Pregnancy in a Non-Diabetic White British Population.

    PubMed

    Knight, Bridget Ann; Shields, Beverley M; Brook, Adam; Hill, Anita; Bhat, Dattatray S; Hattersley, Andrew T; Yajnik, Chittaranjan S

    2015-01-01

    Vitamin B12 and folate are critical micronutrients needed to support the increased metabolic demands of pregnancy. Recent studies from India have suggested that low vitamin B12 and folate concentrations in pregnancy are associated with increased obesity; however differences in diet, antenatal vitamin supplementation, and socioeconomic status may limit the generalisability of these findings. We aimed to explore the cross-sectional relationship of circulating serum vitamin B12 and folate at 28 weeks' gestation with maternal adiposity and related biochemical markers in a white non diabetic UK obstetric cohort. Anthropometry and biochemistry data was available on 995 women recruited at 28 weeks gestation to the Exeter Family Study of Childhood Health. Associations between B12 and folate with maternal BMI and other obesity-related biochemical factors (HOMA-R, fasting glucose, triglycerides, HDL and AST) were explored using regression analysis, adjusting for potential confounders (socioeconomic status, vegetarian diet, vitamin supplementation, parity, haemodilution (haematocrit)). Higher 28 week BMI was associated with lower circulating vitamin B12 (r = -0.25; P<0.001) and folate (r = -0.15; P<0.001). In multiple regression analysis higher 28 week BMI remained an independent predictor of lower circulating B12 (β (95% CI) = -0.59 (-0.74, -0.44) i.e. for every 1% increase in BMI there was a 0.6% decrease in circulating B12). Other markers of adiposity/body fat metabolism (HOMA-R, triglycerides and AST) were also independently associated with circulating B12. In a similar multiple regression AST was the only independent obesity-related marker associated with serum folate (β (95% CI) = 0.16 (0.21, 0.51)). In conclusion, our study has replicated the previous Indian findings of associations between lower serum B12 and higher obesity and insulin resistance during pregnancy in a non-diabetic White British population. These findings may have important implications for fetal and

  11. IL-10 prevents aging-associated inflammation and insulin resistance in skeletal muscle

    PubMed Central

    Dagdeviren, Sezin; Jung, Dae Young; Friedline, Randall H.; Noh, Hye Lim; Kim, Jong Hun; Patel, Payal R.; Tsitsilianos, Nicholas; Inashima, Kunikazu; Tran, Duy A.; Hu, Xiaodi; Loubato, Marilia M.; Craige, Siobhan M.; Kwon, Jung Yeon; Lee, Ki Won; Kim, Jason K.

    2017-01-01

    Altered energy balance and insulin resistance are important characteristics of aging. Skeletal muscle is a major site of glucose disposal, and the role of aging-associated inflammation in skeletal muscle insulin resistance remains unclear. To investigate, we examined glucose metabolism in 18-mo-old transgenic mice with muscle-specific overexpression of IL-10 (MIL10) and in wild-type mice during hyperinsulinemic–euglycemic clamping. Despite similar fat mass and energy balance, MIL10 mice were protected from aging-associated insulin resistance with significant increases in glucose infusion rates, whole-body glucose turnover, and skeletal muscle glucose uptake (∼60%; P < 0.05), as compared to age-matched WT mice. This protective effect was associated with decreased muscle inflammation, but no changes in adipose tissue inflammation in aging MIL10 mice. These results demonstrate the importance of skeletal muscle inflammation in aging-mediated insulin resistance, and our findings further implicate a potential therapeutic role of anti-inflammatory cytokine in the treatment of aging-mediated insulin resistance.—Dagdeviren, S., Jung, D. Y., Friedline, R. H., Noh, H. L., Kim, J. H., Patel, P. R., Tsitsilianos, N., Inashima, K., Tran, D. A., Hu, X., Loubato, M. M., Craige, S. M., Kwon, J. Y., Lee, K. W., Kim, J. K. IL-10 prevents aging-associated inflammation and insulin resistance in skeletal muscle. PMID:27811060

  12. Curcumin rescues high fat diet-induced obesity and insulin sensitivity in mice through regulating SREBP pathway

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ding, Lili; Li, Jinmei

    Obesity and its major co-morbidity, type 2 diabetes, have reached an alarming epidemic prevalence without an effective treatment available. It has been demonstrated that inhibition of SREBP pathway may be a useful strategy to treat obesity with type 2 diabetes. Sterol regulatory element-binding proteins (SREBPs) are major transcription factors regulating the expression of genes involved in biosynthesis of cholesterol, fatty acid and triglyceride. In current study, we identified a small molecule, curcumin, inhibited the SREBP expression in vitro. The inhibition of SREBP by curcumin decreased the biosynthesis of cholesterol and fatty acid. In vivo, curcumin ameliorated HFD-induced body weight gainmore » and fat accumulation in liver or adipose tissues, and improved serum lipid levels and insulin sensitivity in HFD-induced obese mice. Consistently, curcumin regulates SREBPs target genes and metabolism associated genes in liver or adipose tissues, which may directly contribute to the lower lipid level and improvement of insulin resistance. Take together, curcumin, a major active component of Curcuma longa could be a potential leading compound for development of drugs for the prevention of obesity and insulin resistance. - Highlights: • Curcumin decreases biosynthesis of cholesterol and fatty acid in vitro. • Curcumin as a SREBP inhibitor ameliorates HFD-induced obesity. • Curcumin as a SREBP inhibitor improves insulin resistance.« less

  13. The value of different insulin resistance indices in assessment of non-alcoholic fatty liver disease in overweight/obese children.

    PubMed

    El-Karaksy, Hanaa M; El-Raziky, Mona S; Fouad, Hanan M; Anwar, Ghada M; El-Mougy, Fatma M; El-Koofy, Nehal M; El-Hennawy, Ahmad M

    2015-01-01

    The aim of the present study was to determine the association between insulin resistance (IR) and both non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS) in a group of Egyptian overweight/obese children and adolescents and to evaluate different IR indices in detection of NAFLD. The study included 76 overweight/obese children aged 2-15 years; 52.6% were males. Laboratory analysis included fasting blood glucose, serum insulin, lipid profile, liver biochemical profile, and liver ultrasound. IR was calculated using the following indices; the homeostasis model assessment method (HOMA-IR), the quantitative insulin-sensitivity check index (QUICKI) and hepatic insulin sensitivity. The National Cholesterol Education Program Adult Treatment Panel III criteria were used to estimate prevalence of MetS. Liver biopsy was done when medically indicated and accepted by parents. IR was detected in 43.4% and 34.2% by using QUICKI and HOMA, respectively. MetS was detected in 36.8% and NAFLD was detected in 45.5% among those performing liver biopsy. Cases with NAFLD had more frequent IR than children with normal histology. QUICKI showed significant difference between normal subjects and both steatosis and non-alcoholic steatohepatitis; while HOMA-IR was sensitive in cases with NASH only. MetS was present in 100% of patients with NASH and in 75% of those with steatosis and they were all obese. Patients with NASH had significantly higher ALT than those with normal histology. IR was significantly associated with NAFLD. QUICKI is considered more sensitive than HOMA-IR in differentiating simple steatosis from normal liver histology. Copyright © 2013 Diabetes India. Published by Elsevier Ltd. All rights reserved.

  14. Association between triglyceride to HDL-C ratio and insulin resistance in indigenous Argentinean children.

    PubMed

    Hirschler, V; Maccallini, G; Sanchez, M; Gonzalez, C; Molinari, C

    2015-12-01

    Insulin resistance is considered one of the major risk factors for the development of type 2 diabetes mellitus (T2DM). Thus, early identification, preferably by using simple and inexpensive diagnostic tools, is essential for preventing T2DM. Triglyceride (TG) to high-density lipoprotein cholesterol (HDL-C) ratio (TG/HDL-C) has been proposed as an inexpensive tool to identify individuals at high risk of T2DM. The objective of this study was to determine the relationship between insulin resistance and TG/HDL-C in indigenous Argentinean children. A cross-sectional study of 501 (243 boys) indigenous school children aged 10.0 ± 2.4 yr were assessed for anthropometry, lipids, glucose, and insulin levels from November 2011 to November 2013. Insulin resistance was defined as the upper third quartile of homeostasis model assessment (HOMA-IR). The prevalence of overweight/obesity was 11.4% per Centers for Disease Control. Mean levels of various characteristics were: body mass index (BMI) 17.2 ± 2.6, HDL-C 39 ± 9 mg/dL, TGs 121 ± 58 mg/dL, TG/HDL-C 2.9 ± 1.8, glucose 77 ± 8 mg/dL, HOMA-IR 1.0 ± 0.8, and insulin 44 ± 9 mUI/L. Children in the higher quartiles of TG/HDL-C had significantly higher HOMA-IR values than children in the lower quartiles. Multiple linear regression analysis showed that TG/HDL-C was significantly associated with HOMA-IR (r² = 0.19) adjusted for age, gender, and BMI. Furthermore, for a 1-unit increase in log TG/HDL-C, the odds of being insulin resistant (HOMA-IR>III quartile) increased by 2.58 times [odds ratio (OR), 2.58 (1.63-4.05); p < 0.01], adjusted for age, gender, and BMI. This study suggests that TG/HDL-C may be a good marker to identify insulin resistant indigenous Argentinean children. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. Insulin resistance in non-obese women with polycystic ovary syndrome: relation to byproducts of oxidative stress.

    PubMed

    Macut, D; Simic, T; Lissounov, A; Pljesa-Ercegovac, M; Bozic, I; Djukic, T; Bjekic-Macut, J; Matic, M; Petakov, M; Suvakov, S; Damjanovic, S; Savic-Radojevic, A

    2011-07-01

    To get more insight into molecular mechanisms underlying oxidative stress and its link with insulin resistance, oxidative stress parameters, as well as, antioxidant enzyme activities were studied in young, non-obese women with polycystic ovary syndrome (PCOS). Study was performed in 34 PCOS women and 23 age and body mass index (BMI)-matched healthy controls. Plasma nitrotyrosine and malondialdehyde (MDA), representative byproducts of protein and lipid oxidative damage, were determined by enzyme immunoassay. Antioxidant enzyme activities, superoxide dismutase (SOD) and glutathione peroxidase (GPX) were studied spectrophotometrically. Insulin resistance was calculated using homeostasis assessment model (HOMA-IR). Plasma nitrotyrosine and MDA were increased, but only nitrotyrosine was significantly higher (p < 0.05) in PCOS women compared to controls. Uric acid (surrogate marker of × antine oxidase) was also significantly elevated in PCOS (p < 0.05). Both plasma SOD and GPX activity showed no statistically significant difference between PCOS and controls. Indices of insulin resistance (insulin and HOMAIR) were significantly higher in PCOS group and positively correlated with level of MDA (r = 0.397 and r = 0.523, respectively; p < 0.05) as well as GPX activity (r = 0.531 and r = 0.358, respectively; p < 0.05). Our results indicate that insulin resistance could be responsible for the existence of subtle form of oxidative stress in young, nonobese PCOS women. Hence, presence of insulin resistance, hyperinsulinemia and oxidative damage are likely to accelerate slow development of cardiovascular disease in PCOS. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.

  16. Plasma sterol evidence for decreased absorption and increased synthesis of cholesterol in insulin resistance and obesity1234

    PubMed Central

    Knopp, Robert H; Kahn, Steven E; Retzlaff, Barbara M; Fish, Brian; Ma, Lina; Ostlund, Richard E

    2011-01-01

    Background: The rise in LDL with egg feeding in lean insulin-sensitive (LIS) participants is 2- and 3-fold greater than in lean insulin-resistant (LIR) and obese insulin-resistant (OIR) participants, respectively. Objective: We determined whether differences in cholesterol absorption, synthesis, or both could be responsible for these differences by measuring plasma sterols as indexes of cholesterol absorption and endogenous synthesis. Design: Plasma sterols were measured by gas chromatography–mass spectrometry in a random subset of 34 LIS, 37 LIR, and 37 OIR participants defined by the insulin sensitivity index (SI) and by BMI criteria selected from a parent group of 197 participants. Cholestanol and plant sterols provide a measure of cholesterol absorption, and lathosterol provides a measure of cholesterol synthesis. Results: The mean (±SD) ratio of plasma total absorption biomarker sterols to cholesterol was 4.48 ± 1.74 in LIS, 3.25 ± 1.06 in LIR, and 2.82 ± 1.08 in OIR participants. After adjustment for age and sex, the relations of the absorption sterol–cholesterol ratios were as follows: LIS > OIR (P < 0.001), LIS > LIR (P < 0.001), and LIR > OIR (P = 0.11). Lathosterol-cholesterol ratios were 0.71 ± 0.32 in the LIS participants, 0.95 ± 0.47 in the LIR participants, and 1.29 ± 0.55 in the OIR participants. After adjustment for age and sex, the relations of lathosterol-cholesterol ratios were as follows: LIS < OIR (P < 0.001), LIS < LIR (P = 0.03), and LIR < OIR (P = 0.002). Total sterol concentrations were positively associated with SI and negatively associated with obesity, whereas lathosterol correlations were the opposite. Conclusions: Cholesterol absorption was highest in the LIS participants, whereas cholesterol synthesis was highest in the LIR and OIR participants. Therapeutic diets for hyperlipidemia should emphasize low-cholesterol diets in LIS persons and weight loss to improve SI and to decrease cholesterol overproduction in LIR and OIR

  17. Association between haptoglobin gene and insulin resistance in Arab-Americans.

    PubMed

    Burghardt, Kyle J; Masri, Dana El; Dass, Sabrina E; Shikwana, Sara S; Jaber, Linda A

    2017-11-01

    To analyze associations between variation in the HP gene and lipid and glucose-related measures in Arab-Americans. Secondary analyses were performed based on sex. Genomic DNA was extracted from samples obtained from a previous epidemiological study of diabetes in Arab-Americans. The HP 1 and 2 alleles were analyzed by polymerase chain reaction and gel electrophoresis. Associations were analyzed by linear regression. Associations were identified between the heterozygous haptoglobin 2-1 genotype and insulin resistance, fasting insulin and fasting c-peptide. The effect of sex did not remain significant after adjustment for relevant variables. HP genetic variation may have utility as a biomarker of insulin resistance and diabetes risk in Arab-Americans, however, future prospective studies are needed.

  18. Glycerol-3-Phosphate Acyltransferase 1 Deficiency in ob/ob Mice Diminishes Hepatic Steatosis but Does Not Protect Against Insulin Resistance or Obesity

    PubMed Central

    Wendel, Angela A.; Li, Lei O.; Li, Yue; Cline, Gary W.; Shulman, Gerald I.; Coleman, Rosalind A.

    2010-01-01

    OBJECTIVE Hepatic steatosis is strongly associated with insulin resistance, but a causal role has not been established. In ob/ob mice, sterol regulatory element binding protein 1 (SREBP1) mediates the induction of steatosis by upregulating target genes, including glycerol-3-phosphate acyltransferase-1 (Gpat1), which catalyzes the first and committed step in the pathway of glycerolipid synthesis. We asked whether ob/ob mice lacking Gpat1 would have reduced hepatic steatosis and improved insulin sensitivity. RESEARCH DESIGN AND METHODS Hepatic lipids, insulin sensitivity, and hepatic insulin signaling were compared in lean (Lep+/?), lean-Gpat1−/−, ob/ob (Lepob/ob), and ob/ob-Gpat1−/− mice. RESULTS Compared with ob/ob mice, the lack of Gpat1 in ob/ob mice reduced hepatic triacylglycerol (TAG) and diacylglycerol (DAG) content 59 and 74%, respectively, but increased acyl-CoA levels. Despite the reduction in hepatic lipids, fasting glucose and insulin concentrations did not improve, and insulin tolerance remained impaired. In both ob/ob and ob/ob-Gpat1−/− mice, insulin resistance was accompanied by elevated hepatic protein kinase C-ε activation and blunted insulin-stimulated Akt activation. CONCLUSIONS These results suggest that decreasing hepatic steatosis alone does not improve insulin resistance, and that factors other than increased hepatic DAG and TAG contribute to hepatic insulin resistance in this genetically obese model. They also show that the SREBP1-mediated induction of hepatic steatosis in ob/ob mice requires Gpat1. PMID:20200319

  19. Parasympathetic cardiac activity is associated with cardiorespiratory fitness in overweight and obese adolescents.

    PubMed

    da Silva, Danilo Fernandes; Bianchini, Josiane Aparecida Alves; Antonini, Vanessa Drieli Seron; Hermoso, Danielle Aparecida Munhos; Lopera, Carlos Andres; Pagan, Bruno Guilherme Morais; McNeil, Jessica; Nardo Junior, Nelson

    2014-04-01

    The aim of this study was to investigate the association between cardiac parasympathetic activity and cardiorespiratory fitness, insulin, and hemodynamic profile in overweight and obese adolescent girls and boys (aged 12-16 years). Data were taken from the Multidisciplinary Obesity Treatment Program. Only post-intervention measurements are presented herein. Body composition, cardiorespiratory fitness, blood pressure, and metabolic profile (insulin and glucose profile) of adolescents were assessed. Cardiac parasympathetic activity was determined by resting heart rate variability, which was analyzed using a heart rate monitor. Greater parasympathetic cardiac activity was associated with higher levels of cardiorespiratory fitness in both girls and boys (0.375 ≤ r ≤ 0.900), while the sympathetic-vagal balance was negatively related to maximal oxygen uptake (VO2max) in girls (r = 0.478). An association between lower parasympathetic activity and insulin resistance was noted in girls (mean of R-R intervals [RRmean] and homeostasis model assessment insulin-resistance index [HOMA-IR]: r = -0.678), while greater systolic blood pressure (SBP) and lower parasympathetic activity were associated in both sexes (RRmean and SBP: r = -0.526; high frequency [HF (nu)] and SBP: r = -0.754). In conclusion, autonomic nervous system activity was associated with cardiorespiratory fitness, insulin resistance, and SBP in overweight and obese adolescents. The identification of these potential relationships assists with the establishment of future long-term exercise interventions that evaluate the improvements in parasympathetic nervous system activity, in addition to metabolic profile and cardiorespiratory fitness in overweight and obese adolescents.

  20. Plasminogen activator inhibitor-1 deficiency ameliorates insulin resistance and hyperlipidemia but not bone loss in obese female mice.

    PubMed

    Tamura, Yukinori; Kawao, Naoyuki; Yano, Masato; Okada, Kiyotaka; Matsuo, Osamu; Kaji, Hiroshi

    2014-05-01

    We previously demonstrated that plasminogen activator inhibitor-1 (PAI-1), an inhibitor of fibrinolysis, is involved in type 1 diabetic bone loss in female mice. PAI-1 is well known as an adipogenic factor induced by obesity. We therefore examined the effects of PAI-1 deficiency on bone and glucose and lipid metabolism in high-fat and high-sucrose diet (HF/HSD)-induced obese female mice. Female wild-type (WT) and PAI-1-deficient mice were fed with HF/HSD or normal diet for 20 weeks from 10 weeks of age. HF/HSD increased the levels of plasma PAI-1 in WT mice. PAI-1 deficiency suppressed the levels of blood glucose, plasma insulin, and total cholesterol elevated by obesity. Moreover, PAI-1 deficiency improved glucose intolerance and insulin resistance induced by obesity. Bone mineral density (BMD) at trabecular bone as well as the levels of osterix, alkaline phosphatase, and receptor activator of nuclear factor κB ligand mRNA in tibia were decreased by HF/HSD in WT mice, and those changes by HF/HSD were not affected by PAI-1 deficiency. HF/HSD increased the levels of plasma TNF-α in both WT and PAI-1-deficient mice, and the levels of plasma TNF-α were negatively correlated with trabecular BMD in tibia of female mice. In conclusion, we revealed that PAI-1 deficiency does not affect the trabecular bone loss induced by obesity despite the amelioration of insulin resistance and hyperlipidemia in female mice. Our data suggest that the changes of BMD and bone metabolism by obesity might be independent of PAI-1 as well as glucose and lipid metabolism.

  1. Polymorphism rs3123554 in the cannabinoid receptor gene type 2 (CNR2) reveals effects on body weight and insulin resistance in obese subjects.

    PubMed

    de Luis, Daniel Antonio; Izaola, Olatz; Primo, David; de la Fuente, Beatriz; Aller, Rocio

    2017-10-01

    Few studies assessing the relationship between single nucleotide polymorphisms in CNR2 and obesity or its related metabolic parameters are available. To investigate the influence of polymorphism rs3123554 in the CNR2 receptor gene on obesity anthropometric parameters, insulin resistance, and adipokines in subjects with obesity. The study population consisted of 1027 obese subjects, who were performed bioelectrical impedance analyses, blood pressure measurements, serial assessments of dietary intake during three days, and biochemical tests. Genotypes GG, GA, and AA were found in 339 (33.0%), 467 (45.5%), and 221 (21.5%) respectively. Body mass index, weight, fat mass, waist circumference, insulin, HOMA-IR, and triglyceride and leptin levels were higher in A-allele carriers as compared to non A-allele carriers. No differences were seen in these parameters between the GA and AA genotypes. There were no statistical differences in dietary intake. The main study finding was the association of the minor allele of the SNP rs3123554 in the CNR2 gene with body weight and triglyceride, HOMA-IR, insulin, and leptin levels. Copyright © 2017 SEEN y SED. Publicado por Elsevier España, S.L.U. All rights reserved.

  2. DsbA-L prevents obesity-induced inflammation and insulin resistance by suppressing the mtDNA release-activated cGAS-cGAMP-STING pathway

    USDA-ARS?s Scientific Manuscript database

    Chronic inflammation in adipose tissue plays a key role in obesity-induced insulin resistance. However, the mechanisms underlying obesity-induced inflammation remain elusive. Here we show that obesity promotes mtDNA release into the cytosol, where it triggers inflammatory responses by activating the...

  3. Exercise and dietary change ameliorate high fat diet induced obesity and insulin resistance via mTOR signaling pathway.

    PubMed

    Bae, Ju Yong; Shin, Ki Ok; Woo, Jinhee; Woo, Sang Heon; Jang, Ki Soeng; Lee, Yul Hyo; Kang, Sunghwun

    2016-06-01

    The purpose of this study was to investigate the effect of exercise and dietary change on obesity and insulin resistance and mTOR signaling protein levels in skeletal muscles of obese rats. Sixty male Sprague-Dawley rats were divided into CO (Normal diet) and HF (High Fat diet) groups in order to induce obesity for 15 weeks. The rats were then subdivided into CO, COT (CO + Training), HF, HFT (HF + Training), HFND (Dietary change), and HFNDT (HFND + Training) groups (10 rats / group). The training groups underwent moderate-intensity treadmill exercise for 8 weeks, after which soleus muscles were excised and analyzed. Data was statistically analyzed by independent t-test and One-way ANOVA tests with a 0.05 significance level. Fasting blood glucose, plasma insulin, and HOMA-IR in the HF group were significantly higher, as compared with other groups (p <.05). Protein levels of insulin receptor subunit-1 (IRS-1), IRS-2, and p-Akt were significantly higher in the HFT, HFND, and HFNDT groups, as compared with HF group. In addition, the protein levels of the mammalian target of rapamycin complex 1 (mTORC1) and ribosomal S6 protein kinase 1 were significantly decreased by exercise and dietary change (p <.05). However, mTORC2 and phosphoinositide 3-kinase were significantly increased (p <.05). In summary, despite the negative impact of continuous high fat intake, regular exercise and dietary change showed a positive effect on insulin resistance and mTOR signaling protein levels.

  4. Effects of aging and insulin resistant states on protein anabolic responses in older adults.

    PubMed

    Morais, Jose A; Jacob, Kathryn Wright; Chevalier, Stéphanie

    2018-07-15

    -body anabolic response in elderly subjects is mediated by the failure of insulin to stimulate protein synthesis to the same extent as in the young, especially in men. This blunted response can be overcome at the whole-body and muscle levels during an intravenous fed state supplying a generous amount of protein, in active healthy elderly women. Obese elderly women with and without type 2 diabetes have insulin resistance of protein anabolism at the whole-body level, but this resistance is worsened with diabetes when glucose metabolism is further impaired. More investigation is needed to determine the exact role of insulin in promoting anabolism with aging. The findings from our group are relevant for the field of sarcopenia research as they provide a rationale to offer low cost nutritional interventions for overcoming this detrimental condition associated with aging and diabetes. Copyright © 2018. Published by Elsevier Inc.

  5. Brain iron overload, insulin resistance, and cognitive performance in obese subjects: a preliminary MRI case-control study.

    PubMed

    Blasco, Gerard; Puig, Josep; Daunis-I-Estadella, Josep; Molina, Xavier; Xifra, Gemma; Fernández-Aranda, Fernando; Pedraza, Salvador; Ricart, Wifredo; Portero-Otín, Manuel; Fernández-Real, José Manuel

    2014-11-01

    The linkage among the tissue iron stores, insulin resistance (IR), and cognition remains unclear in the obese population. We aimed to identify the factors that contribute to increased hepatic iron concentration (HIC) and brain iron overload (BIO), as evaluated by MRI, and to evaluate their impact on cognitive performance in obese and nonobese subjects. We prospectively recruited 23 middle-aged obese subjects without diabetes (13 women; age 50.4 ± 7.7 years; BMI 43.7 ± 4.48 kg/m2) and 20 healthy nonobese volunteers (10 women; age 48.8 ± 9.5 years; BMI 24.3 ± 3.54 kg/m2) in whom iron load was assessed in white and gray matter and the liver by MRI. IR was measured from HOMA-IR and an oral glucose tolerance test. A battery of neuropsychological tests was used to evaluate the cognitive performance. Multivariate regression analysis was used to identify the independent associations of BIO and cognitive performance. A significant increase in iron load was detected at the caudate nucleus (P < 0.001), lenticular nucleus (P = 0.004), hypothalamus (P = 0.002), hippocampus (P < 0.001), and liver (P < 0.001) in obese subjects. There was a positive correlation between HIC and BIO at caudate (r = 0.517, P < 0.001), hypothalamus (r = 0.396, P = 0.009), and hippocampus (r = 0.347, P < 0.023). The area under the curve of insulin was independently associated with BIO at the caudate (P = 0.001), hippocampus (P = 0.028), and HIC (P = 0.025). BIOs at the caudate (P = 0.028), hypothalamus (P = 0.006), and lenticular nucleus (P = 0.012) were independently associated with worse cognitive performance. Obesity and IR may contribute to increased HIC and BIO being associated with worse cognitive performance. BIO could be a potentially useful MRI biomarker for IR and obesity-associated cognitive dysfunction. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  6. Obesity modifies the association between serum 25-hydroxyvitamin D and insulin resistance in Korean general population without increased fasting glucose levels.

    PubMed

    Lee, Sung Woo; Kim, Myounghee; Kim, Ho; Han, Seung Seok; Lee, Hajeong; Lee, Jung Pyo; Kim, Dong Ki; Lim, Chun Soo; Kim, Yon Su; Park, Ae Kyung; Joo, Kwon Wook

    2014-10-01

    The inverse relationship between 25-hydroxyvitamin D [25(OH)D] status and insulin resistance (IR) has been reported, but many interventional studies failed to reduce IR with 25(OH)D supplementation. In addition, there has been a paucity of literature on the interaction between 25(OH)D status and IR according to the degree of obesity in Asian subjects. We therefore evaluated the association between 25(OH)D status and IR according to the degree of obesity. Data from the Korea National Health and Nutrition Examination Survey in 2008-2010 were analyzed. The study subjects comprised 10,629 participants aged ≥20 years with fasting glucose<100 mg/dL. IR was estimated by the homeostasis model assessment (HOMA). We found an inverse linear association between 25(OH)D and loge(HOMA-IR) in multiple linear regression analysis; namely, 10 ng/mL increase of 25(OH)D was associated with 0.018 decrease of loge(HOMA-IR) (p<0.0001). In the subgroup analysis, we identified a distinct trend that the inverse linear association between 25(OH)D and loge(HOMA-IR) became more prominent with the progression of body mass index, waist circumference, or fat mass quartile (Q): -0.009, -0.004, -0.029 and -0.037 in Q1-Q4 of body mass index, -0.004, -0.014, -0.02 and -0.038 in Q1-Q4 of waist circumference, and -0.002, -0.001, -0.017 and -0.025 in Q1-Q4 of fat mass. Thus, the IR-lowering effect of 25(OH)D became more evident with the progression of obesity in an adult Korean population without increased fasting glucose levels. We suggest that proper supplementation of vitamin D might be beneficial in obese Korean adults.

  7. Reduced Socs3 expression in adipose tissue protects female mice against obesity-induced insulin resistance.

    PubMed

    Palanivel, R; Fullerton, M D; Galic, S; Honeyman, J; Hewitt, K A; Jorgensen, S B; Steinberg, G R

    2012-11-01

    Inflammation in obesity increases the levels of the suppressor of cytokine signalling-3 (SOCS3) protein in adipose tissue, but the physiological importance of this protein in regulating whole-body insulin sensitivity in obesity is not known. We generated Socs3 floxed (wild-type, WT) and Socs3 aP2 (also known as Fabp4)-Cre null (Socs3 AKO) mice. Mice were maintained on either a regular chow or a high-fat diet (HFD) for 16 weeks during which time body mass, adiposity, glucose homeostasis and insulin sensitivity were assessed. The HFD increased SOCS3 levels in adipose tissue of WT but not Socs3 AKO mice. WT and Socs3 AKO mice had similar body mass and adiposity, assessed using computed tomography (CT) imaging, irrespective of diet or sex. On a control chow diet there were no differences in insulin sensitivity or glucose tolerance. When fed a HFD, female but not male Socs3 AKO mice had improved glucose tolerance as well as lower fasting glucose and insulin levels compared with WT littermates. Hyperinsulinaemic-euglycaemic clamps and positron emission tomography (PET) imaging demonstrated that improved insulin sensitivity was due to elevated adipose tissue glucose uptake. Increased insulin-stimulated glucose uptake in adipose tissue was associated with enhanced levels and activating phosphorylation of insulin receptor substrate-1 (IRS1). These data demonstrate that inhibiting SOCS3 production in adipose tissue of female mice is effective for improving whole-body insulin sensitivity in obesity.

  8. [The effect of N-stearoylethanolamine on liver phospholipid composition of rats with insulin resistance caused by alimentary obesity].

    PubMed

    Onopchenko, O V; Kosiakova, H V; Horid'ko, T M; Klimashevskyĭ, V M; Hula, N M

    2014-01-01

    We used alimentary obesity-induced insulin resistance (IR) model in rats to investigate the influence of N-stearoylethanolamine on the content of phospholipids and their fatty acid composition. Our results show that prolonged high-fat diet triggers considerable aberrations in the composition of main phospholipids in the liver and can be one of the causes of IR in rats. In particular, the increase of phosphatidylcholine, phosphatidylethanolamine and significant decrease of other phospholipids: lysophosphatidylcholine, lysophosphatidylethanolamine, sphingomyelin, phosphatidylinositol, phosphatidylserine and diphosphaglicerol were observed. The levels of monounsaturated (erucic, nervonic, oleic) and polyunsaturated (eicosatrienoic, docosatrienoic, arachidonic) fatty acids were increased; meanwhile the content of diunsaturated acids was decreased. The NSE administration (50 mg/kg of body weight) caused restoration of the phospholipids content in the liver of rats with diet-induced IR that highly correlated with the decrease in plasma insulin level and the improvement of insulin sensitivity. Moreover, the effect of NSE was accompanied by the normalization of fatty acids composition of phospholipids that could be related to modulating influence of NSE on the activity of the main fatty acid desaturases. It is known that the imbalance in phospholipid composition of the rat liver causes substantial metabolic alterations that are associated with the development of IR. Accordingly, the compensations of the imbalance by NSE can help to restore insulin sensitivity, inhibit the development of obesity, IR and type 2 diabetes.

  9. Childhood obesity and insulin resistance in a Yucatan mini-piglet model: putative roles of IGF-1 and muscle PPARs in adipose tissue activity and development.

    PubMed

    Sébert, S P; Lecannu, G; Kozlowski, F; Siliart, B; Bard, J M; Krempf, M; Champ, M M-J

    2005-03-01

    To explore metabolic and cellular modifications induced during childhood obesity, in a novel animal model of obese mini-piglets. A total of 10 four-month old Yucatan mini-pigs were followed from prepuberty to adulthood. Animals were divided into two groups. The first one had been overfed (OF) a western-type diet and the second one had been normally fed a control recommended human-type diet (NF). Plasma insulin-like growth factor 1 (IGF-1), insulin, leptin, nonesterified fatty acids, triglycerides (TGs) and glucose were determined at sexual maturity and at young adulthood. Quantitative gene expressions of peroxysome-proliferator-activated receptors (PPARs), glucose transporter 4, insulin receptor, IGF-1, leptin and interleukin-6 (IL-6) in skeletal muscle, adipose tissue and liver were also measured at both stages. Adult insulin sensitivity was measured via euglycaemic-hyperinsulinaemic clamps. Increased body weight in adult OF pigs was associated with increased body size and low insulin sensitivity. Sexually mature OF pigs had higher IGF-1 plasma concentrations than their lean littermates (P < 0.05). In the OF group, TGs and glucose were both decreased (P < 0.05). Muscle PPARgamma and alpha in OF pubescent pigs as compared to NF pigs were 11 times higher and 20 times lower, respectively (P < 0.01). Obesity and insulin resistance induced by overfeeding mini-pigs during development and puberty were not associated with the cluster of metabolic modifications frequently observed in their adult littermates. Increased IGF-1 concentrations and modifications of skeletal muscle PPAR (alpha and gamma) expressions may help the young obese pig to partially regulate its glycaemia and triglyceridaemia through an increase of fat mass, which maintains its high insulin sensitivity.

  10. Hyperleptinaemia rather than fasting hyperinsulinaemia is associated with obesity following hypothalamic damage in children.

    PubMed

    Shaikh, M Guftar; Grundy, Richard G; Kirk, Jeremy M W

    2008-12-01

    Obesity following hypothalamic damage is often severe and resistant to lifestyle changes. Disruption of hypothalamic feedback mechanisms that maintain energy homeostasis may be responsible for this intractable obesity. Adipocytokines including insulin and leptin are also known to be important regulators of appetite and weight. To investigate the role of insulin, leptin, adiponectin and resistin in the aetiology of hypothalamic obesity (HO). This was a cross-sectional study of three groups of children, those with HO, congenital hypopituitarism (CH) and simple obesity (SO). A total of 69 children (HO=28, CH=18, SO=23) had leptin, resistin, adiponectin and insulin measured. Although fasting hyperinsulinaemia and insulin resistance were demonstrated, no differences in insulin or insulin resistance were seen between the groups. The HO group, however, had higher levels of leptin, adiponectin and resistin, which persisted even after adjusting for fat mass, compared with the other groups (P<0.05). No differences in fasting hyperinsulinaemia or insulin resistance were seen between the groups; however, leptin levels are elevated, even after adjusting for fat mass, suggesting that an element of leptin resistance is associated with HO. This is consistent with the inability of leptin to act on the hypothalamus, either due to transport across the blood-brain barrier or dysfunctional receptors. The lack of response to leptin may be more important in the development of obesity in these individuals, and the fasting hyperinsulinaemia is a result of the increased adipose tissue rather than the cause of the weight gain.

  11. Nutrient sensing and insulin signaling in neuropeptide-expressing immortalized, hypothalamic neurons: A cellular model of insulin resistance.

    PubMed

    Fick, Laura J; Belsham, Denise D

    2010-08-15

    Obesity and type 2 diabetes mellitus represent a significant global health crisis. These two interrelated diseases are typified by perturbed insulin signaling in the hypothalamus. Using novel hypothalamic cell lines, we have begun to elucidate the molecular and intracellular mechanisms involved in the hypothalamic control of energy homeostasis and insulin resistance. In this review, we present evidence of insulin and glucose signaling pathways that lead to changes in neuropeptide gene expression. We have identified some of the molecular mechanisms involved in the control of de novo hypothalamic insulin mRNA expression. And finally, we have defined key mechanisms involved in the etiology of cellular insulin resistance in hypothalamic neurons that may play a fundamental role in cases of high levels of insulin or saturated fatty acids, often linked to the exacerbation of obesity and diabetes.

  12. Inverse association between soya food consumption and insulin resistance in Japanese adults.

    PubMed

    Nakamoto, Mariko; Uemura, Hirokazu; Sakai, Tohru; Katsuura-Kamano, Sakurako; Yamaguchi, Miwa; Hiyoshi, Mineyoshi; Arisawa, Kokichi

    2015-08-01

    The purpose of the present study was to examine the association between soya food consumption and insulin resistance using baseline data of the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study in Tokushima, Japan. This cross-sectional study included 1274 subjects, aged 34-70 years at baseline, living in Tokushima Prefecture between 2008 and 2013. Fasting blood samples were collected and information on lifestyle characteristics including soya food intake and medical history were obtained using a structured self-administered questionnaire. The homeostasis model assessment of insulin resistance (HOMA-IR) was measured and those with HOMA-IR ≥ 2.5 were defined as having insulin resistance. Multiple logistic regression models were used to analyse the association between soya product intake and the prevalence of insulin resistance. Rural communities located in Tokushima Prefecture, Japan, between 2008 and 2013. A total of 1148 adults (565 men and 583 women), aged 34-70 years. The frequency of intake of miso soup, total non-fried soya products and total soya products showed significant inverse dose-response relationships with insulin resistance, after adjustments for potential confounders. When soya product intake was calculated as soya protein and isoflavone, the odds ratios of insulin resistance decreased significantly as the estimated intake of soya protein increased. Furthermore, significant inverse dose-response relationships were observed for total non-fried soya products and total soya products, after adjustment for total vegetable or total fibre consumption. The present results indicate that the intake of soya products and non-fried soya products is associated with reduced insulin resistance in the Japanese population.

  13. Interaction of insulin-like growth factor-I and insulin resistance-related genetic variants with lifestyle factors on postmenopausal breast cancer risk.

    PubMed

    Jung, Su Yon; Ho, Gloria; Rohan, Thomas; Strickler, Howard; Bea, Jennifer; Papp, Jeanette; Sobel, Eric; Zhang, Zuo-Feng; Crandall, Carolyn

    2017-07-01

    Genetic variants and traits in metabolic signaling pathways may interact with obesity, physical activity, and exogenous estrogen (E), influencing postmenopausal breast cancer risk, but these inter-related pathways are incompletely understood. We used 75 single-nucleotide polymorphisms (SNPs) in genes related to insulin-like growth factor-I (IGF-I)/insulin resistance (IR) traits and signaling pathways, and data from 1003 postmenopausal women in Women's Health Initiative Observation ancillary studies. Stratifying via obesity and lifestyle modifiers, we assessed the role of IGF-I/IR traits (fasting IGF-I, IGF-binding protein 3, insulin, glucose, and homeostatic model assessment-insulin resistance) in breast cancer risk as a mediator or influencing factor. Seven SNPs in IGF-I and INS genes were associated with breast cancer risk. These associations differed between non-obese/active and obese/inactive women and between exogenous E non-users and users. The mediation effects of IGF-I/IR traits on the relationship between these SNPs and cancer differed between strata, but only roughly 35% of the cancer risk due to the SNPs was mediated by traits. Similarly, carriers of 20 SNPs in PIK3R1, AKT1/2, and MAPK1 genes (signaling pathways-genetic variants) had different associations with breast cancer between strata, and the proportion of the SNP-cancer relationship explained by traits varied 45-50% between the strata. Our findings suggest that IGF-I/IR genetic variants interact with obesity and lifestyle factors, altering cancer risk partially through pathways other than IGF-I/IR traits. Unraveling gene-phenotype-lifestyle interactions will provide data on potential genetic targets in clinical trials for cancer prevention and intervention strategies to reduce breast cancer risk.

  14. Association between Triglyceride to HDL-C Ratio (TG/HDL-C) and Insulin Resistance in Chinese Patients with Newly Diagnosed Type 2 Diabetes Mellitus

    PubMed Central

    Ren, Xingxing; Chen, Zeng.ai; Zheng, Shuang; Han, Tingting; Li, Yangxue; Liu, Wei; Hu, Yaomin

    2016-01-01

    Objectives To explore the association between the triglyceride to HDL-C ratio (TG/HDL-C) and insulin resistance in Chinese patients with newly diagnosed type 2 diabetes mellitus. Methods Patients with newly diagnosed type 2 diabetes mellitus (272 men and 288 women) were enrolled and divided into three groups according to TG/HDL-C tertiles. Insulin resistance was defined by homeostatic model assessment of insulin resistance (HOMA-IR). Demographic information and clinical characteristics were obtained. Spearman’s correlation was used to estimate the association between TG/HDL-C and other variables. Multiple logistic regression analyses were adopted to obtain probabilities of insulin resistance. A receiver operating characteristic analysis was conducted to evaluate the ability of TG/HDL-C to discriminate insulin resistance. Results TG/HDL-C was associated with insulin resistance in Chinese patients with newly diagnosed T2DM (Spearman’s correlation coefficient = 0.21, P < 0.01). Patients in the higher tertiles of TG/HDL-C had significantly higher HOMA-IR values than patients in the lower tertiles [T1: 2.68(1.74–3.70); T2: 2.96(2.29–4.56); T3: 3.09(2.30–4.99)]. Multiple logistic regression analysis showed that TG/HDL-C was significantly associated with HOMA-IR, and patients in the higher TG/HDL-C tertile had a higher OR than those in the lower TG/HDL-C tertile, after adjusting for multiple covariates including indices for central obesity [T1: 1; T2: 4.02(1.86–8.71); T3: 4.30(1.99–9.29)]. Following stratification of waist circumference into quartiles, the effect of TG/HDL-C on insulin resistance remained significant irrespective of waist circumference. Conclusions TG/HDL-C was associated with insulin resistance independent of waist circumference. Whether it could be a surrogate marker for insulin resistance in Chinese patients with newly diagnosed type 2 diabetes mellitus still needs to be confirmed by more researches. PMID:27115999

  15. Association between Triglyceride to HDL-C Ratio (TG/HDL-C) and Insulin Resistance in Chinese Patients with Newly Diagnosed Type 2 Diabetes Mellitus.

    PubMed

    Ren, Xingxing; Chen, Zeng Ai; Zheng, Shuang; Han, Tingting; Li, Yangxue; Liu, Wei; Hu, Yaomin

    2016-01-01

    To explore the association between the triglyceride to HDL-C ratio (TG/HDL-C) and insulin resistance in Chinese patients with newly diagnosed type 2 diabetes mellitus. Patients with newly diagnosed type 2 diabetes mellitus (272 men and 288 women) were enrolled and divided into three groups according to TG/HDL-C tertiles. Insulin resistance was defined by homeostatic model assessment of insulin resistance (HOMA-IR). Demographic information and clinical characteristics were obtained. Spearman's correlation was used to estimate the association between TG/HDL-C and other variables. Multiple logistic regression analyses were adopted to obtain probabilities of insulin resistance. A receiver operating characteristic analysis was conducted to evaluate the ability of TG/HDL-C to discriminate insulin resistance. TG/HDL-C was associated with insulin resistance in Chinese patients with newly diagnosed T2DM (Spearman's correlation coefficient = 0.21, P < 0.01). Patients in the higher tertiles of TG/HDL-C had significantly higher HOMA-IR values than patients in the lower tertiles [T1: 2.68(1.74-3.70); T2: 2.96(2.29-4.56); T3: 3.09(2.30-4.99)]. Multiple logistic regression analysis showed that TG/HDL-C was significantly associated with HOMA-IR, and patients in the higher TG/HDL-C tertile had a higher OR than those in the lower TG/HDL-C tertile, after adjusting for multiple covariates including indices for central obesity [T1: 1; T2: 4.02(1.86-8.71); T3: 4.30(1.99-9.29)]. Following stratification of waist circumference into quartiles, the effect of TG/HDL-C on insulin resistance remained significant irrespective of waist circumference. TG/HDL-C was associated with insulin resistance independent of waist circumference. Whether it could be a surrogate marker for insulin resistance in Chinese patients with newly diagnosed type 2 diabetes mellitus still needs to be confirmed by more researches.

  16. Metabolic endotoxemia and saturated fat contribute to circulating NGAL concentrations in subjects with insulin resistance.

    PubMed

    Moreno-Navarrete, J M; Manco, M; Ibáñez, J; García-Fuentes, E; Ortega, F; Gorostiaga, E; Vendrell, J; Izquierdo, M; Martínez, C; Nolfe, G; Ricart, W; Mingrone, G; Tinahones, F; Fernández-Real, J M

    2010-02-01

    Lipocalin-2 (neutrophil gelatinase-associated lipocalin, NGAL) is an innate immune system protein that has been linked to insulin resistance and obesity, but the mechanisms behind these associations are poorly known. We hypothesized that endotoxin (lipopolysaccharide, LPS) and fat intake were in the background of these associations. We studied four cohorts: (1) a cross-sectional study in 194 subjects; (2) the changes in NGAL concentration induced by diet and weight loss in 36 obese women (with circadian rhythm in 8 of them); (3) the effects of acute fat intake on circulating NGAL concentration in 42 morbidly obese subjects; and (4) LPS-induced NGAL secretion ex vivo (whole blood and adipose tissue explants). Serum NGAL concentration was significantly associated with fasting triglycerides and LPS-binding protein in patients with type 2 diabetes. In obese subjects, the intake of saturated fatty acids was the factor that best explained the variance of NGAL changes after weight loss (contributing independently to 14% of NGAL variance). In fact, weight loss significantly changed the circadian rhythm of NGAL. The acute increase in circulating NGAL after fat overload was significantly associated with fasting insulin (r=0.52, P<0.001), homeostasis model assessment of insulin resistance (HOMA-IR) (r=0.36, P=0.02) and post-load triglyceride concentrations (r=0.38, P=0.018). LPS-induced NGAL secretion from adipose tissue explants did not change significantly, but LPS led to a significant increase in NGAL concentration in the whole blood obtained from patients with type 2 diabetes. Metabolic endotoxemia and saturated fat might contribute to circulating NGAL concentration in patients with insulin resistance.

  17. Leptin Resistance: A Possible Interface of Inflammation and Metabolism in Obesity-Related Cardiovascular Disease

    PubMed Central

    Martin, Seth S.; Qasim, Atif; Reilly, Muredach P.

    2015-01-01

    Nonstructured Abstract Leptin is an adipocyte-derived hormone and cytokine that regulates energy balance through a wide range of functions, including several important to cardiovascular health. Increased circulating leptin, a marker of leptin resistance, is common in obesity and independently associated with insulin resistance and cardiovascular disease (CVD) in humans. Mechanisms of leptin resistance include genetic mutation, leptin self regulation, limited tissue access and cellular or circulating molecular regulation. Evidence suggests that central leptin resistance causes obesity and that obesity-induced leptin resistance injures numerous peripheral tissues, including liver, pancreas, platelets, vasculature, and myocardium. This metabolic- and inflammatory-mediated injury may result from either resistance to leptin’s action in selective tissues, or excess leptin action from adiposity associated hyperleptinemia. In this sense, the term “leptin resistance” encompasses a complex pathophysiological phenomenon. The leptin axis has functional interactions with elements of metabolism, such as insulin, and inflammation, including mediators of innate immunity such as interleukin-6. Leptin is even purported to physically interact with C-reactive protein (CRP), resulting in leptin resistance, which is particularly intriguing given CRP’s well-studied relationship to CVD. Given that plasma levels of leptin and inflammatory markers are correlated and also predict cardiovascular risk, it is conceivable that part of this risk may be mediated through leptin-resistance related insulin resistance, chronic inflammation, type II diabetes, hypertension, atherothrombosis and myocardial injury. Leptin resistance and its interactions with metabolic and inflammatory factors, therefore, represent potential novel diagnostic and therapeutic targets in obesity-related cardiovascular disease. PMID:18926322

  18. Prevalence of diabetes and obesity in association with prematurity and growth restriction.

    PubMed

    Kopec, Gretchen; Shekhawat, Prem S; Mhanna, Maroun J

    2017-01-01

    Intrauterine growth restriction (IUGR) is when fetuses and newborn infants have not reached their true growth potential as genetically defined. Fetuses with IUGR develop in a less than ideal environment that leads to epigenetic changes and marks infants' metabolism for the rest of their lives. Epigenetic changes affect insulin-like growth factor-1 (IGF-1) levels and lead to insulin resistance and ultimately to a metabolic syndrome. The metabolic syndrome is a constellation of illnesses that raise one's risk for type 2 diabetes mellitus, coronary artery disease, and ischemic heart disease, including hypertension, dyslipidemia, central obesity, insulin resistance, and inflammation. The association between IUGR or prematurity and long-term insulin resistance, obesity, hypertension, and metabolic syndrome remains unclear. While studies have shown an association, others have not supported such association. If alteration of intrauterine growth can ultimately lead to the development of metabolic derangements in childhood and adulthood, and if such association is true, then early interventions targeting the health of pregnant women will ensure the health of the population to follow.

  19. New insights into insulin action and resistance in the vasculature

    PubMed Central

    Manrique, Camila; Lastra, Guido; Sowers, James R.

    2014-01-01

    Two-thirds of adults in the United States are overweight or obese, and another 26 million have type 2 diabetes. Decreased insulin sensitivity in cardiovascular tissue is an underlying abnormality in these individuals. Insulin metabolic signaling increases endothelial cell nitric oxide production. Impaired vascular insulin sensitivity is an early defect leading to impaired vascular relaxation. In overweight and obese persons, as well as in those with hypertension, systemic and vascular insulin resistance often occurs in conjunction with activation of the cardiovascular tissue renin–angiotensin–aldosterone system (RAAS). Activated angiotensin II type 1 receptor and mineralocorticoid receptor signaling promote the development of vascular insulin resistance and impaired endothelial nitric oxide–mediated relaxation. Research in this area has implicated excessive serine phosphorylation and proteasomal degradation of the docking protein insulin receptor substrate and enhanced signaling through hybrid insulin/insulin-like growth factor (IGF-1) receptor as important mechanisms underlying RAAS impediment of downstream vascular insulin metabolic signaling. This review will present recent evidence supporting the notion that RAAS signaling represents a potential pathway for the development of vascular insulin resistance and impaired endothelial-mediated vasodilation. PMID:24650277

  20. Delayed Intervention With Pyridoxamine Improves Metabolic Function and Prevents Adipose Tissue Inflammation and Insulin Resistance in High-Fat Diet-Induced Obese Mice.

    PubMed

    Maessen, Dionne E; Brouwers, Olaf; Gaens, Katrien H; Wouters, Kristiaan; Cleutjens, Jack P; Janssen, Ben J; Miyata, Toshio; Stehouwer, Coen D; Schalkwijk, Casper G

    2016-04-01

    Obesity is associated with an increased risk for the development of type 2 diabetes and vascular complications. Advanced glycation end products are increased in adipose tissue and have been associated with insulin resistance, vascular dysfunction, and inflammation of adipose tissue. Here, we report that delayed intervention with pyridoxamine (PM), a vitamin B6 analog that has been identified as an antiglycating agent, protected against high-fat diet (HFD)-induced body weight gain, hyperglycemia, and hypercholesterolemia, compared with mice that were not treated. In both HFD-induced and db/db obese mice, impaired glucose metabolism and insulin resistance were prevented by PM supplementation. PM inhibited the expansion of adipose tissue and adipocyte hypertrophy in mice. In addition, adipogenesis of murine 3T3-L1 and human Simpson-Golabi-Behmel Syndrome preadipocytes was dose- and time-dependently reduced by PM, as demonstrated by Oil Red O staining and reduced expression of adipogenic differentiation genes. No ectopic fat deposition was found in the liver of HFD mice. The high expression of proinflammatory genes in visceral adipose tissue of the HFD group was significantly attenuated by PM. Treatment with PM partially prevented HFD-induced mild vascular dysfunction. Altogether, these findings highlight the potential of PM to serve as an intervention strategy in obesity. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  1. A Major Locus for Fasting Insulin Concentrations and Insulin Resistance on Chromosome 6q with Strong Pleiotropic Effects on Obesity-Related Phenotypes in Nondiabetic Mexican Americans

    PubMed Central

    Duggirala, Ravindranath; Blangero, John; Almasy, Laura; Arya, Rector; Dyer, Thomas D.; Williams, Kenneth L.; Leach, Robin J.; O’Connell, Peter; Stern, Michael P.

    2001-01-01

    Insulin resistance and hyperinsulinemia are strong correlates of obesity and type 2 diabetes, but little is known about their genetic determinants. Using data on nondiabetics from Mexican American families and a multipoint linkage approach, we scanned the genome and identified a major locus near marker D6S403 for fasting “true” insulin levels (LOD score 4.1, empirical P<.0001), which do not crossreact with insulin precursors. Insulin resistance, as assessed by the homeostasis model using fasting glucose and specific insulin (FSI) values, was also strongly linked (LOD score 3.5, empirical P<.0001) with this region. Two other regions across the genome were found to be suggestively linked to FSI: a location on chromosome 2q, near marker D2S141, and another location on chromosome 6q, near marker D6S264. Since several insulin-resistance syndrome (IRS)–related phenotypes were mapped independently to the regions on chromosome 6q, we conducted bivariate multipoint linkage analyses to map the correlated IRS phenotypes. These analyses implicated the same chromosomal region near marker D6S403 (6q22-q23) as harboring a major gene with strong pleiotropic effects on obesity and on lipid measures, including leptin concentrations (e.g., LODeq for traits-specific insulin and leptin was 4.7). A positional candidate gene for insulin resistance in this chromosomal region is the plasma cell-membrane glycoprotein PC-1 (6q22-q23). The genetic location on chromosome 6q, near marker D6S264 (6q25.2-q26), was also identified by the bivariate analysis as exerting significant pleiotropic influences on IRS-related phenotypes (e.g., LODeq for traits-specific insulin and leptin was 4.1). This chromosomal region harbors positional candidate genes, such as the insulin-like growth factor 2 receptor (IGF2R, 6q26) and acetyl-CoA acetyltransferase 2 (ACAT2, 6q25.3-q26). In sum, we found substantial evidence for susceptibility loci on chromosome 6q that influence insulin concentrations and other

  2. Reduced sCD36 following weight loss corresponds to improved insulin sensitivity, dyslipidemia and liver fat in obese children.

    PubMed

    Knøsgaard, L; Kazankov, K; Birkebæk, N H; Holland-Fischer, P; Lange, A; Solvig, J; Hørlyck, A; Kristensen, K; Rittig, S; Vilstrup, H; Grønbæk, H; Handberg, A

    2016-09-01

    Childhood obesity is a major health problem with serious long-term metabolic consequences. CD36 is important for the development of obesity-related complications among adults. We aimed to investigate circulating sCD36 during weight loss in childhood obesity and its associations with insulin resistance, dyslipidemia, hepatic fat accumulation and low-grade inflammation. The impact of a 10-week weight loss camp for obese children (N=113) on plasma sCD36 and further after a 12-month follow-up (N=68) was investigated. Clinical and biochemical data were collected, and sCD36 was measured by an in-house assay. Liver fat was estimated by ultrasonography and insulin resistance by the homeostasis model assessment (HOMA-IR). Along with marked weight loss, sCD36 was reduced by 21% (P=0.0013) following lifestyle intervention, and individual sCD36 reductions were significantly associated with the corresponding decreases in HOMA-IR, triglycerides and total cholesterol. The largest sCD36 decrease occurred among children who reduced HOMA-IR and liver fat. After 12 months of follow-up, sCD36 was increased (P=0.014) and the metabolic improvements were largely lost. Weight-loss-induced sCD36 reduction, coincident with improved insulin resistance, circulating lipids and hepatic fat accumulation, proposes that sCD36 may be an early marker of long-term health risk associated with obesity-related complications.

  3. Beneficial effects of exercise on offspring obesity and insulin resistance are reduced by maternal high-fat diet

    PubMed Central

    Schreiber, Saskia; Klaus, Susanne; Kanzleiter, Isabel

    2017-01-01

    Scope We investigated the long-term effects of maternal high-fat consumption and post-weaning exercise on offspring obesity susceptibility and insulin resistance. Methods C57BL/6J dams were fed either a high-fat (HFD, 40% kcal fat) or low-fat (LFD, 10% kcal fat) semi-synthetic diet during pregnancy and lactation. After weaning, male offspring of both maternal diet groups (mLFD; mHFD) received a LFD. At week 7, half of the mice got access to a running wheel (+RW) as voluntary exercise training. To induce obesity, all offspring groups (mLFD +/-RW and mHFD +/-RW) received HFD from week 15 until week 25. Results Compared to mLFD, mHFD offspring were more prone to HFD-induced body fat gain and exhibited an increased liver mass which was not due to increased hepatic triglyceride levels. RW improved the endurance capacity in mLFD, but not in mHFD offspring. Additionally, mHFD offspring +RW exhibited higher plasma insulin levels during glucose tolerance test and an elevated basal pancreatic insulin production compared to mLFD offspring. Conclusion Taken together, maternal HFD reduced offspring responsiveness to the beneficial effects of voluntary exercise training regarding the improvement of endurance capacity, reduction of fat mass gain, and amelioration of HFD-induced insulin resistance. PMID:28235071

  4. HPMC supplementation reduces abdominal fat content, intestinal permeability, inflammation, and insulin resistance in diet-induced obese mice

    USDA-ARS?s Scientific Manuscript database

    The effects of hydroxypropyl methylcellulose (HPMC), a highly viscous non-fermentable soluble dietary fiber, were evaluated on adipose tissue inflammation and insulin resistance in diet induced obese (DIO) mice fed a high fat (HF) diet supplemented with either HPMC or insoluble fiber. DIO C57BL/6J m...

  5. Adiposity and insulin resistance correlate with telomere length in middle-aged Arabs: the influence of circulating adiponectin.

    PubMed

    Al-Attas, Omar S; Al-Daghri, Nasser M; Alokail, Majed S; Alfadda, Assim; Bamakhramah, Ahmed; Sabico, Shaun; Pritlove, Dave; Harte, Alison; Tripathi, Gyanendra; McTernan, Philip G; Kumar, Sudhesh; Chrousos, George

    2010-10-01

    Studies in obesity have implicated adipocytokines in the development of insulin resistance, which in turn may lead to accelerated aging. In this study, we determined associations of chromosomal telomere length (TL) to markers of obesity and insulin resistance in middle-aged adult male and female Arabs with and without diabetes mellitus type 2 (DMT2). One hundred and ninety-three non-diabetic and DMT2 subjects without complications (97 males and 96 females) participated in this cross-sectional study. Clinical data, as well as fasting blood samples, were collected. Serum glucose and lipid profile were determined using routine laboratory methods. Serum insulin, leptin, adiponectin, resistin, tumor necrosis factor-α, and PAI-1 were quantified using customized multiplex assay kits. High sensitive C-reactive protein (hsCRP) and angiotensin II (ANG II) were measured using ELISAs. Circulating leukocyte TL was examined by quantitative real-time PCR. Circulating chromosomal leukocyte TL had significant inverse associations with body mass index (BMI), systolic blood pressure, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), low-density lipoprotein (LDL)- and total cholesterol, ANG II and hsCRP levels. Adiponectin, BMI, systolic blood pressure, and LDL cholesterol predicted 47% of the variance in TL (P<0.0001). HOMA-IR was the most significant predictor for TL in males, explaining 35% of the variance (P=0.01). In females, adiponectin accounted for 28% of the variance in TL (P=0.01). Obesity and insulin resistance are associated with chromosomal TL among adult Arabs. Evidence of causal relations needs further investigation. The positive association of adiponectin to TL has clinical implications as to the possible protective effects of this hormone from accelerated aging.

  6. A descriptive study of facial acanthosis nigricans and its association with body mass index, waist circumference and insulin resistance using HOMA2 IR.

    PubMed

    Verma, Shyam; Vasani, Resham; Joshi, Rajiv; Phiske, Meghana; Punjabi, Pritesh; Toprani, Tushar

    2016-01-01

    The term facial acanthosis nigricans (FAN) lacks definition of precise clinical and histopathological features. We present a descriptive study of patients with FAN to define pigmentary patterns and estimate the prevalence of obesity and insulin resistance in these cases. It is a prospective study that included all patients with classical AN of the neck and/or other areas with facial acanthosis nigricans described as brown-to-black macular pigmentation with blurred ill-defined margins, found on the zygomatic and malar areas. The body mass index (BMI) and waist circumference (WC) of the included patients were used as parameters of obesity. Homeostatic Model of Assessment of Insulin Resistance (HOMA2 IR) was used as a parameter to evaluate insulin resistance. Histopathological features of the 6 skin biopsies that were possible were reviewed. Among the 102 included individuals, the patterns of facial pigmentation seen in addition to the classic pattern involving zygomatic and malar areas were a hyperpigmented band on the forehead in 59.80%, periorbital darkening in 17.64%, perioral darkening in 12.74%, and generalized darkening in 9.8% of cases. 85.29% of the males and 100% of the females were found to be obese. Varying degrees of insulin resistance was noted in 82.34% of the individuals. Six biopsies available for evaluation showed changes such as mild epidermal hyperplasia with prominent basal melanin, however, without the typical papillomatosis seen in AN of the flexures. We document an increased prevalence of obesity and insulin resistance in patients presenting with FAN and its presentations in addition to the classical description. We propose that FAN can be considered a cutaneous marker of insulin resistance and that HOMA2 IR can serve as a parameter of insulin resistance in such cases.

  7. A descriptive study of facial acanthosis nigricans and its association with body mass index, waist circumference and insulin resistance using HOMA2 IR

    PubMed Central

    Verma, Shyam; Vasani, Resham; Joshi, Rajiv; Phiske, Meghana; Punjabi, Pritesh; Toprani, Tushar

    2016-01-01

    Introduction: The term facial acanthosis nigricans (FAN) lacks definition of precise clinical and histopathological features. We present a descriptive study of patients with FAN to define pigmentary patterns and estimate the prevalence of obesity and insulin resistance in these cases. Materials and Methods: It is a prospective study that included all patients with classical AN of the neck and/or other areas with facial acanthosis nigricans described as brown-to-black macular pigmentation with blurred ill-defined margins, found on the zygomatic and malar areas. The body mass index (BMI) and waist circumference (WC) of the included patients were used as parameters of obesity. Homeostatic Model of Assessment of Insulin Resistance (HOMA2 IR) was used as a parameter to evaluate insulin resistance. Histopathological features of the 6 skin biopsies that were possible were reviewed. Results: Among the 102 included individuals, the patterns of facial pigmentation seen in addition to the classic pattern involving zygomatic and malar areas were a hyperpigmented band on the forehead in 59.80%, periorbital darkening in 17.64%, perioral darkening in 12.74%, and generalized darkening in 9.8% of cases. 85.29% of the males and 100% of the females were found to be obese. Varying degrees of insulin resistance was noted in 82.34% of the individuals. Six biopsies available for evaluation showed changes such as mild epidermal hyperplasia with prominent basal melanin, however, without the typical papillomatosis seen in AN of the flexures. Conclusion: We document an increased prevalence of obesity and insulin resistance in patients presenting with FAN and its presentations in addition to the classical description. We propose that FAN can be considered a cutaneous marker of insulin resistance and that HOMA2 IR can serve as a parameter of insulin resistance in such cases. PMID:27990384

  8. Reduced Socs3 expression in adipose tissue protects female mice against obesity-induced insulin resistance

    PubMed Central

    Palanivel, R.; Fullerton, M. D.; Galic, S.; Honeyman, J.; Hewitt, K. A.; Jorgensen, S. B.; Steinberg, G. R.

    2017-01-01

    Aims/hypothesis Inflammation in obesity increases the levels of the suppressor of cytokine signalling-3 (SOCS3) protein in adipose tissue, but the physiological importance of this protein in regulating whole-body insulin sensitivity in obesity is not known. Methods We generated Socs3 floxed (wild-type, WT) and Socs3 aP2 (also known as Fabp4)-Cre null (Socs3 AKO) mice. Mice were maintained on either a regular chow or a high-fat diet (HFD) for 16 weeks during which time body mass, adiposity, glucose homeostasis and insulin sensitivity were assessed. Results The HFD increased SOCS3 levels in adipose tissue of WT but not Socs3 AKO mice. WT and Socs3 AKO mice had similar body mass and adiposity, assessed using computed tomography (CT) imaging, irrespective of diet or sex. On a control chow diet there were no differences in insulin sensitivity or glucose tolerance. When fed a HFD, female but not male Socs3 AKO mice had improved glucose tolerance as well as lower fasting glucose and insulin levels compared with WT littermates. Hyperinsulinaemic–euglycaemic clamps and positron emission tomography (PET) imaging demonstrated that improved insulin sensitivity was due to elevated adipose tissue glucose uptake. Increased insulin-stimulated glucose uptake in adipose tissue was associated with enhanced levels and activating phosphorylation of insulin receptor substrate-1 (IRS1). Conclusions/interpretation These data demonstrate that inhibiting SOCS3 production in adipose tissue of female mice is effective for improving whole-body insulin sensitivity in obesity. PMID:22872213

  9. LKB1-AMPK signaling in muscle from obese insulin-resistant Zucker rats and effects of training.

    PubMed

    Sriwijitkamol, Apiradee; Ivy, John L; Christ-Roberts, Christine; DeFronzo, Ralph A; Mandarino, Lawrence J; Musi, Nicolas

    2006-05-01

    AMPK is a key regulator of fat and carbohydrate metabolism. It has been postulated that defects in AMPK signaling could be responsible for some of the metabolic abnormalities of type 2 diabetes. In this study, we examined whether insulin-resistant obese Zucker rats have abnormalities in the AMPK pathway. We compared AMPK and ACC phosphorylation and the protein content of the upstream AMPK kinase LKB1 and the AMPK-regulated transcriptional coactivator PPARgamma coactivator-1 (PGC-1) in gastrocnemius of sedentary obese Zucker rats and sedentary lean Zucker rats. We also examined whether 7 wk of exercise training on a treadmill reversed abnormalities in the AMPK pathway in obese Zucker rats. In the obese rats, AMPK phosphorylation was reduced by 45% compared with lean rats. Protein expression of the AMPK kinase LKB1 was also reduced in the muscle from obese rats by 43%. In obese rats, phosphorylation of ACC and protein expression of PGC-1alpha, two AMPK-regulated proteins, tended to be reduced by 50 (P = 0.07) and 35% (P = 0.1), respectively. There were no differences in AMPKalpha1, -alpha2, -beta1, -beta2, and -gamma3 protein content between lean and obese rats. Training caused a 1.5-fold increase in AMPKalpha1 protein content in the obese rats, although there was no effect of training on AMPK phosphorylation and the other AMPK isoforms. Furthermore, training also significantly increased LKB1 and PGC-1alpha protein content 2.8- and 2.5-fold, respectively, in the obese rats. LKB1 protein strongly correlated with hexokinase II activity (r = 0.75, P = 0.001), citrate synthase activity (r = 0.54, P = 0.02), and PGC-1alpha protein content (r = 0.81, P < 0.001). In summary, obese insulin-resistant rodents have abnormalities in the LKB1-AMPK-PGC-1 pathway in muscle, and these abnormalities can be restored by training.

  10. Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance.

    PubMed

    Lotta, Luca A; Gulati, Pawan; Day, Felix R; Payne, Felicity; Ongen, Halit; van de Bunt, Martijn; Gaulton, Kyle J; Eicher, John D; Sharp, Stephen J; Luan, Jian'an; De Lucia Rolfe, Emanuella; Stewart, Isobel D; Wheeler, Eleanor; Willems, Sara M; Adams, Claire; Yaghootkar, Hanieh; Forouhi, Nita G; Khaw, Kay-Tee; Johnson, Andrew D; Semple, Robert K; Frayling, Timothy; Perry, John R B; Dermitzakis, Emmanouil; McCarthy, Mark I; Barroso, Inês; Wareham, Nicholas J; Savage, David B; Langenberg, Claudia; O'Rahilly, Stephen; Scott, Robert A

    2017-01-01

    Insulin resistance is a key mediator of obesity-related cardiometabolic disease, yet the mechanisms underlying this link remain obscure. Using an integrative genomic approach, we identify 53 genomic regions associated with insulin resistance phenotypes (higher fasting insulin levels adjusted for BMI, lower HDL cholesterol levels and higher triglyceride levels) and provide evidence that their link with higher cardiometabolic risk is underpinned by an association with lower adipose mass in peripheral compartments. Using these 53 loci, we show a polygenic contribution to familial partial lipodystrophy type 1, a severe form of insulin resistance, and highlight shared molecular mechanisms in common/mild and rare/severe insulin resistance. Population-level genetic analyses combined with experiments in cellular models implicate CCDC92, DNAH10 and L3MBTL3 as previously unrecognized molecules influencing adipocyte differentiation. Our findings support the notion that limited storage capacity of peripheral adipose tissue is an important etiological component in insulin-resistant cardiometabolic disease and highlight genes and mechanisms underpinning this link.

  11. Evaluation of the association of vitamin D deficiency with gonadotropins and sex hormone in obese and non-obese women with polycystic ovary syndrome.

    PubMed

    Velija-Ašimi, Zelija

    2014-02-01

    To evaluate the association of vitamin D (VD) deficiency with gonadotropins and sex hormone in obese and non-obese women with polycystic ovary syndrome (PCOS). Of the total of 140 women, thirty obese and thirty nonobese, aged 20-40 years, were included in the study. Inclusion criteria were the women with normal level of thyroid-stimulating hormone (TSH), prolactin (PRL), parathyroid hormone (PTH), and calcium, and those who had not received any medication or VD supplementation within the last 6 months. Serum 25- hydroxyvitamin D (25(OH)D), C-reactive protein (CRP), lipid profile, fasting serum glucose, basal insulin, homeostasis model analysis of insulin resistance (HOMA-IR) index, follicle-stimulating hormone (FSH), luteinizing hormone (LH), oestrogen, total testosterone, dehidroepiandrostendion-sulphat (DHEA-S), androstendione, and sex hormone binding globulin (SHBG) were determined at follicular phase. Body mass index (BMI), weight, waist, lipids, and CRP were significantly higher in obese than in non-obese PCOS women (p=0.000). Meanwhile, insulin and HOMA-IR were also higher in the obese PCOS (p less than 0.000), and so was the fasting glucose (p=0.004). Furthermore, obese PCOS showed significantly higher level of LH (p=0.012), but lower level of progesterone (p=0.001) and androstendione (p=0.006) than in non-obese PCOS. In total 68% of PCOS women had VD deficiency but without significant difference among groups according to BMI. There was no association of VD deficiency with gonadotropins and sex hormones except SHBG. Insulin resistance was a better independent risk factor for the presence of vitamin D deficiency than SHBG. The insulin resistance and vitamin D deficiency significantly predicted the obesity risk in PCOS women.

  12. Polycystic ovary morphology is associated with insulin resistance in women with polycystic ovary syndrome.

    PubMed

    Hong, So-Hyeon; Sung, Yeon-Ah; Hong, Young Sun; Jeong, Kyungah; Chung, Hyewon; Lee, Hyejin

    2017-10-01

    Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by chronic anovulation, hyperandrogenism, polycystic ovary morphology (PCOM) and metabolic disturbances including insulin resistance and type 2 diabetes mellitus. Although insulin resistance could be associated with PCOM, recent studies have shown controversial results. The aim of this study was to determine the relationship between PCOM and insulin resistance. This was a cross-sectional clinical study. A total of 679 women with PCOS who were diagnosed using the National Institute of Child Health and Human Disease (NICHD) criteria and 272 control women were analysed. We measured fasting glucose and insulin levels, 75 g oral glucose tolerance test-derived glucose and insulin levels, testosterone levels, ovarian volume and follicle number. Polycystic ovary morphology was described in 543 women (80.0%) with PCOS. Women with PCOS had significantly higher 2 hours postload glucose, fasting and 2 hours postload insulin levels, ovarian volume, ovarian follicle numbers and lower insulin sensitivity compared with those of the controls (all P<.01). In women with PCOS, ovarian volume and ovarian follicle number were negatively associated with the quantitative insulin sensitivity check index after adjusting for age, body mass index and total testosterone; however, this association was not observed in the controls. In the logistic regression analysis, increased ovarian follicle number was associated with decreased insulin sensitivity in women with PCOS. In PCOS, enlarged ovarian volume and follicle excess were associated with insulin resistance, and the number of ovarian follicles could be a predictor of insulin resistance. © 2017 John Wiley & Sons Ltd.

  13. Associations of prenatal growth with metabolic syndrome, insulin resistance, and nutritional status in Chilean children.

    PubMed

    Mardones, Francisco; Arnaiz, Pilar; Pacheco, Paz; Dominguez, Angelica; Villarroel, Luis; Eriksson, Johan G; Barja, Salesa; Farías, Marcelo; Castillo, Oscar

    2014-01-01

    The association of prenatal growth with nutritional status, metabolic syndrome (MS), and insulin resistance (IR) was studied in school-age children. A retrospective cohort study was designed linking present data of children with perinatal records. 3325 subjects were enrolled. Anthropometry, blood pressure (BP), and pubertal status were assessed. Blood lipids, glucose, and insulin were measured. Linear associations were assessed using the Cochran-Armitage test. Odds ratios and nonlinear associations were computed. 3290 children (52% females, mean age of 11.4 ± 1 years) were analyzed. Prevalence of obesity, stunting, MS, and IR was 16.0%, 3.6%, 7.3%, and 25.5%, respectively. The strongest positive association was between birth weight (BW) and obesity (OR 2.97 (95% CI 2.01-4.40) at BW ≥ 4,000 g compared to BW 2,500-2,999). The strongest inverse association was between birth length (BL) and stunting (OR 8.70 (95% CI 3.66-20.67) at BL < 48 cm compared to BL 52-53 cm). A U-shaped association between BL and BP ≥ 90th percentile was observed. Significant ORs were also found for MS and IR. Adjustments for present fat mass increased or maintained the most prenatal growth influences. Prenatal growth influences MS, IR, and nutritional status. Prenatal growth was more important than present body composition in determining these outcomes.

  14. Prevalence and predictors of overweight and insulin resistance in offspring of mothers with gestational diabetes mellitus.

    PubMed

    Boerschmann, Heike; Pflüger, Maren; Henneberger, Lydia; Ziegler, Anette-G; Hummel, Sandra

    2010-08-01

    Gestational diabetes mellitus (GDM) is associated with high birth weight in the offspring. This may lead to overweight and insulin resistance during childhood. The aim of the study was to assess the impact of GDM on overweight risk and insulin resistance in offspring. BMI measurements were collected at age 2, 8, and 11 years from 232 offspring of mothers with GDM (OGDM) and compared with those from 757 offspring of mothers with type 1 diabetes (OT1D) and 431 offspring of nondiabetic mothers (ONDM) born between 1989 and 2000. Insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR]) was determined at age 8 and 11 years in 751 children (74 OGDM). Overweight was defined as BMI percentile >or=90; insulin resistance was defined by HOMA-IR. Overweight prevalence was increased in OGDM compared with OT1D and to ONDM throughout childhood (age 11 years 31.1, 15.8, and 15.5%; P = 0.005). Maternal obesity was an important predictor of overweight risk in children (age 11 years odds ratio 7.0 [95% CI 1.8-27.7]; P = 0.006); birth size and maternal smoking during pregnancy were inconsistently associated with and treatment of GDM during pregnancy did not affect overweight risk. HOMA-IR was increased in OGDM compared with offspring of ONDM mothers (P = 0.01, adjusted for sex and age) and was associated with the child's BMI (P = 0.004). Overweight and insulin resistance in children is increased in OGDM compared with OT1D or ONDM. The finding that overweight risk is associated mainly with maternal obesity suggests that familial predisposition contributes to childhood growth in these offspring.

  15. Sleep Architecture and Glucose and Insulin Homeostasis in Obese Adolescents

    PubMed Central

    Koren, Dorit; Levitt Katz, Lorraine E.; Brar, Preneet C.; Gallagher, Paul R.; Berkowitz, Robert I.; Brooks, Lee J.

    2011-01-01

    OBJECTIVE Sleep deprivation is associated with increased risk of adult type 2 diabetes mellitus (T2DM). It is uncertain whether sleep deprivation and/or altered sleep architecture affects glycemic regulation or insulin sensitivity or secretion. We hypothesized that in obese adolescents, sleep disturbances would associate with altered glucose and insulin homeostasis. RESEARCH DESIGN AND METHODS This cross-sectional observational study of 62 obese adolescents took place at the Clinical and Translational Research Center and Sleep Laboratory in a tertiary care children’s hospital. Subjects underwent oral glucose tolerance test (OGTT), anthropometric measurements, overnight polysomnography, and frequently sampled intravenous glucose tolerance test (FSIGT). Hemoglobin A1c (HbA1c) and serial insulin and glucose levels were obtained, indices of insulin sensitivity and secretion were calculated, and sleep architecture was assessed. Correlation and regression analyses were performed to assess the association of total sleep and sleep stages with measures of insulin and glucose homeostasis, adjusted for confounding variables. RESULTS We found significant U-shaped (quadratic) associations between sleep duration and both HbA1c and serial glucose levels on OGTT and positive associations between slow-wave sleep (N3) duration and insulin secretory measures, independent of degree of obesity, pubertal stage, sex, and obstructive sleep apnea measures. CONCLUSIONS Insufficient and excessive sleep was associated with short-term and long-term hyperglycemia in our obese adolescents. Decreased N3 was associated with decreased insulin secretion. These effects may be related, with reduced insulin secretory capacity leading to hyperglycemia. We speculate that optimizing sleep may stave off the development of T2DM in obese adolescents. PMID:21933909

  16. Using Metabolomic Profiles as Biomarkers for Insulin Resistance in Childhood Obesity: A Systematic Review.

    PubMed

    Zhao, Xue; Gang, Xiaokun; Liu, Yujia; Sun, Chenglin; Han, Qing; Wang, Guixia

    2016-01-01

    A growing body of evidence has shown the intimate relationship between metabolomic profiles and insulin resistance (IR) in obese adults, while little is known about childhood obesity. In this review, we searched available papers addressing metabolomic profiles and IR in obese children from inception to February 2016 on MEDLINE, Web of Science, the Cochrane Library, ClinicalTrials.gov, and EMASE. HOMA-IR was applied as surrogate markers of IR and related metabolic disorders at both baseline and follow-up. To minimize selection bias, two investigators independently completed this work. After critical selection, 10 studies (including 2,673 participants) were eligible and evaluated by using QUADOMICS for quality assessment. Six of the 10 studies were classified as "high quality." Then we generated all the metabolites identified in each study and found amino acid metabolism and lipid metabolism were the main affected metabolic pathways in obese children. Among identified metabolites, branched-chain amino acids (BCAAs), aromatic amino acids (AAAs), and acylcarnitines were reported to be associated with IR as biomarkers most frequently. Additionally, BCAAs and tyrosine seemed to be relevant to future metabolic risk in the long-term follow-up cohorts, emphasizing the importance of early diagnosis and prevention strategy. Because of limited scale and design heterogeneity of existing studies, future studies might focus on validating above findings in more large-scale and longitudinal studies with elaborate design.

  17. Effect of Common Genetic Variants of Growth Arrest-Specific 6 Gene on Insulin Resistance, Obesity and Type 2 Diabetes in an Asian Population.

    PubMed

    Hsieh, Chang-Hsun; Chung, Ren-Hua; Lee, Wen-Jane; Lin, Ming-Wei; Chuang, Lee-Ming; Quertermous, Thomas; Assimes, Themistocles; Hung, Yi-Jen; Yu, Ya-Wen

    2015-01-01

    Growth arrest-specific 6 (Gas6), a vitamin K-dependent protein, has been implicated in systemic inflammation, obesity, and insulin resistance (IR). Data from recent studies suggest that polymorphisms in the Gas6 gene are associated with cardiovascular disorders and type 2 diabetes (T2D). However, the association of Gas6 gene variants with obesity, IR, and T2D development has not been explored. Four common single nucleotide polymorphisms (SNPs) in the Gas6 gene were genotyped in 984 participants from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family cohort. An insulin suppression test was performed to determine IR based on steady-state plasma glucose (SSPG). Associations between IR indices and obesity, and SNP genotypes, based on previously-reported data for this cohort (Phase I), were analyzed. In the present follow-up study (Phase II), the effects of gene variants of Gas6 on the progression to T2D were explored in individuals who were free of T2D in Phase I. The mean follow-up period for Phase II was 5.7 years. The mean age of the study population in Phase I was 49.5 years and 16.7% of individuals developed T2D during follow-up. After adjusting for covariates, three SNPs (rs8191973, rs8197974, and rs7323932) were found to be associated with SSPG levels (p = 0.007, p = 0.03, and p = 0.011, respectively). This association remained significant after multiple testing and showed a significant interaction with physical activity for SNP rs8191973. However, no other significant correlations were observed between Gas6 polymorphisms and other indices of IR or obesity. A specific haplotype, AACG (from rs8191974, rs7323932, rs7331124, and rs8191973), was positively associated with SSPG levels (p = 0.0098). None of the polymorphisms were associated with an increased risk of T2D development. Our results suggest that Gas6 gene variants are associated with IR, although their effects on subsequent progression to T2D were minimal in this

  18. [Research advances in association between childhood obesity and gut microbiota].

    PubMed

    Gao, Xiao-Lin; Wan, Chao-Min

    2017-03-01

    In recent years, more and more studies have noted the close association between gut microbiota and the development and progression of obesity. Gut microbiota may act on obesity by increasing energy intake, affecting the secretion of intestinal hormones, inducing chronic systemic inflammation, and producing insulin resistance. This article reviews the association between childhood obesity and gut microbiota, as well as possible mechanisms, in an attempt to provide a reference for the etiology, prevention and treatment of childhood obesity.

  19. Parity and increased risk of insulin resistance in postmenopausal women: the 2010 Korean National Health and Nutrition Examination Survey.

    PubMed

    Kim, Jin Hwi; Lee, Sung Jong

    2017-07-01

    The objective of this study was to assess the association between parity and insulin resistance in nondiabetic, postmenopausal women. This cross-sectional study was conducted using data from the 2010 Korean National Health and Nutrition Examination Survey administered by the Korean Ministry of Health and Welfare. A total of 1,243 nondiabetic postmenopausal women were included in this study and subdivided into three groups according to parity (1-2, 3-4, and ≥5 live births). Insulin resistance was measured using the homeostasis model assessment of insulin resistance (HOMA-IR) index. The relationship between parity and insulin resistance was investigated using analysis of covariance. HOMA-IR showed a positive relationship with parity. Mean HOMA-IR (geometric mean and 95% CI) increased according to increasing parity group (1-2, 3-4, and ≥5 live births) after adjustment for age, smoking, alcohol consumption, exercise, education, income, and body mass index as follows: 2.1 (2.0-2.2) < 2.2 (2.1-2.3) < 2.5 (2.2-2.8) (P = 0.040 and P for trend = 0.012). In addition, this positive association was more apparent when insulin resistance was accompanied by obesity. The mean parity of the obese and insulin-resistant group was significantly higher than that of the nonobese insulin-sensitive group (3.6 ± 0.1 vs 3.2 ± 0.1, P = 0.047). Our study provides the first evidence that parity is significantly associated with insulin resistance in nondiabetic postmenopausal women. Further prospective longitudinal studies are needed to confirm the impact of parity on insulin resistance.

  20. Sunflower Oil Supplementation Has Proinflammatory Effects and Does Not Reverse Insulin Resistance in Obesity Induced by High-Fat Diet in C57BL/6 Mice

    PubMed Central

    Masi, Laureane Nunes; Martins, Amanda Roque; Neto, José César Rosa; do Amaral, Cátia Lira; Crisma, Amanda Rabello; Vinolo, Marco Aurélio Ramirez; de Lima Júnior, Edson Alves; Hirabara, Sandro Massao; Curi, Rui

    2012-01-01

    High consumption of polyunsaturated fatty acids, such as sunflower oil has been associated to beneficial effects in plasma lipid profile, but its role on inflammation and insulin resistance is not fully elucidated yet. We evaluated the effect of sunflower oil supplementation on inflammatory state and insulin resistance condition in HFD-induced obese mice. C57BL/6 male mice (8 weeks) were divided in four groups: (a) control diet (CD), (b) HFD, (c) CD supplemented with n-6 (CD + n-6), and (d) HFD supplemented with n-6 (HFD + n-6). CD + n-6 and HFD + n-6 were supplemented with sunflower oil by oral gavage at 2 g/Kg of body weight, three times per week. CD and HFD were supplemented with water instead at the same dose. HFD induced whole and muscle-specific insulin resistance associated with increased inflammatory markers in insulin-sensitive tissues and macrophage cells. Sunflower oil supplementation was not efficient in preventing or reducing these parameters. In addition, the supplementation increased pro-inflammatory cytokine production by macrophages and tissues. Lipid profile, on the other hand, was improved with the sunflower oil supplementation in animals fed HFD. In conclusion, sunflower oil supplementation improves lipid profile, but it does not prevent or attenuate insulin resistance and inflammation induced by HFD in C57BL/6 mice. PMID:22988427