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Sample records for insulin resistant status

  1. Insulin and Insulin Resistance

    PubMed Central

    2005-01-01

    As obesity and diabetes reach epidemic proportions in the developed world, the role of insulin resistance and its consequences are gaining prominence. Understanding the role of insulin in wide-ranging physiological processes and the influences on its synthesis and secretion, alongside its actions from the molecular to the whole body level, has significant implications for much chronic disease seen in Westernised populations today. This review provides an overview of insulin, its history, structure, synthesis, secretion, actions and interactions followed by a discussion of insulin resistance and its associated clinical manifestations. Specific areas of focus include the actions of insulin and manifestations of insulin resistance in specific organs and tissues, physiological, environmental and pharmacological influences on insulin action and insulin resistance as well as clinical syndromes associated with insulin resistance. Clinical and functional measures of insulin resistance are also covered. Despite our incomplete understanding of the complex biological mechanisms of insulin action and insulin resistance, we need to consider the dramatic social changes of the past century with respect to physical activity, diet, work, socialisation and sleep patterns. Rapid globalisation, urbanisation and industrialisation have spawned epidemics of obesity, diabetes and their attendant co-morbidities, as physical inactivity and dietary imbalance unmask latent predisposing genetic traits. PMID:16278749

  2. Adherence to a low-fat vs. low-carbohydrate diet differs by insulin resistance status.

    PubMed

    McClain, A D; Otten, J J; Hekler, E B; Gardner, C D

    2013-01-01

    Previous research shows diminished weight loss success in insulin-resistant (IR) women assigned to a low-fat (LF) diet compared to those assigned to a low-carbohydrate (LC) diet. These secondary analyses examined the relationship between insulin-resistance status and dietary adherence to either a LF-diet or LC-diet among 81 free-living, overweight/obese women [age = 41.9 ± 5.7 years; body mass index (BMI) = 32.6 ± 3.6 kg/m(2)]. This study found differential adherence by insulin-resistance status only to a LF-diet, not a LC-diet. IR participants were less likely to adhere and lose weight on a LF-diet compared to insulin-sensitive (IS) participants assigned to the same diet. There were no significant differences between IR and IS participants assigned to LC-diet in relative adherence or weight loss. These results suggest that insulin resistance status may affect dietary adherence to weight loss diets, resulting in higher recidivism and diminished weight loss success of IR participants advised to follow LF-diets for weight loss. © 2012 Blackwell Publishing Ltd.

  3. Vitamin D status is not related to insulin resistance in different phenotypes of moderate obesity.

    PubMed

    Al Masri, Manal; Romain, Ahmed Jerome; Boegner, Catherine; Maimoun, Laurent; Mariano-Goulart, Denis; Attalin, Vincent; Leprieur, Elodie; Picandet, Marion; Avignon, Antoine; Sultan, Ariane

    2017-04-01

    Low plasma 25-hydroxy-vitamin D (25OHD) and high levels of parathyroid hormone (PTH) are associated with obesity and could play a role in the occurrence of complications such as insulin resistance. The objective of the study was to evaluate whether the relationship between 25OHD status and phosphocalcic parameters differs between metabolically healthy obese (MHO) and insulin-resistant obese (IRO). This cross-sectional study included 158 consecutive adults (121 females) with obesity (body mass index (BMI) 35.15 ± 2.8 kg/m(2)), aged 43.21 ± 13.6 years. Serum 25OHD, calcemia, phosphatemia, PTH, plasma lipids, fasting plasma glucose, insulin levels, and body composition were measured. Participants were classified as MHO (n = 65) or IRO (n = 93) based on homeostatic model assessment insulin-resistance value. IRO patients had a higher BMI (p = 0.001), waist circumference (p = 0.03), and trunk fat mass (p = 0.007) than MHO patients. Mean HbA1c (p = 0.03), triglycerides (p = 0.02), and hsCRP (p = 0.04) plasmatic levels were increased in the IRO group. No between-group difference was found on 25OHD, PTH, calcium, or phosphorus plasmatic levels. Only age-predicted 25OHD levels were identified among IRO participants, whereas no factors were identified in MHO. No predictive factors of PTH plasmatic level were identified in the IRO and MHO groups. Although MHO and IRO patients have different metabolic profiles, we did not detect any difference regarding either 25OHD or PTH. Insulin resistance was not a predictive factor of vitamin D status. Our results confirm the absence of link between vitamin D status and insulin resistance in moderate obesity.

  4. Evaluation of 25(OH) Vitamin D3 with Reference to Magnesium Status and Insulin Resistance in T2DM

    PubMed Central

    Gandhe, Mahendra Bhauraoji; Jain, Keerthi; Gandhe, Swapnali Mahendra

    2013-01-01

    Introduction: Calcium is a recognized second messenger implicated in insulin secretion. Vitamin D (1,25-dihydroxycholecalciferol, Calcitriol) plays a role in calcium metabolism. This explains the indirect role of Vitamin D in insulin secretion and insulin sensitivity. Hence, low Vitamin D levels are implicated in decreased insulin secretion and increased insulin resistance. In this study, we tried to find out the probable association of Vitamin D3, calcium and magnesium with reference to insulin resistance in type 2 diabetes mellitus (T2DM) cases. It is well documented that measurement of circulating 25-Hydroxycholecalciferol {25 (OH)Vitamin D3} is a marker of total Vitamin D status. Methodology: We measured 25(OH) Vitamin D3 levels in thirty T2DM subjects with thirty age and sex matched healthy controls. We estimated Vitamin D status, calcium and magnesium levels in the light of insulin resistance. Insulin resistance was measured by homeostasis model assessment of insulin resistance (HOMA-IR). Results: Twenty five (OH) Vitamin-D3 level was significantly low among T2DM cases (12.29+2.32ng/ml) in comparison to healthy controls (19.55+0.50ng/ml) (p<0.01). The levels of calcium and magnesium were also significantly low in T2DM cases as compared to healthy controls (p<0.01). There was significant negative correlation between Vitamin D status and insulin levels, and insulin resistance (p<0.01). Implication: A significant negative correlation between Vitamin D status and insulin levels suggest that the supplementation of Vitamin D has the potential to increase insulin sensitivity and lower the risk of developing type 2 diabetes mellitus. PMID:24392366

  5. Adiponectin in children on peritoneal dialysis: relationship to insulin resistance and nutritional status.

    PubMed

    Kamariski, Mariana; Biscardi, Mónica; Cestino, Laura; Miatello, Roberto; Guntsche, Enrique; Valles, Patricia G

    2009-01-01

    To study whether adiponectin and resistin serum concentrations in children on peritoneal dialysis (PD) were related to insulin resistance (IR) and anthropometric parameters of nutritional status, 11 PD patients, 9 chronic kidney disease (CKD) patients and 10 healthy children were studied. Glucose and insulin were measured during the oral glucose tolerance test. Levels of adiponectin and resistin were evaluated by ELISA, insulin by RIA. In CKD patients, higher homeostasis model assessment-insulin resistance (HOMA-IR), fasting and 2-hour serum insulin levels were shown compared to control and to PD patients. Body mass index (BMI) and body fat content were severely decreased while serum adiponectin levels were significantly higher in PD patients relative to controls. No differences among groups were shown in resistin levels. On regression modeling, inverse independent associations were observed between adiponectin with percentile BMI, weight and height z-score, and with body fat content. In contrast, no relationship was found between adiponectin and IR parameters. In multiple regression analysis, adiponectin was negatively correlated with BMI. A negative association of adiponectin and resistin with glomerular filtration rate was also shown. A role for adiponectin in terms of its association with clinical wasting parameters in PD pediatric patients might be suggested.

  6. Insulin signaling and insulin resistance.

    PubMed

    Beale, Elmus G

    2013-01-01

    Insulin resistance or its sequelae may be the common etiology of maladies associated with metabolic syndrome (eg, hypertension, type 2 diabetes, atherosclerosis, heart attack, stroke, and kidney failure). It is thus important to understand those factors that affect insulin sensitivity. This review stems from the surprising discovery that interference with angiotensin signaling improves insulin sensitivity, and it provides a general overview of insulin action and factors that control insulin sensitivity.

  7. Iron and Obesity Status-Associated Insulin Resistance Influence Circulating Fibroblast-Growth Factor-23 Concentrations

    PubMed Central

    Fernández-Real, José Manuel; Puig, Josep; Serrano, Marta; Sabater, Mónica; Rubió, Antoni; Moreno-Navarrete, José María; Fontan, Marina; Casamitjana, Roser; Xifra, Gemma; Ortega, Francisco José; Salvador, Javier; Frühbeck, Gema; Ricart, Wifredo

    2013-01-01

    Fibroblast growth factor 23 (FGF-23) is known to be produced by the bone and linked to metabolic risk. We aimed to explore circulating FGF-23 in association with fatness and insulin sensitivity, atherosclerosis and bone mineral density (BMD). Circulating intact FGF-23 (iFGF-23) and C-terminal (CtFGF-23) concentrations (ELISA) were measured in 133 middle aged men from the general population in association with insulin sensitivity (Cohort 1); and in association with fat mass and bone mineral density (DEXA) and atherosclerosis (intima media thickness, IMT) in 78 subjects (52 women) with a wide range of adiposity (Cohort 2). Circulating iFGF-23 was also measured before and after weight loss. In all subjects as a whole, serum intact and C-terminal concentrations were linearly and positively associated with BMI. In cohort 1, both serum iFGF-23 and CtFGF-23 concentrations increased with insulin resistance. Serum creatinine contributed to iFGF-23 variance, while serum ferritin and insulin sensitivity (but not BMI, age or serum creatinine) contributed to 17% of CtFGF-23 variance. In cohort 2, CtFGF-23 levels were higher in women vs. men, and increased with BMI, fat mass, fasting and post-load serum glucose, insulin, HOMA-IR and PTH, being negatively associated with circulating vitamin D and ferritin levels. The associations of CtFGF-23 with bone density in the radius, lumbar spine and carotid IMT were no longer significant after controlling for BMI. Weight loss led to decreased iFGF-23 concentrations. In summary, the associations of circulating FGF-23 concentration with parameters of glucose metabolism, bone density and atherosclerosis are dependent on iron and obesity status-associated insulin resistance. PMID:23555610

  8. Iron and obesity status-associated insulin resistance influence circulating fibroblast-growth factor-23 concentrations.

    PubMed

    Fernández-Real, José Manuel; Puig, Josep; Serrano, Marta; Sabater, Mónica; Rubió, Antoni; Moreno-Navarrete, José María; Fontan, Marina; Casamitjana, Roser; Xifra, Gemma; Ortega, Francisco José; Salvador, Javier; Frühbeck, Gema; Ricart, Wifredo

    2013-01-01

    Fibroblast growth factor 23 (FGF-23) is known to be produced by the bone and linked to metabolic risk. We aimed to explore circulating FGF-23 in association with fatness and insulin sensitivity, atherosclerosis and bone mineral density (BMD). Circulating intact FGF-23 (iFGF-23) and C-terminal (CtFGF-23) concentrations (ELISA) were measured in 133 middle aged men from the general population in association with insulin sensitivity (Cohort 1); and in association with fat mass and bone mineral density (DEXA) and atherosclerosis (intima media thickness, IMT) in 78 subjects (52 women) with a wide range of adiposity (Cohort 2). Circulating iFGF-23 was also measured before and after weight loss. In all subjects as a whole, serum intact and C-terminal concentrations were linearly and positively associated with BMI. In cohort 1, both serum iFGF-23 and CtFGF-23 concentrations increased with insulin resistance. Serum creatinine contributed to iFGF-23 variance, while serum ferritin and insulin sensitivity (but not BMI, age or serum creatinine) contributed to 17% of CtFGF-23 variance. In cohort 2, CtFGF-23 levels were higher in women vs. men, and increased with BMI, fat mass, fasting and post-load serum glucose, insulin, HOMA-IR and PTH, being negatively associated with circulating vitamin D and ferritin levels. The associations of CtFGF-23 with bone density in the radius, lumbar spine and carotid IMT were no longer significant after controlling for BMI. Weight loss led to decreased iFGF-23 concentrations. In summary, the associations of circulating FGF-23 concentration with parameters of glucose metabolism, bone density and atherosclerosis are dependent on iron and obesity status-associated insulin resistance.

  9. [Insulin signaling and insulin resistance].

    PubMed

    Ferré, Pascal

    2007-01-01

    Insulin controls carbohydrate and lipid metabolism. Among other things, it stimulates glucose storage as glycogen and lipid storage as triglycerides. Insulin acts through a membrane receptor which is a tyrosine kinase. When activated by insulin binding, the tyrosine kinase will recruit and phosphorylate intracellular substrates called IRS (insulin receptor substrate). Phosphorylated IRS will be used as docking sites for proteins which will transmit the insulin signal through several systems (e.g. PI3-kinase). The insulin resistance which is concomitant with type 2 diabetes and obesity is linked to an increased intracellular availability of fatty acids which are precursors of lipid mediators inducing a decreased efficiency of insulin signal transmission. Therapies aimed at improving insulin sensitivity could then target proteins involved in the regulation of intacellular fatty acid availibility.

  10. 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.

  11. Associations of Prenatal Growth with Metabolic Syndrome, Insulin Resistance, and Nutritional Status in Chilean Children

    PubMed Central

    Mardones, Francisco; Arnaiz, Pilar; Pacheco, Paz; Dominguez, Angelica; Villarroel, Luis; Eriksson, Johan G.; Barja, Salesa; Farías, Marcelo; Castillo, Oscar

    2014-01-01

    Introduction. The association of prenatal growth with nutritional status, metabolic syndrome (MS), and insulin resistance (IR) was studied in school-age children. Methods. 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. Results. 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. Conclusions. Prenatal growth influences MS, IR, and nutritional status. Prenatal growth was more important than present body composition in determining these outcomes. PMID:25025054

  12. All about Insulin Resistance

    MedlinePlus

    Toolkit No. 2 All About Insulin Resistance Insulin resistance is a condition that raises your risk for type 2 diabetes and heart disease. ... Diabetes Association, Inc. 1/15 Toolkit No. 2: All About Insulin Resistance continued J Order the smallest ...

  13. Low maternal vitamin B-12 status is associated with offspring insulin resistance regardless of antenatal micronutrient supplementation in rural Nepal.

    PubMed

    Stewart, Christine P; Christian, Parul; Schulze, Kerry J; Arguello, Margia; LeClerq, Steven C; Khatry, Subarna K; West, Keith P

    2011-10-01

    Questions have been raised about potentially negative effects of antenatal folic acid use in populations with a high prevalence of vitamin B-12 deficiency. Our objective was to examine the association between maternal folate and vitamin B-12 status in pregnancy on offspring insulin resistance and examine whether the effects of maternal micronutrient supplementation varied by baseline maternal folate and/or vitamin B-12 status. Pregnant women were cluster randomized to receive daily supplements containing vitamin A alone or with folic acid, folic acid+iron, folic acid+iron+zinc, or a multiple micronutrient. In a subsample (n = 1132), micronutrient status biomarkers were analyzed at baseline and late pregnancy. Children born to the women who participated in the trial were visited at 6-8 y of age. Fasting plasma glucose and insulin were used to estimate insulin resistance using the homeostasis model assessment (HOMA-IR). Children whose mothers were deficient in vitamin B-12 (<148 pmol/L, 27%) during early pregnancy had a 26.7% increase in HOMA-IR (P = 0.02), but there was no association with maternal folate status. Among children born to women who were vitamin B-12 deficient at baseline, the percent difference in HOMA-IR compared to the control group was 15.1% (95% CI: -35.9, 106.4), 4.9% (-41.6, 88.5), 3.3% (-38.4, 73.5), and 18.1% (-29.0, 96.7) in the folic acid, folic acid-iron, folic acid-iron-zinc, and multiple micronutrient supplementation groups, respectively, none of which were significant. Maternal vitamin B-12 deficiency is associated with an elevated risk of insulin resistance, but supplementation with folic acid or other micronutrients led to no significant change in insulin resistance in school-aged offspring.

  14. Insulin resistance and atherosclerosis

    PubMed Central

    Semenkovich, Clay F.

    2006-01-01

    Considerable evidence supports the association between insulin resistance and vascular disease, and this has led to wide acceptance of the clustering of hyperlipidemia, glucose intolerance, hypertension, and obesity as a clinical entity, the metabolic syndrome. While insulin resistance, by promoting dyslipidemia and other metabolic abnormalities, is part of the proatherogenic milieu, it is possible that insulin resistance itself in the vascular wall does not promote atherosclerosis. Recent findings suggest that insulin resistance and atherosclerosis could represent independent and ultimately maladaptive responses to the disruption of cellular homeostasis caused by the excess delivery of fuel. PMID:16823479

  15. Infliximab and insulin resistance.

    PubMed

    Ursini, Francesco; Naty, Saverio; Grembiale, Rosa Daniela

    2010-06-01

    Insulin resistance is the most important pathophysiologic feature of obesity, type 2 diabetes mellitus and prediabetic states. TNF-alpha, a proinflammatory cytokine, plays a pivotal role in the pathogenesis of inflammation-associated insulin resistance during the course of rheumatic diseases. Therapies aimed at neutralizing TNF-alpha, such as the monoclonal antibody infliximab, represent a novel approach for the treatment of rheumatic diseases and allow to obtain significant results in terms of control of the inflammatory process. In this article we reviewed the scientific evidence published in the literature about a potential role of TNF-alpha blockade in improving insulin resistance in non-diabetic rheumatic patients.

  16. Relationship of insulin resistance to vitamin d status in children with nondiabetic chronic kidney disease.

    PubMed

    Conkar, Seçil; Mir, Sevgi

    2017-01-01

    Insulin Resistance is common in patients with mild-to-moderate stage chronic kidney disease (CKD), even when the glomerular filtration rate is within the normal range. This study aimed to investigate the association of IR and 25-hydroxyvitamin D levels. In this study, we evaluated the frequency of IR in predialysis patients and the association with 25-hydroxyvitamin (OH)D levels. A total of 32 non-diabetic patients with predialysis were included in the study. Homeostasis model assessment for insulin resistance (HOMA-IR) index was calculated to show presence of IR. Data were analyzed with the Statistical Package for the Social Sciences (SPSS) program version 13.0 (SPSS Inc, Chicago, Ill, USA) using the Chi-square, Student t-test, and logistic regression analysis. Nineteen of 32 subjects (59.4%) were detected to have IR. There was no consistent relationship was detected between IR and glomerular filtration rate, body mass index, and blood pressure in chronic kidney disease (CKD). However; significant difference was detected in 25(OH)D levels with IR in CKD (P = 0.49). The regression analysis showed that 25(OH)D was an independent predictor of IR with an odds ratio of 1.2. In our study, we demonstrated that IR was high in different stages of CKD. Insulin-resistance in non-diabetic CKD was correlated with 25(OH)D levels. 25(OH) vitamin D levels can play a significant role in the development of IR in pediatric patients with CKD. This is important for the early detection and intervention of vitamin D deficiency thereby preventing potentially future complications related to IR.

  17. Chromium and insulin resistance.

    PubMed

    Anderson, Richard A

    2003-12-01

    Insulin resistance leads to the inability of insulin to control the utilization and storage of glucose. It is associated initially with elevated levels of circulating insulin followed by glucose intolerance which may progress to type 2 diabetes, hyperlipidaemia, hypertension, obesity and cardiovascular diseases. While the causes of these diseases are multifactorial, one nutrient that is associated with all of these abnormalities is Cr. In the presence of Cr, in a biologically active form, much lower levels of insulin are required. Modern diets, which are often high in refined carbohydrates, are not only low in Cr, but lead to enhanced Cr losses. In response to the consumption of refined carbohydrates, there is a rapid rise in blood sugar leading to elevations in insulin that cause a mobilization of Cr. Once mobilized, Cr is not reabsorbed but lost via the urine leading to decreased Cr stores. Several studies involving both human subjects and experimental animals have reported improvements in insulin sensitivity, blood glucose, insulin, lipids, haemoglobin A1c, lean body mass and related variables in response to improved Cr nutrition. However, not all studies have reported beneficial effects associated with improved Cr nutrition. Well-controlled human studies are needed to document an unequivocal effect of Cr on insulin sensitivity in human subjects. Studies need to involve a significant number of subjects with insulin resistance, glucose intolerance or early stages of diabetes, who have not been taking supplements containing Cr for at least 4 months, and involve at least 400 to 600 microg supplemental Cr daily or more. Studies should be at least 4 months to document sustained effects of supplemental Cr on insulin resistance and related variables. Cr is a nutrient and not a therapeutic agent and therefore will only be of benefit to those whose problems are due to suboptimal intake of Cr.

  18. Effects of Diet Composition and Insulin Resistance Status on Plasma Lipid Levels in a Weight Loss Intervention in Women.

    PubMed

    Le, Tran; Flatt, Shirley W; Natarajan, Loki; Pakiz, Bilge; Quintana, Elizabeth L; Heath, Dennis D; Rana, Brinda K; Rock, Cheryl L

    2016-01-25

    Optimal macronutrient distribution of weight loss diets has not been established. The distribution of energy from carbohydrate and fat has been observed to promote differential plasma lipid responses in previous weight loss studies, and insulin resistance status may interact with diet composition and affect weight loss and lipid responses. Overweight and obese women (n=245) were enrolled in a 1-year behavioral weight loss intervention and randomly assigned to 1 of 3 study groups: a lower fat (20% energy), higher carbohydrate (65% energy) diet; a lower carbohydrate (45% energy), higher fat (35% energy) diet; or a walnut-rich, higher fat (35% energy), lower carbohydrate (45% energy) diet. Blood samples and data available from 213 women at baseline and at 6 months were the focus of this analysis. Triglycerides, total cholesterol, and high- and low-density lipoprotein cholesterol were quantified and compared between and within groups. Triglycerides decreased in all study arms at 6 months (P<0.05). The walnut-rich diet increased high-density lipoprotein cholesterol more than either the lower fat or lower carbohydrate diet (P<0.05). The walnut-rich diet also reduced low-density lipoprotein cholesterol in insulin-sensitive women, whereas the lower fat diet reduced both total cholesterol and high-density lipoprotein cholesterol in insulin-sensitive women (P<0.05). Insulin sensitivity and C-reactive protein levels also improved. Weight loss was similar across the diet groups, although insulin-sensitive women lost more weight with a lower fat, higher carbohydrate diet versus a higher fat, lower carbohydrate diet. The walnut-rich, higher fat diet resulted in the most favorable changes in lipid levels. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01424007. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  19. Immunologic insulin resistance.

    PubMed

    Davidson, J K; DeBra, D W

    1978-03-01

    The efficacy of sulfated beef insulin for plasma glucose control in 35 patients with immunologic insulin resistance was studied. Patients were on a mean dose of 550 U./day (range 200--2,000) of U-500 regular beef insulin. Mean maximum 125I-insulin-binding capacity was 191 mU./ml. serum (range 13--1,080). Mean in vivo half-life (T 1/2) of 125I-regular beef insulin was 614 minutes (range 114--1,300), as against a mean T 1/2 of 13.9 minutes (range 11.8--16.5) in normal controls. Treatment was successful in 34 patients and unsuccessful in one with lipoatrophic diabetes. The mean initial dose of sulfated insulin was 89 U./day (range 15--400) and at three months was 66 U./day (range 20--400). Twenty-eight patients who responded and survived have been on sulfated insulin for a mean of 39 months (range 2-66) and are on a mean dose of 25 U./day (range 0--100). The mean maximum binding capacity fell to 9 mU./ml. (range 0--34) during therapy (p less than 0.01). Mean 125I-insulin T 1/2 fell from 614 to 249 minutes after sulfated insulin therapy (p less than 0.001). A comparative study of 15 patients on consecutive days showed a 35 sulfated insulin T 1/2 of 60 minutes (range 15--94) and a mean 125I-regular insulin T 1/2 of 246 minutes (range 62--560, p less than 0.001). These results indicate that sulfated insulin is less antigenic than regular beef insulin and combines less avidly with human antibodies to regular beef insulin. The response to sulfated insulin therapy was significantly better than the response reported by other investigators to pork insulin or to steroid therapy in similar patients.

  20. 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

  1. Predisposition to insulin resistance and obesity due to staple consumption of rice: Amylose content versus germination status.

    PubMed

    Abubakar, Bilyaminu; Zawawi, Norhasnida; Omar, Abdul Rahman; Ismail, Maznah

    2017-01-01

    Type 2 diabetes is a metabolic disorder with established, well-defined precursors. Obesity and insulin resistance are amongst most important factors in predisposition to diabetes. Rice is a staple for about half the global population and its consumption has been strongly linked with diabetogenesis. We assert that tackling the prevalence of predisposing factors by modifying certain rice cultivars could reduce the global burden of obesity and insulin resistance, and by extension type 2 diabetes. Several rice cultivars with various properties were fed to nulliparous rats (five weeks old at the start of the experiment) for 90 days. They were then returned to a diet of standard pellets and mated with males raised on a standard diet. The resulting pups and dams were investigated for obesity and insulin resistance markers. We found that germination did more to reduce predisposition to obesity and insulin resistance than high amylose content. The combined reducing effect of germination and high amylose content on predisposition to obesity and insulin resistance was greater than the sum of their independent effects. Polished (white) rice with a low amylose content predisposed dams on a high-fat diet to markers of insulin resistance and obesity and this predisposition was inherited (in biochemical terms) by their F1 offspring. Overall, the results suggest that harnessing the beneficial properties of germination and amylose in rice would reduce the burden of obesity and insulin resistance, which are known to be key risk factors for development of type 2 diabetes.

  2. Vitamin D Status, Insulin Resistance, Leptin-To-Adiponectin Ratio in Adolescents: Results of a 1-Year Lifestyle Intervention

    PubMed Central

    Rambhojan, Christine; Larifla, Laurent; Clepier, Josiane; Bouaziz-Amar, Elodie; Velayoudom-Cephise, Fritz-Line; Blanchet-Deverly, Anne; Armand, Christophe; Plumasseau, Jean; Lacorte, Jean-Marc; Foucan, Lydia

    2016-01-01

    AIM: We aimed to study the relationships between circulating 25-hydroxyvitamin D [25(OH)D], insulin resistance and leptin-to-adiponectin (L/A) ratio in Guadeloupean children and adolescents and to analyse the changes in 25(OH)D levels after a 1-year lifestyle intervention program. METHODS: 25(OH)D concentrations were measured via a chemiluminescence assay. Cardiometabolic risk factors, homoeostasis model assessment of insulin resistance (HOMA-IR), and adipokines were measured. The lifestyle intervention included dietary counselling, regular physical activity. RESULTS: Among 117 girls and boys (11–15 years old, 31.6% obese), 40% had vitamin D deficiency (25(OH)D levels < 20 ng/mL). With linear regression models where 25(OH)D and HOMA-IR acted as independent variables and age, sex, BMI, L/A ratio as covariates, 25(OH)D was significantly associated with HOMA-IR alone (P = 0.036). HOMA-IR was also associated with BMI z-score ≥ 2, L/A ratio and an interaction term BMI z-score ≥ 2*L/A ratio (P < 0.001 for all). After one year, in 78 children/adolescent, mean serum 25(OH)D increased significantly from 21.4 ± 4.9 ng/mL at baseline to 23.2 ± 6.0 after 1 year; P = 0.003 whereas BMI z-score, HOMA-IR and L/A ratio decreased significantly (P = 0.003, P < 0.001 and P = 0.012; respectively). CONCLUSION: The association between 25(OH)D and HOMA-IR, independently of obesity and the high prevalence of vitamin D deficiency should be considered in order to prevent the later incidence of T2DM. A healthy lifestyle including non-sedentary and outdoor activities could be a way for improving vitamin D status. PMID:28028397

  3. Relationship between circulating visfatin/NAMPT, nutritional status and insulin resistance in an elderly population - results from the PolSenior substudy.

    PubMed

    Olszanecka-Glinianowicz, Magdalena; Owczarek, Aleksander; Bożentowicz-Wikarek, Maria; Brzozowska, Aniceta; Mossakowska, Małgorzata; Zdrojewski, Tomasz; Grodzicki, Tomasz; Więcek, Andrzej; Chudek, Jerzy

    2014-11-01

    Circulating visfatin/nicotinamide phosphoribosyltransferase (visfatin/NAMPT) levels according to some studies are related to nutritional status and insulin resistance. These associations have not been studied in large elderly populations. Therefore, the aim of our study was to assess the relationships between circulating visfatin/NAMPT levels, nutritional status, and insulin resistance in a large population of the elderly. Concentrations of glucose, albumin, creatinine, CRP, interleukin-6, insulin, and visfatin/NAMPT (by ELISA) were assessed, and HOMA-IR calculated in 3050 elderly participants of the PolSenior study. The highest plasma visfatin/NAMPT levels were observed in obese, as well as in non-diabetic insulin resistant subjects; however there were only significant differences found in women. The regression models showed that plasma visfatin/NAMPT levels decline with age and increased with waist circumference, BMI, and hs-CRP. Waist circumference was better correlated than BMI for visfatin/NAMPT levels in statistical models not adjusted by sex, and just the opposite in models which were. We demonstrated a 0.023ng/mL increase of Visfatin/NAMPT levels for 1mg/L increase of hs-CRP, and a 0.007ng/mL decline for each year of age. Our study revealed that in elderly subjects, circulating visfatin/NAMPT levels are related to age, nutritional status, especially visceral obesity, and inflammation. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Insulin Resistance in Alzheimer's Disease

    PubMed Central

    Dineley, Kelly T; Jahrling, Jordan B; Denner, Larry

    2014-01-01

    Insulin is a key hormone regulating metabolism. Insulin binding to cell surface insulin receptors engages many signaling intermediates operating in parallel and in series to control glucose, energy, and lipids while also regulating mitogenesis and development. Perturbations in the function of any of these intermediates, which occur in a variety of diseases, cause reduced sensitivity to insulin and insulin resistance with consequent metabolic dysfunction. Chronic inflammation ensues which exacerbates compromised metabolic homeostasis. Since insulin has a key role in learning and memory as well as directly regulating ERK, a kinase required for the type of learning and memory compromised in early Alzheimer's disease (AD), insulin resistance has been identified as a major risk factor for the onset of AD. Animal models of AD or insulin resistance or both demonstrate that AD pathology and impaired insulin signaling form a reciprocal relationship. Of note are human and animal model studies geared toward improving insulin resistance that have led to the identification of the nuclear receptor and transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ) as an intervention tool for early AD. Strategic targeting of alternate nodes within the insulin signaling network has revealed disease-stage therapeutic windows in animal models that coalesce with previous and ongoing clinical trial approaches. Thus, exploiting the connection between insulin resistance and AD provides powerful opportunities to delineate therapeutic interventions that slow or block the pathogenesis of AD. PMID:25237037

  5. Insulin resistance in Alzheimer's disease.

    PubMed

    Dineley, Kelly T; Jahrling, Jordan B; Denner, Larry

    2014-12-01

    Insulin is a key hormone regulating metabolism. Insulin binding to cell surface insulin receptors engages many signaling intermediates operating in parallel and in series to control glucose, energy, and lipids while also regulating mitogenesis and development. Perturbations in the function of any of these intermediates, which occur in a variety of diseases, cause reduced sensitivity to insulin and insulin resistance with consequent metabolic dysfunction. Chronic inflammation ensues which exacerbates compromised metabolic homeostasis. Since insulin has a key role in learning and memory as well as directly regulating ERK, a kinase required for the type of learning and memory compromised in early Alzheimer's disease (AD), insulin resistance has been identified as a major risk factor for the onset of AD. Animal models of AD or insulin resistance or both demonstrate that AD pathology and impaired insulin signaling form a reciprocal relationship. Of note are human and animal model studies geared toward improving insulin resistance that have led to the identification of the nuclear receptor and transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ) as an intervention tool for early AD. Strategic targeting of alternate nodes within the insulin signaling network has revealed disease-stage therapeutic windows in animal models that coalesce with previous and ongoing clinical trial approaches. Thus, exploiting the connection between insulin resistance and AD provides powerful opportunities to delineate therapeutic interventions that slow or block the pathogenesis of AD. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Vegetarianism, vitamin B12 status, and insulin resistance in a group of predominantly overweight/obese South Asian women.

    PubMed

    Gammon, Cheryl S; von Hurst, Pamela R; Coad, Jane; Kruger, Rozanne; Stonehouse, Welma

    2012-01-01

    Asian Indians are an at-risk group for vitamin B12 deficiency (because of vegetarianism) and insulin resistance (IR). Vegetarianism and consequent vitamin B12 deficiency may be associated with IR. This study aimed to describe the vitamin B12 status of predominantly overweight/obese women of South Asian origin living in Auckland and to correlate serum vitamin B12 and vegetarian status with IR as part of the larger Surya Study looking at health and lifestyle in this population. This was a cross-sectional study of 135 women at least 20 y of age who were not taking vitamin B supplements or medications that could affect vitamin B12 concentrations (serum vitamin B12 < 800 pmol/L). Data collection included serum vitamin B12, serum folate, measurements of IR (HOMA2-IR), and anthropometry. Vegetarian status was established for 124 subjects (90 non-vegetarians, 34 vegetarians). Mean serum vitamin B12 was 227 pmol/L (95% confidence interval 210-245), serum folate was 19.1 nmol/L (18.0-20.2), and HOMA2-IR was 1.24 (1.13-1.36). Non-vegetarians had higher serum vitamin B12 levels (257 pmol/L, 235-281) than vegetarians (181 pmol/L, 159-207), P < 0.001. Vitamin B12 deficiency (<150 pmol/L) in vegetarians was 24% versus 9% in non-vegetarians. Non-vegetarians had increased body mass index (25.9 kg/m², 25.0-26.9, versus 23.9 kg/m², 22.6-25.3), waist circumference (81 ± 10.1 versus 75.8 ± 9.88 cm), and HOMA2-IR levels (1.30, 1.17-1.46, versus 1.00, 0.83-1.22). No correlation was found between serum vitamin B12 and HOMA2-IR. A significant positive correlation between non-vegetarian status and IR disappeared after controlling for body mass index. This study population has a low serum vitamin B12 status, especially if vegetarian. The high rates of observed obesity may have overshadowed any other contributing factor to IR. Copyright © 2012 Elsevier Inc. All rights reserved.

  7. Weight loss on low-fat vs. low-carbohydrate diets by insulin resistance status among overweight adults and adults with obesity: A randomized pilot trial.

    PubMed

    Gardner, Christopher D; Offringa, Lisa C; Hartle, Jennifer C; Kapphahn, Kris; Cherin, Rise

    2016-01-01

    To test for differential weight loss response to low-fat (LF) vs. low-carbohydrate (LC) diets by insulin resistance status with emphasis on overall quality of both diets. Sixty-one adults, BMI 28-40 kg/m(2) , were randomized in a 2 × 2 design to LF or LC by insulin resistance status in this pilot study. Primary outcome was 6-month weight change. Participants were characterized as more insulin resistant (IR) or more insulin sensitive (IS) by median split of baseline insulin-area-under-the-curve from an oral glucose tolerance test. Intervention consisted of 14 one-hour class-based educational sessions. Baseline % carbohydrate:% fat:% protein was 44:38:18. At 6 months, the LF group reported 57:21:22 and the LC group reported 22:53:25 (IR and IS combined). Six-month weight loss (kg) was 7.4 ± 6.0 (LF-IR), 10.4 ± 7.8 (LF-IS), 9.6 ± 6.6 (LC-IR), and 8.6 ± 5.6 (LC-IS). No significant main effects were detected for weight loss by diet group or IR status; there was no significant diet × IR interaction. Significant differences in several secondary outcomes were observed. Substantial weight loss was achieved overall, but a significant diet × IR status interaction was not observed. Opportunity to detect differential response may have been limited by the focus on high diet quality for both diet groups and sample size. © 2015 The Obesity Society.

  8. Selective insulin resistance in adipocytes.

    PubMed

    Tan, Shi-Xiong; Fisher-Wellman, Kelsey H; Fazakerley, Daniel J; Ng, Yvonne; Pant, Himani; Li, Jia; Meoli, Christopher C; Coster, Adelle C F; Stöckli, Jacqueline; James, David E

    2015-05-01

    Aside from glucose metabolism, insulin regulates a variety of pathways in peripheral tissues. Under insulin-resistant conditions, it is well known that insulin-stimulated glucose uptake is impaired, and many studies attribute this to a defect in Akt signaling. Here we make use of several insulin resistance models, including insulin-resistant 3T3-L1 adipocytes and fat explants prepared from high fat-fed C57BL/6J and ob/ob mice, to comprehensively distinguish defective from unaffected aspects of insulin signaling and its downstream consequences in adipocytes. Defective regulation of glucose uptake was observed in all models of insulin resistance, whereas other major actions of insulin such as protein synthesis and anti-lipolysis were normal. This defect corresponded to a reduction in the maximum response to insulin. The pattern of change observed for phosphorylation in the Akt pathway was inconsistent with a simple defect at the level of Akt. The only Akt substrate that showed consistently reduced phosphorylation was the RabGAP AS160 that regulates GLUT4 translocation. We conclude that insulin resistance in adipose tissue is highly selective for glucose metabolism and likely involves a defect in one of the components regulating GLUT4 translocation to the cell surface in response to insulin. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. Selective Insulin Resistance in Adipocytes*

    PubMed Central

    Tan, Shi-Xiong; Fisher-Wellman, Kelsey H.; Fazakerley, Daniel J.; Ng, Yvonne; Pant, Himani; Li, Jia; Meoli, Christopher C.; Coster, Adelle C. F.; Stöckli, Jacqueline; James, David E.

    2015-01-01

    Aside from glucose metabolism, insulin regulates a variety of pathways in peripheral tissues. Under insulin-resistant conditions, it is well known that insulin-stimulated glucose uptake is impaired, and many studies attribute this to a defect in Akt signaling. Here we make use of several insulin resistance models, including insulin-resistant 3T3-L1 adipocytes and fat explants prepared from high fat-fed C57BL/6J and ob/ob mice, to comprehensively distinguish defective from unaffected aspects of insulin signaling and its downstream consequences in adipocytes. Defective regulation of glucose uptake was observed in all models of insulin resistance, whereas other major actions of insulin such as protein synthesis and anti-lipolysis were normal. This defect corresponded to a reduction in the maximum response to insulin. The pattern of change observed for phosphorylation in the Akt pathway was inconsistent with a simple defect at the level of Akt. The only Akt substrate that showed consistently reduced phosphorylation was the RabGAP AS160 that regulates GLUT4 translocation. We conclude that insulin resistance in adipose tissue is highly selective for glucose metabolism and likely involves a defect in one of the components regulating GLUT4 translocation to the cell surface in response to insulin. PMID:25720492

  10. Mouse models of insulin resistance.

    PubMed

    Hribal, Marta Letizia; Oriente, Francesco; Accili, Domenico

    2002-05-01

    The hallmarks of type 2 diabetes are impaired insulin action in peripheral tissues and decreased pancreatic beta-cell function. Classically, the two defects have been viewed as separate entities, with insulin resistance arising primarily from impaired insulin-dependent glucose uptake in skeletal muscle, and beta-cell dysfunction arising from impaired coupling of glucose sensing to insulin secretion. Targeted mutagenesis and transgenesis involving components of the insulin action pathway have changed our understanding of these phenomena. It appears that the role of insulin signaling in the pathogenesis of type 2 diabetes has been overestimated in classic insulin target tissues, such as skeletal muscle, whereas it has been overlooked in liver, pancreatic beta-cells, and brain, which had been thought not to be primary insulin targets. We review recent progress and try to reconcile areas of apparent controversy surrounding insulin signaling in skeletal muscle and pancreatic beta-cells.

  11. 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

  12. Relationship between the degree of insulin resistance during late gestation and postpartum performance in dairy cows and factors that affect growth and metabolic status of their calves

    PubMed Central

    KAWASHIMA, Chiho; MUNAKATA, Megumi; SHIMIZU, Takashi; MIYAMOTO, Akio; KIDA, Katsuya; MATSUI, Motozumi

    2016-01-01

    This study aimed to investigate the effects of insulin resistance (IR) during the close-up dry period on the metabolic status and performance of dairy cows as well as to determine the effects on body weight (BW) and metabolic status of their calves. An insulin tolerance test (ITT) was conducted by administering 0.05 IU/kg BW of insulin to 34 multiparous Holstein cows at 3 weeks prepartum. Blood samples were collected at 0, 30, 45 and 60 min after insulin injection, and cows were divided into two groups based on the time required for glucose to reach the minimum levels [non-IR (NIR), 45 min (n=28); and IR, 60 min (n=6)]. Blood or milk sampling and body condition score (BCS) estimation were performed twice weekly during the experimental period. Blood samples from calves were collected immediately after birth. Cows with IR showed lower BCS (P<0.05) and serum urea nitrogen (P<0.05) and glucose concentration (P=0.05) before calving, and lower serum non-esterified fatty acid concentration (P<0.05) and milk yield (P<0.05) and earlier resumption of luteal activity (P<0.05) after calving; their calves showed lower BW (P<0.05) and plasma insulin-like growth factor-I concentration (P<0.001) and higher plasma insulin concentration (P<0.05). In conclusion, IR at 3 weeks prepartum in dairy cows is related to postpartum metabolic status and performance along with growth and metabolic status of their calves. PMID:26781705

  13. Nutritional status, genetic susceptibility, and insulin resistance--important precedents to atherosclerosis.

    PubMed

    McGillicuddy, Fiona C; Roche, Helen M

    2012-07-01

    Atherosclerosis is a progressive disease that starts early in life and is manifested clinically as coronary artery disease (CAD), cerebrovascular disease, or peripheral artery disease. CAD remains the leading cause of morbidity and mortality in Western society despite the great advances made in understanding its underlying pathophysiology. The key risk factors associated with CAD include hypercholesterolemia, hypertension, poor diet, obesity, age, male gender, smoking, and physical inactivity. Genetics also play an important role that may interact with environmental factors, including diet, nutritional status, and physiological parameters. Furthermore, certain chronic inflammatory conditions also predispose to the development of CAD. The spiraling increase in obesity rates worldwide has made it more pertinent than ever before to understand the metabolic perturbations that link over nutrition to enhanced cardiovascular risk. Great breakthroughs have been made at the pharmacological level to manage CAD; statins and aspirin have revolutionized treatment of CAD and prolonged lifespan. Nonetheless, lifestyle intervention prior to clinical presentation of CAD symptoms would negate/delay the need for chronic pharmacotherapy in at-risk individuals which in turn would relieve healthcare systems of a costly burden. Throughout this review, we debate the relative impact of nutrition versus genetics in driving CAD. We will investigate how overnutrition affects adipose tissue biology and drives IR and will discuss the subsequent implications for the cardiovascular system. Furthermore, we will discuss how lifestyle interventions including diet modification and weight loss can improve both IR and metabolic dyslipidemia that is associated with obesity. We will conclude by delving into the concept that nutritional status interacts with genetic susceptibility, such that perhaps a more personalized nutrition approach may be more effective in determining diet-related risk as well as

  14. [Obesity, adipogenesis and insulin resistance].

    PubMed

    Ros Pérez, Manuel; Medina-Gómez, Gema

    2011-01-01

    Insulin resistance precedes the development of type 2 diabetes mellitus and is also a common denominator in the so-called metabolic syndrome. Although the cause of insulin resistance has not been fully elucidated, it seems clear that lifestyle changes, including little physical exercise and constant access to food, particularly in developed and economically emergent countries, as well as genetic factors, appear to have triggered the escalating incidence of diseases related to insulin resistance, including type 2 diabetes and metabolic syndrome. Obesity is considered as a risk factor for developing insulin resistance. Increased adipose tissue has been related to an increased production of pro-inflammatory cytokines which, together with fatty acids, appear to be responsible for the development of insulin resistance. Thus, a greater or lesser expansibility or ability of adipose tissue to store lipids also appears to play a significant role in the development of insulin resistance because overcoming of this capacity, which is variable in each case, would result in leaking of lipids to other tissues where they could interfere with insulin signaling. This article reviews various molecular mechanisms related to the development of insulin resistance and its relationship to expansibility of adipose tissue and obesity. Copyright © 2011 SEEN. Published by Elsevier Espana. All rights reserved.

  15. Insulin Resistance and Mitochondrial Dysfunction.

    PubMed

    Gonzalez-Franquesa, Alba; Patti, Mary-Elizabeth

    2017-01-01

    Insulin resistance precedes and predicts the onset of type 2 diabetes (T2D) in susceptible humans, underscoring its important role in the complex pathogenesis of this disease. Insulin resistance contributes to multiple tissue defects characteristic of T2D, including reduced insulin-stimulated glucose uptake in insulin-sensitive tissues, increased hepatic glucose production, increased lipolysis in adipose tissue, and altered insulin secretion. Studies of individuals with insulin resistance, both with established T2D and high-risk individuals, have consistently demonstrated a diverse array of defects in mitochondrial function (i.e., bioenergetics, biogenesis and dynamics). However, it remains uncertain whether mitochondrial dysfunction is primary (critical initiating defect) or secondary to the subtle derangements in glucose metabolism, insulin resistance, and defective insulin secretion present early in the course of disease development. In this chapter, we will present the evidence linking mitochondrial dysfunction and insulin resistance, and review the potential for mitochondrial targets as a therapeutic approach for T2D.

  16. Lipid mediators of insulin resistance.

    PubMed

    Holland, William L; Knotts, Trina A; Chavez, Jose A; Wang, Li-Ping; Hoehn, Kyle L; Summers, Scott A

    2007-06-01

    Lipid abnormalities such as obesity, increased circulating free fatty acid levels, and excess intramyocellular lipid accumulation are frequently associated with insulin resistance. These observations have prompted investigators to speculate that the accumulation of lipids in tissues not suited for fat storage (e.g., skeletal muscle and liver) is an underlying component of insulin resistance and the metabolic syndrome. We review the metabolic fates of lipids in insulin-responsive tissues and discuss the roles of specific lipid metabolites (e.g., ceramides, GM3 ganglioside, and diacylglycerol) as antagonists of insulin signaling and action.

  17. 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.

  18. Adipocyte lipolysis and insulin resistance.

    PubMed

    Morigny, Pauline; Houssier, Marianne; Mouisel, Etienne; Langin, Dominique

    2016-06-01

    Obesity-induced insulin resistance is a major risk factor for the development of type 2 diabetes. Basal fat cell lipolysis (i.e., fat cell triacylglycerol breakdown into fatty acids and glycerol in the absence of stimulatory factors) is elevated during obesity and is closely associated with insulin resistance. Inhibition of adipocyte lipolysis may therefore be a promising therapeutic strategy for treating insulin resistance and preventing obesity-associated type 2 diabetes. In this review, we explore the relationship between adipose lipolysis and insulin sensitivity. After providing an overview of the components of fat cell lipolytic machinery, we describe the hypotheses that may support the causality between lipolysis and insulin resistance. Excessive circulating fatty acids may ectopically accumulate in insulin-sensitive tissues and impair insulin action. Increased basal lipolysis may also modify the secretory profile of adipose tissue, influencing whole body insulin sensitivity. Finally, excessive fatty acid release may also worsen adipose tissue inflammation, a well-known parameter contributing to insulin resistance. Partial genetic or pharmacologic inhibition of fat cell lipases in mice as well as short term clinical trials using antilipolytic drugs in humans support the benefit of fat cell lipolysis inhibition on systemic insulin sensitivity and glucose metabolism, which occurs without an increase of fat mass. Modulation of fatty acid fluxes and, putatively, of fat cell secretory pattern may explain the amelioration of insulin sensitivity whereas changes in adipose tissue immune response do not seem involved. Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  19. [Chromium and insulin resistance].

    PubMed

    Kleefstra, N; Bilo, H J; Bakker, S J; Houweling, S T

    2004-01-31

    Since as early as the 50s of the last century, it has been known that chromium is essential for normal glucose metabolism. Too little chromium in the diet may lead to insulin resistance. However, there is still no standard against which chromium deficiency can be established. Nevertheless, chromium supplements are becoming increasingly popular. Various systematic reviews have been unable to demonstrate any effects of chromium on glycaemic regulation (possibly due partly to the low dosages used), but there is a slight reduction in body weight averaging 1 kg. In a double-blind randomised placebo-controlled trial in a Chinese population with type-2 diabetes mellitus, supplementation with 1000 micrograms of chromium led to a fall in the glycosylated haemoglobin level (HbA1c) by 2%. Toxic effects of chromium are seldom seen; recently, however, the safety of one of the dosage forms of chromium, chromium picolinate, has been questioned. One should be aware that individual patients with type-2 diabetes mellitus may have an increased risk of hypoglycaemic episodes when taking chromium supplements as self-medication.

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

    PubMed Central

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

    2016-01-01

    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 > 85th 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. PMID:27824069

  1. Sleep disturbances and insulin resistance.

    PubMed

    Van Cauter, E

    2011-12-01

    The causes and risk factors of insulin resistance remain insufficiently understood. After taking into account the important roles of adiposity, age, sex and race/ethnicity, up to 50% of the individual variability in insulin resistance remains unexplained. In recent years, evidence has accumulated to support a role for sleep disturbances, including insufficient sleep, poor sleep quality and insomnia, and obstructive sleep apnoea, as independent risk factors for the development and exacerbation of insulin resistance. The present review summarizes the evidence. We will start with a brief introduction to sleep and its disorders and then examine in succession the role of the three major types of sleep disturbances of modern society, namely insufficient sleep, poor sleep quality and/or insomnia and obstructive sleep apnoea. Insulin resistance is a hallmark of the polycystic ovary syndrome, the most common endocrine pathology in women, and the last section of this review will discuss the role of obstructive sleep apnoea in the insulin resistance and metabolic disturbances of polycystic ovary syndrome. © 2011 The Author. Diabetic Medicine © 2011 Diabetes UK.

  2. Sympathovagal Imbalance Contributes to Prehypertension Status and Cardiovascular Risks Attributed by Insulin Resistance, Inflammation, Dyslipidemia and Oxidative Stress in First Degree Relatives of Type 2 Diabetics

    PubMed Central

    Pal, Gopal Krushna; Adithan, Chandrasekaran; Ananthanarayanan, Palghat Hariharan; Pal, Pravati; Nanda, Nivedita; Durgadevi, Thiyagarajan; Lalitha, Venugopal; Syamsunder, Avupati Naga; Dutta, Tarun Kumar

    2013-01-01

    Background Though cardiovascular (CV) risks are reported in first-degree relatives (FDR) of type 2 diabetics, the pathophysiological mechanisms contributing to these risks are not known. We investigated the association of sympathovagal imbalance (SVI) with CV risks in these subjects. Subjects and Methods Body mass index (BMI), basal heart rate (BHR), blood pressure (BP), rate-pressure product (RPP), spectral indices of heart rate variability (HRV), autonomic function tests, insulin resistance (HOMA-IR), lipid profile, inflammatory markers, oxidative stress (OS) marker, rennin, thyroid profile and serum electrolytes were measured and analyzed in subjects of study group (FDR of type 2 diabetics, n = 72) and control group (subjects with no family history of diabetes, n = 104). Results BMI, BP, BHR, HOMA-IR, lipid profile, inflammatory and OS markers, renin, LF-HF (ratio of low-frequency to high-frequency power of HRV, a sensitive marker of SVI) were significantly increased (p<0.0001) in study group compared to the control group. SVI in study group was due to concomitant sympathetic activation and vagal inhibition. There was significant correlation and independent contribution of markers of insulin resistance, dyslipidemia, inflammation and OS to LF-HF ratio. Multiple-regression analysis demonstrated an independent contribution of LF-HF ratio to prehypertension status (standardized beta 0.415, p<0.001) and bivariate logistic-regression showed significant prediction (OR 2.40, CI 1.128–5.326, p = 0.002) of LF-HF ratio of HRV to increased RPP, the marker of CV risk, in study group. Conclusion SVI in FDR of type 2 diabetics occurs due to sympathetic activation and vagal withdrawal. The SVI contributes to prehypertension status and CV risks caused by insulin resistance, dyslipidemia, inflammation and oxidative stress in FDR of type 2 diabetics. PMID:24265679

  3. Sympathovagal imbalance contributes to prehypertension status and cardiovascular risks attributed by insulin resistance, inflammation, dyslipidemia and oxidative stress in first degree relatives of type 2 diabetics.

    PubMed

    Pal, Gopal Krushna; Adithan, Chandrasekaran; Ananthanarayanan, Palghat Hariharan; Pal, Pravati; Nanda, Nivedita; Durgadevi, Thiyagarajan; Lalitha, Venugopal; Syamsunder, Avupati Naga; Dutta, Tarun Kumar

    2013-01-01

    Though cardiovascular (CV) risks are reported in first-degree relatives (FDR) of type 2 diabetics, the pathophysiological mechanisms contributing to these risks are not known. We investigated the association of sympathovagal imbalance (SVI) with CV risks in these subjects. Body mass index (BMI), basal heart rate (BHR), blood pressure (BP), rate-pressure product (RPP), spectral indices of heart rate variability (HRV), autonomic function tests, insulin resistance (HOMA-IR), lipid profile, inflammatory markers, oxidative stress (OS) marker, rennin, thyroid profile and serum electrolytes were measured and analyzed in subjects of study group (FDR of type 2 diabetics, n = 72) and control group (subjects with no family history of diabetes, n = 104). BMI, BP, BHR, HOMA-IR, lipid profile, inflammatory and OS markers, renin, LF-HF (ratio of low-frequency to high-frequency power of HRV, a sensitive marker of SVI) were significantly increased (p<0.0001) in study group compared to the control group. SVI in study group was due to concomitant sympathetic activation and vagal inhibition. There was significant correlation and independent contribution of markers of insulin resistance, dyslipidemia, inflammation and OS to LF-HF ratio. Multiple-regression analysis demonstrated an independent contribution of LF-HF ratio to prehypertension status (standardized beta 0.415, p<0.001) and bivariate logistic-regression showed significant prediction (OR 2.40, CI 1.128-5.326, p = 0.002) of LF-HF ratio of HRV to increased RPP, the marker of CV risk, in study group. SVI in FDR of type 2 diabetics occurs due to sympathetic activation and vagal withdrawal. The SVI contributes to prehypertension status and CV risks caused by insulin resistance, dyslipidemia, inflammation and oxidative stress in FDR of type 2 diabetics.

  4. Insulin action and insulin resistance in vascular endothelium.

    PubMed

    Muniyappa, Ranganath; Quon, Michael J

    2007-07-01

    Vasodilator actions of insulin are mediated by phosphatidylinositol 3-kinase dependent insulin signaling pathways in endothelium, which stimulate production of nitric oxide. Insulin-stimulated nitric oxide mediates capillary recruitment, vasodilation, increased blood flow, and subsequent augmentation of glucose disposal in skeletal muscle. Distinct mitogen-activated protein kinase dependent insulin signaling pathways regulate secretion of the vasoconstrictor endothelin-1 from endothelium. These vascular actions of insulin contribute to the coupling of metabolic and hemodynamic homeostasis that occurs under healthy conditions. Insulin resistance is characterized by pathway-specific impairment in phosphatidylinositol 3-kinase dependent signaling in both metabolic and vascular insulin target tissues. Here we discuss consequences of pathway-specific insulin resistance in endothelium and therapeutic interventions targeting this selective impairment. Shared causal factors such as glucotoxicity, lipotoxicity, and inflammation selectively impair phosphatidylinositol 3-kinase dependent insulin signaling pathways, creating reciprocal relationships between insulin resistance and endothelial dysfunction. Diet, exercise, cardiovascular drugs, and insulin sensitizers simultaneously modulate phosphatidylinositol 3-kinase and mitogen-activated protein kinase dependent pathways, improving metabolic and vascular actions of insulin. Pathway-specific impairment in insulin action contributes to reciprocal relationships between endothelial dysfunction and insulin resistance, fostering clustering of metabolic and cardiovascular diseases in insulin-resistant states. Therapeutic interventions that target this selective impairment often simultaneously improve both metabolic and vascular function.

  5. Metabolic flexibility and insulin resistance.

    PubMed

    Galgani, Jose E; Moro, Cedric; Ravussin, Eric

    2008-11-01

    Metabolic flexibility is the capacity for the organism to adapt fuel oxidation to fuel availability. The inability to modify fuel oxidation in response to changes in nutrient availability has been implicated in the accumulation of intramyocellular lipid and insulin resistance. The metabolic flexibility assessed by the ability to switch from fat to carbohydrate oxidation is usually impaired during a hyperinsulinemic clamp in insulin-resistant subjects; however, this "metabolic inflexibility" is mostly the consequence of impaired cellular glucose uptake. Indeed, after controlling for insulin-stimulated glucose disposal rate (amount of glucose available for oxidation), metabolic flexibility is not altered in obesity regardless of the presence of type 2 diabetes. To understand how intramyocellular lipids accumulate and cause insulin resistance, the assessment of metabolic flexibility to high-fat diets is more relevant than metabolic flexibility during a hyperinsulinemic clamp. An impaired capacity to upregulate muscle lipid oxidation in the face of high lipid supply may lead to increased muscle fat accumulation and insulin resistance. Surprisingly, very few studies have investigated the response to high-fat diets. In this review, we discuss the role of glucose disposal rate, adipose tissue lipid storage, and mitochondrial function on metabolic flexibility. Additionally, we emphasize the bias of using the change in respiratory quotient to calculate metabolic flexibility and propose novel approaches to assess metabolic flexibility. On the basis of current evidence, one cannot conclude that impaired metabolic flexibility is responsible for the accumulation of intramyocellular lipid and insulin resistance. We propose to study metabolic flexibility in response to high-fat diets in individuals having contrasting degree of insulin sensitivity and/or mitochondrial characteristics.

  6. Insulin resistance in liver cirrhosis.

    PubMed

    Goral, Vedat; Atalay, Roni; Kucukoner, Mehmet; Kucukoren, Mehmet

    2010-01-01

    Liver cirrhosis is a chronic disease by degeneration, regeneration and fibrosis in the liver parenchyma, caused by many diseases. Insulin resistance can be defined as any type of decrease in the effect that may occur at the phases following insulin's secretion from beta-cells of the pancreas, where it is produced, until it has the expected effects in the target cells. The aim of the present study is to demonstrate the presence of insulin resistance in LC, which is common in our country and region, and investigate the existence of association between insulin resistance occuring in LC and cytokine levels, age, gender, CRP, Hs-CRP, Child-Pugh score and etiology of LC. A total of 79 patients with liver cirrhosis (group 1) were included in the study, and 50 subjects as controls (group 2). Of liver cirrhosis patients, 49 (62%) were male and 30 (38%) were female, with a mean age of 54.71 +/- 14.68. Of the controls, 23 (46%) were male and 27 (54%) were female, with a mean age of 41.9 +/- 11.54. Severity of cirrhosis was assessed by Modified Child-Turcoutte-Pugh score. Seven cases (8.9%) were at the Child-Pugh stage A, 35 cases (44.3%) at the Child-Pough stage B, and 37 cases (46.8%) at the Child-Pough stage C. HOMA-IR was calculated and values > 2.7 were regarded as presence of insulin resistance (HOMA-IR +). Serum glucose, albumin, bilirubin values were studied with enzymatic method (Architect C-16000); serum CRP, Hs-CRP values with nephelometric method by Beckman Coulter Image Nephelometer (immunochemistry system); insulin, C-peptide with electrochemiluminance immunological method; prothrombin time with radiation method by ACL-Advance brand device. In this study, glucose (p = 0.004), insulin (p = 0.010), C-peptide (p < 0.001), HOMA-IR (p < 0.001), TNF-alpha (p < 0.001), IL-2RES (p < 0.001), IL-6 (p = 0.002), CRP (p < 0.001) and HsCRP (p = 0.006) levels are elevated in LC patients, compared to control group. Consequently, high HOMA-IR in LC supports the fact that insulin

  7. Insulin resistance and hypertension: new insights.

    PubMed

    Soleimani, Manoocher

    2015-03-01

    Insulin resistance is associated with hypertension. Nakamura et al. demonstrate in rodents and humans with insulin resistance that while the stimulatory effect of insulin on glucose uptake in adipocytes, mediated via insulin receptor substrate 1 (IRS1), was severely diminished, its effect on salt reabsorption in the kidney proximal tubule, mediated via IRS2, was preserved. Compensatory hyperinsulinemia in individuals with insulin resistance may enhance salt absorption in the proximal tubule, resulting in a state of salt overload and hypertension.

  8. Nutritional Modulation of Insulin Resistance

    PubMed Central

    Weickert, Martin O.

    2012-01-01

    Insulin resistance has been proposed as the strongest single predictor for the development of Type 2 Diabetes (T2DM). Chronic oversupply of energy from food, together with inadequate physical activity, have been recognized as the most relevant factors leading to overweight, abdominal adiposity, insulin resistance, and finally T2DM. Conversely, energy reduced diets almost invariably to facilitate weight loss and reduce abdominal fat mass and insulin resistance. However, sustained weight loss is generally difficult to achieve, and distinct metabolic characteristics in patients with T2DM further compromise success. Therefore, investigating the effects of modulating the macronutrient composition of isoenergetic diets is an interesting concept that may lead to additional important insights. Metabolic effects of various different dietary concepts and strategies have been claimed, but results from randomized controlled studies and particularly from longer-term-controlled interventions in humans are often lacking. However, some of these concepts are supported by recent research, at least in animal models and short-term studies in humans. This paper provides an update of the current literature regarding the role of nutrition in the modulation of insulin resistance, which includes the discussion of weight-loss-independent metabolic effects of commonly used dietary concepts. PMID:24278690

  9. 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

  10. Molecular mechanisms of insulin resistance in diabetes.

    PubMed

    Soumaya, Kouidhi

    2012-01-01

    Molecular components of impaired insulin signaling pathway have emerged with growing interest to understand how the environment and genetic susceptibility combine to cause defects in this fundamental pathway that lead to insulin resistance. When insulin resistance is combined with beta-cell defects in glucose-stimulated insulin secretion, impaired glucose tolerance, hyperglycemia, or Type 2 diabetes can result. The most common underlying cause is obesity, although primary insulin resistance in normal-weight individuals is also possible. The adipose tissue releases free fatty acids that contribute to insulin resistance and also acts as a relevant endocrine organ producing mediators (adipokines) that can modulate insulin signalling. This chapter deals with the core elements promoting, insulin resistance, associated with impaired insulin signalling pathway and adipocyte dysfunction. A detailed understanding of these basic pathophysiological mechanisms is critical for the development of novel therapeutic strategies to treat diabetes.

  11. Nitrosative stress and pathogenesis of insulin resistance.

    PubMed

    Kaneki, Masao; Shimizu, Nobuyuki; Yamada, Daisuke; Chang, Kyungho

    2007-03-01

    Insulin resistance is a major causative factor for type 2 diabetes and is associated with increased risk of cardiovascular disease. Despite intense investigation for a number of years, molecular mechanisms underlying insulin resistance remain to be determined. Recently, chronic inflammation has been highlighted as a culprit for obesity-induced insulin resistance. Nonetheless, upstream regulators and downstream effectors of chronic inflammation in insulin resistance remain unclarified. Inducible nitric oxide synthase (iNOS), a mediator of inflammation, has emerged as an important player in insulin resistance. Obesity is associated with increased iNOS expression in insulin-sensitive tissues in rodents and humans. Inhibition of iNOS ameliorates obesity-induced insulin resistance. However, molecular mechanisms by which iNOS mediates insulin resistance remain largely unknown. Protein S-nitrosylation, a covalent attachment of NO moiety to thiol sulfhydryls, has emerged as a major mediator of a broad array of NO actions. S-nitrosylation is elevated in patients with type 2 diabetes, and increased S-nitrosylation of insulin signaling molecules, including insulin receptor, insulin receptor substrate-1, and Akt/PKB, has been shown in skeletal muscle of obese, diabetic mice. Akt/PKB is reversibly inactivated by S-nitrosylation. Based on these findings, S-nitrosylation has recently been proposed to play an important role in the pathogenesis of insulin resistance.

  12. Mechanisms of insulin resistance in obesity.

    PubMed

    Ye, Jianping

    2013-03-01

    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.

  13. 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

  14. Insulin and insulin signaling play a critical role in fat induction of insulin resistance in mouse

    PubMed Central

    Ning, Jie; Hong, Tao; Yang, Xuefeng; Mei, Shuang; Liu, Zhenqi; Liu, Hui-Yu

    2011-01-01

    The primary player that induces insulin resistance has not been established. Here, we studied whether or not fat can cause insulin resistance in the presence of insulin deficiency. Our results showed that high-fat diet (HFD) induced insulin resistance in C57BL/6 (B6) mice. The HFD-induced insulin resistance was prevented largely by the streptozotocin (STZ)-induced moderate insulin deficiency. The STZ-induced insulin deficiency prevented the HFD-induced ectopic fat accumulation and oxidative stress in liver and gastrocnemius. The STZ-induced insulin deficiency prevented the HFD- or insulin-induced increase in hepatic expression of long-chain acyl-CoA synthetases (ACSL), which are necessary for fatty acid activation. HFD increased mitochondrial contents of long-chain acyl-CoAs, whereas it decreased mitochondrial ADP/ATP ratio, and these HFD-induced changes were prevented by the STZ-induced insulin deficiency. In cultured hepatocytes, we observed that expressions of ACSL1 and -5 were stimulated by insulin signaling. Results in cultured cells also showed that blunting insulin signaling by the PI3K inhibitor LY-294002 prevented fat accumulation, oxidative stress, and insulin resistance induced by the prolonged exposure to either insulin or oleate plus sera that normally contain insulin. Finally, knockdown of the insulin receptor prevented the oxidative stress and insulin resistance induced by the prolonged exposure to insulin or oleate plus sera. Together, our results show that insulin and insulin signaling are required for fat induction of insulin resistance in mice and cultured mouse hepatocytes. PMID:21586696

  15. Interactions of endothelin and insulin: expanding parameters of insulin resistance.

    PubMed

    Strawbridge, Andrew B; Elmendorf, Jeffrey S; Mather, Kieren J

    2006-08-01

    Since the discovery of endothelin peptides in the mid-1980s by Yanigasawa and colleagues, accumulating evidence demonstrates that these peptides may function beyond vasoconstriction. Strong epidemiologic associations between insulin resistance and increased endothelin levels or activity have been found, and these associations have prompted studies investigating the interactions of endothelin with insulin. In this review we explore the evidence for such interactions at multiple levels of physiology, ranging from effects on tissue perfusion through modulation of vascular tone to subcellular interactions of endothelin signaling with insulin signaling. The evidence implicating endothelin in insulin resistance and its associated vascular and metabolic abnormalities is reviewed.

  16. Insulin resistance and skin diseases.

    PubMed

    Napolitano, Maddalena; Megna, Matteo; Monfrecola, Giuseppe

    2015-01-01

    In medical practice, almost every clinician may encounter patients with skin disease. However, it is not always easy for physicians of all specialties to face the daily task of determining the nature and clinical implication of dermatologic manifestations. Are they confined to the skin, representing a pure dermatologic event? Or are they also markers of internal conditions relating to the patient's overall health? In this review, we will discuss the principal cutaneous conditions which have been linked to metabolic alterations. Particularly, since insulin has an important role in homeostasis and physiology of the skin, we will focus on the relationships between insulin resistance (IR) and skin diseases, analyzing strongly IR-associated conditions such as acanthosis nigricans, acne, and psoriasis, without neglecting emerging and potential scenarios as the ones represented by hidradenitis suppurativa, androgenetic alopecia, and hirsutism.

  17. Insulin Resistance and Skin Diseases

    PubMed Central

    Napolitano, Maddalena; Megna, Matteo; Monfrecola, Giuseppe

    2015-01-01

    In medical practice, almost every clinician may encounter patients with skin disease. However, it is not always easy for physicians of all specialties to face the daily task of determining the nature and clinical implication of dermatologic manifestations. Are they confined to the skin, representing a pure dermatologic event? Or are they also markers of internal conditions relating to the patient's overall health? In this review, we will discuss the principal cutaneous conditions which have been linked to metabolic alterations. Particularly, since insulin has an important role in homeostasis and physiology of the skin, we will focus on the relationships between insulin resistance (IR) and skin diseases, analyzing strongly IR-associated conditions such as acanthosis nigricans, acne, and psoriasis, without neglecting emerging and potential scenarios as the ones represented by hidradenitis suppurativa, androgenetic alopecia, and hirsutism. PMID:25977937

  18. Animal models of insulin resistance: A review.

    PubMed

    Sah, Sangeeta Pilkhwal; Singh, Barinder; Choudhary, Supriti; Kumar, Anil

    2016-12-01

    Insulin resistance can be seen as a molecular and genetic mystery, with a role in the pathophysiology of type 2 diabetes mellitus. It is a basis for a number of chronic diseases like hypertension, dyslipidemia, glucose intolerance, coronary heart disease, cerebral vascular disease along with T2DM, thus the key is to cure and prevent insulin resistance. Critical perspicacity into the etiology of insulin resistance have been gained by the use of animal models where insulin action has been modulated by various transgenic and non-transgenic models which is not possible in human studies. The following review comprises the pathophysiology involved in insulin resistance, various factors causing insulin resistance, their screening and various genetic and non-genetic animal models highlighting the pathological and metabolic characteristics of each.

  19. Steroids and insulin resistance in pregnancy.

    PubMed

    Vejrazkova, Daniela; Vcelak, Josef; Vankova, Marketa; Lukasova, Petra; Bradnova, Olga; Halkova, Tereza; Kancheva, Radmila; Bendlova, Bela

    2014-01-01

    Metabolism of glucose during pregnancy reflects the equilibrium between lactogenic hormones stimulating insulin production and counterregulatory hormones inducing insulin resistance. In physiological pregnancies, insulin-mediated glucose uptake is substantially decreased and insulin secretion increased to maintain euglycemia. This common state of peripheral insulin resistance arises also due to steroid spectra changes. In this review article, we have focused on the role of steroid hormones (androgens, estrogens, gestagens, mineralocorticoids, glucocorticoids, as well as secosteroid vitamin D) in the impairment of glucose tolerance in pregnancy and in the pathogenesis of gestational diabetes mellitus. This article is part of a Special Issue entitled 'Pregnancy and Steroids'.

  20. Selective Insulin Resistance in the Kidney

    PubMed Central

    Horita, Shoko; Nakamura, Motonobu; Suzuki, Masashi; Satoh, Nobuhiko; Suzuki, Atsushi; Seki, George

    2016-01-01

    Insulin resistance has been characterized as attenuation of insulin sensitivity at target organs and tissues, such as muscle and fat tissues and the liver. The insulin signaling cascade is divided into major pathways such as the PI3K/Akt pathway and the MAPK/MEK pathway. In insulin resistance, however, these pathways are not equally impaired. For example, in the liver, inhibition of gluconeogenesis by the insulin receptor substrate (IRS) 2 pathway is impaired, while lipogenesis by the IRS1 pathway is preserved, thus causing hyperglycemia and hyperlipidemia. It has been recently suggested that selective impairment of insulin signaling cascades in insulin resistance also occurs in the kidney. In the renal proximal tubule, insulin signaling via IRS1 is inhibited, while insulin signaling via IRS2 is preserved. Insulin signaling via IRS2 continues to stimulate sodium reabsorption in the proximal tubule and causes sodium retention, edema, and hypertension. IRS1 signaling deficiency in the proximal tubule may impair IRS1-mediated inhibition of gluconeogenesis, which could induce hyperglycemia by preserving glucose production. In the glomerulus, the impairment of IRS1 signaling deteriorates the structure and function of podocyte and endothelial cells, possibly causing diabetic nephropathy. This paper mainly describes selective insulin resistance in the kidney, focusing on the proximal tubule. PMID:27247938

  1. Angiotensin and insulin resistance: conspiracy theory.

    PubMed

    Townsend, Raymond R

    2003-04-01

    Resistance to the metabolic effects of insulin is a contender for the short list of major cardiovascular risk factors. Since the elements of the syndrome of insulin resistance were first articulated together in 1988, numerous epidemiologic investigations and treatment endeavors have established a relationship between the metabolic disarray of impaired insulin action and cardiovascular disease. Angiotensin II, the primary effector of the renin-angiotensin system, has also achieved a place in the chronicles of cardiovascular risk factors. Conspiracy mechanisms by which angiotensin II and insulin resistance interact in the pathogenesis of cardiovascular disease are reviewed, with particular attention to recent developments in this engaging area of human research.

  2. Neferine enhances insulin sensitivity in insulin resistant rats.

    PubMed

    Pan, Yang; Cai, Baochang; Wang, Kelin; Wang, Sumin; Zhou, Shuyuan; Yu, Xiaochun; Xu, Bin; Chen, Long

    2009-07-06

    Neferine was isolated from green seed embryo of Nelumbo nucifera Gaertn which has been used as an anti-obesity agent in traditional Chinese herbal medicine. This study was conducted to investigate the effects of neferine on enhancing insulin sensitivity in insulin resistant rats compared with rosiglitazone and to potentially reveal its role in mediating the anti-obesity properties of Nelumbo nucifera Gaertn. Fasting blood glucose (FBG), fasting blood insulin (FINS), triglycerides (TG) and tumor necrosis factor-alpha (TNF-alpha) were measured, and the oral glucose tolerance test for 2-h plasma glucose level (2-h PG) was carried out. The glucose infusion rate (GIR) was used to measure the insulin sensitivity by hyperinsulinemic euglycemic clamp technique. The levels of FBG, FINS, TG, TNF-alpha and 2-h PG all decreased significantly in the rosiglitazone and neferine groups compared with the insulin resistance (IR) model group. Neferine diminished the 2-h PG more than did rosiglitazone treatment. Compared to the IR model group, the treatments of neferine and rosiglitazone remarkably increased GIRs but no difference between these two treatments themselves was evident. These data demonstrate that neferine has effects similar to rosiglitazone in decreasing fasting blood glucose, insulin, TG, TNF-alpha and enhancing insulin sensitivity in insulin resistant rats.

  3. Effect of fensuccinal on experimental insulin resistance.

    PubMed

    Gorbenko, N I; Poltorak, V V; Gladkikh, A I; Ivanova, O V

    2000-07-01

    The effects of new antioxidant fensuccinal on dexamethasone-induced insulin resistance in rats were studied. Oral administration of fensuccinal in a dose of 25 mg/kg for 2 weeks prevented basal hyperinsulinemia and insulin insensitivity of peripheral tissues. Fensuccinal also attenuated oxidative stress by decreasing the concentrations of primary and secondary lipid peroxidation products in liver homogenates. The ability of fensuccinal to prevent dexamethasone-induced insulin resistance is probably due to its antioxidant properties.

  4. [Insulin resistance pathogenesis in metabolic obesity].

    PubMed

    Litvinova, L S; Kirienkova, E V; Mazunin, I O; Vasilenko, M A; Fattakhov, N S

    2015-01-01

    In this review we discuss the molecular mechanisms of insulin resistance concomitant with metabolic inflammation. We also analyze the world results of experimental and clinical studies which aimed at identifying the molecular targets for the development of new prevention and treatment of insulin resistance.

  5. Genetics Home Reference: type A insulin resistance syndrome

    MedlinePlus

    ... Conditions type A insulin resistance syndrome type A insulin resistance syndrome Enable Javascript to view the expand/ ... PDF Open All Close All Description Type A insulin resistance syndrome is a rare disorder characterized by ...

  6. Treatment Approach to Patients With Severe Insulin Resistance

    PubMed Central

    Church, Timothy J.

    2016-01-01

    In Brief Patients with severe insulin resistance require >2 units/kg of body weight or 200 units/day of insulin. Yet, many patients do not achieve glycemic targets despite using very high doses of insulin. Insulin can cause weight gain, which further contributes to worsening insulin resistance. This article describes the pharmacological options for managing patients with severe insulin resistance, including the use of U-500 insulin and newer agents in combination with insulin. PMID:27092020

  7. Effect of cigarette smoking on insulin resistance risk.

    PubMed

    Haj Mouhamed, D; Ezzaher, A; Neffati, F; Douki, W; Gaha, L; Najjar, M F

    2016-02-01

    Smoking is one of the main risk factors for cardiovascular disease (CVD). The mechanism(s) of the effects of smoking on CVD are not clearly understood; however, a number of atherogenic characteristics, such as insulin resistance have been reported. We aim to investigate the effects of cigarette smoking on insulin resistance and to determine the correlation between this parameter with smoking status characteristics. This study was conducted on 138 non-smokers and 162 smokers aged respectively 35.6±16.0 and 38.5±21.9 years. All subjects are not diabetic. Fasting glucose was determined by enzymatic methods and insulin by chemiluminescence method. Insulin resistance (IR) was estimated using the Homeostasis Model of Assessment equation: HOMA-IR=[fasting insulin (mU/L)×fasting glucose (mmol/L)]/22.5. IR was defined as the upper quartile of HOMA-IR. Values above 2.5 were taken as abnormal and reflect insulin resistance. Compared to non-smokers, smokers had significantly higher levels of fasting glucose, fasting insulin and HOMA-IR index. These associations remained significant after adjustment for confounding factors (age, gender, BMI and alcohol consumption). A statistically significant association was noted between the smoking status parameters, including both the number of cigarettes smoked/day and the duration of smoking, and fasting insulin levels as well for HOMA-IR index. Among smokers, we noted a positive correlation between HOMA-IR index and both plasma thiocyanates and urinary cotinine. Our results show that smokers have a high risk to developing an insulin resistance and hyperinsulinemia, compared with a matched group of non-smokers, and may help to explain the high risk of cardiovascular diseases in smokers. Copyright © 2015. Published by Elsevier SAS.

  8. Related factors of insulin resistance in Korean children: adiposity and maternal insulin resistance.

    PubMed

    Cho, Young-Gyu; Kang, Jae-Heon; Hur, Yang-Im; Song, Jihyun; Lee, Kang-Sook

    2011-12-01

    Increased adiposity and unhealthy lifestyle augment the risk for type 2 diabetes in children with familial predisposition. Insulin resistance (IR) is an excellent clinical marker for identifying children at high risk for type 2 diabetes. This study was conducted to investigate parental, physiological, behavioral and socio-economic factors related to IR in Korean children. This study is a cross-sectional study using data from 111 children aged 7 years and their parents. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated using fasting glucose and insulin level as a marker of IR. All children's adiposity indices (r = 0.309-0.318, all P-value = 0.001) and maternal levels of fasting insulin (r = 0.285, P-value = 0.003) and HOMA-IR (r = 0.290, P-value = 0.002) were positively correlated with children's HOMA-IR level. There was no statistical difference of children's HOMA-IR level according to children's lifestyle habits and socioeconomic status of families. An increase of 1 percentage point in body fat was related to 2.7% increase in children's HOMA-IR (P-value < 0.001) and an increase of 1% of maternal level of HOMA-IR was related to 0.2% increase in children's HOMA-IR (P-value = 0.002). This study shows that children's adiposity and maternal IR are positively associated with children's IR.

  9. Increased insulin translation from an insulin splice-variant overexpressed in diabetes, obesity, and insulin resistance.

    PubMed

    Minn, Alexandra H; Lan, Hong; Rabaglia, Mary E; Harlan, David M; Peculis, Brenda A; Attie, Alan D; Shalev, Anath

    2005-03-01

    Type 2 diabetes occurs when pancreatic beta-cells become unable to compensate for the underlying insulin resistance. Insulin secretion requires beta-cell insulin stores to be replenished by insulin biosynthesis, which is mainly regulated at the translational level. Such translational regulation often involves the 5'-untranslated region. Recently, we identified a human insulin splice-variant (SPV) altering only the 5'-untranslated region and conferring increased translation efficiency. We now describe a mouse SPV (mSPV) that is found in the cytoplasm and exhibits increased translation efficiency resulting in more normal (prepro)insulin protein per RNA. The RNA stability of mSPV is not increased, but the predicted secondary RNA structure is altered, which may facilitate translation. To determine the role of mSPV in insulin resistance and diabetes, mSPV expression was measured by quantitative real-time RT-PCR in islets from three diabetic and/or insulin-resistant, obese and nonobese, mouse models (BTBRob/ob, C57BL/6ob/ob, and C57BL/6azip). Interestingly, mSPV expression was significantly higher in all diabetic/insulin-resistant mice compared with wild-type littermates and was dramatically induced in primary mouse islets incubated at high glucose. This raises the possibility that the mSPV may represent a compensatory beta-cell mechanism to enhance insulin biosynthesis when insulin requirements are elevated by hyperglycemia/insulin resistance.

  10. Insulin Resistance, Hyperinsulinemia, and Energy Intake in Overweight Children

    PubMed Central

    Han, Joan C.; Rutledge, Margaret S.; Kozlosky, Merel; Salaita, Christine G.; Gustafson, Jennifer K.; Keil, Margaret F.; Fleisch, Abby F.; Roberts, Mary D.; Ning, Cong; Yanovski, Jack A.

    2008-01-01

    Objective To examine the relationship between energy intake during a buffet meal and indices of insulin dynamics in overweight children. Study design 95 non-diabetic, overweight (BMI ≥95th percentile) children (age 10.3±1.4y) selected lunch from a 9,835kcal buffet eaten ad libitum after an overnight fast. The associations between energy intake and measures of insulin dynamics, in the post-absorptive state and during a 2h-hyperglycemic clamp, were determined. Covariates in the statistical model included race, sex, skeletal age, fat-free mass, fat mass, socioeconomic status, and number of foods in the buffet rated as acceptable. Results Energy intake was positively associated with the fasting homeostasis model assessment for insulin resistance index (HOMA-IR; β=0.24, p=0.042), fasting insulin/glucose ratio (β=0.24, p=0.044), 1st-phase insulin (β=0.23, p=0.032), and 1st-phase C-peptide (β=0.21, p=0.046); energy intake was negatively associated with clamp-derived insulin sensitivity (SIclamp; β= -0.29, p=0.042). Each 10% decrease in SIclamp predicted 27 kcal greater energy intake. Conclusions Insulin resistance and hyperinsulinemia are associated with greater energy intake after an overnight fast in overweight children. These associations suggest mechanisms whereby insulin resistance may contribute to excessive weight gain in children. PMID:18410761

  11. Insulin resistance in porphyria cutanea tarda.

    PubMed

    Calcinaro, F; Basta, G; Lisi, P; Cruciani, C; Pietropaolo, M; Santeusanio, F; Falorni, A; Calafiore, R

    1989-06-01

    It has been reported that patients with porphyria cutanea tarda (PCT) develop carbohydrate (CHO) intolerance and manifest diabetes melitus (DM) more frequently than the normal population. In order to verify whether this is due to insulin resistance we studied 5 patients with PCT and 5 normal subjects matched for age, sex and weight. In all the patients an evaluation consisted of the glycemic curve and insulin response to an iv glucose tolerance test (IVGTT: 0.33 g/kg) as well as of an evaluation of the circulating monocyte insulin receptors. Blood samples were drawn in the basal state to measure plasma levels of NEFA, glycerol, and intermediate metabolites. The patients with PCT showed normal glucose tolerance which was obtained, however, at the expense of the elevated insulin levels: therefore a condition of insulin resistance was demonstrated in these subjects. An involvement of the lipid metabolism, observed by the raised levels of plasma NEFA and glycerol, was also evident. The insulin binding to circulating monocytes was reduced but not enough to justify the degree of insulin resistance observed. Therefore, it could be hypothesized, in agreement with similar studies, that a postreceptor defect is responsible for the insulin-resistance observed in patients with PCT and that the reduction of insulin receptors is determined by the down regulation in response to elevated insulinemic levels. An alteration of the porphyrin metabolism might be responsible for this disorder.

  12. Insulin Receptor Signaling in Normal and Insulin-Resistant States

    PubMed Central

    Boucher, Jérémie; Kleinridders, André; Kahn, C. Ronald

    2014-01-01

    In the wake of the worldwide increase in type-2 diabetes, a major focus of research is understanding the signaling pathways impacting this disease. Insulin signaling regulates glucose, lipid, and energy homeostasis, predominantly via action on liver, skeletal muscle, and adipose tissue. Precise modulation of this pathway is vital for adaption as the individual moves from the fed to the fasted state. The positive and negative modulators acting on different steps of the signaling pathway, as well as the diversity of protein isoform interaction, ensure a proper and coordinated biological response to insulin in different tissues. Whereas genetic mutations are causes of rare and severe insulin resistance, obesity can lead to insulin resistance through a variety of mechanisms. Understanding these pathways is essential for development of new drugs to treat diabetes, metabolic syndrome, and their complications. PMID:24384568

  13. Selective insulin resistance in hepatocyte senescence

    SciTech Connect

    Aravinthan, Aloysious; Challis, Benjamin; Shannon, Nicholas; Hoare, Matthew; Heaney, Judith; Alexander, Graeme J.M.

    2015-02-01

    Insulin resistance has been described in association with chronic liver disease for decades. Hepatocyte senescence has been demonstrated in chronic liver disease and as many as 80% of hepatocytes show a senescent phenotype in advanced liver disease. The aim of this study was to understand the role of hepatocyte senescence in the development of insulin resistance. Senescence was induced in HepG2 cells via oxidative stress. The insulin metabolic pathway was studied in control and senescent cells following insulin stimulation. GLUT2 and GLUT4 expressions were studied in HepG2 cells and human liver tissue. Further, GLUT2 and GLUT4 expressions were studied in three independent chronic liver disease cohorts. Signalling impairment distal to Akt in phosphorylation of AS160 and FoxO1 was evident in senescent HepG2 cells. Persistent nuclear localisation of FoxO1 was demonstrated in senescent cells despite insulin stimulation. Increased GLUT4 and decreased GLUT2 expressions were evident in senescent cells, human cirrhotic liver tissue and publically available liver disease datasets. Changes in GLUT expressions were associated with a poor clinical prognosis. In conclusion, selective insulin resistance is evident in senescent HepG2 cells and changes in GLUT expressions can be used as surrogate markers of hepatocyte senescence. - Highlights: • Senescent hepatocytes demonstrate selective insulin resistance. • GLUT changes act as markers of hepatocyte senescence and have prognostic value. • Study offers insight into long noticed intimacy of cirrhosis and insulin resistance.

  14. [Beyond immunopathogenesis. Insulin resistance and "epidermal dysfunction"].

    PubMed

    Boehncke, W-H; Boehncke, S; Buerger, C

    2012-03-01

    Insulin is a central player in the regulation of metabolic as well as non-metabolic cells: inefficient signal transduction (insulin resistance) not only represents the cornerstone in the pathogenesis of type 2 diabetes mellitus, but also drives atherosclerosis through inducing endothelial dysfunction. Last but not least epidermal homeostasis depends on insulin. We summarize the effects of insulin on proliferation and differentiation of human keratinocytes as well as the relevance of cytokine-induced insulin resistance for alterations in epidermal homeostasis characteristic for psoriasis. Kinases involved in both insulin- as well as cytokine-receptor signaling represent potential targets for innovative therapeutics. Such small molecules would primarily normalize "epidermal dysfunction", thus complementing the immunomodulatory strategies of today's biologics.

  15. 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

  16. Acute Glucagon Induces Postprandial Peripheral Insulin Resistance

    PubMed Central

    Patarrão, Rita S.; Lautt, W. Wayne; Macedo, M. Paula

    2015-01-01

    Glucagon levels are often moderately elevated in diabetes. It is known that glucagon leads to a decrease in hepatic glutathione (GSH) synthesis that in turn is associated with decreased postprandial insulin sensitivity. Given that cAMP pathway controls GSH levels we tested whether insulin sensitivity decreases after intraportal (ipv) administration of a cAMP analog (DBcAMP), and investigated whether glucagon promotes insulin resistance through decreasing hepatic GSH levels.Insulin sensitivity was determined in fed male Sprague-Dawley rats using a modified euglycemic hyperinsulinemic clamp in the postprandial state upon ipv administration of DBcAMP as well as glucagon infusion. Glucagon effects on insulin sensitivity was assessed in the presence or absence of postprandial insulin sensitivity inhibition by administration of L-NMMA. Hepatic GSH and NO content and plasma levels of NO were measured after acute ipv glucagon infusion. Insulin sensitivity was assessed in the fed state and after ipv glucagon infusion in the presence of GSH-E. We founf that DBcAMP and glucagon produce a decrease of insulin sensitivity, in a dose-dependent manner. Glucagon-induced decrease of postprandial insulin sensitivity correlated with decreased hepatic GSH content and was restored by administration of GSH-E. Furthermore, inhibition of postprandial decrease of insulin sensitivity L-NMMA was not overcome by glucagon, but glucagon did not affect hepatic and plasma levels of NO. These results show that glucagon decreases postprandial insulin sensitivity through reducing hepatic GSH levels, an effect that is mimicked by increasing cAMP hepatic levels and requires physiological NO levels. These observations support the hypothesis that glucagon acts via adenylate cyclase to decrease hepatic GSH levels and induce insulin resistance. We suggest that the glucagon-cAMP-GSH axis is a potential therapeutic target to address insulin resistance in pathological conditions. PMID:25961284

  17. Acute glucagon induces postprandial peripheral insulin resistance.

    PubMed

    Patarrão, Rita S; Lautt, W Wayne; Macedo, M Paula

    2015-01-01

    Glucagon levels are often moderately elevated in diabetes. It is known that glucagon leads to a decrease in hepatic glutathione (GSH) synthesis that in turn is associated with decreased postprandial insulin sensitivity. Given that cAMP pathway controls GSH levels we tested whether insulin sensitivity decreases after intraportal (ipv) administration of a cAMP analog (DBcAMP), and investigated whether glucagon promotes insulin resistance through decreasing hepatic GSH levels.Insulin sensitivity was determined in fed male Sprague-Dawley rats using a modified euglycemic hyperinsulinemic clamp in the postprandial state upon ipv administration of DBcAMP as well as glucagon infusion. Glucagon effects on insulin sensitivity was assessed in the presence or absence of postprandial insulin sensitivity inhibition by administration of L-NMMA. Hepatic GSH and NO content and plasma levels of NO were measured after acute ipv glucagon infusion. Insulin sensitivity was assessed in the fed state and after ipv glucagon infusion in the presence of GSH-E. We founf that DBcAMP and glucagon produce a decrease of insulin sensitivity, in a dose-dependent manner. Glucagon-induced decrease of postprandial insulin sensitivity correlated with decreased hepatic GSH content and was restored by administration of GSH-E. Furthermore, inhibition of postprandial decrease of insulin sensitivity L-NMMA was not overcome by glucagon, but glucagon did not affect hepatic and plasma levels of NO. These results show that glucagon decreases postprandial insulin sensitivity through reducing hepatic GSH levels, an effect that is mimicked by increasing cAMP hepatic levels and requires physiological NO levels. These observations support the hypothesis that glucagon acts via adenylate cyclase to decrease hepatic GSH levels and induce insulin resistance. We suggest that the glucagon-cAMP-GSH axis is a potential therapeutic target to address insulin resistance in pathological conditions.

  18. Caffeine and insulin resistance in pregnancy

    PubMed Central

    Laughon, S. Katherine; Powers, Robert W.; Roberts, James M.; Parana, Sarah; Catov, Janet

    2011-01-01

    Outside pregnancy, acute caffeine consumption is associated with insulin resistance. We investigated if during pregnancy plasma concentrations of caffeine and its metabolite, paraxanthine, were associated with insulin resistance. Caffeine, paraxanthine, glucose and insulin were measured and insulin resistance estimated by homeostasis model assessment (HOMA) in banked samples from 251 fasting subjects at mean gestational age of 20.3 ± 2.0 weeks. Analysis of covariance and adjusted logistic regression were performed. Most (96.4%) women had caffeine and/or paraxanthine present. Caffeine concentrations in the upper two quartiles (> 266 ng/ml) were associated with 3-fold higher odds of having higher insulin resistance estimated by log HOMA ≥ 75th percentile (3rd quartile OR, 3.02; 95% CI: 1.21 – 7.54 and 4th quartile OR, 2.95; 95% CI: 1.19 – 7.31). Paraxanthine concentrations in the upper quartile (> 392 ng/ml) were also associated with 3-fold higher odds of having higher insulin resistance (OR, 3.04; 95% CI: 1.28 – 7.25). Adjusted mean HOMA in the 1st caffeine to paraxanthine ratio quartile was 1.5 ± 2.2 versus 1.3 ± 2.3 in the 4th quartile (P < .01). Both high caffeine and paraxanthine concentrations were associated with insulin resistance, but slow versus fast metabolism did not make an important difference. PMID:21380987

  19. Association Between Insulin Resistance and Luminal B Subtype Breast Cancer in Postmenopausal Women.

    PubMed

    Nam, Sanggeun; Park, Seho; Park, Hyung Seok; Kim, Sanghwa; Kim, Jee Ye; Kim, Seung Il

    2016-03-01

    Currently, there is limited information on the clinical characteristics of breast cancer patients with insulin resistance. Hence, the purpose of this study was to investigate the association between insulin resistance and clinicopathological factors in newly diagnosed breast cancer patients without diabetes. We assessed 760 patients with breast cancer treated between 2012 and 2014. We compared the clinicopathological characteristics between patients with and without insulin resistance using univariate and multivariate analyses, including after stratification by menopausal status. Insulin resistance was defined according to the homeostatic model assessment of insulin resistance. Of 760 patients, 26.4% had insulin resistance. Age, menopausal status, body mass index, tumor size, histologic grade, Ki-67 expression, and breast cancer subtype significantly differed according to the presence of insulin resistance. Multivariate analysis revealed that postmenopausal status and obesity were significantly associated with insulin resistance. In postmenopausal women, older age, obesity, larger tumor size, advanced stage, and high proliferative luminal B subtype were significantly associated with insulin resistance. In contrast, in premenopausal patients, only obesity was related to insulin resistance. Multivariate analysis indicated that insulin resistance was independently correlated with obesity, larger tumor size, and the luminal B/human epidermal growth factor receptor-2-negative subtype in postmenopausal but not premenopausal patients. Insulin resistance was significantly associated with larger tumors and proliferative luminal B subtype breast cancer in postmenopausal women only. These findings suggest that insulin resistance could mechanistically induce tumor progression and might be a good prognostic factor, and that it could represent a therapeutic target in postmenopausal patients with breast cancer.

  20. Association Between Insulin Resistance and Luminal B Subtype Breast Cancer in Postmenopausal Women

    PubMed Central

    Nam, Sanggeun; Park, Seho; Park, Hyung Seok; Kim, Sanghwa; Kim, Jee Ye; Kim, Seung Il

    2016-01-01

    Abstract Currently, there is limited information on the clinical characteristics of breast cancer patients with insulin resistance. Hence, the purpose of this study was to investigate the association between insulin resistance and clinicopathological factors in newly diagnosed breast cancer patients without diabetes. We assessed 760 patients with breast cancer treated between 2012 and 2014. We compared the clinicopathological characteristics between patients with and without insulin resistance using univariate and multivariate analyses, including after stratification by menopausal status. Insulin resistance was defined according to the homeostatic model assessment of insulin resistance. Of 760 patients, 26.4% had insulin resistance. Age, menopausal status, body mass index, tumor size, histologic grade, Ki-67 expression, and breast cancer subtype significantly differed according to the presence of insulin resistance. Multivariate analysis revealed that postmenopausal status and obesity were significantly associated with insulin resistance. In postmenopausal women, older age, obesity, larger tumor size, advanced stage, and high proliferative luminal B subtype were significantly associated with insulin resistance. In contrast, in premenopausal patients, only obesity was related to insulin resistance. Multivariate analysis indicated that insulin resistance was independently correlated with obesity, larger tumor size, and the luminal B/human epidermal growth factor receptor-2-negative subtype in postmenopausal but not premenopausal patients. Insulin resistance was significantly associated with larger tumors and proliferative luminal B subtype breast cancer in postmenopausal women only. These findings suggest that insulin resistance could mechanistically induce tumor progression and might be a good prognostic factor, and that it could represent a therapeutic target in postmenopausal patients with breast cancer. PMID:26945364

  1. Resistin: insulin resistance to malignancy.

    PubMed

    Codoñer-Franch, Pilar; Alonso-Iglesias, Eulalia

    2015-01-01

    Adipose tissue is recognized as an endocrine organ that secretes bioactive substances known as adipokines. Excess adipose tissue and adipose tissue dysfunction lead to dysregulated adipokine production that can contribute to the development of obesity-related co-morbidities. Among the various adipokines, resistin, which was initially considered as a determinant of the emergence of insulin resistance in obesity, has appeared as an important link between obesity and inflammatory processes. Several experimental and clinical studies have suggested an association between increased resistin levels and severe conditions associated with obesity such as cardiovascular disease and malignancies. In this review, we present the growing body of evidence that human resistin is an inflammatory biomarker and potential mediator of obesity-associated diseases. A common pathway seems to involve the combined alteration of immune and inflammatory processes that favor metabolic disturbances, atherosclerosis and carcinogenesis. The mode of action and the signaling pathways utilized by resistin in its interactions with target cells could involve oxidative and nitrosative stress. Therefore, resistin could function as a key molecule in the complications of obesity development and could potentially be used as a diagnostic and prognostic marker. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. Fatty Acids, Obesity and Insulin Resistance.

    PubMed

    Arner, Peter; Rydén, Mikael

    2015-01-01

    Although elevated free fatty acid (FFA) levels in obesity have been considered to be of importance for insulin resistance, a recent meta-analysis suggested normal FFA levels in obese subjects. We investigated fasting circulating FFA and glycerol levels in a large cohort of non-obese and obese subjects. Subjects recruited for a study on obesity genetics were investigated in the morning after an overnight fast (n = 3,888). Serum FFA (n = 3,306), plasma glycerol (n = 3,776), and insulin sensitivity index (HOMA-IR,n = 3,469) were determined. Obesity was defined as BMI ≥ 30 kg/m 2 and insulin resistance as HOMA-IR ≥ 2.21. In obese subjects, circulating FFA and glycerol levels were higher than in non-obese individuals (by 26% and 47%, respectively; both p < 0.0001). Similar results were obtained if only men, women or medication-free subjects were investigated. Insulin resistance and type 2 diabetes were associated with a further minor increase in FFA/glycerol among obese subjects. When comparing insulin-sensitive non-obese with insulin-sensitive or -resistant obese individuals, FFA and glycerol were 21–29% and 43–49% higher in obese individuals, respectively. Circulating FFA and glycerol levels are markedly elevated in obesity but only marginally influenced by insulin resistance and type 2 diabetes. Whether these differences persist during diurnal variations in circulating FFA/glycerol, remains to be established

  3. Measuring psychological insulin resistance: barriers to insulin use.

    PubMed

    Larkin, Mary E; Capasso, Virginia A; Chen, Chien-Lin; Mahoney, Ellen K; Hazard, Barbara; Cagliero, Enrico; Nathan, David M

    2008-01-01

    The purpose of this study is to explore the attitudes that contribute to psychological insulin resistance (PIR) in insulin-naive patients with type 2 diabetes and to identify predictors of PIR. A prospective study using 2 self-report surveys and incorporating demographic and health variables was conducted to determine the prevalence of PIR among a sample of 100 adult, insulin-naive patients with type 2 diabetes at an outpatient diabetes center in a university-affiliated teaching hospital. Thirty-three percent of patients with type 2 diabetes were unwilling to take insulin. The most commonly expressed negative attitudes were concern regarding hypoglycemia, permanent need for insulin therapy, less flexibility, and feelings of failure. Less than 40% expressed fear of self-injection or thought that injections were painful. However, compared with willing subjects, unwilling subjects were more likely to fear injections and thought injections would be painful, life would be less flexible, and taking insulin meant health would deteriorate (P< .005 for all comparisons). Poorer general health and higher depression scores also correlated with PIR. The results of the surveys, which were generally consistent, identified several remediable misconceptions regarding insulin therapy and suggest targets for educational interventions.

  4. Insulin, glucose, insulin resistance, and pancreatic cancer in male smokers.

    PubMed

    Stolzenberg-Solomon, Rachael Z; Graubard, Barry I; Chari, Suresh; Limburg, Paul; Taylor, Philip R; Virtamo, Jarmo; Albanes, Demetrius

    2005-12-14

    Obesity, diabetes mellitus, and glucose intolerance have been associated with increased pancreatic cancer risk; however, prediagnostic serum insulin concentration has not been evaluated as a predictor of this malignancy. To investigate whether prediagnostic fasting glucose and insulin concentrations and insulin resistance are associated with subsequent incidence of exocrine pancreatic cancer in a cohort of male smokers. A case-cohort prospective study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (1985-1988) cohort of 29,133 male Finnish smokers ages 50 to 69 years. The study included 400 randomly sampled subcohort control participants and 169 incident pancreatic cancer cases that occurred after the fifth year of follow-up. All participants were followed up through December 2001 (up to 16.7 years of follow-up). Incident exocrine pancreatic cancer identified from the Finnish Cancer Registry. After adjusting for age, smoking, and body mass index, higher baseline fasting serum concentrations of glucose, insulin, and insulin resistance were positively associated with pancreatic cancer. The presence of biochemically defined diabetes mellitus (glucose, > or =126 mg/dL [> or =6.99 mmol/L]) and insulin concentration in the highest vs lowest quartile both showed a significant 2-fold increased risk (hazard ratio [HR], 2.13; 95% confidence interval [CI], 1.04-4.35; and HR, 2.01; 95% CI, 1.03-3.93; respectively). There were significant interactions for all the biomarker exposures by follow-up time, such that the positive associations were stronger among the cases that occurred more than 10 years after baseline (highest vs lowest quartile: glucose, HR, 2.16; 95% CI, 1.05-4.42; P for trend = .02; insulin, HR, 2.90; 95% CI, 1.22-6.92; P for trend = .005; and insulin resistance, HR, 2.71; 95% CI, 1.19-6.18; P for trend = .006). These results support the hypothesis that exposure to higher insulin concentrations and insulin resistance predicts the risk of

  5. Perpetuating Effects of Androgen Deficiency on Insulin-resistance

    PubMed Central

    Cameron, Judy L.; Jain, Ruhee; Rais, Maham; White, Ashley E.; Beer, Tomasz M.; Kievit, Paul; Winters-Stone, Kerri; Messaoudi, Ilhem; Varlamov, Oleg

    2016-01-01

    Background/Objectives Androgen deprivation therapy (ADT) is commonly used for treatment of prostate cancer, but is associated with side effects such as sarcopenia and insulin resistance. The role of lifestyle factors such as diet and exercise on insulin sensitivity and body composition in testosterone-deficient males is poorly understood. The aim of the present study was to examine the relationships between androgen status, diet, and insulin sensitivity. Subjects/Methods Middle-aged (11–12-yo) intact and orchidectomized male rhesus macaques were maintained for two months on a standard chow diet, and then exposed for six months to a Western-style, high-fat/calorie-dense diet (WSD) followed by four months of caloric restriction (CR). Body composition, insulin sensitivity, physical activity, serum cytokine levels, and adipose biopsies were evaluated before and after each dietary intervention. Results Both intact and orchidectomized animals gained similar proportions of body fat, developed visceral and subcutaneous adipocyte hypertrophy, and became insulin resistant in response to the WSD. CR reduced body fat in both groups, but reversed insulin resistance only in intact animals. Orchidectomized animals displayed progressive sarcopenia, which persisted after the switch to CR. Androgen deficiency was associated with increased levels of interleukin-6 and macrophage-derived chemokine (CCL22), both of which were elevated during CR. Physical activity levels showed a negative correlation with body fat and insulin sensitivity. Conclusion Androgen deficiency exacerbated the negative metabolic side effects of the WSD, such that CR alone was not sufficient to improve altered insulin sensitivity, suggesting that ADT patients will require additional interventions to reverse insulin resistance and sarcopenia. PMID:27534842

  6. Insulin resistance and outcome in bipolar disorder.

    PubMed

    Calkin, Cynthia V; Ruzickova, Martina; Uher, Rudolf; Hajek, Tomas; Slaney, Claire M; Garnham, Julie S; O'Donovan, M Claire; Alda, Martin

    2015-01-01

    Little is known about the impact of insulin resistance on bipolar disorder. To examine the relationships between insulin resistance, type 2 diabetes and clinical course and treatment outcomes in bipolar disorder. We measured fasting glucose and insulin in 121 adults with bipolar disorder. We diagnosed type 2 diabetes and determined insulin resistance. The National Institute of Mental Health Life Chart was used to record the course of bipolar disorder and the Alda scale to establish response to prophylactic lithium treatment. Patients with bipolar disorder and type 2 diabetes or insulin resistance had three times higher odds of a chronic course of bipolar disorder compared with euglycaemic patients (50% and 48.7% respectively v. 27.3%, odds ratio (OR) = 3.07, P = 0.007), three times higher odds of rapid cycling (38.5% and 39.5% respectively v. 18.2%, OR = 3.13, P = 0.012) and were more likely to be refractory to lithium treatment (36.8% and 36.7% respectively v. 3.2%, OR = 8.40, P<0.0001). All associations remained significant after controlling for antipsychotic exposure and body mass index in sensitivity analyses. Comorbid insulin resistance may be an important factor in resistance to treatment in bipolar disorder. Royal College of Psychiatrists.

  7. Corticosterone-induced insulin resistance is not associated with alterations of insulin receptor number and kinase activity in chicken kidney.

    PubMed

    Bisbis, S; Taouis, M; Derouet, M; Chevalier, B; Simon, J

    1994-12-01

    Chicken renal insulin receptors have been recently characterized; their number and kinase activities vary in response to altered nutritional status. In the present study, the effect of chronic corticosterone treatment was examined in 5-week-old chickens. The development of an insulin resistance following corticosterone was suggested after 1 and 2 weeks of treatment by a significant increases in plasma insulin levels (1.63 +/- 0.13 vs 0.56 +/- 0.14 ng insulin/ml in controls) and in renal cytosolic phosphoenolpyruvate carboxykinase activity (17.2 +/- 0.8 vs 13.7 +/- 0.7 nm/mn/mg tissue in controls). No significant changes were present at the level of insulin receptor number and kinase activity. Therefore, in kidney and, as previously observed, in muscles, corticosterone can induce insulin resistance at postreceptor steps in the cascade of events leading to insulin action.

  8. Insulin resistance and chronic liver disease

    PubMed Central

    Kawaguchi, Takumi; Taniguchi, Eitaro; Itou, Minoru; Sakata, Masahiro; Sumie, Shuji; Sata, Michio

    2011-01-01

    Increased insulin resistance is frequently associated with chronic liver disease and is a pathophysiological feature of hepatogenous diabetes. Distinctive factors including hepatic parenchymal cell damage, portal-systemic shunting and hepatitis C virus are responsible for the development of hepatogenous insulin resistance/diabetes. Although it remains unclear whether insulin secretion from pancreatic beta cells is impaired as it is in type 2 diabetes, retinopathic and cardiovascular risk is low and major causes of death in cirrhotic patients with diabetes are liver failure, hepatocellular carcinoma and gastrointestinal hemorrhage. Hemoglobin A1c is an inaccurate marker for the assessment and management of hepatogenous diabetes. Moreover, exogenous insulin or sulfonylureas may be harmful because these agents may promote hepatocarcinogenesis. Thus, pathogenesis, cause of death, assessment and therapeutic strategy for hepatogenous insulin resistance/diabetes differ from those for lifestyle-related type 2 diabetes. In this article, we review features of insulin resistance in relationship to chronic liver disease. We also discuss the impact of anti-diabetic agents on interferon treatment and hepatocarcinogenesis. PMID:21731901

  9. Insulin resistance: pathophysiology and rationale for treatment.

    PubMed

    Muntoni, Sergio; Muntoni, Sandro

    2011-01-01

    After binding to its receptor and activating the β-subunit, insulin is faced with two divergent pathways: one is phosphatidylinositol 3-kinase (PI 3-K) dependent, while another is dependent upon activation of mitogen-activated protein kinase (MAP-K). The former is absolutely necessary for mediating most metabolic and antiapoptotic effects; the latter is linked to nonmetabolic, proliferative and mitogenic effects. In obese patients, especially with type 2 diabetes mellitus (DM2), only the PI 3-K, but not the MAP-K, is resistant to insulin stimulation: hence insulin resistance is better defined as metabolic insulin resistance. The resulting 'compensatory hyperinsulinemia' is an unsuccessful attempt to overcome the inhibition of the metabolic pathway at the price of unopposed stimulation of the MAP-K pathway, and the administration of exogenous insulin might worsen the metabolic dysfunction. As the preferential activation of the MAP-K pathway in insulin-resistant patients has atherogenic and mitogenic properties, this leads to atherosclerosis and cancer. Metformin may carry out direct protective action on human β cells, inasmuch as it improves both primary and secondary endpoints through selective inhibition of fatty acyl oxidation. Copyright © 2011 S. Karger AG, Basel.

  10. Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance.

    PubMed Central

    Steinberg, H O; Chaker, H; Leaming, R; Johnson, A; Brechtel, G; Baron, A D

    1996-01-01

    To test the hypothesis that obesity/insulin resistance impairs both endothelium-dependent vasodilation and insulin-mediated augmentation of endothelium-dependent vasodilation, we studied leg blood flow (LBF) responses to graded intrafemoral artery infusions of methacholine chloride (MCh) or sodium nitroprusside (SNP) during saline infusion and euglycemic hyperinsulinemia in lean insulin-sensitive controls (C), in obese insulin-resistant subjects (OB), and in subjects with non-insulin-dependent diabetes mellitus (NIDDM). MCh induced increments in LBF were approximately 40% and 55% lower in OB and NIDDM, respectively, as compared with C (P < 0.05). Euglycemic hyperinsulinemia augmented the LBF response to MCh by - 50% in C (P < 0.05 vs saline) but not in OB and NIDDM. SNP caused comparable increments in LBF in all groups. Regression analysis revealed a significant inverse correlation between the maximal LBF change in response to MCh and body fat content. Thus, obesity/insulin resistance is associated with (a) blunted endothelium-dependent, but normal endothelium-independent vasodilation and (b) failure of euglycemic hyperinsulinemia to augment endothelium-dependent vasodilation. Therefore, obese/insulin-resistant subjects are characterized by endothelial dysfunction and endothelial resistance to insulin's effect on enhancement of endothelium-dependent vasodilation. This endothelial dysfunction could contribute to the increased risk of atherosclerosis in obese insulin-resistant subjects. PMID:8647954

  11. 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.

  12. Insulin resistance in young, lean male subjects with essential hypertension.

    PubMed

    Penesova, A; Cizmarova, E; Belan, V; Blazicek, P; Imrich, R; Vlcek, M; Vigas, M; Selko, D; Koska, J; Radikova, Z

    2011-06-01

    Impaired insulin action, frequently found in essential hypertension (HT), is modified by other factors, such as higher age, accumulation of body fat, dyslipidaemia, impaired glucose metabolism and endothelial dysfunction. In addition, antihypertensive and insulin-sensitizing medication itself may significantly affect cardiovascular and metabolic milieu. The aim of this study was to assess insulin sensitivity, acute insulin response, lipidaemic status and the adipokines' concentrations with regard to abdominal fat distribution in young, lean male subjects with treatment-naïve essential HT and in matched healthy normotensive (NT) subjects. We studied 27 HT patients (age: 19.9±0.6 years; body mass index (BMI): 22.9±0.5 kg m(-2)) and 15 NT controls (age: 22.3±1.0 years; BMI: 23.7±0.6 kg m(-2)). The subjects underwent an oral and an intravenous glucose tolerance test (OGTT, IVGTT) on separate days in random order. Higher fasting insulin (P<0.001), non-esterified fatty acids (P<0.05) and plasminogen activator inhibitor factor 1 concentrations (P<0.05) were found in HT patients when compared with NT patients. Despite comparable anthropometric parameters and body fat distribution assessed by magnetic resonance imaging in both groups, newly diagnosed untreated young hypertensive male subjects showed decreased insulin sensitivity, augmented insulin response to both oral and intravenous glucose load (P<0.01; P<0.05 respectively) and 'higher still normal' 2-h plasma glucose levels during OGTT. Untreated, young, lean hypertensive male subjects, with distribution of abdominal adipose tissue and lipid profile comparable with their healthy NT matched counterparts, showed considerable signs of insulin resistance and hyperinsulinaemia. We hypothesize that insulin resistance is the initial feature, which is influenced by several environmental factors, and HT is one of their common consequences.

  13. Insulin resistance, metabolic stress, and atherosclerosis

    PubMed Central

    Pansuria, Meghana; Xi, Hang; Li, Le; Yang, Xiao-Feng; Wang, Hong

    2012-01-01

    Atherosclerosis, a pathological process that underlies the development of cardiovascular disease, is the primary cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). T2DM is characterized by hyperglycemia and insulin resistance (IR), in which target tissues fail to respond to insulin. Systemic IR is associated with impaired insulin signaling in the metabolic tissues and vasculature. Insulin receptor is highly expressed in the liver, muscle, pancreas, and adipose tissue. It is also expressed in vascular cells. It has been suggested that insulin signaling in vascular cells regulates cell proliferation and vascular function. In this review, we discuss the association between IR, metabolic stress, and atherosclerosis with focus on 1) tissue and cell distribution of insulin receptor and its differential signaling transduction and 2) potential mechanism of insulin signaling impairment and its role in the development of atherosclerosis and vascular function in metabolic disorders including hyperglycemia, hypertension, dyslipidemia, and hyperhomocysteinemia. We propose that insulin signaling impairment is the foremost biochemical mechanism underlying increased cardiovascular morbidity and mortality in atherosclerosis, T2DM, and metabolic syndrome. PMID:22202099

  14. Nonalcoholic steatohepatitis and insulin resistance in children

    PubMed Central

    Arata, Mikage; Nakajima, Junya; Nishimata, Shigeo; Nagata, Tomomi; Kawashima, Hisashi

    2014-01-01

    Various pathological conditions can cause fatty liver in children. Nonalcoholic steatohepatitis (NASH) in children has been known since 1983. However, NASH diagnosed in childhood does not have a favorable outcome. The pathological characteristics of NASH are significantly different between children and adults. Nonalcoholic fatty liver disease (NAFLD)/NASH is accompanied by insulin resistance, which plays a pivotal role in its pathophysiology in both children and adults. In NASH, a “two-hit” model involving triglyceride accumulation (first hit) and liver damage (second hit) has been accepted. Insulin resistance was found to correlate with changes in fat levels; however, it did not correlate with fibrosis or NAFLD activity score in children. Therefore, insulin resistance may be important in the first hit. Because there is obvious familial clustering in NASH, genetic predisposition as well as environmental factors including diet might be the second hit of NAFLD/NASH. PMID:25512797

  15. Treatment of insulin resistance in the neurodegeneration.

    PubMed

    Stefanelli, Manuela; Martocchia, Antonio; De Marinis, Elisabetta Adele; Falaschi, Giulia Maria; Romano, Gloria; Rufo, Maddalena; Falaschi, Paolo

    2014-04-01

    The association between diabetes and neurodegenerative diseases is increasing with aging. Several common mechanisms are involved in both these diseases. The endothelial cells of the blood brain barrier, neurons and glia express typical and different receptors of the glucose metabolism (glucose transporters, insulin receptors and glucagon-like peptide-1 receptors). The impairment in insulin signaling leads to an impairment of neuronal function and increases neurodegeneration, and, conversely, neurodegeneration causes a reduction of insulin signaling on neurons. Increased detailed knowledge of common physiological processes opens up the opportunities for developing new treatments that may prevent or reduce the onset of neurodegenerative diseases. The aim of the review is to discuss the potential neuroprotective effects of the antidiabetic drugs. The article presents some promising patents on the treatment of insulin resistance in the neurodegeneration.

  16. Metabolic syndrome and insulin resistance: perioperative considerations.

    PubMed

    Bagry, Hema S; Raghavendran, Sreekrishna; Carli, Franco

    2008-03-01

    Metabolic syndrome represents a constellation of risk factors associated with increased incidence of cardiovascular disease and progression to diabetes mellitus. Insulin resistance, a state of decreased biologic response to physiologic concentrations of insulin, is a key component of this syndrome and seems to be the result of a primary defect at the skeletal muscle glucose transporter. Acute illness and the perioperative period are characterized by a state of insulin resistance that manifests as hyperglycemia and leads to various other metabolic and biochemical alterations that adversely affect end organ function. Hyperglycemia in acutely ill patients adversely affects outcome. Achieving euglycemia seems beneficial in certain clinical situations, but considerable disagreement exists regarding the target blood sugar levels, the duration of therapy, and the modality. Pharmacotherapy, exercise, and nutrition to improve insulin sensitivity seem promising but require further evaluation to confirm their efficacy for perioperative risk reduction. This review discusses the pathophysiology and the clinical implications of metabolic syndrome and insulin resistance in the acutely ill patient with an emphasis on perioperative modulation strategies.

  17. Beneficial effects of ethanol consumption on insulin resistance are only applicable to subjects without obesity or insulin resistance; drinking is not necessarily a remedy for metabolic syndrome.

    PubMed

    Yokoyama, Hirokazu

    2011-07-01

    Although moderate drinking has been shown to lower insulin resistance levels, it is still unclear whether alcoholic beverages could be remedies for insulin resistance. To elucidate this, the correlation between levels of ethanol consumption and insulin resistance were cross-sectionally examined in 371 non-diabetic male Japanese workers. Multiple regression analysis demonstrated that the ethanol consumption level was inversely correlated with the insulin resistance level assessed by homeostatic model assessment (HOMA-IR, p = 0.0014), the serum insulin level (p = 0.0007), and pancreatic β-cell function, also assessed by HOMA (HOMA-β, p = 0.0002), independently from age, body mass index (BMI), and blood pressure, liver function tests, and lipid profiles status, as well as serum adiponectin. The correlations were true in subjects with normal BMIs (up to 25.0 kg/m(2), n = 301) or normal HOMA-IR (up to 2.0 μIU·mg/μL·dL n = 337), whereas all of them were non-significant in those with excessive BMIs (n = 70) or in those with HOMA-IR of more than 2.0 (n = 34). Although it is still unclear whether the reductions of these parameters by ethanol consumption are truly due to the improvement of insulin resistance, at least, these effects are not applicable to subjects with obesity and/or insulin resistance. Thus, alcoholic beverages could not be remedies for insulin resistance or metabolic syndrome.

  18. Beneficial Effects of Ethanol Consumption on Insulin Resistance Are Only Applicable to Subjects Without Obesity or Insulin Resistance; Drinking is not Necessarily a Remedy for Metabolic Syndrome

    PubMed Central

    Yokoyama, Hirokazu

    2011-01-01

    Although moderate drinking has been shown to lower insulin resistance levels, it is still unclear whether alcoholic beverages could be remedies for insulin resistance. To elucidate this, the correlation between levels of ethanol consumption and insulin resistance were cross-sectionally examined in 371 non-diabetic male Japanese workers. Multiple regression analysis demonstrated that the ethanol consumption level was inversely correlated with the insulin resistance level assessed by homeostatic model assessment (HOMA-IR, p = 0.0014), the serum insulin level (p = 0.0007), and pancreatic β-cell function, also assessed by HOMA (HOMA-β, p = 0.0002), independently from age, body mass index (BMI), and blood pressure, liver function tests, and lipid profiles status, as well as serum adiponectin. The correlations were true in subjects with normal BMIs (up to 25.0 kg/m2, n = 301) or normal HOMA-IR (up to 2.0 μIU·mg/μL·dL n = 337), whereas all of them were non-significant in those with excessive BMIs (n = 70) or in those with HOMA-IR of more than 2.0 (n = 34). Although it is still unclear whether the reductions of these parameters by ethanol consumption are truly due to the improvement of insulin resistance, at least, these effects are not applicable to subjects with obesity and/or insulin resistance. Thus, alcoholic beverages could not be remedies for insulin resistance or metabolic syndrome. PMID:21845171

  19. Serum leptin levels in gastric cancer patients and the relationship with insulin resistance

    PubMed Central

    Aslan, Mehmet; Dulger, Ahmet Cumhur; Emre, Habib; Kemik, Ahu; Kemik, Ozgur; Esen, Ramazan

    2015-01-01

    Introduction Serum leptin levels have been examined in various cancers, with conflicting results. However, there is limited information regarding serum leptin levels and insulin resistance in gastric cancer patients. Therefore, we aimed to investigate serum leptin levels, performance status, insulin levels and insulin resistance in patients with gastric cancer. In addition, we examined the relationship between these measurements and leptin levels. Material and methods Thirty-nine patients with gastric cancer and 30 control subjects were enrolled in the study. Serum leptin, total protein, albumin, growth hormone, insulin and glucose levels were measured. The homeostasis model assessment (HOMA) was used to assess insulin resistance. Results Serum levels of insulin, glucose and growth hormone and insulin resistance were significantly lower in gastric cancer patients than controls (p < 0.05 for all). In the Pearson correlation analysis, insulin resistance was found to be significantly correlated with serum leptin levels in gastric cancer patients (r = 0.320, p = 0.047). We observed a significant negative correlation between performance status and insulin resistance in patients with cachexia (r = –0.512, p = 0.030), while no association was found in non-cachectic patients. Conclusions We concluded that serum leptin levels are significantly lower in gastric cancer patients. In addition, gastric cancer patients have decreases in insulin levels, insulin resistance and growth hormone levels. This study found a positive association between serum leptin levels and insulin resistance. Moreover, there is a negative association between serum leptin levels and growth hormone levels. Thus, low insulin and growth hormone levels may suppress the production of leptin in gastric cancer patients. PMID:25995751

  20. Resistive Training Improves Insulin Sensitivity after Stroke

    PubMed Central

    Ivey, Frederick M.; Ryan, Alice S.

    2013-01-01

    Background Insulin resistance is highly prevalent after stroke, contributing to comorbid cardiovascular conditions that are the leading cause of death in the stroke population. This study determined the effects of unilateral resistive training (RT) of both the paretic and nonparetic legs on insulin sensitivity in stroke survivors. Methods We studied 10 participants (mean age 65 ± 2 years; mean body mass index 27 ± 4 kg/m2) with hemiparetic gait after remote (>6 months) ischemic stroke. All subjects underwent 1-repetition maximum (1-RM) strength testing, 9 had an oral glucose tolerance test (OGTT), and 7 completed a 2-hour hyperglycemic clamp (with glucose elevation targeted at 98 mg/dL above baseline fasting level) before and after 12 weeks (3×/week) of progressive, high repetition, high-intensity RT. Body composition was assessed by dual-energy x-ray absorbtiometry in all participants. Results Leg press and leg extension 1-RM increased in the paretic leg by 22% (P < .05) and 45% (P < .01), respectively. Fasting insulin decreased 23% (P < .05), with no change in fasting glucose. The 16% reduction in OGTT insulin area under the curve (AUC) across training was not statistically significant (P = .18). There was also no change in glucose AUC. First-phase insulin response during the hyperglycemic clamp (0–10 minutes) decreased 24% (P < .05), and second-phase insulin response (10–120 minutes) decreased 26% (P < .01). Insulin sensitivity increased by 31% after RT according to clamp calculations (P < .05). Conclusions These findings provide the first preliminary evidence that RT may reduce hyperinsulinemia and improve insulin sensitivity after disabling stroke. PMID:23352685

  1. Resistive training improves insulin sensitivity after stroke.

    PubMed

    Ivey, Frederick M; Ryan, Alice S

    2014-02-01

    Insulin resistance is highly prevalent after stroke, contributing to comorbid cardiovascular conditions that are the leading cause of death in the stroke population. This study determined the effects of unilateral resistive training (RT) of both the paretic and nonparetic legs on insulin sensitivity in stroke survivors. We studied 10 participants (mean age 65 ± 2 years; mean body mass index 27 ± 4 kg/m2) with hemiparetic gait after remote (>6 months) ischemic stroke. All subjects underwent 1-repetition maximum (1-RM) strength testing, 9 had an oral glucose tolerance test (OGTT), and 7 completed a 2-hour hyperglycemic clamp (with glucose elevation targeted at 98 mg/dL above baseline fasting level) before and after 12 weeks (3×/week) of progressive, high repetition, high-intensity RT. Body composition was assessed by dual-energy x-ray absorbtiometry in all participants. Leg press and leg extension 1-RM increased in the paretic leg by 22% (P < .05) and 45% (P < .01), respectively. Fasting insulin decreased 23% (P < .05), with no change in fasting glucose. The 16% reduction in OGTT insulin area under the curve (AUC) across training was not statistically significant (P = .18). There was also no change in glucose AUC. First-phase insulin response during the hyperglycemic clamp (0-10 minutes) decreased 24% (P < .05), and second-phase insulin response (10-120 minutes) decreased 26% (P < .01). Insulin sensitivity increased by 31% after RT according to clamp calculations (P < .05). These findings provide the first preliminary evidence that RT may reduce hyperinsulinemia and improve insulin sensitivity after disabling stroke. Published by Elsevier Inc.

  2. Mechanistic interplay between ceramide and insulin resistance

    PubMed Central

    Reali, Federico; Morine, Melissa J.; Kahramanoğulları, Ozan; Raichur, Suryaprakash; Schneider, Hans-Christoph; Crowther, Daniel; Priami, Corrado

    2017-01-01

    Recent research adds to a growing body of literature on the essential role of ceramides in glucose homeostasis and insulin signaling, while the mechanistic interplay between various components of ceramide metabolism remains to be quantified. We present an extended model of C16:0 ceramide production through both the de novo synthesis and the salvage pathways. We verify our model with a combination of published models and independent experimental data. In silico experiments of the behavior of ceramide and related bioactive lipids in accordance with the observed transcriptomic changes in obese/diabetic murine macrophages at 5 and 16 weeks support the observation of insulin resistance only at the later phase. Our analysis suggests the pivotal role of ceramide synthase, serine palmitoyltransferase and dihydroceramide desaturase involved in the de novo synthesis and the salvage pathways in influencing insulin resistance versus its regulation. PMID:28112248

  3. Antidiabetogenic effects of chromium mitigate hyperinsulinemia-induced cellular insulin resistance via correction of plasma membrane cholesterol imbalance.

    PubMed

    Horvath, Emily M; Tackett, Lixuan; McCarthy, Alicia M; Raman, Priya; Brozinick, Joseph T; Elmendorf, Jeffrey S

    2008-04-01

    Previously, we found that a loss of plasma membrane (PM) phosphatidylinositol 4,5-bisphosphate (PIP2)-regulated filamentous actin (F-actin) structure contributes to insulin-induced insulin resistance. Interestingly, we also demonstrated that chromium picolinate (CrPic), a dietary supplement thought to improve glycemic status in insulin-resistant individuals, augments insulin-regulated glucose transport in insulin-sensitive 3T3-L1 adipocytes by lowering PM cholesterol. Here, to gain mechanistic understanding of these separate observations, we tested the prediction that CrPic would protect against insulin-induced insulin resistance by improving PM features important in cytoskeletal structure and insulin sensitivity. We found that insulin-induced insulin-resistant adipocytes display elevated PM cholesterol with a reciprocal decrease in PM PIP2. This lipid imbalance and insulin resistance was corrected by the cholesterol-lowering action of CrPic. The PM lipid imbalance did not impair insulin signaling, nor did CrPic amplify insulin signal transduction. In contrast, PM analyses corroborated cholesterol and PIP2 interactions influencing cytoskeletal structure. Because extensive in vitro study documents an essential role for cytoskeletal capacity in insulin-regulated glucose transport, we next evaluated intact skeletal muscle from obese, insulin-resistant Zucker (fa/fa) rats. Because insulin resistance in these animals likely involves multiple mechanisms, findings that cholesterol-lowering restored F-actin cytoskeletal structure and insulin sensitivity to that witnessed in lean control muscle were striking. Also, experiments using methyl-beta-cyclodextrin to shuttle cholesterol into or out of membranes respectively recapitulated the insulin-induced insulin-resistance and protective effects of CrPic on membrane/cytoskeletal interactions and insulin sensitivity. These data predict a PM cholesterol basis for hyperinsulinemia-associated insulin resistance and importantly

  4. Antidiabetogenic Effects of Chromium Mitigate Hyperinsulinemia-Induced Cellular Insulin Resistance via Correction of Plasma Membrane Cholesterol Imbalance

    PubMed Central

    Horvath, Emily M.; Tackett, Lixuan; McCarthy, Alicia M.; Raman, Priya; Brozinick, Joseph T.; Elmendorf, Jeffrey S.

    2008-01-01

    Previously, we found that a loss of plasma membrane (PM) phosphatidylinositol 4,5-bisphosphate (PIP2)-regulated filamentous actin (F-actin) structure contributes to insulin-induced insulin resistance. Interestingly, we also demonstrated that chromium picolinate (CrPic), a dietary supplement thought to improve glycemic status in insulin-resistant individuals, augments insulin-regulated glucose transport in insulin-sensitive 3T3-L1 adipocytes by lowering PM cholesterol. Here, to gain mechanistic understanding of these separate observations, we tested the prediction that CrPic would protect against insulin-induced insulin resistance by improving PM features important in cytoskeletal structure and insulin sensitivity. We found that insulin-induced insulin-resistant adipocytes display elevated PM cholesterol with a reciprocal decrease in PM PIP2. This lipid imbalance and insulin resistance was corrected by the cholesterol-lowering action of CrPic. The PM lipid imbalance did not impair insulin signaling, nor did CrPic amplify insulin signal transduction. In contrast, PM analyses corroborated cholesterol and PIP2 interactions influencing cytoskeletal structure. Because extensive in vitro study documents an essential role for cytoskeletal capacity in insulin-regulated glucose transport, we next evaluated intact skeletal muscle from obese, insulin-resistant Zucker (fa/fa) rats. Because insulin resistance in these animals likely involves multiple mechanisms, findings that cholesterol-lowering restored F-actin cytoskeletal structure and insulin sensitivity to that witnessed in lean control muscle were striking. Also, experiments using methyl-β-cyclodextrin to shuttle cholesterol into or out of membranes respectively recapitulated the insulin-induced insulin-resistance and protective effects of CrPic on membrane/cytoskeletal interactions and insulin sensitivity. These data predict a PM cholesterol basis for hyperinsulinemia-associated insulin resistance and importantly

  5. B-1a Lymphocytes Attenuate Insulin Resistance

    PubMed Central

    Shen, Lei; Chng, MH; Alonso, Michael N.; Yuan, Robert

    2015-01-01

    Obesity-associated insulin resistance, a common precursor of type 2 diabetes, is characterized by chronic inflammation of tissues, including visceral adipose tissue (VAT). Here we show that B-1a cells, a subpopulation of B lymphocytes, are novel and important regulators of this process. B-1a cells are reduced in frequency in obese high-fat diet (HFD)-fed mice, and EGFP interleukin-10 (IL-10) reporter mice show marked reductions in anti-inflammatory IL-10 production by B cells in vivo during obesity. In VAT, B-1a cells are the dominant producers of B cell–derived IL-10, contributing nearly half of the expressed IL-10 in vivo. Adoptive transfer of B-1a cells into HFD-fed B cell–deficient mice rapidly improves insulin resistance and glucose tolerance through IL-10 and polyclonal IgM-dependent mechanisms, whereas transfer of B-2 cells worsens metabolic disease. Genetic knockdown of B cell–activating factor (BAFF) in HFD-fed mice or treatment with a B-2 cell–depleting, B-1a cell–sparing anti-BAFF antibody attenuates insulin resistance. These findings establish B-1a cells as a new class of immune regulators that maintain metabolic homeostasis and suggest manipulation of these cells as a potential therapy for insulin resistance. PMID:25249575

  6. Epigenetic markers to further understand insulin resistance.

    PubMed

    Ling, Charlotte; Rönn, Tina

    2016-11-01

    Epigenetic variation in human adipose tissue has been linked to type 2 diabetes and its related risk factors including age and obesity. Insulin resistance, a key risk factor for type 2 diabetes, may also be associated with altered DNA methylation in visceral and subcutaneous adipose tissue. Furthermore, linking epigenetic variation in target tissues to similar changes in blood cells may identify new blood-based biomarkers. In this issue of Diabetologia, Arner et al studied the transcriptome and methylome in subcutaneous and visceral adipose tissue of 80 obese women who were either insulin-sensitive or -resistant (DOI 10.1007/s00125-016-4074-5 ). While they found differences in gene expression between the two groups, no alterations in DNA methylation were found after correction for multiple testing. Nevertheless, based on nominal p values, their methylation data overlapped with methylation differences identified in adipose tissue of individuals with type 2 diabetes compared with healthy individuals. Differential methylation of these overlapping CpG sites may predispose to diabetes by occurring already in the insulin-resistant state. Furthermore, some methylation changes may contribute to an inflammatory process in adipose tissue since the identified CpG sites were annotated to genes encoding proteins involved in inflammation. Finally, the methylation pattern in circulating leucocytes did not mirror the adipose tissue methylome of these 80 women. Together, identifying novel molecular mechanisms contributing to insulin resistance and type 2 diabetes may help advance the search for new therapeutic alternatives.

  7. Uncoupling Proteins: Role in Insulin Resistance and Insulin Insufficiency

    PubMed Central

    Chan, Catherine B.; Harper, Mary-Ellen

    2010-01-01

    Uncoupling proteins (UCPs) are modulators of mitochondrial metabolism that have been implicated in the development of both insulin resistance and insulin insufficiency, the two major pathophysiological events associated with type 2 diabetes. UCP2 mRNA is expressed in a wide range of tissues; however UCP2 protein expression is restricted to fewer tissues, including the endocrine pancreas, spleen, stomach, brain and the lung. To date, its role in the pathophysiology of diabetes has been most strongly associated with impaired glucose-stimulated insulin secretion from the β-cell, particularly after its induction by free fatty acids. The physiological role of UCP2 remains controversial, but it may act as a downstream signal transducer of superoxide. UCP3 mRNA and protein are expressed in relatively few tissues, predominately skeletal muscle, brown adipose tissue and heart. Increased expression of UCP3 in skeletal muscle is associated with protection from diet-induced insulin resistance in mice. In patients with type 2 diabetes UCP3 protein in muscle is reduced by 50% compared to healthy controls. The primary physiological role of the novel UCPs does not appear to be protection against positive energy balance and obesity; this is based largely on findings from studies of UCP2 and UCP3 knockout mice and from observed increases in UCP3 expression with fasting. The mechanism(s) of action of UCP2 and UCP3 are poorly understood. However, findings support roles for UCP2 and UCP3 as modifiers of fatty acid metabolism and in mitigating damage from reactive oxygen species. PMID:18220632

  8. Acrolein metabolites, diabetes and insulin resistance.

    PubMed

    Feroe, Aliya G; Attanasio, Roberta; Scinicariello, Franco

    2016-07-01

    Acrolein is a dietary and environmental pollutant that has been associated in vitro to dysregulate glucose transport. We investigated the association of urinary acrolein metabolites N-acetyl-S-(3-hydroxypropyl)-l-cysteine (3-HPMA) and N-acetyl-S-(carboxyethyl)-l-cysteine (CEMA) and their molar sum (∑acrolein) with diabetes using data from investigated 2027 adults who participated in the 2005-2006 National Health and Nutrition Examination Survey (NHANES). After excluding participants taking insulin or other diabetes medication we, further, investigated the association of the compounds with insulin resistance (n=850), as a categorical outcome expressed by the homeostatic model assessment (HOMA-IR>2.6). As secondary analyses, we investigated the association of the compounds with HOMA-IR, HOMA-β, fasting insulin and fasting plasma glucose. The analyses were performed using urinary creatinine as independent variable in the models, and, as sensitivity analyses, the compounds were used as creatinine corrected variables. Diabetes as well as insulin resistance (defined as HOMA-IR>2.6) were positively associated with the 3-HPMA, CEMA and ∑Acrolein with evidence of a dose-response relationship (p<0.05). The highest 3rd and 4th quartiles of CEMA compared to the lowest quartile were significantly associated with higher HOMA-IR, HOMA-β and fasting insulin with a dose-response relationship. The highest 3rd quartile of 3-HPMA and ∑Acrolein were positively and significantly associated with HOMA-IR, HOMA-β and fasting insulin. These results suggest a need of further studies to fully understand the implications of acrolein with type 2 diabetes and insulin.

  9. 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

  10. Activation of insulin signaling and energy sensing network by AICAR, an AMPK activator in insulin resistant rat tissues.

    PubMed

    Radika, Mutlur Krishnamoorthy; Anuradha, Carani Venkatraman

    2015-11-01

    The energy status of the cell is regulated by the energy sensing network constituted by AMP-activated protein kinase (AMPK), the NAD+-dependent type III deacetylase silence information regulator T1 (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). This study investigates the potential effect of 5-aminoimidazole-4-carboximide-1-b-D-ribofuranoside (AICAR), an AMPK activator on insulin signaling and energy sensing network in insulin resistant rats. Adult male albino Wistar rats with body weight of 150-180 g were fed high-fructose diet (HFD) for 60 days to induce insulin resistance. Rats fed HFD were divided into two and were treated or untreated with AICAR (0.7 mg/kg bw, i.p.) for the last 2 weeks. Insulin resistant rats displayed increased glucose and insulin levels and reduced tyrosine phosphorylation of insulin resistance receptor and insulin receptor substrate 1. The downstream signaling and glucose transport were also affected. Phosphorylation of AMPK, SIRT1 protein abundance and mRNA expression of PGC-1α were reduced. Treatment with AICAR reduced hyperglycemia and hyperinsulinemia and improved the activation of the key molecules of insulin signaling. Improved action of energy sensing network was noted after AICAR treatment. AICAR showed higher binding affinity with Akt (-8.2 kcal/mol) than with AMPK or insulin receptor (-8.0 kcal/mol) in the in silico study. The findings suggest that AICAR, the AMPK activator, influences insulin signaling proteins and molecules involved in energy modulation during insulin resistance.

  11. Influence of Gut Microbiota on Subclinical Inflammation and Insulin Resistance

    PubMed Central

    Carvalho, Bruno Melo; Abdalla Saad, Mario Jose

    2013-01-01

    Obesity is the main condition that is correlated with the appearance of insulin resistance, which is the major link among its comorbidities, such as type 2 diabetes, nonalcoholic fatty liver disease, cardiovascular and neurodegenerative diseases, and several types of cancer. Obesity affects a large number of individuals worldwide; it degrades human health and quality of life. Here, we review the role of the gut microbiota in the pathophysiology of obesity and type 2 diabetes, which is promoted by a bacterial diversity shift mediated by overnutrition. Whole bacteria, their products, and metabolites undergo increased translocation through the gut epithelium to the circulation due to degraded tight junctions and the consequent increase in intestinal permeability that culminates in inflammation and insulin resistance. Several strategies focusing on modulation of the gut microbiota (antibiotics, probiotics, and prebiotics) are being experimentally employed in metabolic derangement in order to reduce intestinal permeability, increase the production of short chain fatty acids and anorectic gut hormones, and promote insulin sensitivity to counteract the inflammatory status and insulin resistance found in obese individuals. PMID:23840101

  12. MODELS OF INSULIN RESISTANCE AND HEART FAILURE

    PubMed Central

    Velez, Mauricio; Kohli, Smita; Sabbah, Hani N.

    2013-01-01

    The incidence of heart failure (HF) and diabetes mellitus is rapidly increasing and is associated with poor prognosis. In spite of the advances in therapy, HF remains a major health problem with high morbidity and mortality. When HF and diabetes coexist, clinical outcomes are significantly worse. The relationship between these two conditions has been studied in various experimental models. However, the mechanisms for this interrelationship are complex, incompletely understood, and have become a matter of considerable clinical and research interest. There are only few animal models that manifest both HF and diabetes. However, the translation of results from these models to human disease is limited and new models are needed to expand our current understanding of this clinical interaction. In this review, we discuss mechanisms of insulin signaling and insulin resistance, the clinical association between insulin resistance and HF and its proposed pathophysiologic mechanisms. Finally, we discuss available animal models of insulin resistance and HF and propose requirements for future new models. PMID:23456447

  13. Acceptance of insulin therapy: a long shot? Psychological insulin resistance in primary care.

    PubMed

    Woudenberg, Y J C; Lucas, C; Latour, C; Scholte op Reimer, W J M

    2012-06-01

    To explore which factors are associated with psychological insulin resistance in insulin-naive patients with Type 2 diabetes in primary care. A sample of 101 insulin-naive patients with Type 2 diabetes completed self-administered questionnaires including demographic and clinical characteristics, the Insulin Treatment Appraisal Scale and the Center for Epidemiological Studies Depression scale. Psychological insulin resistance was denoted by negative appraisal of insulin (Insulin Treatment Appraisal Scale). Thirty-nine per cent of the sample were unwilling to accept insulin therapy. Unwilling participants perceived taking insulin more often as a failure to control their diabetes with tablets or lifestyle compared with willing participants (59 vs. 33%), unwilling participants were more reluctant to accept the responsibilities of everyday management of insulin therapy (49 vs. 24%). Multiple linear regression analysis revealed that depression and objection to lifelong insulin therapy were independently associated with psychological insulin resistance. In this study in primary care, depression and objection to lifelong insulin therapy are associated with psychological insulin resistance. Analysis of the objection to the indefiniteness of insulin therapy showed a sense of limitation of daily life and loss of independence that should not be underestimated. Insulin should be offered as a means to improve health as this might facilitate the acceptance of insulin therapy. © 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK.

  14. Fluctuation of insulin resistance in a leprechaun with a primary defect in insulin binding.

    PubMed

    Kobayashi, M; Takata, Y; Sasaoka, T; Shigeta, Y; Goji, K

    1988-05-01

    A 3-month-old female leprechaun demonstrated extreme insulin resistance with hyperinsulinemia (330 mumol/L) and resistance to exogenous insulin. Insulin binding to erythrocytes, cultured lymphocytes, and fibroblasts from the patient were decreased to less than 20% of normal, whereas insulin-like growth factor I binding to fibroblasts was normal. Antiinsulin receptor antibody binding to cultured lymphocytes was also decreased to 20% of normal, indicating a decreased concentration of insulin receptors on the cell surface. The ability of insulin to stimulate D-[14C]glucose uptake was decreased to 35% of normal in the patient's fibroblasts, and the dose-response curve was shifted to the right. With time, the insulin resistance fluctuated from near normal (fasting insulin, 244.0 pmol/L) to severe resistance (fasting insulin, 5740-9328 pmol/L), and an insulin tolerance test revealed amelioration of insulin resistance during remission. However, insulin binding to erythrocytes and adipocytes was decreased persistently to 20% of normal. These results indicate that the patient had a primary defect in her insulin receptors, i.e. decreased insulin receptor concentration. The variable degree of insulin resistance was possibly due to variable receptor function in the signal transmission process.

  15. VDR Gene variation and insulin resistance related diseases.

    PubMed

    Han, Fei-Fei; Lv, Ya-Li; Gong, Li-Li; Liu, He; Wan, Zi-Rui; Liu, Li-Hong

    2017-08-19

    Vitamin D status may influence the risk of Insulin resistance related diseases such as Type 2 diabetes (T2DM), metabolic syndrome (MetS), and polycystic ovarian syndrome (PCOS). Several studies have assessed vitamin D receptor (VDR) gene polymorphism in relationship with these diseases; however, results remain inconsistent. Our study was conducted to elucidate whether VDR Gene polymorphisms could predict insulin resistance on a large scale. A meta-analysis using MEDLINE and EMBASE, was performed up to December 16th, 2016. Studies reporting association of vitamin D gene polymorphism with incident T2DM, MetS and PCOS outcomes were included and sub-group analysis by pigment of skin and latitude were performed. A total of 28 articles based on four gene variation, and comprising 9232 participants with 5193 Insulin resistance related diseases patients were included. No significant associations of the VDR ApaI, BsmI, FokI and TaqI variant with Insulin resistance related diseases were found. However, sub-group analysis analysis showed that PCOS in TaqI (OR = 1.47, 95% CI = 1.03-2.09, P = 0.03) for T allele and MetS for G allele (OR = 1.41, 95% CI = 1.07-1.85, P = 0.01) in BsmI was significant association with VDR gene polymorphism. Simultaneously, sub-group analysis showed VDR ApaI rs7975232(G > T)variant was associated with insulin resistance related diseases in Asians (GG/GT + TT) (OR, 1.62; 95% CI, 1.03-2.53; P = 0.04) and population who lived in middle latitude district (30-60°) (GG/GT + TT) (OR, 1.22; 95% CI, 1.04-1.43; P = 0.02), VDR BsmI rs1544410 (A > G)and VDR Taq1rs731236 (T/C) variant were associated with insulin resistance related diseases in Caucasian (dark-pigmented). The results suggested that the association between insulin resistance related diseases and VDR ApaI, BsmI, FokI variant was more obvious in dark-pigmented Caucasians and Asians but not in Caucasian with white skin.

  16. Association of Serum Osteocalcin with Insulin Resistance and Coronary Atherosclerosis

    PubMed Central

    2016-01-01

    Background To determine the associations between serum osteocalcin level and insulin resistance, coronary atherosclerosis by using dual-source coronary computed tomography angiography. Methods A total of 98 subjects (24 men and 74 women) were selected for this retrospective cross-sectional study who voluntarily visited a health examination center for routine health check-up including the blood test for serum osteocalcin level and coronary computed tomography angiography. Multiple regression analysis was used to determine which variables were independently related to osteocalcin levels and coronary atherosclerosis. Results Stepwise multiple regression analysis adjusted for age, sex, menopausal status, body mass index, serum alkaline phosphatase, serum calcium and phosphate showed that osteocalcin negatively correlated with serum glucose (β=-0.145, P=0.001) and homeostasis model assessment of insulin resistance (HOMA-IR) index (β=-1.794, P=0.027) independently. The age, serum glucose, smoking status but not osteocalcin level were independent risk factors for coronary atherosclerosis by use of multiple logistic regression analysis after controlling for other variables. Conclusions Serum osteocalcin level was inversely associated with fasting glucose level and insulin resistance measured by HOMA-IR, suggesting that osteocalcin is important for glucose metabolism. However, in this study, no significant difference was observed in the serum osteocalcin level according to the presence of coronary atherosclerotic plaques. PMID:27965939

  17. Insulin-induced cytokine production in macrophages causes insulin resistance in hepatocytes.

    PubMed

    Manowsky, Julia; Camargo, Rodolfo Gonzalez; Kipp, Anna P; Henkel, Janin; Püschel, Gerhard P

    2016-06-01

    Overweight and obesity are associated with hyperinsulinemia, insulin resistance, and a low-grade inflammation. Although hyperinsulinemia is generally thought to result from an attempt of the β-cell to compensate for insulin resistance, there is evidence that hyperinsulinaemia itself may contribute to the development of insulin resistance and possibly the low-grade inflammation. To test this hypothesis, U937 macrophages were exposed to insulin. In these cells, insulin induced expression of the proinflammatory cytokines IL-1β, IL-8, CCL2, and OSM. The insulin-elicited induction of IL-1β was independent of the presence of endotoxin and most likely mediated by an insulin-dependent activation of NF-κB. Supernatants of the insulin-treated U937 macrophages rendered primary cultures of rat hepatocytes insulin resistant; they attenuated the insulin-dependent induction of glucokinase by 50%. The cytokines contained in the supernatants of insulin-treated U937 macrophages activated ERK1/2 and IKKβ, resulting in an inhibitory serine phosphorylation of the insulin receptor substrate. In addition, STAT3 was activated and SOCS3 induced, further contributing to the interruption of the insulin receptor signal chain in hepatocytes. These results indicate that hyperinsulinemia per se might contribute to the low-grade inflammation prevailing in overweight and obese patients and thereby promote the development of insulin resistance particularly in the liver, because the insulin concentration in the portal circulation is much higher than in all other tissues. Copyright © 2016 the American Physiological Society.

  18. 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.

  19. Insulin receptor internalization defect in an insulin-resistant mouse melanoma cell line

    SciTech Connect

    Androlewicz, M.J.; Straus, D.S. ); Brandenburg, D.F. )

    1989-12-12

    Previous studies from this laboratory demonstrated that the PG19 mouse melanoma cell line does not exhibit a biological response to insulin, whereas melanoma x mouse embryo fibroblast hybrids do respond to insulin. To investigate the molecular basis of the insulin resistance of the PG19 melanoma cells, insulin receptors from the insulin-resistant melanoma cells and insulin-sensitive fibroblast x melanoma hybrid cells were analyzed by the technique of photoaffinity labeling using the photoprobe {sup 125}I-NAPA-DP-insulin. Photolabeled insulin receptors from the two cell types have identical molecular weights as determined by SDS gel electrophoresis under reducing and nonreducing conditions, indicating that the receptors on the two cell lines are structurally similar. Insulin receptor internalization studies revealed that the hybrid cells internalize receptors to a high degree at 37{degree}C, whereas the melanoma cells internalize receptors to a very low degree or not at all. The correlation between ability to internalize insulin receptors and sensitivity to insulin action in this system suggests that uptake of the insulin-receptor complex may be required for insulin action in these cells. Insulin receptors from the two cell lines autophosphorylate in a similar insulin-dependent manner both in vitro and in intact cells, indicating that insulin receptors on the melanoma and hybrid cells have functional tyrosine protein kinase activity. Therefore, the block in insulin action in the PG19 melanoma cells appears to reside at a step beyond insulin-stimulated receptor autophosphorylation.

  20. Obesity, insulin resistance, and microvascular adaptation.

    PubMed

    Frisbee, Jefferson C

    2017-02-01

    Two of the primary risk factors for the progressive evolution of cardiovascular disease are obesity and impaired glycemic control-including both insulin resistance and overt type 2 diabetes mellitus, leading to increased research emphasis on these conditions, their mechanistic bases, and their health outcomes. This Special Topics Issue of the journal Microcirculation summarizes a symposium at the recent Joint Meeting of the American Physiological Society and the Physiological Society, held in Dublin, Ireland, on July 30, 2016. This symposium, "Adaptive outcomes of microvascular networks to obesity and type 2 diabetes mellitus/insulin resistance," presented four lectures, each of which addressed the larger issue from a different perspective. © 2016 John Wiley & Sons Ltd.

  1. Race and the insulin resistance syndrome.

    PubMed

    Kramer, Holly; Dugas, Lara; Rosas, Sylvia E

    2013-09-01

    Type 2 diabetes remains an important cause of morbidity and mortality. The metabolic syndrome affects 25% of the adult US population based on the Third Report of the Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults from the National Cholesterol Education Program. Knowledge on the impact of obesity on metabolic health parameters has increased greatly over the past decade. This review discusses the limitations of the National Cholesterol Education Program metabolic syndrome definition and the racial disparities in the clinical presentation of the insulin resistance syndrome. We also examine the current literature with particular emphasis on albuminuria, nonalcoholic fatty liver disease, and intramyocellular lipid content. This review explores potential environmental and genetic reasons for differences in the manifestation of insulin resistance across racial/ethnic groups and highlights several promising areas for further study.

  2. Insulin signaling pathways in a patient with insulin resistance of difficult management - a case report

    PubMed Central

    2009-01-01

    Insulin signalling pathways were investigated in a 33 year-old woman with immunologic insulin resistance. Her past medical history was remarkable for intermittent use of insulin and allergic reactions to several drugs, and measure of plasma anti-insulin antibodies level corroborated the clinical suspicion of immune mediated insulin resistance (8074 nU/ml - RIA - Ref value: <60). Treatment with several immunosuppressive regimens was tried, however the results were disappointing. Possible subcellular mechanisms of insulin resistance were investigated by performing analysis of insulin receptor and post receptor signaling in skeletal muscle biopsy. The expression of insulin receptor (IR), insulin receptor substrate 1 (IRS-1) and glucose transporter 4 (GLUT-4) was evaluated in total extract from muscle tissue by Western blotting. Basal IR, IRS-1 and GLUT-4 expression was detected, however receptor autophosphorylation was not observed. A study of translocation of GLUT-4 to plasma membrane showed that tissue presented low levels of membrane-associated GLUT-4. When in vitro stimulation was undertaken, tissue was capable to be responsive to insulin. Our results suggest that even though IR expression was normally occurring, IR β-subunit tyrosine kinase activity in muscle was down-regulated leading to alterations in insulin post receptor signaling. Consistent with normal insulin receptor and post receptor signaling, our results were compatible with decreased insulin binding to IR probably due to neutralization by anti-insulin antibodies. In conclusion, this patient has immunologic insulin resistance and treatment should be based on immunosuppressive drugs as tolerated. PMID:19941665

  3. 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.

  4. [Severe type A insulin resistance syndrome due to a mutation in the insulin receptor gene].

    PubMed

    Ros, P; Colino-Alcol, E; Grasso, V; Barbetti, F; Argente, J

    2015-01-01

    Insulin resistance syndromes without lipodystrophy are an infrequent and heterogeneous group of disorders with variable clinical phenotypes, associated with hyperglycemia and hyperinsulinemia. The three conditions related to mutations in the insulin receptor gene are leprechaunism or Donohue syndrome, Rabson-Mendenhall syndrome, and Type A syndrome. A case is presented on a patient diagnosed with type A insulin resistance, defined by the triad of extreme insulin resistance, acanthosis nigricans, and hyperandrogenism, carrying a heterozygous mutation in exon 19 of the insulin receptor gene coding for its tyrosine kinase domain that is crucial for the catalytic activity of the receptor. The molecular basis of the syndrome is reviewed, focusing on the structure-function relationships of the insulin receptor, knowing that the criteria for survival are linked to residual insulin receptor function. It is also pointed out that, although type A insulin resistance appears to represent a somewhat less severe condition, these patients have a high morbidity and their treatment is still unsatisfactory.

  5. Lipid-induced insulin resistance: unravelling the mechanism

    PubMed Central

    Samuel, Varman T; Petersen, Kitt Falk; Shulman, Gerald I

    2010-01-01

    Insulin resistance has long been associated with obesity. More than 40 years ago, Randle and colleagues postulated that lipids impaired insulin-stimulated glucose use by muscles through inhibition of glycolysis at key points. However, work over the past two decades has shown that lipid-induced insulin resistance in skeletal muscle stems from defects in insulin-stimulated glucose transport activity. The steatotic liver is also resistant to insulin in terms of inhibition of hepatic glucose production and stimulation of glycogen synthesis. In muscle and liver, the intracellular accumulation of lipids—namely, diacylglycerol—triggers activation of novel protein kinases C with subsequent impairments in insulin signalling. This unifying hypothesis accounts for the mechanism of insulin resistance in obesity, type 2 diabetes, lipodystrophy, and ageing; and the insulin-sensitising effects of thiazolidinediones. PMID:20609972

  6. Adrenocortical tumors and insulin resistance: What is the first step?

    PubMed

    Altieri, Barbara; Tirabassi, Giacomo; Della Casa, Silvia; Ronchi, Cristina L; Balercia, Giancarlo; Orio, Francesco; Pontecorvi, Alfredo; Colao, Annamaria; Muscogiuri, Giovanna

    2016-06-15

    The pathogenetic mechanisms underlying the onset of adrenocortical tumors (ACTs) are still largely unknown. Recently, more attention has been paid to the role of insulin and insulin-like growth factor (IGF) system on general tumor development and progression. Increased levels of insulin, IGF-1 and IGF-2 are associated with tumor cell growth and increased risk of cancer promotion and progression in patients with type 2 diabetes. Insulin resistance and compensatory hyperinsulinemia may play a role in adrenal tumor growth through the activation of insulin and IGF-1 receptors. Interestingly, apparently non-functioning ACTs are often associated with a high prevalence of insulin resistance and metabolic syndrome. However, it is unclear if ACT develops from a primary insulin resistance and compensatory hyperinsulinemia or if insulin resistance is only secondary to the slight cortisol hypersecretion by ACT. The aim of this review is to summarize the current evidence regarding the relationship between hyperinsulinemia and adrenocortical tumors. © 2015 UICC.

  7. Tau deletion promotes brain insulin resistance

    PubMed Central

    Marciniak, Elodie; Leboucher, Antoine; Caron, Emilie; Ahmed, Tariq; Tailleux, Anne; Dumont, Julie; Issad, Tarik; Gerhardt, Ellen; Pagesy, Patrick; Vileno, Margaux; Hamdane, Malika; Bantubungi, Kadiombo; Lancel, Steve; Demeyer, Dominique; Eddarkaoui, Sabiha; Vallez, Emmanuelle; Vieau, Didier; Humez, Sandrine; Faivre, Emilie; Grenier-Boley, Benjamin; Outeiro, Tiago F.; Amouyel, Philippe; Balschun, Detlef

    2017-01-01

    The molecular pathways underlying tau pathology–induced synaptic/cognitive deficits and neurodegeneration are poorly understood. One prevalent hypothesis is that hyperphosphorylation, misfolding, and fibrillization of tau impair synaptic plasticity and cause degeneration. However, tau pathology may also result in the loss of specific physiological tau functions, which are largely unknown but could contribute to neuronal dysfunction. In the present study, we uncovered a novel function of tau in its ability to regulate brain insulin signaling. We found that tau deletion leads to an impaired hippocampal response to insulin, caused by altered IRS-1 and PTEN (phosphatase and tensin homologue on chromosome 10) activities. Our data also demonstrate that tau knockout mice exhibit an impaired hypothalamic anorexigenic effect of insulin that is associated with energy metabolism alterations. Consistently, we found that tau haplotypes are associated with glycemic traits in humans. The present data have far-reaching clinical implications and raise the hypothesis that pathophysiological tau loss-of-function favors brain insulin resistance, which is instrumental for cognitive and metabolic impairments in Alzheimer’s disease patients. PMID:28652303

  8. Is insulin resistance the cause of the metabolic syndrome?

    PubMed

    Ferrannini, Ele

    2006-01-01

    Following up on original descriptions of clustering of cardiovascular risk factors (chiefly, glucose intolerance, dyslipidaemia and hypertension) around the presence of insulin resistance, the metabolic syndrome has recently been upgraded to the status of a disease entity with an inherent predictive value for cardiovascular disease. In pathophysiological terms, insulin resistance (of glucose metabolism) and the attendant compensatory hyperinsulinaemia are causally related to each of glucose intolerance, dyslipidaemia, high blood pressure and vascular dysfunction. The physiological mechanisms are concisely reviewed here. However, insulin resistance/hyperinsulinaemia alone is insufficient to cause these abnormalities, for which other pathogenic factors (e.g. ss-cell dysfunction for glucose intolerance) are required. The metabolic syndrome, on the other hand, has evolved from a set of statistical associations believed to carry an excess of cardiovascular risk. In the various existing definitions, a mixture of physical, metabolic and clinical variables have been used on grounds of predictive value or practical ease. These variables belong to different phenotypes, which are upstream, intermediate and proximal, respectively, in their relation to clinical disease. The resulting 'syndromes' usually lack a cogent conceptual structure, may reflect the particular data set from which they are extracted and may be of limited applicability. While overt diabetes, clinical hypertension and frank dyslipidaemia are often present together in the same patient, a subclinical syndrome with a distinct, probable aetiology and a proven power as a risk indicator remains to be identified.

  9. Measurement of insulin resistance in chronic kidney disease.

    PubMed

    Pham, Hien; Utzschneider, Kristina M; de Boer, Ian H

    2011-11-01

    Insulin resistance is a known complication of end-stage renal disease that also appears to be present in earlier stages of chronic kidney disease (CKD). It is a risk factor for cardiovascular disease and an important potential therapeutic target in this population. Measurement of insulin resistance is reviewed in the context of known pathophysiologic abnormalities in CKD. Insulin resistance in CKD is due to a high prevalence of known risk factors (e.g. obesity) and to unique metabolic abnormalities. The site of insulin resistance in CKD is localized to skeletal muscle. Estimates based on fasting insulin concentration may not adequately capture insulin resistance in CKD because they largely reflect hepatic defects and because CKD impairs insulin catabolism. A variety of dynamic tests are available to directly measure insulin-mediated glucose uptake. Insulin resistance may be an important therapeutic target in CKD. Complementary methods are available to assess insulin resistance, and each method has unique advantages, disadvantages, and levels of complexity. These characteristics, and the likelihood that CKD alters the performance of some insulin resistance measurements, must be considered when designing and interpreting clinical studies.

  10. Lipid-induced insulin resistance does not impair insulin access to skeletal muscle

    PubMed Central

    Richey, Joyce M.; Castro, Ana Valeria B.; Broussard, Josiane L.; Ionut, Viorica; Bergman, Richard N.

    2015-01-01

    Elevated plasma free fatty acids (FFA) induce insulin resistance in skeletal muscle. Previously, we have shown that experimental insulin resistance induced by lipid infusion prevents the dispersion of insulin through the muscle, and we hypothesized that this would lead to an impairment of insulin moving from the plasma to the muscle interstitium. Thus, we infused lipid into our anesthetized canine model and measured the appearance of insulin in the lymph as a means to sample muscle interstitium under hyperinsulinemic euglycemic clamp conditions. Although lipid infusion lowered the glucose infusion rate and induced both peripheral and hepatic insulin resistance, we were unable to detect an impairment of insulin access to the lymph. Interestingly, despite a significant, 10-fold increase in plasma FFA, we detected little to no increase in free fatty acids or triglycerides in the lymph after lipid infusion. Thus, we conclude that experimental insulin resistance induced by lipid infusion does not reduce insulin access to skeletal muscle under clamp conditions. This would suggest that the peripheral insulin resistance is likely due to reduced cellular sensitivity to insulin in this model, and yet we did not detect a change in the tissue microenvironment that could contribute to cellular insulin resistance. PMID:25852002

  11. Lipid-induced insulin resistance does not impair insulin access to skeletal muscle.

    PubMed

    Kolka, Cathryn M; Richey, Joyce M; Castro, Ana Valeria B; Broussard, Josiane L; Ionut, Viorica; Bergman, Richard N

    2015-06-01

    Elevated plasma free fatty acids (FFA) induce insulin resistance in skeletal muscle. Previously, we have shown that experimental insulin resistance induced by lipid infusion prevents the dispersion of insulin through the muscle, and we hypothesized that this would lead to an impairment of insulin moving from the plasma to the muscle interstitium. Thus, we infused lipid into our anesthetized canine model and measured the appearance of insulin in the lymph as a means to sample muscle interstitium under hyperinsulinemic euglycemic clamp conditions. Although lipid infusion lowered the glucose infusion rate and induced both peripheral and hepatic insulin resistance, we were unable to detect an impairment of insulin access to the lymph. Interestingly, despite a significant, 10-fold increase in plasma FFA, we detected little to no increase in free fatty acids or triglycerides in the lymph after lipid infusion. Thus, we conclude that experimental insulin resistance induced by lipid infusion does not reduce insulin access to skeletal muscle under clamp conditions. This would suggest that the peripheral insulin resistance is likely due to reduced cellular sensitivity to insulin in this model, and yet we did not detect a change in the tissue microenvironment that could contribute to cellular insulin resistance. Copyright © 2015 the American Physiological Society.

  12. Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy

    PubMed Central

    Jia, Guanghong; DeMarco, Vincent G.; Sowers, James R.

    2016-01-01

    Insulin resistance, type 2 diabetes mellitus and associated hyperinsulinaemia can promote the development of a specific form of cardiomyopathy that is independent of coronary artery disease and hypertension. Termed diabetic cardiomyopathy, this form of cardiomyopathy is a major cause of morbidity and mortality in developed nations, and the prevalence of this condition is rising in parallel with increases in the incidence of obesity and type 2 diabetes mellitus. Of note, female patients seem to be particularly susceptible to the development of this complication of metabolic disease. The diabetic cardiomyopathy observed in insulin-resistant or hyperinsulinaemic states is characterized by impaired myocardial insulin signalling, mitochondrial dysfunction, endoplasmic reticulum stress, impaired calcium homeostasis, abnormal coronary microcirculation, activation of the sympathetic nervous system, activation of the renin–angiotensin–aldosterone system and maladaptive immune responses. These pathophysiological changes result in oxidative stress, fibrosis, hypertrophy, cardiac diastolic dysfunction and eventually systolic heart failure. This Review highlights a surge in diabetic cardiomyopathy research, summarizes current understanding of the molecular mechanisms underpinning this condition and explores potential preventive and therapeutic strategies. PMID:26678809

  13. β-Adrenergic Receptor and Insulin Resistance in the Heart.

    PubMed

    Mangmool, Supachoke; Denkaew, Tananat; Parichatikanond, Warisara; Kurose, Hitoshi

    2017-01-01

    Insulin resistance is characterized by the reduced ability of insulin to stimulate tissue uptake and disposal of glucose including cardiac muscle. These conditions accelerate the progression of heart failure and increase cardiovascular morbidity and mortality in patients with cardiovascular diseases. It is noteworthy that some conditions of insulin resistance are characterized by up-regulation of the sympathetic nervous system, resulting in enhanced stimulation of β-adrenergic receptor (βAR). Overstimulation of βARs leads to the development of heart failure and is associated with the pathogenesis of insulin resistance in the heart. However, pathological consequences of the cross-talk between the βAR and the insulin sensitivity and the mechanism by which βAR overstimulation promotes insulin resistance remain unclear. This review article examines the hypothesis that βARs overstimulation leads to induction of insulin resistance in the heart.

  14. β-Adrenergic Receptor and Insulin Resistance in the Heart

    PubMed Central

    Mangmool, Supachoke; Denkaew, Tananat; Parichatikanond, Warisara; Kurose, Hitoshi

    2017-01-01

    Insulin resistance is characterized by the reduced ability of insulin to stimulate tissue uptake and disposal of glucose including cardiac muscle. These conditions accelerate the progression of heart failure and increase cardiovascular morbidity and mortality in patients with cardiovascular diseases. It is noteworthy that some conditions of insulin resistance are characterized by up-regulation of the sympathetic nervous system, resulting in enhanced stimulation of β-adrenergic receptor (βAR). Over-stimulation of βARs leads to the development of heart failure and is associated with the pathogenesis of insulin resistance in the heart. However, pathological consequences of the cross-talk between the βAR and the insulin sensitivity and the mechanism by which βAR over-stimulation promotes insulin resistance remain unclear. This review article examines the hypothesis that βARs over-stimulation leads to induction of insulin resistance in the heart. PMID:28035081

  15. [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.

  16. Globular adiponectin ameliorates metabolic insulin resistance via AMPK-mediated restoration of microvascular insulin responses.

    PubMed

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

    2015-09-01

    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 microvascular recruitment. We demonstrated that a high-fat diet induces vascular adiponectin and insulin resistance but globular adiponectin administration can restore vascular insulin responses and improve insulin's metabolic action via an AMPK- and nitric oxide-dependent mechanism. This suggests that globular adiponectin might have a therapeutic potential for improving insulin resistance and preventing cardiovascular complications in patients with diabetes via modulation of microvascular insulin responses. 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

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

    PubMed Central

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

    2013-01-01

    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 are 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 contribute 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. PMID:23932846

  18. Insulin Resistance Influences Central Opioid Activity in Polycystic Ovary Syndrome

    PubMed Central

    Berent-Spillson, Alison; Love, Tiffany; Pop-Busui, Rodica; Sowers, MaryFran; Persad, Carol C.; Pennington, Kathryn P.; Eyvazaddeh, Aimee D.; Padmanabhan, Vasantha; Zubieta, Jon-Kar; Smith, Yolanda R.

    2011-01-01

    This pilot study describes a relationship between insulin resistance and µ-opioid neurotransmission in limbic appetite and mood-regulating regions in women with polycystic ovary syndrome, suggesting that insulin-opioid interactions may contribute to behavioral and reproductive pathologies of PCOS. We found that 1) insulin resistant PCOS patients (n=7) had greater limbic µ-opioid receptor availability (non-displaceable binding potential) than controls (n=5), 2) receptor availability was correlated with severity of insulin resistance, and 3) receptor availability normalized after insulin-regulating treatment. PMID:21486668

  19. Insulin resistance influences central opioid activity in polycystic ovary syndrome.

    PubMed

    Berent-Spillson, Alison; Love, Tiffany; Pop-Busui, Rodica; Sowers, MaryFran; Persad, Carol C; Pennington, Kathryn P; Eyvazaddeh, Aimee D; Padmanabhan, Vasantha; Zubieta, Jon-Kar; Smith, Yolanda R

    2011-06-30

    This pilot study describes a relationship between insulin resistance and μ-opioid neurotransmission in limbic appetite and mood-regulating regions in women with polycystic ovary syndrome (PCOS), suggesting that insulin-opioid interactions may contribute to behavioral and reproductive pathologies of PCOS. We found that [1] patients with PCOS who are insulin-resistant (n = 7) had greater limbic μ-opioid receptor availability (nondisplaceable binding potential) than controls (n = 5); [2] receptor availability was correlated with severity of insulin resistance; and [3] receptor availability normalized after insulin-regulating treatment.

  20. Insulin resistance in severe acne vulgaris.

    PubMed

    Emiroğlu, Nazan; Cengiz, Fatma Pelin; Kemeriz, Funda

    2015-08-01

    Acne vulgaris is a pilosebaceous gland disease that usually affects people from puberty to young adulthood. It is seen especially on the face, neck, trunk and arms. Its severity differs from patient to patient and its pathogenesis is multifactorial. The main pathogenic factors of acne are high sebaceous gland secretion, follicular hyperproliferation, high androgen effects, propionibacterium acnes colonization and inflammation. Diet is always thought a probable reason for acne and many studies are done about acne and diet. To determine the effect of insulin resistance in severe acne vulgaris. Two hundred and forty-three acne vulgaris patients and 156 healthy controls were enrolled into the study. The blood levels of insulin and glucose were measured. Homeostasis Model Assessment (HOMA) Index was calculated. The values were compared with the control group. All of the patients were in the severe acne group according to their scores on the global acne scoring scale. While fasting blood glucose levels were not different between the groups (p > 0.05, 82.91 ±9.76 vs. 80.26 ±8.33), the fasting insulin levels were significantly higher in the patient group than in the control group (p < 0.001, 14.01 ±11.94 vs. 9.12 ±3.53). Additionally, there was a highly significant difference between the patient and control groups in terms of HOMA values (p < 0.001, 2.87 ±2.56 vs. 1.63 ±0.65). These results suggest that insulin resistance may have a role in the pathogenesis of acne.

  1. Insulin resistance in severe acne vulgaris

    PubMed Central

    Cengiz, Fatma Pelin; Kemeriz, Funda

    2015-01-01

    Introduction Acne vulgaris is a pilosebaceous gland disease that usually affects people from puberty to young adulthood. It is seen especially on the face, neck, trunk and arms. Its severity differs from patient to patient and its pathogenesis is multifactorial. The main pathogenic factors of acne are high sebaceous gland secretion, follicular hyperproliferation, high androgen effects, propionibacterium acnes colonization and inflammation. Diet is always thought a probable reason for acne and many studies are done about acne and diet. Aim To determine the effect of insulin resistance in severe acne vulgaris. Material and methods Two hundred and forty-three acne vulgaris patients and 156 healthy controls were enrolled into the study. The blood levels of insulin and glucose were measured. Homeostasis Model Assessment (HOMA) Index was calculated. The values were compared with the control group. Results All of the patients were in the severe acne group according to their scores on the global acne scoring scale. While fasting blood glucose levels were not different between the groups (p > 0.05, 82.91 ±9.76 vs. 80.26 ±8.33), the fasting insulin levels were significantly higher in the patient group than in the control group (p < 0.001, 14.01 ±11.94 vs. 9.12 ±3.53). Additionally, there was a highly significant difference between the patient and control groups in terms of HOMA values (p < 0.001, 2.87 ±2.56 vs. 1.63 ±0.65). Conclusions These results suggest that insulin resistance may have a role in the pathogenesis of acne. PMID:26366152

  2. Effect of curative parathyroidectomy on insulin resistance

    PubMed Central

    Putnam, Rachel; Dhibar, Deba Prasad; Varshney, Shweta; Behera, Arunanshu; Mittal, B. R.; Bhansali, Anil; Rao, Sudhaker D.; Bhadada, Sanjay Kumar

    2016-01-01

    Background: Primary hyperparathyroidism (PHPT) is characterized by inappropriately elevated serum parathyroid hormone (PTH) level despite elevated serum calcium. Insulin resistant is the basic pathophysiology, behind the higher prevalence of diabetes mellitus in patients with PHPT. However, the improvement in insulin resistance (IR) after curative parathyroidectomy (CPTX) has not been established yet, as the study results are conflicting. Materials and Methods: In this prospective interventional study, ten patients with mild PHPT (Group 1) and another ten patients with moderate to severe PHPT (Group 2) were undergone CPTX. The IR was assessed by homeostasis model assessment-IR (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), fasting plasma glucose (FPG), and fasting serum insulin (FSI), before and 3 months after CPTX. Results: There was no significant change of FPG and FSI, before and after CPTX in Group 1 (P = 0.179 and P = 0.104) and Group 2 (P = 0.376 and P = 0.488). Before surgery, HOMA-IR was higher, and QUICKI was significantly lower, in both Group 1 (P = 0.058 and P = 0.009) and Group 2 (P = 0.023 and P = 0.005) as compared to published normal reference mean, with no significant difference between the groups. Three months after surgery HOMA-IR increased further and QUICKI remained unchanged as compared to baseline, in both Group 1 (P = 0.072 and 0.082) and Group 2 (P = 0.54 and 0.56), but statistically insignificant. Conclusion: IR remained unchanged after CPTX in mild as well as moderate to severe PHPT. Asymptomatic PHPT with abnormal IR should not be used as criteria for parathyroidectomy. PMID:27867880

  3. Heart Rate Variability, Insulin Resistance, and Insulin Sensitivity in Japanese Adults: The Toon Health Study

    PubMed Central

    Saito, Isao; Hitsumoto, Shinichi; Maruyama, Koutatsu; Nishida, Wataru; Eguchi, Eri; Kato, Tadahiro; Kawamura, Ryoichi; Takata, Yasunori; Onuma, Hiroshi; Osawa, Haruhiko; Tanigawa, Takeshi

    2015-01-01

    Background Although impaired cardiac autonomic function is associated with an increased risk of type 2 diabetes in Caucasians, evidence in Asian populations with a lower body mass index is limited. Methods Between 2009–2012, the Toon Health Study recruited 1899 individuals aged 30–79 years who were not taking medication for diabetes. A 75-g oral glucose tolerance test was used to diagnose type 2 diabetes, and fasting and 2-h-postload glucose and insulin concentrations were measured. We assessed the homeostasis model assessment index for insulin resistance (HOMA-IR) and Gutt’s insulin sensitivity index (ISI). Pulse was recorded for 5 min, and time-domain heart rate variability (HRV) indices were calculated: the standard deviation of normal-to-normal intervals (SDNN) and the root mean square of successive difference (RMSSD). Power spectral analysis provided frequency domain measures of HRV: high frequency (HF) power, low frequency (LF) power, and the LF:HF ratio. Results Multivariate-adjusted logistic regression models showed decreased SDNN, RMSSD, and HF, and increased LF:HF ratio were associated significantly with increased HOMA-IR and decreased ISI. When stratified by overweight status, the association of RMSSD, HF, and LF:HF ratio with decreased ISI was also apparent in non-overweight individuals. The interaction between LF:HF ratio and decreased ISI in overweight individuals was significant, with the odds ratio for decreased ISI in the highest quartile of LF:HF ratio in non-overweight individuals being 2.09 (95% confidence interval, 1.41–3.10). Conclusions Reduced HRV was associated with insulin resistance and lower insulin sensitivity. Decreased ISI was linked with parasympathetic dysfunction, primarily in non-overweight individuals. PMID:26277879

  4. 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.

  5. Fructose, insulin resistance, and metabolic dyslipidemia

    PubMed Central

    Basciano, Heather; Federico, Lisa; Adeli, Khosrow

    2005-01-01

    Obesity and type 2 diabetes are occurring at epidemic rates in the United States and many parts of the world. The "obesity epidemic" appears to have emerged largely from changes in our diet and reduced physical activity. An important but not well-appreciated dietary change has been the substantial increase in the amount of dietary fructose consumption from high intake of sucrose and high fructose corn syrup, a common sweetener used in the food industry. A high flux of fructose to the liver, the main organ capable of metabolizing this simple carbohydrate, perturbs glucose metabolism and glucose uptake pathways, and leads to a significantly enhanced rate of de novo lipogenesis and triglyceride (TG) synthesis, driven by the high flux of glycerol and acyl portions of TG molecules from fructose catabolism. These metabolic disturbances appear to underlie the induction of insulin resistance commonly observed with high fructose feeding in both humans and animal models. Fructose-induced insulin resistant states are commonly characterized by a profound metabolic dyslipidemia, which appears to result from hepatic and intestinal overproduction of atherogenic lipoprotein particles. Thus, emerging evidence from recent epidemiological and biochemical studies clearly suggests that the high dietary intake of fructose has rapidly become an important causative factor in the development of the metabolic syndrome. There is an urgent need for increased public awareness of the risks associated with high fructose consumption and greater efforts should be made to curb the supplementation of packaged foods with high fructose additives. The present review will discuss the trends in fructose consumption, the metabolic consequences of increased fructose intake, and the molecular mechanisms leading to fructose-induced lipogenesis, insulin resistance and metabolic dyslipidemia. PMID:15723702

  6. Insulin resistance modifies the association between obesity and current asthma in adults.

    PubMed

    Cardet, Juan Carlos; Ash, Samuel; Kusa, Tope; Camargo, Carlos A; Israel, Elliot

    2016-08-01

    Insulin resistance potentiates the association between obesity and childhood asthma, but this relationship appears inconsistent in relatively small studies of adults. We investigated effect modification in adults using the National Health and Nutrition Examination Survey 2003-2012, a large, nationally representative database.Insulin resistance and a history of physician-diagnosed current asthma were obtained from 12 421 adults, ages 18-85 years. We used logistic regression to determine associations between obesity and current asthma, adjusting for age, sex, race/ethnicity, poverty income ratio and smoking status. An interaction term evaluated effect modification by insulin resistance of the obesity-asthma association.As expected, obesity was positively associated with current asthma. Insulin resistance modified this association, with obesity measured as body mass index, waist circumference or waist-to-height ratio. The relationship between obesity and current asthma was stronger with increasing insulin resistance tertiles (OR 2.05, 95% CI 2.76-3.00; p-value for interaction 0.03). This association was robust to adjustments for other components of the metabolic syndrome (hypertriglyceridaemia, hypertension, hyperglycaemia and systemic inflammation). None of these components were themselves effect modifiers of the obesity-asthma association.In this large, nationally representative sample, insulin resistance modified the association between obesity and current asthma in adults. Targeting insulin resistance may represent a novel therapeutic strategy for obese patients with asthma.

  7. Understanding insulin resistance. What are the clinical implications?

    PubMed

    Sivitz, William I

    2004-07-01

    Insulin resistance is an important clinical issue in patients with other prominent components of metabolic syndrome, such as central adiposity and diabetes. However, its presence may be less evident in patients who are neither obese nor diabetic. Is measurement of insulin resistance important in clinical practice? How might its presence change management in individual patients? In this concise review, Dr Sivitz discusses the underlying mechanisms involved in insulin resistance, the issues surrounding assessment, and the implications for management in patients in whom insulin resistance is either detected or suspected.

  8. Serum Insulin, Glucose, Indices of Insulin Resistance, and Risk of Lung Cancer.

    PubMed

    Argirion, Ilona; Weinstein, Stephanie J; Männistö, Satu; Albanes, Demetrius; Mondul, Alison M

    2017-07-11

    Background: Although insulin may increase the risk of some cancers, few studies have examined fasting serum insulin and lung cancer risk.Methods: We examined serum insulin, glucose, and indices of insulin resistance [insulin:glucose molar ratio and homeostasis model assessment of insulin resistance (HOMA-IR)] and lung cancer risk using a case-cohort study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish men. A total of 196 cases and 395 subcohort members were included. Insulin and glucose were measured in fasting serum collected 5 to 12 years before diagnosis. Cox proportional hazards models were utilized to estimate the relative risk of lung cancer.Results: The average time between blood collection and lung cancer was 9.6 years. Fasting serum insulin levels were 8.7% higher in subcohort members than cases. After multivariable adjustment, men in the fourth quartile of insulin had a significantly higher risk of lung cancer than those in the first quartile [HR = 2.10; 95% confidence interval (CI), 1.12-3.94]. A similar relationship was seen with HOMA-IR (HR = 1.83; 95% CI, 0.99-3.38). Risk was not strongly associated with glucose or the insulin:glucose molar ratio (Ptrend = 0.55 and Ptrend = 0.27, respectively).Conclusions: Higher fasting serum insulin concentrations, as well as the presence of insulin resistance, appear to be associated with an elevated risk of lung cancer development.Impact: Although insulin is hypothesized to increase risk of some cancers, insulin and lung cancer remain understudied. Higher insulin levels and insulin resistance were associated with increased lung cancer risk. Although smoking cessation is the best method of lung cancer prevention, other lifestyle changes that affect insulin concentrations and sensitivity may reduce lung cancer risk. Cancer Epidemiol Biomarkers Prev; 26(10); 1-6. ©2017 AACR. ©2017 American Association for Cancer Research.

  9. Skeletal Muscle Insulin Resistance and Absence of Inflammation Characterize Insulin-Resistant Grade I Obese Women

    PubMed Central

    Bourret, Annick; Lambert, Karen; Birot, Olivier; Fédou, Christine; Dupuy, Anne-Marie; Cristol, Jean-Paul; Sutra, Thibault; Molinari, Nicolas; Maimoun, Laurent; Mariano-Goulart, Denis; Galtier, Florence; Avignon, Antoine; Stanke-Labesque, Françoise; Mercier, Jacques; Sultan, Ariane; Bisbal, Catherine

    2016-01-01

    Context Obesity is associated with insulin-resistance (IR), the key feature of type 2 diabetes. Although chronic low-grade inflammation has been identified as a central effector of IR development, it has never been investigated simultaneously at systemic level and locally in skeletal muscle and adipose tissue in obese humans characterized for their insulin sensitivity. Objectives We compared metabolic parameters and inflammation at systemic and tissue levels in normal-weight and obese subjects with different insulin sensitivity to better understand the mechanisms involved in IR development. Methods 30 post-menopausal women were classified as normal-weight insulin-sensitive (controls, CT) and obese (grade I) insulin-sensitive (OIS) or insulin-resistant (OIR) according to their body mass index and homeostasis model assessment of IR index. They underwent a hyperinsulinemic-euglycemic clamp, blood sampling, skeletal muscle and subcutaneous adipose tissue biopsies, an activity questionnaire and a self-administrated dietary recall. We analyzed insulin sensitivity, inflammation and IR-related parameters at the systemic level. In tissues, insulin response was assessed by P-Akt/Akt expression and inflammation by macrophage infiltration as well as cytokines and IκBα expression. Results Systemic levels of lipids, adipokines, inflammatory cytokines, and lipopolysaccharides were equivalent between OIS and OIR subjects. In subcutaneous adipose tissue, the number of anti-inflammatory macrophages was higher in OIR than in CT and OIS and was associated with higher IL-6 level. Insulin induced Akt phosphorylation to the same extent in CT, OIS and OIR. In skeletal muscle, we could not detect any inflammation even though IκBα expression was lower in OIR compared to CT. However, while P-Akt/Akt level increased following insulin stimulation in CT and OIS, it remained unchanged in OIR. Conclusion Our results show that systemic IR occurs without any change in systemic and tissues

  10. Hypothalamic Insulin Resistance in Obesity: Effects on Glucose Homeostasis.

    PubMed

    Chen, Weiyi; Balland, Eglantine; Cowley, Michael A

    2017-01-01

    The central link between obesity and type 2 diabetes is the development of insulin resistance. To date, it is still not clear whether hyperinsulinemia causes insulin resistance, which underlies the pathogenesis of obesity-associated type 2 diabetes, owing to the sophisticated regulatory mechanisms that exist in the periphery and in the brain. In recent years, accumulating evidence has demonstrated the existence of insulin resistance within the hypothalamus. In this review, we have integrated the recent discoveries surrounding both central and peripheral insulin resistance to provide a comprehensive overview of insulin resistance in obesity and the regulation of systemic glucose homeostasis. In particular, this review will discuss how hyperinsulinemia and hyperleptinemia in obesity impair insulin sensitivity in tissues such as the liver, skeletal muscle, adipose tissue, and the brain. In addition, this review highlights insulin transport into the brain, signaling pathways associated with hypothalamic insulin receptor expression in the regulation of hepatic glucose production, and finally the perturbation of systemic glucose homeostasis as a consequence of central insulin resistance. We also suggest future approaches to overcome both central and peripheral insulin resistance to treat obesity and type 2 diabetes. © 2017 S. Karger AG, Basel.

  11. [A case of leprechaunism with extreme insulin resistance due to a primary defect in insulin receptors].

    PubMed

    Goji, K; Takata, Y; Kobayashi, M

    1985-09-20

    This report describes a 3-month-old female infant with the typical physical features of leprechaunism. The patient demonstrated glucose intolerance and marked hyperinsulinemia (4600 microU/ml). Since an intravenous insulin injection (actrapid insulin: 0.15 U/kg) caused no significant decrease in the blood glucose level, the presence of insulin resistance was suggested. Neither insulin antibodies nor insulin receptor antibodies were were found in the patient's plasma, and other circulating insulin antagonists such as glucagon, growth hormone, and cortisol were within normal limits. [125I]Insulin binding to the erythrocytes from the patient was as low as 1.02% (control infants: 4.89 +/- 1.08% [mean +/- SD]). [125I]Insulin binding to the cultured transformed lymphocytes from the patient was similarly reduced to 3.58% (control: 20.9 +/- 2.71% [mean +/- SD]). From these findings we concluded that the insulin resistance was due to a primary defect in insulin receptors. Interestingly, transient remissions of the patient's glucose intolerance and hyperinsulinemia were observed during a year of follow-up study. The insulin tolerance test which was performed at the remission period showed an improvement in insulin resistance. However, the insulin binding defect to erythrocytes remained unchanged even at the remission period. The exact cause of these remissions was not clear and remained to be elucidated.

  12. Role of sialic acid in insulin action and the insulin resistance of diabetes mellitus

    SciTech Connect

    Salhanick, A.I.; Amatruda, J.M. )

    1988-08-01

    Adipocytes treated with neuraminidase show markedly reduced responsiveness to insulin without any alteration in insulin binding. In addition, several studies have separately demonstrated both insulin resistance and decreases in membrane sialic acid content and associated biosynthetic enzymes in diabetes mellitus. In the present study, the authors investigated the role that sialic acid residues may play in insulin action and in the hepatic insulin resistance associated with nonketotic diabetes. Primary cultures of hepatocytes from normal rats treated with neuraminidase demonstrated a dose-dependent decrease in insulin-stimulated lipogenesis. At a concentration of neuraminidase that decreases insulin action by 50%, 23% of total cellular sialic acid content was released. Neuraminidase-releasable sialic acid was significantly decreased in hepatocytes from diabetic rats and this was associated with significant insulin resistance. Treatment of hepatocytes from diabetic rats with cytidine 5{prime}-monophospho-N-acetylneuraminic acid (CMP-NANA) enhanced insulin responsiveness 39%. The enhanced insulin responsiveness induced by CMP-NANA was blocked by cytidine 5{prime}-monophosphate (CMP) suggesting that the CMP-NANA effect was catalyzed by a cell surface sialyl-transferase. CMP reduced neuraminidase-releasable ({sup 14}C)sialic acid incorporation into hepatocytes by 43%. The data demonstrate a role for cell surface sialic acid residues in hepatic insulin action and support a role for decreased cell surface sialic acid residues in the insulin resistance of diabetes mellitus.

  13. Effects of sleeve gastrectomy on insulin resistance

    PubMed Central

    CĂTOI, ADRIANA FLORINELA; PÂRVU, ALINA; MIRONIUC, AUREL; GALEA, ROMEO FLORIN; MUREŞAN, ADRIANA; BIDIAN, CRISTINA; POP, IOANA

    2016-01-01

    Background and aim Obesity is a major risk factor for the onset of insulin resistance (IR), hyperinsulinemia and type 2 diabetes mellitus (T2DM) Evidence data has proven that beyond important weight loss bariatric surgery especially Roux-en-Y gastric bypass (RYGB) and bilio-pancreatic diversion (BPD) leads to significant early reduction of insulinemia and of IR calculated through the homeostatic model assessment (HOMA-IR), independently of fat mass decrease. Sleeve gastrectomy (SG) is now used as a sole weight loss operation with good results. Therefore, the aim of the present study was to investigate the early changes of fasting blood glucose, insulin and HOMA-IR in a group of morbidly obese (MO) patients i.e. at 7, 30 and 90 days after SG. Methods The study included 20 MO patients (7 male and 13 female) submitted to SG. Anthropometrical (weight, body mass index –BMI, percent excess BMI loss -%EBMIL) and biochemical (plasma glucose, insulin and calculated HOMA-IR ) evaluation were performed before and at 7, 30 and 90 days after SG. In addition, a second group of 10 normal weight healthy subjects with a BMI ranging form 19 kg/m2 to 23.14 kg/m2, matched for age and gender was investigated. Results Plasma glucose (p=0.018), insulin (p=0.004) and HOMA-IR (p=0.006) values were statistically different between the studied groups. After surgery, at every follow-up point, there were statistically different weight and BMI mean values relative to the operation day (p<0.003). BMI, decreased at 7 days (estimated reduction=2.79; 95% CI:[2.12;3.45]), at 30 days (estimated reduction=5.65; 95% CI:[3.57;7.73]) and at 90 days (estimated reduction=10.88; 95% CI:[7.35;14.41]) respectively after SG. We noted a tendency toward statistical significant change of mean insulin values at 7 days after surgery (corrected p=0.075), no statistical change at 30 days (corrected p=0.327) and a significant change at 90 days (corrected p=0.027) after SG as compared to baseline. There was a

  14. 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

  15. Peripheral nervous system insulin resistance in ob/ob mice

    PubMed Central

    2013-01-01

    Background A reduction in peripheral nervous system (PNS) insulin signaling is a proposed mechanism that may contribute to sensory neuron dysfunction and diabetic neuropathy. Neuronal insulin resistance is associated with several neurological disorders and recent evidence has indicated that dorsal root ganglion (DRG) neurons in primary culture display altered insulin signaling, yet in vivo results are lacking. Here, experiments were performed to test the hypothesis that the PNS of insulin-resistant mice displays altered insulin signal transduction in vivo. For these studies, nondiabetic control and type 2 diabetic ob/ob mice were challenged with an intrathecal injection of insulin or insulin-like growth factor 1 (IGF-1) and downstream signaling was evaluated in the DRG and sciatic nerve using Western blot analysis. Results The results indicate that insulin signaling abnormalities documented in other “insulin sensitive” tissues (i.e. muscle, fat, liver) of ob/ob mice are also present in the PNS. A robust increase in Akt activation was observed with insulin and IGF-1 stimulation in nondiabetic mice in both the sciatic nerve and DRG; however this response was blunted in both tissues from ob/ob mice. The results also suggest that upregulated JNK activation and reduced insulin receptor expression could be contributory mechanisms of PNS insulin resistance within sensory neurons. Conclusions These findings contribute to the growing body of evidence that alterations in insulin signaling occur in the PNS and may be a key factor in the pathogenesis of diabetic neuropathy. PMID:24252636

  16. 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

  17. Divergent role of sphingosine 1-phosphate on insulin resistance.

    PubMed

    Fayyaz, Susann; Japtok, Lukasz; Kleuser, Burkhard

    2014-01-01

    Insulin resistance is a complex metabolic disorder in which insulin-sensitive tissues fail to respond to the physiological action of insulin. There is a strong correlation of insulin resistance and the development of type 2 diabetes both reaching epidemic proportions. Dysfunctional lipid metabolism is a hallmark of insulin resistance and a risk factor for several cardiovascular and metabolic disorders. Numerous studies in humans and rodents have shown that insulin resistance is associated with elevations of non-esterified fatty acids (NEFA) in the plasma. Moreover, bioactive lipid intermediates such as diacylglycerol (DAG) and ceramides appear to accumulate in response to NEFA, which may interact with insulin signaling. However, recent work has also indicated that sphingosine 1-phosphate (S1P), a breakdown product of ceramide, modulate insulin signaling in different cell types. In this review, we summarize the current state of knowledge about S1P and insulin signaling in insulin sensitive cells. A specific focus is put on the action of S1P on hepatocytes, pancreatic β-cells and skeletal muscle cells. In particular, modulation of S1P-signaling can be considered as a potential therapeutic target for the treatment of insulin resistance and type 2 diabetes.

  18. Syndromic insulin resistance: Models for the therapeutic basis of the metabolic syndrome and other targets of insulin resistance

    PubMed Central

    Gorden, Phillip; Zadeh, Elika Safar; Cochran, Elaine; Brown, Rebecca J.

    2013-01-01

    Objective Insulin resistance is the key feature of the “metabolic syndrome,” a cluster of risk factors for cardiovascular disease and diabetes that includes hypertension, dyslipidemia, obesity, and hyperglycemia. Existing treatments target individual metabolic syndrome components, and act non-specifically with respect to disease pathophysiology. Our goal is to understand the link between insulin resistance and the metabolic syndrome, and how to develop treatment approaches. Methods We present three cases of extreme, syndromic insulin resistance: lipodystrophy, autoantibodies to the insulin receptor, and mutations of the insulin receptor, with discussion of pathophysiology and treatment. Results In lipodystrophy, insulin resistance is a direct consequence of leptin deficiency, and thus leptin replacement reverses metabolic syndrome abnormalities, including diabetes and hypertriglyeridemia. The insulin “receptoropathies”, including autoantibodies to the insulin receptor and insulin receptor mutations, are characterized by extreme insulin resistance and ovarian hyperandrogenism, without dyslipidemia or fatty liver disease. Autoantibodies to the insulin receptor can be treated using an immunosuppressive paradigm adapted from treatment of other autoimmune and neoplastic conditions. Leptin treatment has shown some success in treating hyperglycemia in insulin receptor mutations. Treatment for this condition remains inadequate, and novel therapies that bypass insulin receptor signaling, such as enhancers of brown adipose tissue, are needed. Conclusion We presented a clinical approach to treatment of syndromic insulin resistance. The study of rare diseases that replicate the metabolic syndrome, with clear-cut pathophysiology, allows the opportunity to understand novel physiology, and develop targeted therapies that may be applicable to the broader population with obesity, insulin resistance, and diabetes. PMID:23047930

  19. Oxidative stress in severely obese persons is greater in those with insulin resistance.

    PubMed

    Tinahones, Francisco J; Murri-Pierri, Mora; Garrido-Sánchez, Lourdes; García-Almeida, Jose M; García-Serrano, Sara; García-Arnés, Juan; García-Fuentes, Eduardo

    2009-02-01

    The postprandial state seems to have a direct influence on oxidative status and insulin resistance. We determined the effect of an increase in plasma triglycerides after a high-fat meal on oxidative stress in severely obese patients with differing degrees of insulin resistance. The study was undertaken in 60 severely obese persons who received a 60-g fat overload with a commercial preparation. Measurements were made of insulin resistance, the plasma activity of various antioxidant enzymes, the total antioxidant capacity (TAC) and the plasma concentration of thiobarbituric acid reactive substances (TBARS). The patients with greater insulin resistance had a lower plasma superoxide dismutase (SOD) activity (P < 0.05) and a greater glutathione peroxidase (GSH-Px) activity (P < 0.05). The high-fat meal caused a significant reduction in SOD activity and an increase in the plasma concentration of TBARS in all the patients. Only the patients with lower insulin resistance experienced a significant increase in plasma catalase activity (2.22 +/- 1.02 vs. 2.93 +/- 1.22 nmol/min/ml, P < 0.01), remaining stable in the patients with greater insulin resistance. These latter patients had a reduction in plasma TAC (6.92 +/- 1.93 vs. 6.29 +/- 1.80 mmol/l, P < 0.01). In conclusion, our results show a close association between the degree of insulin resistance and markers of oxidative stress, both before and after a high-fat meal. The postprandial state causes an important increase in oxidative stress, especially in severely obese persons with greater insulin resistance. However, we are unable to determine from this study whether there is first an increase in oxidative stress or in insulin resistance.

  20. 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

  1. γ-Carboxylation of osteocalcin and insulin resistance in older men and women1234

    PubMed Central

    Shea, M Kyla; Gundberg, Caren M; Meigs, James B; Dallal, Gerard E; Saltzman, Edward; Yoshida, Makiko; Jacques, Paul F

    2009-01-01

    Background: The skeletal protein osteocalcin is γ-carboxylated by vitamin K. High serum uncarboxylated osteocalcin reflects low vitamin K status. In vitro and animal studies indicate that high uncarboxylated osteocalcin is associated with reduced insulin resistance. However, associations between osteocalcin and measures of insulin resistance in humans are less clear. Objective: Our aim was to examine cross-sectional and longitudinal associations between circulating forms of osteocalcin (total, uncarboxylated, and carboxylated) and insulin resistance in older men and women. Design: Cross-sectional associations between serum measures of total osteocalcin, carboxylated osteocalcin, and uncarboxylated osteocalcin and insulin resistance were examined in 348 nondiabetic men and women (mean age: 68 y; 58% female) by using the homeostasis model assessment of insulin resistance (HOMA-IR). Associations between each form of osteocalcin at baseline and 3-y change in HOMA-IR were examined in 162 adults (mean age: 69 y; 63% female) who did not receive vitamin K supplementation. Results: Lower circulating uncarboxylated osteocalcin was not associated with higher HOMA-IR at baseline or at 3-y follow-up. Those in the lowest tertiles of total osteocalcin and carboxylated osteocalcin at baseline had higher baseline HOMA-IR (P = 0.006 and P = 0.02, respectively). The concentration of carboxylated osteocalcin at baseline was inversely associated with a 3-y change in HOMA-IR (P = 0.002). Conclusions: In older adults, circulating uncarboxylated osteocalcin was not associated with insulin resistance. In contrast, elevated carboxylated osteocalcin and total osteocalcin were associated with lower insulin resistance, which supports a potential link between skeletal physiology and insulin resistance in humans. The role of vitamin K status in this association remains unclear and merits further investigation. This trial is registered at clinicaltrials.gov as NCT00183001. PMID:19776145

  2. 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

  3. Resistance Management Research Status

    EPA Science Inventory

    Long-term sustainability of genetically modified corn expressing Bt relies on the validity of assumptions underlying IRM models used by the EPA and the ability of EPA to monitor, detect and react to insect resistance when it develops. The EPA is developing a multi-tiered approac...

  4. Resistance Management Research Status

    EPA Science Inventory

    Long-term sustainability of genetically modified corn expressing Bt relies on the validity of assumptions underlying IRM models used by the EPA and the ability of EPA to monitor, detect and react to insect resistance when it develops. The EPA is developing a multi-tiered approac...

  5. Cerebral blood flow links insulin resistance and baroreflex sensitivity.

    PubMed

    Ryan, John P; Sheu, Lei K; Verstynen, Timothy D; Onyewuenyi, Ikechukwu C; Gianaros, Peter J

    2013-01-01

    Insulin resistance confers risk for diabetes mellitus and associates with a reduced capacity of the arterial baroreflex to regulate blood pressure. Importantly, several brain regions that comprise the central autonomic network, which controls the baroreflex, are also sensitive to the neuromodulatory effects of insulin. However, it is unknown whether peripheral insulin resistance relates to activity within central autonomic network regions, which may in turn relate to reduced baroreflex regulation. Accordingly, we tested whether resting cerebral blood flow within central autonomic regions statistically mediated the relationship between insulin resistance and an indirect indicator of baroreflex regulation; namely, baroreflex sensitivity. Subjects were 92 community-dwelling adults free of confounding medical illnesses (48 men, 30-50 years old) who completed protocols to assess fasting insulin and glucose levels, resting baroreflex sensitivity, and resting cerebral blood flow. Baroreflex sensitivity was quantified by measuring the magnitude of spontaneous and sequential associations between beat-by-beat systolic blood pressure and heart rate changes. Individuals with greater insulin resistance, as measured by the homeostatic model assessment, exhibited reduced baroreflex sensitivity (b = -0.16, p < .05). Moreover, the relationship between insulin resistance and baroreflex sensitivity was statistically mediated by cerebral blood flow in central autonomic regions, including the insula and cingulate cortex (mediation coefficients < -0.06, p-values < .01). Activity within the central autonomic network may link insulin resistance to reduced baroreflex sensitivity. Our observations may help to characterize the neural pathways by which insulin resistance, and possibly diabetes mellitus, relates to adverse cardiovascular outcomes.

  6. Cerebral Blood Flow Links Insulin Resistance and Baroreflex Sensitivity

    PubMed Central

    Ryan, John P.; Sheu, Lei K.; Verstynen, Timothy D.; Onyewuenyi, Ikechukwu C.; Gianaros, Peter J.

    2013-01-01

    Insulin resistance confers risk for diabetes mellitus and associates with a reduced capacity of the arterial baroreflex to regulate blood pressure. Importantly, several brain regions that comprise the central autonomic network, which controls the baroreflex, are also sensitive to the neuromodulatory effects of insulin. However, it is unknown whether peripheral insulin resistance relates to activity within central autonomic network regions, which may in turn relate to reduced baroreflex regulation. Accordingly, we tested whether resting cerebral blood flow within central autonomic regions statistically mediated the relationship between insulin resistance and an indirect indicator of baroreflex regulation; namely, baroreflex sensitivity. Subjects were 92 community-dwelling adults free of confounding medical illnesses (48 men, 30-50 years old) who completed protocols to assess fasting insulin and glucose levels, resting baroreflex sensitivity, and resting cerebral blood flow. Baroreflex sensitivity was quantified by measuring the magnitude of spontaneous and sequential associations between beat-by-beat systolic blood pressure and heart rate changes. Individuals with greater insulin resistance, as measured by the homeostatic model assessment, exhibited reduced baroreflex sensitivity (b = -0.16, p < .05). Moreover, the relationship between insulin resistance and baroreflex sensitivity was statistically mediated by cerebral blood flow in central autonomic regions, including the insula and cingulate cortex (mediation coefficients < -0.06, p-values < .01). Activity within the central autonomic network may link insulin resistance to reduced baroreflex sensitivity. Our observations may help to characterize the neural pathways by which insulin resistance, and possibly diabetes mellitus, relates to adverse cardiovascular outcomes. PMID:24358272

  7. Blueberries’ Impact on Insulin Resistance and Glucose Intolerance

    PubMed Central

    Stull, April J.

    2016-01-01

    Blueberries are a rich source of polyphenols, which include anthocyanin bioactive compounds. Epidemiological evidence indicates that incorporating blueberries into the diet may lower the risk of developing type 2 diabetes (T2DM). These findings are supported by pre-clinical and clinical studies that have shown improvements in insulin resistance (i.e., increased insulin sensitivity) after obese and insulin-resistant rodents or humans consumed blueberries. Insulin resistance was assessed by homeostatic model assessment-estimated insulin resistance (HOMA-IR), insulin tolerance tests, and hyperinsulinemic-euglycemic clamps. Additionally, the improvements in glucose tolerance after blueberry consumption were assessed by glucose tolerance tests. However, firm conclusions regarding the anti-diabetic effect of blueberries cannot be drawn due to the small number of existing clinical studies. Although the current evidence is promising, more long-term, randomized, and placebo-controlled trials are needed to establish the role of blueberries in preventing or delaying T2DM. PMID:27916833

  8. Energy balance, insulin-resistance biomarkers and breast cancer risk

    PubMed Central

    Fair, Alecia Malin; Dai, Qi; Shu, Xiao-Ou; Matthews, Charles E.; Yu, Herbert; Jin, Fan; Gao, Yu-Tang; Zheng, Wei

    2007-01-01

    Background American women are five times more likely to be at risk for breast cancer than women from Asian countries. Epidemiologic studies have linked energy balance to an increased risk of breast cancer, yet few studies have investigated potential mediators of this association with Chinese women. We examined the above association by blood levels of insulin-like growth factors, binding proteins, and C-peptide in the Shanghai Breast Cancer Study (SBCS), a case-control study conducted among 1459 breast cancer cases and 1556 healthy Chinese women from 1996 and 1998. Methods In-person surveys were used to collect data on energy intake, anthropometric measures, exercise/sport activity, and occupational activity. The present analyses consisted of 397 cases and 397 controls whose blood samples were measured for levels of insulin-like growth factors ( IGFs), insulin growth-factor binding protein 3, (IGFBP-3) C-peptide and the relationship with physical activity status, total energy intake, and body fat distribution. Results Body mass index [BMI] and waist-to-hip ratio [WHR] were significantly positively correlated with IGFBP-3 and C-peptide. Adult exercise/sport activity was significantly negatively correlated with insulin-like growth factor 1(IGF-I). C-peptide levels increased with increasing quartiles of WHR (p for trend <0.01). Additional analyses were performed to evaluate whether the association of energy balance measures with breast cancer risk changed after adjustment for IGFs, IGFBP-3 and C-peptide biomarkers. The associations attenuated, but none of them changed substantially. Conclusions Insulin resistance biomarkers may partially explain the association between positive energy balance and breast cancer risk, but future studies are needed to identify the underlying complex biological mechanisms of action for breast cancer prevention. PMID:17646056

  9. Integrating Mechanisms for Insulin Resistance: Common Threads and Missing Links

    PubMed Central

    Samuel, Varman T.; Shulman, Gerald I.

    2012-01-01

    Insulin resistance is a complex metabolic disorder that defies a single etiological pathway. Accumulation of ectopic lipid metabolites, activation of the unfolded protein response (UPR) pathway and innate immune pathways have all been implicated in the pathogenesis of insulin resistance. However, these pathways are also closely linked to changes in fatty acid uptake, lipogenesis, and energy expenditure that can impact ectopic lipid deposition. Ultimately, accumulation of specific lipid metabolites (diacylglycerols and/or ceramides) in liver and skeletal muscle, may be a common pathway leading to impaired insulin signaling and insulin resistance. PMID:22385956

  10. Insulin resistance and metabolic syndrome in normal-weight individuals.

    PubMed

    Chen, Shanying; Chen, Youming; Liu, Xinyu; Li, Mi; Wu, Bide; Li, Yongqiang; Liang, Yan; Shao, Xiaofei; Holthöfer, Harry; Zou, Hequn

    2014-08-01

    We performed this study to investigate the prevalences of insulin resistance and metabolic syndrome (MetS) in a Chinese population with normal weight. We also examined whether fat mass is associated with insulin resistance and MetS in normal-weight individuals. Data were drawn from a cross-sectional study in China. Subjects with diabetes were excluded. The prevalences of insulin resistance and MetS were calculated. Multivariate logistic regression analysis was performed repeated separately for body mass index (BMI) and waist circumference (WC) in both men and women. We also used the combination of BMI and WC to predict insulin resistance and MetS. 8.55 % of normal-weight men and 12.62 % of normal-weight women had insulin resistance. 7.41 % of normal-weight men and 10.24 % of normal-weight women had MetS. WC was associated with incident insulin resistance and MetS independent of BMI in both men and women. BMI was independently associated with incident MetS in women. Normal-weight individuals with insulin resistance and/or MetS are not rare in the Chinese population. Fat mass is associated with insulin resistance and MetS in normal-weight subjects. The current findings support using both BMI and WC in clinical practice.

  11. Acylcarnitines: potential implications for skeletal muscle insulin resistance

    USDA-ARS?s Scientific Manuscript database

    Insulin resistance is linked to increased acylcarnitine species in a number of tissues including skeletal muscle, due to incomplete fatty acid oxidation (FAO). It is not known if acylcarnitines participate in muscle insulin resistance or simply reflect dysregulated metabolism. The aim of this stud...

  12. C16:0-Ceramide Signals Insulin Resistance

    PubMed Central

    Hla, Timothy; Kolesnick, Richard

    2015-01-01

    A substantive literature has accumulated implicating sphingolipids, in particular ceramides, as mediators of insulin resistance in metabolic syndrome. Thanks to recent technical advances in mouse genetics and lipidomics, two independent laboratories identify the same sphingolipid, C16:0-ceramide, as principal mediator of obesity-related insulin resistance. PMID:25440051

  13. Insulin Resistance and Metabolic Syndrome in Young Men With Acne.

    PubMed

    Nagpal, Mohit; De, Dipankar; Handa, Sanjeev; Pal, Arnab; Sachdeva, Naresh

    2016-04-01

    Robust evidence of the association of insulin resistance and metabolic syndrome with acne in male patients is lacking. To assess the prevalence of metabolic syndrome and insulin resistance in male patients 20 years or older with acne. We performed a cross-sectional study in 100 male patients with acne and 100 age-matched male controls without acne from a dermatology outpatient department of a tertiary care institute. Postadolescent patients were recruited only to negate the effects of physiologic insulin resistance that are seen at the time of puberty and adolescence. Twenty-five patients were included in each of the 4 individual severity groups according to the Global Acne Grading System and were age matched to 100 male controls without acne. Clinical examination, Global Acne Rating System, National Cholesterol Education Programme Adult Treatment Panel III (NCEP-ATP III), and Homeostasis Model Assessment-Insulin Resistance (HOMA-IR). Metabolic syndrome was diagnosed as per the criteria of the modified NCEP-ATP III. Insulin resistance was assessed by the HOMA-IR. A HOMA-IR value greater than 2.5 was arbitrarily considered as insulin resistance. Prevalence of insulin resistance was significantly higher in cases (22%) compared with controls (11%) (P = .03). The prevalence of metabolic syndrome was comparable between cases (17%) and controls (9%) (P = .09). Prevalence of insulin resistance and metabolic syndrome did not differ significantly among the acne severity groups. Postadolescent male patients with acne more commonly have insulin resistance. This resistance may be a stage of prediabetes, and the patients may develop hyperinsulinemia or type 2 diabetes in the future. These patients should be followed up for a prolonged time to determine whether they develop conditions associated with insulin resistance.

  14. Insulin Resistance in Children: Consensus, Perspective, and Future Directions

    PubMed Central

    Levy-Marchal, Claire; Arslanian, Silva; Cutfield, Wayne; Sinaiko, Alan; Druet, Celine; Marcovecchio, M. Loredana; Chiarelli, Francesco

    2010-01-01

    Objective: Emerging data indicate that insulin resistance is common among children and adolescents and is related to cardiometabolic risk, therefore requiring consideration early in life. However, there is still confusion on how to define insulin resistance, how to measure it, what its risk factors are, and whether there are effective strategies to prevent and treat it. A consensus conference was organized in order to clarify these points. Participants: The consensus was internationally supported by all the major scientific societies in pediatric endocrinology and 37 participants. Evidence: An independent and systematic search of the literature was conducted to identify key articles relating to insulin resistance in children. Consensus Process: The conference was divided into five themes and working groups: background and definition; methods of measurement and screening; risk factors and consequences; prevention; and treatment. Each group selected key issues, searched the literature, and developed a draft document. During a 3-d meeting, these papers were debated and finalized by each group before presenting them to the full forum for further discussion and agreement. Conclusions: Given the current childhood obesity epidemic, insulin resistance in children is an important issue confronting health care professionals. There are no clear criteria to define insulin resistance in children, and surrogate markers such as fasting insulin are poor measures of insulin sensitivity. Based on current screening criteria and methodology, there is no justification for screening children for insulin resistance. Lifestyle interventions including diet and exercise can improve insulin sensitivity, whereas drugs should be implemented only in selected cases. PMID:20829185

  15. 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.

  16. Pulmonary vascular function in insulin resistance and diabetes.

    PubMed

    Moral-Sanz, Javier; Moreno, Laura; Cogolludo, Angel; Perez-Vizcaino, Francisco

    2014-05-01

    Insulin resistance and diabetes are current clinical concerns due to their increasing prevalence in western societies and in developing countries. Cardiovascular alterations, affecting both macro- and microcirculation, are among the major causes of illness and premature death within patients with insulin resistance or diabetes. However, the detrimental effects of insulin resistance and diabetes in the lungs are less clinically apparent, or at least masked by the progression of these metabolic diseases on other target organs. Epidemiological and experimental data suggest a link between pulmonary arterial hypertension and diabetes. Thereby, hemodynamic derangements in uncontrolled diabetes or insulin resistance are predisposing factors leading to early pulmonary alterations that in association with a second hit might accelerate the onset of pulmonary vascular disease and pulmonary hypertension. The present article reviewed the current knowledge about the effects of insulin resistance and diabetes in a territory which has received little attention until recently: the pulmonary circulation.

  17. 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

  18. Acylcarnitines: potential implications for skeletal muscle insulin resistance.

    PubMed

    Aguer, Céline; McCoin, Colin S; Knotts, Trina A; Thrush, A Brianne; Ono-Moore, Kikumi; McPherson, Ruth; Dent, Robert; Hwang, Daniel H; Adams, Sean H; Harper, Mary-Ellen

    2015-01-01

    Insulin resistance may be linked to incomplete fatty acid β-oxidation and the subsequent increase in acylcarnitine species in different tissues including skeletal muscle. It is not known if acylcarnitines participate in muscle insulin resistance or simply reflect dysregulated metabolism. The aims of this study were to determine whether acylcarnitines can elicit muscle insulin resistance and to better understand the link between incomplete muscle fatty acid β-oxidation, oxidative stress, inflammation, and insulin-resistance development. Differentiated C2C12, primary mouse, and human myotubes were treated with acylcarnitines (C4:0, C14:0, C16:0) or with palmitate with or without carnitine acyltransferase inhibition by mildronate. Treatment with C4:0, C14:0, and C16:0 acylcarnitines resulted in 20-30% decrease in insulin response at the level of Akt phosphorylation and/or glucose uptake. Mildronate reversed palmitate-induced insulin resistance concomitant with an ∼25% decrease in short-chain acylcarnitine and acetylcarnitine secretion. Although proinflammatory cytokines were not affected under these conditions, oxidative stress was increased by 2-3 times by short- or long-chain acylcarnitines. Acylcarnitine-induced oxidative stress and insulin resistance were reversed by treatment with antioxidants. Results are consistent with the conclusion that incomplete muscle fatty acid β-oxidation causes acylcarnitine accumulation and associated oxidative stress, raising the possibility that these metabolites play a role in muscle insulin resistance.

  19. 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.

  20. Differential hepatic distribution of insulin receptor substrates causes selective insulin resistance in diabetes and obesity

    PubMed Central

    Kubota, Naoto; Kubota, Tetsuya; Kajiwara, Eiji; Iwamura, Tomokatsu; Kumagai, Hiroki; Watanabe, Taku; Inoue, Mariko; Takamoto, Iseki; Sasako, Takayoshi; Kumagai, Katsuyoshi; Kohjima, Motoyuki; Nakamuta, Makoto; Moroi, Masao; Sugi, Kaoru; Noda, Tetsuo; Terauchi, Yasuo; Ueki, Kohjiro; Kadowaki, Takashi

    2016-01-01

    Hepatic insulin signalling involves insulin receptor substrates (Irs) 1/2, and is normally associated with the inhibition of gluconeogenesis and activation of lipogenesis. In diabetes and obesity, insulin no longer suppresses hepatic gluconeogenesis, while continuing to activate lipogenesis, a state referred to as ‘selective insulin resistance'. Here, we show that ‘selective insulin resistance' is caused by the differential expression of Irs1 and Irs2 in different zones of the liver. We demonstrate that hepatic Irs2-knockout mice develop ‘selective insulin resistance', whereas mice lacking in Irs1, or both Irs1 and Irs2, develop ‘total insulin resistance'. In obese diabetic mice, Irs1/2-mediated insulin signalling is impaired in the periportal zone, which is the primary site of gluconeogenesis, but enhanced in the perivenous zone, which is the primary site of lipogenesis. While hyperinsulinaemia reduces Irs2 expression in both the periportal and perivenous zones, Irs1 expression, which is predominantly in the perivenous zone, remains mostly unaffected. These data suggest that ‘selective insulin resistance' is induced by the differential distribution, and alterations of hepatic Irs1 and Irs2 expression. PMID:27708333

  1. 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.

  2. Differential hepatic distribution of insulin receptor substrates causes selective insulin resistance in diabetes and obesity.

    PubMed

    Kubota, Naoto; Kubota, Tetsuya; Kajiwara, Eiji; Iwamura, Tomokatsu; Kumagai, Hiroki; Watanabe, Taku; Inoue, Mariko; Takamoto, Iseki; Sasako, Takayoshi; Kumagai, Katsuyoshi; Kohjima, Motoyuki; Nakamuta, Makoto; Moroi, Masao; Sugi, Kaoru; Noda, Tetsuo; Terauchi, Yasuo; Ueki, Kohjiro; Kadowaki, Takashi

    2016-10-06

    Hepatic insulin signalling involves insulin receptor substrates (Irs) 1/2, and is normally associated with the inhibition of gluconeogenesis and activation of lipogenesis. In diabetes and obesity, insulin no longer suppresses hepatic gluconeogenesis, while continuing to activate lipogenesis, a state referred to as 'selective insulin resistance'. Here, we show that 'selective insulin resistance' is caused by the differential expression of Irs1 and Irs2 in different zones of the liver. We demonstrate that hepatic Irs2-knockout mice develop 'selective insulin resistance', whereas mice lacking in Irs1, or both Irs1 and Irs2, develop 'total insulin resistance'. In obese diabetic mice, Irs1/2-mediated insulin signalling is impaired in the periportal zone, which is the primary site of gluconeogenesis, but enhanced in the perivenous zone, which is the primary site of lipogenesis. While hyperinsulinaemia reduces Irs2 expression in both the periportal and perivenous zones, Irs1 expression, which is predominantly in the perivenous zone, remains mostly unaffected. These data suggest that 'selective insulin resistance' is induced by the differential distribution, and alterations of hepatic Irs1 and Irs2 expression.

  3. Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer's-like changes.

    PubMed

    Gupta, Amit; Bisht, Bharti; Dey, Chinmoy Sankar

    2011-05-01

    Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide. Pharmacological treatments presently available can slow down the progression of symptoms but can not cure the disease. Currently there is widening recognition that AD is closely associated with impaired insulin signaling and glucose metabolism in brain, suggesting it to be a brain-specific form of diabetes and so also termed as "type 3 diabetes". Hence investigating the role of pharmacological agents that could ameliorate neuronal insulin resistance merit attention in AD therapeutics, however the therapeutics for pathophysiological condition like neuronal insulin resistance itself is largely unknown. In the present study we have determined the effect of metformin on neuronal insulin resistance and AD-associated characteristics in an in vitro model of "type 3 diabetes" by differentiating neuronal cell line Neuro-2a under prolonged presence of insulin. We observed that prolonged hyperinsulinemic conditions in addition to generating insulin resistance also led to development of hallmark AD-associated neuropathological changes. Treatment with metformin sensitized the impaired insulin actions and also prevented appearance of molecular and pathological characteristics observed in AD. The results thus demonstrate possible therapeutic efficacy of peripheral insulin-sensitizer drug metformin in AD by its ability to sensitize neuronal insulin resistance. These findings also provide direct evidences linking hyperinsulinemia and AD and suggest a unique opportunity for prevention and treatment of "type 3 diabetes".

  4. Circadian disruption leads to insulin resistance and obesity

    PubMed Central

    Shi, Shu-qun; Ansari, Tasneem; McGuinness, Owen P.; Wasserman, David H.; Johnson, Carl Hirschie

    2013-01-01

    Summary Background Disruption of circadian (daily) timekeeping enhances the risk of metabolic syndrome, obesity, and Type 2 diabetes. While clinical observations have suggested that insulin action is not constant throughout the 24 hour cycle, its magnitude and periodicity have not been assessed. Moreover, when circadian rhythmicity is absent or severely disrupted, it is not known whether insulin action will lock to the peak, nadir or mean of the normal periodicity of insulin action. Results We used hyperinsulinemic-euglycemic clamps to show a bona fide circadian rhythm of insulin action; mice are most resistant to insulin during their daily phase of relative inactivity. Moreover, clock-disrupted Bmal1-knockout mice are locked into the trough of insulin action and lack rhythmicity in insulin action and activity patterns. When rhythmicity is rescued in the Bmal1-knockout mice by expression of the paralogous gene Bmal2, insulin action and activity patterns are restored. When challenged with a high fat diet, arhythmic mice (either Bmal1-knockout mice or wild type mice made arhythmic by exposure to constant light) were obese prone. Adipose tissue explants obtained from high-fat fed mice have their own periodicity that was longer than animals on a chow fed diet. Conclusions This study provides rigorous documentation for a circadian rhythm of insulin action and demonstrates that disturbing the natural rhythmicity of insulin action will disrupt the rhythmic internal environment of insulin sensitive tissue, thereby predisposing the animals to insulin resistance and obesity. PMID:23434278

  5. The Impact of Adipose Tissue on Insulin Resistance in Acromegaly.

    PubMed

    Olarescu, Nicoleta Cristina; Bollerslev, Jens

    2016-04-01

    Adipose tissue (AT) is recognized as key contributor to the systemic insulin resistance and overt diabetes seen in metabolic syndrome. Acromegaly is a disease characterized by excessive secretion of growth hormone (GH) and insulin-like growth factor I (IGF-I). GH is known both for its action on AT and for its detrimental effect on glucose metabolism and insulin signaling. In active acromegaly, while body fat deports are diminished, insulin resistance is increased. Early studies have demonstrated defects in insulin action, both at the hepatic and extrahepatic (i.e., muscle and fat) levels, in active disease. This review discusses recent data suggesting that AT inflammation, altered AT distribution, and impaired adipogenesis are potential mechanisms contributing to systemic insulin resistance in acromegaly. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Insulin action and resistance in obesity and type 2 diabetes.

    PubMed

    Czech, Michael P

    2017-07-11

    Nutritional excess is a major forerunner of type 2 diabetes. It enhances the secretion of insulin, but attenuates insulin's metabolic actions in the liver, skeletal muscle and adipose tissue. However, conflicting evidence indicates a lack of knowledge of the timing of these events during the development of obesity and diabetes, pointing to a key gap in our understanding of metabolic disease. This Perspective reviews alternate viewpoints and recent results on the temporal and mechanistic connections between hyperinsulinemia, obesity and insulin resistance. Although much attention has addressed early steps in the insulin signaling cascade, insulin resistance in obesity seems to be largely elicited downstream of these steps. New findings also connect insulin resistance to extensive metabolic cross-talk between the liver, adipose tissue, pancreas and skeletal muscle. These and other advances over the past 5 years offer exciting opportunities and daunting challenges for the development of new therapeutic strategies for the treatment of type 2 diabetes.

  7. Docosahexaenoic acid affects insulin deficiency- and insulin resistance-induced alterations in cardiac mitochondria.

    PubMed

    Ovide-Bordeaux, Stéphanie; Grynberg, Alain

    2004-03-01

    The effect of docosahexaenoic acid (DHA) intake on cardiac mitochondrial function was evaluated in permeabilized fibers in insulin deficiency and insulin resistance in rats. The insulin-deficient state was obtained by streptozotocin injection 2 mo before investigations. Insulin resistance was obtained by feeding a 62% fructose diet for 3 mo. DHA was incorporated in the diet to modify the fatty acid composition of cardiac membranes, including mitochondria. Insulin deficiency decreased mitochondrial creatine kinase (mi-CK) activity and mitochondrial sensitivity to ADP. DHA intake prevented these alterations. Moreover, the insulin-deficient state significantly decreased n-3 polyunsaturated fatty acids (PUFA) and slightly increased n-6 PUFA in both cardiac and mitochondrial membranes, inducing a significant increase in the n-6-to-n-3 ratio. DHA intake maintained high myocardial and mitochondrial DHA content. Insulin deficiency also decreased glutamate- and palmitoylcarnitine-supported mitochondrial respiration, but DHA intake did not prevent these effects. In contrast, insulin resistance did not affect mi-CK activity or sensitivity to ADP. However, insulin resistance influenced the myocardial fatty acid composition with decreased n-6 and n-3 PUFA contents and increased monounsaturated fatty acid content. Only slight alterations were observed in mitochondrial fatty acid composition, and they were corrected by DHA intake. Moreover, insulin resistance decreased the glutamate-supported respiration, and DHA intake did not influence this effect. In conclusion, the impairment of cardiac mitochondrial function was more pronounced in the insulin-deficient state than in insulin resistance. The modification of fatty acid composition of cardiac and mitochondrial membranes by DHA partially prevented the mitochondrial alterations induced in the two models.

  8. Gestational Weight Gain in Insulin Resistant Pregnancies

    PubMed Central

    HARPER, Lorie M.; SHANKS, Anthony L.; ODIBO, Anthony O.; COLVIN, Ryan; MACONES, George A.; CAHILL, Alison G.

    2013-01-01

    Objective To examine the Institute of Medicine (IOM) guidelines for gestational weight gain (GWG) in insulin-resistant pregnancy. Study Design Secondary analysis of a prospective cohort of 435 women with type 2 or gestational diabetes from 2006–2010. The exposure was categorized as GWG less than, within, or greater than the IOM recommendations for body mass index. The maternal outcome was a composite of preeclampsia, eclampsia, 3rd–4th degree laceration, readmission, or wound infection. The neonatal outcome was a composite of preterm delivery, level 3 nursery admission, oxygen requirement >6 hours, shoulder dystocia, 5-minute Apgar≤3, umbilical cord arterial pH<7.1, or base excess <−12. Secondary outcomes were cesarean delivery (CD), macrosomia, and small for gestational age (SGA). Results Incidence of the maternal outcome did not differ with GWG (p=0.15). Women gaining more than recommended had an increased risk of CD (relative risk (RR) 1.31, 95% confidence interval (CI) 1.01–1.69) and the neonatal outcome (RR 1.40, 95% CI 1.01–1.95) compared to women gaining within the IOM recommendations. Women gaining less than recommended had an increased risk of SGA (RR 3.29, 95% CI 1.09–9.91) without a decrease in the risk of the maternal outcome (RR 0.93, 95% CI 0.49–1.78) or CD (RR 0.74-0.40-1.37) compared to women gaining within the IOM recommendations. Conclusions Women with insulin resistance should be advised to gain within the current IOM guidelines. PMID:23949833

  9. Hepatitis C Virus, Insulin Resistance, and Steatosis

    PubMed Central

    Kralj, Dominik; Jukić, Lucija Virović; Stojsavljević, Sanja; Duvnjak, Marko; Smolić, Martina; Čurčić, Ines Bilić

    2016-01-01

    Hepatitis C virus (HCV) is one of the main causes of liver disease worldwide. Liver steatosis is a common finding in many hepatic and extrahepatic disorders, the most common being metabolic syndrome (MS). Over time, it has been shown that the frequent coexistence of these two conditions is not coincidental, since many epidemiological, clinical, and experimental studies have indicated HCV to be strongly associated with liver steatosis and numerous metabolic derangements. Here, we present an overview of publications that provide clinical evidence of the metabolic effects of HCV and summarize the available data on the pathogenetic mechanisms of this association. It has been shown that HCV infection can induce insulin resistance (IR) in the liver and peripheral tissues through multiple mechanisms. Substantial research has suggested that HCV interferes with insulin signaling both directly and indirectly, inducing the production of several proinflammatory cytokines. HCV replication, assembly, and release from hepatocytes require close interactions with lipid droplets and host lipoproteins. This modulation of lipid metabolism in host cells can induce hepatic steatosis, which is more pronounced in patients with HCV genotype 3. The risk of steatosis depends on several viral factors (including genotype, viral load, and gene mutations) and host features (visceral obesity, type 2 diabetes mellitus, genetic predisposition, medication use, and alcohol consumption). HCV-related IR and steatosis have been shown to have a remarkable clinical impact on the prognosis of HCV infection and quality of life, due to their association with resistance to antiviral therapy, progression of hepatic fibrosis, and development of hepatocellular carcinoma. Finally, HCV-induced IR, oxidative stress, and changes in lipid and iron metabolism lead to glucose intolerance, arterial hypertension, hyperuricemia, and atherosclerosis, resulting in increased cardiovascular mortality. PMID:27047774

  10. Decreased irisin secretion contributes to muscle insulin resistance in high-fat diet mice.

    PubMed

    Yang, Zaigang; Chen, Xu; Chen, Yujuan; Zhao, Qian

    2015-01-01

    Recent studies have revealed the relationship between irisin and insulin signaling, while positive associations of muscle FNDC5 with insulin resistance is observed. However, the functional mechanism of irisin on muscle insulin resistance is still obscure. This study aims to investigate the effect of irisin on muscle insulin action. Diabetic mouse model was established by high fat diet (HFD) induced obesity in C57BL/6 mice. Body indexes and serum levels of triglyceride (TG), blood glucose and insulin were record. Oral glucose tolerance test (OGTT) was performed before being killed. Circulating irisin level was also detected, while FNDC5/irisin expression was determined by RT-PCR and western blot analysis in both muscle and adipose tissues. Insulin action was further evaluated by the phosphorylation of AKT and Erk, and palmitic acid treated muscle cells were introduced for mimicking diabetic status in vitro. Obvious obese feathers associated with type 2 diabetes were observed in HFD feeding mice, with decreased circulating irisin level and FNDC5/irisin secretion in adipose tissues. Although FNDC5/irisin expression showed little change in skeletal muscle, the insulin action was inhibited significantly. Moreover, palmitic acid treated muscle cells showed similar inhibition of insulin action, and FNDC5/irisin expression change. Besides, insulin action could be reversed by irisin addition in muscle cells. HFD induced obese mice showed decreased irisin secretion from adipose tissues, which might contribute to muscle insulin resistance. Furthermore, irisin addition could recover insulin action in palmitic acid treated muscle cells, indicating the importance of irisin for preserving insulin signaling.

  11. Serum lipid changes and insulin resistance in familial Mediterranean fever

    PubMed Central

    Candan, Zehra; Akdoğan, Ali; Karadağ, Ömer; Kalyoncu, Umut; Şahin, Abdurrahman; Bilgen, Şule; Çalgüneri, Meral; Kiraz, Sedat; Ertenli, Ali

    2014-01-01

    Objective Inflammation is known to alter lipid profiles and to induce insulin resistance. This study was planned to test the hypothesis that familial Mediterranean ferver (FMF) patients and their first-degree asymptomatic relatives may have lipid profile changes and/or insulin resistance, similar to other inflammatory diseases. Material and Methods We studied 72 FMF patients, 30 asymptomatic first-degree relatives, and 75 healthy controls. Fasting and 2-hour postprandial glucose, insulin, apolipoprotein (Apo) A1, Apo B, acute phase reactants, and lipid profiles of all subjects were studied. Insulin resistance was determined by the HOMA (Homeostasis Model Assessment) index. Results There was no difference between the groups with regard to sex, mean systolic and diastolic blood pressure, body mass index, smoking status, fasting and postprandial 2-hour glucose, insulin, acute phase reactants, and HOMA index levels. High-density lipoprotein cholesterol (HDL-C) levels were similar between FMF patients and FMF relatives (48.9±12.4 mg/dL vs 49.3±13.8 mg/dL; p=NS), and both were lower than controls (48.9±12.4 mg/dL vs 59.6±15.1 mg/dL; p<0.001 and 49.3±13.8 mg/dL vs 59.8±15.1 mg/dL; p=0.001, respectively). Apo A1 levels in FMF patients and asymptomatic first-degree FMF relatives were both lower than in controls, similar to the HDL-C levels (126.1±25.7 mg/dL vs 151.2±31.4 mg/dL; p<0.001 and 129.5±29.0 mg/dL vs 151.2±31.4 mg/dL; p=0.002, respectively). TG levels were significantly higher in FMF relatives as compared to controls (113.4±53.6 mg/dL vs 97.1± 54.9 mg/dL; p=0.025). Conclusion Low HDL-C and low Apo A1 levels are found in FMF patients and their first-degree asymptomatic relatives. Low-grade inflammation caused by MEFV mutations may be responsible for these lipid profile changes. PMID:27708899

  12. Serum lipid changes and insulin resistance in familial Mediterranean fever.

    PubMed

    Candan, Zehra; Akdoğan, Ali; Karadağ, Ömer; Kalyoncu, Umut; Şahin, Abdurrahman; Bilgen, Şule; Çalgüneri, Meral; Kiraz, Sedat; Ertenli, Ali

    2014-12-01

    Inflammation is known to alter lipid profiles and to induce insulin resistance. This study was planned to test the hypothesis that familial Mediterranean ferver (FMF) patients and their first-degree asymptomatic relatives may have lipid profile changes and/or insulin resistance, similar to other inflammatory diseases. We studied 72 FMF patients, 30 asymptomatic first-degree relatives, and 75 healthy controls. Fasting and 2-hour postprandial glucose, insulin, apolipoprotein (Apo) A1, Apo B, acute phase reactants, and lipid profiles of all subjects were studied. Insulin resistance was determined by the HOMA (Homeostasis Model Assessment) index. There was no difference between the groups with regard to sex, mean systolic and diastolic blood pressure, body mass index, smoking status, fasting and postprandial 2-hour glucose, insulin, acute phase reactants, and HOMA index levels. High-density lipoprotein cholesterol (HDL-C) levels were similar between FMF patients and FMF relatives (48.9±12.4 mg/dL vs 49.3±13.8 mg/dL; p=NS), and both were lower than controls (48.9±12.4 mg/dL vs 59.6±15.1 mg/dL; p<0.001 and 49.3±13.8 mg/dL vs 59.8±15.1 mg/dL; p=0.001, respectively). Apo A1 levels in FMF patients and asymptomatic first-degree FMF relatives were both lower than in controls, similar to the HDL-C levels (126.1±25.7 mg/dL vs 151.2±31.4 mg/dL; p<0.001 and 129.5±29.0 mg/dL vs 151.2±31.4 mg/dL; p=0.002, respectively). TG levels were significantly higher in FMF relatives as compared to controls (113.4±53.6 mg/dL vs 97.1± 54.9 mg/dL; p=0.025). Low HDL-C and low Apo A1 levels are found in FMF patients and their first-degree asymptomatic relatives. Low-grade inflammation caused by MEFV mutations may be responsible for these lipid profile changes.

  13. G Protein–Coupled Receptor Kinase 2 Plays a Relevant Role in Insulin Resistance and Obesity

    PubMed Central

    Garcia-Guerra, Lucia; Nieto-Vazquez, Iria; Vila-Bedmar, Rocio; Jurado-Pueyo, María; Zalba, Guillermo; Díez, Javier; Murga, Cristina; Fernández-Veledo, Sonia; Mayor, Federico; Lorenzo, Margarita

    2010-01-01

    OBJECTIVE Insulin resistance is associated with the pathogenesis of metabolic disorders as type 2 diabetes and obesity. Given the emerging role of signal transduction in these syndromes, we set out to explore the possible role that G protein–coupled receptor kinase 2 (GRK2), first identified as a G protein–coupled receptor regulator, could have as a modulator of insulin responses. RESEARCH DESIGN AND METHODS We analyzed the influence of GRK2 levels in insulin signaling in myoblasts and adipocytes with experimentally increased or silenced levels of GRK2, as well as in GRK2 hemizygous animals expressing 50% lower levels of this kinase in three different models of insulin resistance: tumor necrosis factor-α (TNF-α) infusion, aging, and high-fat diet (HFD). Glucose transport, whole-body glucose and insulin tolerance, the activation status of insulin pathway components, and the circulating levels of important mediators were measured. The development of obesity and adipocyte size with age and HFD was analyzed. RESULTS Altering GRK2 levels markedly modifies insulin-mediated signaling in cultured adipocytes and myocytes. GRK2 levels are increased by ∼2-fold in muscle and adipose tissue in the animal models tested, as well as in lymphocytes from metabolic syndrome patients. In contrast, hemizygous GRK2 mice show enhanced insulin sensitivity and do not develop insulin resistance by TNF-α, aging, or HFD. Furthermore, reduced GRK2 levels induce a lean phenotype and decrease age-related adiposity. CONCLUSIONS Overall, our data identify GRK2 as an important negative regulator of insulin effects, key to the etiopathogenesis of insulin resistance and obesity, which uncovers this protein as a potential therapeutic target in the treatment of these disorders. PMID:20627936

  14. G protein-coupled receptor kinase 2 plays a relevant role in insulin resistance and obesity.

    PubMed

    Garcia-Guerra, Lucia; Nieto-Vazquez, Iria; Vila-Bedmar, Rocio; Jurado-Pueyo, María; Zalba, Guillermo; Díez, Javier; Murga, Cristina; Fernández-Veledo, Sonia; Mayor, Federico; Lorenzo, Margarita

    2010-10-01

    Insulin resistance is associated with the pathogenesis of metabolic disorders as type 2 diabetes and obesity. Given the emerging role of signal transduction in these syndromes, we set out to explore the possible role that G protein-coupled receptor kinase 2 (GRK2), first identified as a G protein-coupled receptor regulator, could have as a modulator of insulin responses. We analyzed the influence of GRK2 levels in insulin signaling in myoblasts and adipocytes with experimentally increased or silenced levels of GRK2, as well as in GRK2 hemizygous animals expressing 50% lower levels of this kinase in three different models of insulin resistance: tumor necrosis factor-α (TNF-α) infusion, aging, and high-fat diet (HFD). Glucose transport, whole-body glucose and insulin tolerance, the activation status of insulin pathway components, and the circulating levels of important mediators were measured. The development of obesity and adipocyte size with age and HFD was analyzed. Altering GRK2 levels markedly modifies insulin-mediated signaling in cultured adipocytes and myocytes. GRK2 levels are increased by ∼2-fold in muscle and adipose tissue in the animal models tested, as well as in lymphocytes from metabolic syndrome patients. In contrast, hemizygous GRK2 mice show enhanced insulin sensitivity and do not develop insulin resistance by TNF-α, aging, or HFD. Furthermore, reduced GRK2 levels induce a lean phenotype and decrease age-related adiposity. Overall, our data identify GRK2 as an important negative regulator of insulin effects, key to the etiopathogenesis of insulin resistance and obesity, which uncovers this protein as a potential therapeutic target in the treatment of these disorders.

  15. Hypertension genes are genetic markers for insulin sensitivity and resistance.

    PubMed

    Guo, Xiuqing; Cheng, Suzanne; Taylor, Kent D; Cui, Jinrui; Hughes, Randall; Quiñones, Manuel J; Bulnes-Enriquez, Isabel; De la Rosa, Roxana; Aurea, George; Yang, Huiying; Hsueh, Willa; Rotter, Jerome I

    2005-04-01

    Insulin resistance is a determinant of blood pressure variation and risk factor for hypertension. Because insulin resistance and blood pressure cosegregate in Mexican American families, we thus investigated the association between variations in 9 previously reported hypertension genes (ACE, AGT, AGTRI, ADDI, NPPA, ADDRB2, SCNN1A, GNB3, and NOS3) and insulin resistance. Families were ascertained via a coronary artery disease proband in the Mexican American Coronary Artery Disease Project. Individuals from 100 Mexican American families (n=656) were genotyped for 14 polymorphisms in the 9 genes and all adult offspring and offspring spouses were phenotyped for insulin sensitivity by hyperinsulinemic euglycemic clamp (n=449). AGT M235T and NOS3 A(-922)G and E298D polymorphisms were significantly associated with insulin sensitivity (P=0.018, 0.036, 0.039) but were not significant after adjusting for body mass index. ADD1 G460W was associated with insulin sensitivity only after adjusting for body mass index. The NPPA T2238C and SCNN1A A663T were associated with decreased fasting insulin levels after adjusting for body mass index (P=0.015 and 0.028). In conclusion, AGT, NOS3, NPPA, ADRB2, ADD1, and SCNN1A may well be genetic markers for insulin resistance, and adiposity was a potential modifier for only some gene/trait combinations. Our data support the hypothesis that genes in the blood pressure pathway may play a role in insulin resistance in Mexican Americans.

  16. Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis

    PubMed Central

    Semple, Robert K.; Sleigh, Alison; Murgatroyd, Peter R.; Adams, Claire A.; Bluck, Les; Jackson, Sarah; Vottero, Alessandra; Kanabar, Dipak; Charlton-Menys, Valentine; Durrington, Paul; Soos, Maria A.; Carpenter, T. Adrian; Lomas, David J.; Cochran, Elaine K.; Gorden, Phillip; O’Rahilly, Stephen; Savage, David B.

    2009-01-01

    Metabolic dyslipidemia is characterized by high circulating triglyceride (TG) and low HDL cholesterol levels and is frequently accompanied by hepatic steatosis. Increased hepatic lipogenesis contributes to both of these problems. Because insulin fails to suppress gluconeogenesis but continues to stimulate lipogenesis in both obese and lipodystrophic insulin-resistant mice, it has been proposed that a selective postreceptor defect in hepatic insulin action is central to the pathogenesis of fatty liver and hypertriglyceridemia in these mice. Here we show that humans with generalized insulin resistance caused by either mutations in the insulin receptor gene or inhibitory antibodies specific for the insulin receptor uniformly exhibited low serum TG and normal HDL cholesterol levels. This was due at least in part to surprisingly low rates of de novo lipogenesis and was associated with low liver fat content and the production of TG-depleted VLDL cholesterol particles. In contrast, humans with a selective postreceptor defect in AKT2 manifest increased lipogenesis, elevated liver fat content, TG-enriched VLDL, hypertriglyceridemia, and low HDL cholesterol levels. People with lipodystrophy, a disorder characterized by particularly severe insulin resistance and dyslipidemia, demonstrated similar abnormalities. Collectively these data from humans with molecularly characterized forms of insulin resistance suggest that partial postreceptor hepatic insulin resistance is a key element in the development of metabolic dyslipidemia and hepatic steatosis. PMID:19164855

  17. Postreceptor defects causing insulin resistance in normoinsulinemic non-insulin-dependent diabetes mellitus

    SciTech Connect

    Bolinder, J.; Ostman, J.; Arner, P.

    1982-10-01

    The mechanisms of the diminished hypoglycemic response to insulin in non-insulin-dependent diabetes mellitus (NIDDM) with normal levels of circulating plasma insulin were investigated. Specific binding of mono-/sup 125/I (Tyr A14)-insulin to isolated adipocytes and effects of insulin (5--10,000 microunits/ml) on glucose oxidation and lipolysis were determined simultaneously in subcutaneous adipose tissue of seven healthy subjects of normal weight and seven untreated NIDDM patients with normal plasma insulin levels. The two groups were matched for age, sex, and body weight. Insulin binding, measured in terms of receptor number and affinity, was normal in NIDDM, the total number of receptors averaging 350,000 per cell. Neither sensitivity nor the maximum antilipolytic effect of insulin was altered in NIDDM patients as compared with control subjects; the insulin concentration producing half the maximum effect (ED50) was 10 microunits/ml. As regards the effect of insulin on glucose oxidation, for the control subjects ED50 was 30 microunits/ml, whereas in NIDDM patients, insulin exerted no stimulatory effect. The results obtained suggest that the effect of insulin on glucose utilization in normoinsulinemic NIDDM may be diminished in spite of normal insulin binding to receptors. The resistance may be due solely to postreceptor defects, and does not involve antilipolysis.

  18. Insulin resistance is associated with gallstones even in non-obese, non-diabetic Korean men.

    PubMed

    Chang, Yoosoo; Sung, Eunju; Ryu, Seungho; Park, Yong-Woo; Jang, Yu Mi; Park, Minseon

    2008-08-01

    It remains unclear as to whether insulin resistance alone or in the presence of wellknown risk factors, such as diabetes or obesity, is associated with gallstones in men. The aim of this study was to determine whether insulin resistance is associated independently with gallstone disease in non-diabetic men, regardless of obesity. Study subjects were 19,503 Korean men, aged 30-69 yr, with fasting blood glucose level <126 mg/dL and without a documented history of diabetes. Gallbladder status was assessed via abdominal ultrasonography after overnight fast. Body mass index and waist circumference were measured. Insulin resistance was estimated by the Homeostasis Model Assessment of insulin resistance (HOMA-IR). The prevalence of obesity, abdominal obesity, and metabolic syndrome in the subjects with gallstones were higher than in those without. The prevalence of elevated HOMA (>75 percentile) in subjects with gallstones was significantly higher than in those without, and this association remained even after the obesity stratification was applied. In multiple logistic regression analyses, only age and HOMA proved to be independent predictors of gallstones. Insulin resistance was positively associated with gallstones in non-diabetic Korean men, and this occurred regardless of obesity. Gallstones appear to be a marker for insulin resistance, even in non-diabetic, nonobese men.

  19. Testosterone deficiency, insulin-resistant obesity and cognitive function.

    PubMed

    Pintana, Hiranya; Chattipakorn, Nipon; Chattipakorn, Siriporn

    2015-08-01

    Testosterone is an androgenic steroid hormone, which plays an important role in the regulation of male reproduction and behaviors, as well as in the maintenance of insulin sensitivity. Several studies showed that testosterone exerted beneficial effects in brain function, including preventing neuronal cell death, balancing brain oxidative stress and antioxidant activity, improving synaptic plasticity and involving cognitive formation. Although previous studies showed that testosterone deficiency is positively correlated with cognitive impairment and insulin-resistant obesity, several studies demonstrated contradictory findings. Thus, this review comprehensively summarizes the current evidence from in vitro, in vivo and clinical studies of the relationship between testosterone deficiency and insulin-resistant obesity as well as the correlation between either insulin-resistant obesity or testosterone deficiency and cognitive impairment. Controversial reports and the mechanistic insights regarding the roles of testosterone in insulin-resistant obesity and cognitive function are also presented and discussed.

  20. 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

  1. Insulin Resistance and Environmental Pollutants: Experimental Evidence and Future Perspectives

    PubMed Central

    Vanparys, Caroline; Van Gaal, Luc F.; Jorens, Philippe G.; Covaci, Adrian; Blust, Ronny

    2013-01-01

    Background: The metabolic disruptor hypothesis postulates that environmental pollutants may be risk factors for metabolic diseases. Because insulin resistance is involved in most metabolic diseases and current health care prevention programs predominantly target insulin resistance or risk factors thereof, a critical analysis of the role of pollutants in insulin resistance might be important for future management of metabolic diseases. Objectives: We aimed to critically review the available information linking pollutant exposure to insulin resistance and to open the discussion on future perspectives for metabolic disruptor identification and prioritization strategies. Methods: We searched PubMed and Web of Science for experimental studies reporting on linkages between environmental pollutants and insulin resistance and identified a total of 23 studies as the prime literature. Discussion: Recent studies specifically designed to investigate the effect of pollutants on insulin sensitivity show a potential causation of insulin resistance. Based on these studies, a summary of viable test systems and end points can be composed, allowing insight into what is missing and what is needed to create a standardized insulin resistance toxicity testing strategy. Conclusions: It is clear that current research predominantly relies on top-down identification of insulin resistance–inducing metabolic disruptors and that the development of dedicated in vitro or ex vivo screens to allow animal sparing and time- and cost-effective bottom-up screening is a major future research need. Citation: Hectors TL, Vanparys C, Van Gaal LF, Jorens PG, Covaci A, Blust R. 2013. Insulin resistance and environmental pollutants: experimental evidence and future perspectives. Environ Health Perspect 121:1273–1281; http://dx.doi.org/10.1289/ehp.1307082 PMID:24058052

  2. Biomarkers of insulin sensitivity and insulin resistance: Past, present and future.

    PubMed

    Park, Se Eun; Park, Cheol-Young; Sweeney, Gary

    2015-01-01

    Insulin resistance in insulin target tissues including liver, skeletal muscle and adipose tissue is an early step in the progression towards type 2 diabetes. Accurate diagnostic parameters reflective of insulin resistance are essential. Longstanding tests for fasting blood glucose and HbA1c are useful and although the hyperinsulinemic euglycemic clamp remains a "gold standard" for accurately determining insulin resistance, it cannot be implemented on a routine basis. The study of adipokines, and more recently myokines and hepatokines, as potential biomarkers for insulin sensitivity is now an attractive and relatively straightforward approach. This review discusses potential biomarkers including adiponectin, RBP4, chemerin, A-FABP, FGF21, fetuin-A, myostatin, IL-6, and irisin, all of which may play significant roles in determining insulin sensitivity. We also review potential future directions of new biological markers for measuring insulin resistance, including metabolomics and gut microbiome. Collectively, these approaches will provide clinicians with the tools for more accurate, and perhaps personalized, diagnosis of insulin resistance.

  3. Urinary Phthalates and Increased Insulin Resistance in Adolescents

    PubMed Central

    Spanier, Adam J.; Sathyanarayana, Sheela; Attina, Teresa M.; Blustein, Jan

    2013-01-01

    BACKGROUND Di-2-ethylhexylphthalate (DEHP) is an environmental chemical commonly found in processed foods. Phthalate exposures, in particular to DEHP, have been associated with insulin resistance in adults, but have not been studied in adolescents. METHODS: Using cross-sectional data from 766 fasting 12- to 19-year-olds in the 2003–2008 NHANES, we examined associations of phthalate metabolites with continuous and categorical measures of homeostatic model assessment of insulin resistance (HOMA-IR). RESULTS: Controlling for demographic and behavioral factors, diet, continuous age, BMI category, and urinary creatinine, for each log (roughly threefold) increase in DEHP metabolites, a 0.27 increase (95% confidence interval 0.14–0.40; P < .001) in HOMA-IR was identified. Compared with the first tertile of DEHP metabolite in the study population (14.5% insulin resistant), the third tertile had 21.6% prevalence (95% confidence interval 17.2%–26.0%; P = .02). Associations persisted despite controlling for bisphenol A, another endocrine-disrupting chemical commonly found in foods, and HOMA-IR and insulin resistance were not significantly associated with metabolites of lower molecular weight phthalates commonly found in cosmetics and other personal care products. CONCLUSIONS: Urinary DEHP concentrations were associated with increased insulin resistance in this cross-sectional study of adolescents. This study cannot rule out the possibility that insulin-resistant children ingest food with higher phthalate content, or that insulin-resistant children excrete more DEHP. PMID:23958772

  4. Natural killer T cells in adipose tissue prevent insulin resistance

    PubMed Central

    Schipper, Henk S.; Rakhshandehroo, Maryam; van de Graaf, Stan F.J.; Venken, Koen; Koppen, Arjen; Stienstra, Rinke; Prop, Serge; Meerding, Jenny; Hamers, Nicole; Besra, Gurdyal; Boon, Louis; Nieuwenhuis, Edward E.S.; Elewaut, Dirk; Prakken, Berent; Kersten, Sander; Boes, Marianne; Kalkhoven, Eric

    2012-01-01

    Lipid overload and adipocyte dysfunction are key to the development of insulin resistance and can be induced by a high-fat diet. CD1d-restricted invariant natural killer T (iNKT) cells have been proposed as mediators between lipid overload and insulin resistance, but recent studies found decreased iNKT cell numbers and marginal effects of iNKT cell depletion on insulin resistance under high-fat diet conditions. Here, we focused on the role of iNKT cells under normal conditions. We showed that iNKT cell–deficient mice on a low-fat diet, considered a normal diet for mice, displayed a distinctive insulin resistance phenotype without overt adipose tissue inflammation. Insulin resistance was characterized by adipocyte dysfunction, including adipocyte hypertrophy, increased leptin, and decreased adiponectin levels. The lack of liver abnormalities in CD1d-null mice together with the enrichment of CD1d-restricted iNKT cells in both mouse and human adipose tissue indicated a specific role for adipose tissue–resident iNKT cells in the development of insulin resistance. Strikingly, iNKT cell function was directly modulated by adipocytes, which acted as lipid antigen-presenting cells in a CD1d-mediated fashion. Based on these findings, we propose that, especially under low-fat diet conditions, adipose tissue–resident iNKT cells maintain healthy adipose tissue through direct interplay with adipocytes and prevent insulin resistance. PMID:22863618

  5. Natural killer T cells in adipose tissue prevent insulin resistance.

    PubMed

    Schipper, Henk S; Rakhshandehroo, Maryam; van de Graaf, Stan F J; Venken, Koen; Koppen, Arjen; Stienstra, Rinke; Prop, Serge; Meerding, Jenny; Hamers, Nicole; Besra, Gurdyal; Boon, Louis; Nieuwenhuis, Edward E S; Elewaut, Dirk; Prakken, Berent; Kersten, Sander; Boes, Marianne; Kalkhoven, Eric

    2012-09-01

    Lipid overload and adipocyte dysfunction are key to the development of insulin resistance and can be induced by a high-fat diet. CD1d-restricted invariant natural killer T (iNKT) cells have been proposed as mediators between lipid overload and insulin resistance, but recent studies found decreased iNKT cell numbers and marginal effects of iNKT cell depletion on insulin resistance under high-fat diet conditions. Here, we focused on the role of iNKT cells under normal conditions. We showed that iNKT cell-deficient mice on a low-fat diet, considered a normal diet for mice, displayed a distinctive insulin resistance phenotype without overt adipose tissue inflammation. Insulin resistance was characterized by adipocyte dysfunction, including adipocyte hypertrophy, increased leptin, and decreased adiponectin levels. The lack of liver abnormalities in CD1d-null mice together with the enrichment of CD1d-restricted iNKT cells in both mouse and human adipose tissue indicated a specific role for adipose tissue-resident iNKT cells in the development of insulin resistance. Strikingly, iNKT cell function was directly modulated by adipocytes, which acted as lipid antigen-presenting cells in a CD1d-mediated fashion. Based on these findings, we propose that, especially under low-fat diet conditions, adipose tissue-resident iNKT cells maintain healthy adipose tissue through direct interplay with adipocytes and prevent insulin resistance.

  6. Polyphenols activate energy sensing network in insulin resistant models.

    PubMed

    Mutlur Krishnamoorthy, Radika; Carani Venkatraman, Anuradha

    2017-09-25

    Unhealthy diet deficient in fruits and vegetables but rich in calories is considered to be one factor responsible for the increased prevalence of insulin resistance and type 2 diabetes (T2D). The consumption of fast foods and soft drinks increases fructose consumption per se and this is of major concern since prolonged fructose intake induces insulin resistance and thereby T2D. The energy homeostasis is regulated by a network consisting of "fuel gauze" called AMP-activated protein kinase (AMPK), the NAD(+) dependent type III deacetylase (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) which is disrupted in T2D. The present study was aimed to investigate the action of naringenin and quercetin on energy sensing molecules in insulin resistant models. L6 myotubes and albino Wistar rats were rendered insulin resistant with palmitate and fructose respectively. Naringenin, quercetin or metformin were used for treatment. Fructose and palmitate treatment resulted in insulin resistance as evidenced by decreased glucose transporter 4 (GLUT4) translocation. The translocation of GLUT4, phosphorylation of AMPK and the expression of SIRT1 and PGC-1α which were reduced in insulin resistant cells, were increased upon treatment with polyphenols. Further, naringenin and quercetin showed binding affinity with energy sensing molecules. We conclude that drugs from natural resources that target energy sensing molecules might be helpful to prevent insulin resistance. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Insulin Resistance: Metabolic mechanisms and consequences in the heart

    PubMed Central

    Abel, E. Dale; O'Shea, Karen M.; Ramasamy, Ravichandran

    2013-01-01

    Insulin resistance is a characteristic feature of obesity and Type 2 diabetes and impacts the heart in various ways. Impaired insulin-mediated glucose uptake is a uniformly observed characteristic of the heart in these states, although changes in upstream kinase signaling are variable and dependent on the severity and duration of the associated obesity or diabetes. The understanding of the physiological and pathophysiological role of insulin resistance in the heart is evolving. To maintain its high energy demands, the heart is capable of utilizing many metabolic substrates. Although, insulin signaling may directly regulate cardiac metabolism, its main role is likely the regulation of substrate delivery from the periphery to the heart. In addition to promoting glucose uptake, insulin regulates long chain fatty acid uptake, protein synthesis, and vascular function in the normal cardiovascular system. Recent advances in understanding the role of metabolic, signaling, and inflammatory pathways in obesity have provided opportunities to better understand the pathophysiology of insulin resistance in the heart. This review will summarize our current understanding of metabolic mechanisms for and consequences of insulin resistance in the heart and discuss potential new areas for investigating novel mechanisms that contribute to insulin resistance in the heart. PMID:22895668

  8. Insulin resistance: metabolic mechanisms and consequences in the heart.

    PubMed

    Abel, E Dale; O'Shea, Karen M; Ramasamy, Ravichandran

    2012-09-01

    Insulin resistance is a characteristic feature of obesity and type 2 diabetes mellitus and impacts the heart in various ways. Impaired insulin-mediated glucose uptake is a uniformly observed characteristic of the heart in these states, although changes in upstream kinase signaling are variable and dependent on the severity and duration of the associated obesity or diabetes mellitus. The understanding of the physiological and pathophysiological role of insulin resistance in the heart is evolving. To maintain its high energy demands, the heart is capable of using many metabolic substrates. Although insulin signaling may directly regulate cardiac metabolism, its main role is likely the regulation of substrate delivery from the periphery to the heart. In addition to promoting glucose uptake, insulin regulates long-chain fatty acid uptake, protein synthesis, and vascular function in the normal cardiovascular system. Recent advances in understanding the role of metabolic, signaling, and inflammatory pathways in obesity have provided opportunities to better understand the pathophysiology of insulin resistance in the heart. This review will summarize our current understanding of metabolic mechanisms for and consequences of insulin resistance in the heart and will discuss potential new areas for investigating novel mechanisms that contribute to insulin resistance in the heart.

  9. Intramyocellular lipid kinetics and insulin resistance

    PubMed Central

    Guo, ZengKui

    2007-01-01

    More than fifteen years ago it was discovered that intramyocellular triglyceride (imcTG) content in skeletal muscle is abnormally high in conditions of lipid oversupply (e.g. high fat feeding) and, later, obesity, type 2 diabetes (T2D) and other metabolic conditions. This imcTG excess is robustly associated with muscle insulin resistance (MIR). However, to date the pathways responsible for the imcTG excess and the mechanisms underlying the imcTG-MIR correlation remain unclear. A current hypothesis is based on a backward mechanism that impaired fatty acid oxidation by skeletal muscle causes imcTG to accumulate. As such, imcTG excess is considered a marker but not a player in MIR. However, recent results from kinetic studies indicated that imcTG pool in high fat-induced obesity (HFO) model is kinetically dynamic. On one hand, imcTG synthesis is accelerated and contributes to imcTG accumulation. On the other, the turnover of imcTG is also accelerated. A hyperdynamic imcTG pool can impose dual adverse effects on glucose metabolism in skeletal muscle. It increases the release and thus the availability of fatty acids in myocytes that may promote fatty acid oxidation and suppress glucose utilization. Meanwhile, it releases abundant fatty acid products (e.g. diacylglycerol, ceramides) that impair insulin actions via signal transduction, thereby causing MIR. Thus, intramyocellular fatty acids and their products released from imcTG appear to function as a link to MIR. Accordingly, a forward mechanism is proposed that explains the imcTG-MIR correlation. PMID:17650308

  10. Salt sensitivity is associated with insulin resistance in essential hypertension.

    PubMed

    Fuenmayor, N; Moreira, E; Cubeddu, L X

    1998-04-01

    The relationship between salt sensitivity and insulin resistance was investigated in nondiabetic, nonobese (body mass index < or = 28) untreated patients with uncomplicated, mild-to-moderate essential hypertension. Alterations in insulin-mediated glucose disposal were assessed by means of the insulin suppression test. Subjects were classified as salt sensitive and salt resistant according to their blood pressure response to low and high salt intake. Fasting serum glucose levels were within normal limits and did not differ between salt sensitive and salt resistant hypertensives, irrespectively of the level of salt intake. Fasting serum insulin levels increased in salt sensitive patients when on a high intake of salt. The insulin suppression test revealed the existence of marked differences in insulin-mediated glucose uptake between salt sensitive and salt resistant hypertensives. Much higher steady-state glucose values (nanomoles of glucose/ liter) were obtained during the insulin suppression test in salt sensitive than in salt-resistant hypertensives (7.4+/-1.6 v 3.5+/-0.1 under low salt; and 12.5+/-1.1 v 4.3+/-0.1 under high salt intake). The product of glucose times insulin obtained at steady state during low and high salt intakes were 2.5 and 5 times greater, respectively, in salt sensitive than in salt resistant hypertensives. Therefore, the impairment in insulin-mediated glucose disposal observed in salt sensitive hypertensives was present both under low salt (60 to 70 mEq/day) and high salt intake (300 mEq/day). However, it was exacerbated under high salt intake. These results suggest that untreated salt sensitive hypertensives have a considerable impairment in insulin-mediated glucose disposal because of a state of insulin resistance. High salt intake increased BP, induced hyperinsulinemia, and worsened insulin-mediated glucose disposal only in salt sensitive patients. We propose that salt sensitivity contributes, separately from hypertension, to insulin

  11. Does Cardiorespiratory Fitness Modify the Association between Birth Weight and Insulin Resistance in Adult Life?

    PubMed Central

    Aoyama, Tomoko; Tsushita, Kazuyo; Miyatake, Nobuyuki; Numata, Takeyuki; Miyachi, Motohiko; Tabata, Izumi; Cao, Zhen-Bo; Sakamoto, Shizuo; Higuchi, Mitsuru

    2013-01-01

    Objective Lower birth weight is associated with higher insulin resistance in later life. The aim of this study was to determine whether cardiorespiratory fitness modifies the association of birth weight with insulin resistance in adults. Methods The subjects were 379 Japanese individuals (137 males, 242 females) aged 20–64 years born after 1943. Insulin resistance was assessed using a homeostasis model assessment of insulin resistance (HOMA-IR), which is calculated from fasting blood glucose and insulin levels. Cardiorespiratory fitness (maximal oxygen uptake, VO2max) was assessed by a maximal graded exercise test on a cycle ergometer. Birth weight was reported according to the Maternal and Child Health Handbook records or the subject’s or his/her mother’s memory. Results The multiple linear regression analysis revealed that birth weight was inversely associated with HOMA-IR (β = −0.141, p = 0.003), even after adjustment for gender, age, current body mass index, mean blood pressure, triglycerides, HDL cholesterol, and smoking status. Further adjustments for VO2max made little difference in the relationship between birth weight and HOMA-IR (β = −0.148, p = 0.001), although VO2max (β = −0.376, p<0.001) was a stronger predictor of HOMA-IR than birth weight. Conclusions The results showed that the association of lower birth weight with higher insulin resistance was little modified by cardiorespiratory fitness in adult life. However, cardiorespiratory fitness was found to be a stronger predictor of insulin resistance than was birth weight, suggesting that increasing cardiorespiratory fitness may have a much more important role in preventing insulin resistance than an individual’s low birth weight. PMID:24069257

  12. Effect of Insulin Resistance in Assessing the Clinical Outcome of Clinical and Subclinical Hypothyroid Patients

    PubMed Central

    MN, Suma; KM, Srinath; Prashant, Akila; Doddamani, Parveen; SV, Shilpa

    2015-01-01

    Background: The effect of thyroid status on insulin sensitivity is of great interest but despite various studies there is conflicting data on this subject. Hypothyroidism has been associated with disorders of glucose and insulin metabolism involving defective insulin secretion in response to glucose, hyperinsulinemia, altered peripheral glucose disposal and insulin resistance. Thyroid dysfunction leads to alterations in glucose and lipid metabolism which is an important risk factor for cardiovascular diseases. The dyslipidemia and insulin resistance should be managed aggressively to reduce the impending risk. Objectives: The prime objectives of the study were as follows: 1. To compare and correlate insulin resistance levels with T3, T4, and TSH in hypothyroidism patients. 2. To compare and correlate lipid profile with T3, T4, and TSH in hypothyroidism patients with healthy controls. Materials and Methods: Forty hypothyroidism patients and Forty healthy age and sex matched controls in the age group of 18 to 45 years were taken for the study. The venous blood samples collected were used for estimation of thyroid hormones, insulin, glucose and lipid profile. Results and Discussion: There is significant increase in insulin, Homa-IR and glucose levels in hypothyroidism cases when compared to controls. Cholesterol, LDL, VLDL and triglycerides were significantly increased, whereas HDL was significantly decreased in hypothyroidism cases when compared with controls. Insulin was moderately correlated with cholesterol but there was no correlation with other lipid profile parameters in hypothyroidism patients. Homa-IR was significantly correlated with TSH in hypothyroidism cases when compared with controls. TSH was significantly correlated with cholesterol and LDL in hypothyroidism cases (both clinical and subclinical) when compared with controls. The present study helps to evaluate changes in insulin resistance and lipid risk factors. These factors should be managed

  13. Susceptibility to oxidative stress, insulin resistance, and insulin secretory response in the development of diabetes from obesity.

    PubMed

    Kocić, Radivoj; Pavlović, Dusica; Kocić, Gordana; Pesić, Milica

    2007-06-01

    [corrected] Oxidative stress plays a critical role in the pathogenesis of various diseases. Recent reports indicate that obesity may induce systemic oxidative stress. The aim of the study was to potentiate oxidative stress as a factor which may aggravate peripheral insulin sensitivity and insulinsecretory response in obesity in this way to potentiate development of diabetes. The aim of the study was also to establish whether insulin-secretory response after glucagonstimulated insulin secretion is susceptible to prooxidant/antioxidant homeostasis status, as well as to determine the extent of these changes. A mathematical model of glucose/insulin interactions and C-peptide was used to indicate the degree of insulin resistance and to assess their possible relationship with altered antioxidant/prooxidant homeostasis. The study included 24 obese healthy and 16 obese newly diagnozed non-insulin dependent diabetic patients (NIDDM) as well as 20 control healthy subjects, matched in age. Total plasma antioxidative capacity, erythrocyte and plasma reduced glutathione level were significantly decreased in obese diabetic patients, but also in obese healthy subjects, compared to the values in controls. The plasma lipid peroxidation products and protein carbonyl groups were significantly higher in obese diabetics, more than in obese healthy subjects, compared to the control healthy subjects. The increase of erythrocyte lipid peroxidation at basal state was shown to be more pronounced in obese daibetics, but the apparent difference was obtained in both the obese healthy subjects and obese diabetics, compared to the control values, after exposing of erythrocytes to oxidative stress induced by H2O2. Positive correlation was found between the malondialdehyde (MDA) level and index of insulin sensitivity (FIRI). Increased oxidative stress together with the decreased antioxidative defence seems to contribute to decreased insulin sensitivity and impaired insulin secretory response in

  14. Leptolide Improves Insulin Resistance in Diet-Induced Obese Mice

    PubMed Central

    Villa-Pérez, Pablo; Cueto, Mercedes; Moreno, Alfredo; Perdomo, Germán

    2017-01-01

    Type 2 diabetes (T2DM) is a complex disease linked to pancreatic beta-cell failure and insulin resistance. Current antidiabetic treatment regimens for T2DM include insulin sensitizers and insulin secretagogues. We have previously demonstrated that leptolide, a member of the furanocembranolides family, promotes pancreatic beta-cell proliferation in mice. Considering the beneficial effects of leptolide in diabetic mice, in this study, we aimed to address the capability of leptolide to improve insulin resistance associated with the pathology of obesity. To this end, we tested the hypothesis that leptolide should protect against fatty acid-induced insulin resistance in hepatocytes. In a time-dependent manner, leptolide (0.1 µM) augmented insulin-stimulated phosphorylation of protein kinase B (PKB) by two-fold above vehicle-treated HepG2 cells. In addition, leptolide (0.1 µM) counteracted palmitate-induced insulin resistance by augmenting by four-fold insulin-stimulated phosphorylation of PKB in HepG2 cells. In vivo, acute intraperitoneal administration of leptolide (0.1 mg/kg and 1 mg/kg) improved glucose tolerance and insulin sensitivity in lean mice. Likewise, prolonged leptolide treatment (0.1 mg/kg) in diet-induced obese mice improved insulin sensitivity. These effects were paralleled with an ~50% increased of insulin-stimulated phosphorylation of PKB in liver and skeletal muscle and reduced circulating pro-inflammatory cytokines in obese mice. We concluded that leptolide significantly improves insulin sensitivity in vitro and in obese mice, suggesting that leptolide may be another potential treatment for T2DM. PMID:28914811

  15. D-Chiro-Inositol Glycans in Insulin Signaling and Insulin Resistance

    PubMed Central

    Larner, Joseph; Brautigan, David L; Thorner, Michael O

    2010-01-01

    Classical actions of insulin involve increased glucose uptake from the bloodstream and its metabolism in peripheral tissues, the most important and relevant effects for human health. However, nonoxidative and oxidative glucose disposal by activation of glycogen synthase (GS) and mitochondrial pyruvate dehydrogenase (PDH) remain incompletely explained by current models for insulin action. Since the discovery of insulin receptor Tyr kinase activity about 25 years ago, the dominant paradigm for intracellular signaling by insulin invokes protein phosphorylation downstream of the receptor and its primary Tyr phosphorylated substrates—the insulin receptor substrate family of proteins. This scheme accounts for most, but not all, intracellular actions of insulin. Essentially forgotten is the previous literature and continuing work on second messengers generated in cells in response to insulin. Treatment and even prevention of diabetes and metabolic syndrome will benefit from a more complete elucidation of cellular-signaling events activated by insulin, to include the actions of second messengers such as glycan molecules that contain D-chiro-inositol (DCI). The metabolism of DCI is associated with insulin sensitivity and resistance, supporting the concept that second messengers have a role in responses to and resistance to insulin. PMID:20811656

  16. Severe insulin resistance secondary to insulin antibodies: successful treatment with the immunosuppressant MMF.

    PubMed

    Segal, T; Webb, Ea; Viner, R; Pusey, C; Wild, G; Allgrove, J

    2008-06-01

    We have evaluated the use of the immunosuppressant mycophenolate mofetil (MMF) in the treatment of severe insulin resistance caused by neutralising anti-insulin antibodies in type 1 diabetes mellitus (T1DM). A 12-yr-old boy with a 5-month history of T1DM developed severe immunological insulin resistance secondary to human insulin antibodies. Various different treatment modalities, including lispro insulin, intravenous insulin, prednisolone and immunoabsorption, were tried, all without a sustained response to treatment. Although the introduction of the immunosuppressant MMF only resulted in a small reduction in haemoglobin A1c (from 10.9 to 9.8%), it did result in a significant reduction in insulin requirements from 6000 to 250 U/d (75 to 3.1 U/kg/d), disappearance of the severe nocturnal hypoglycaemia associated with high titres of insulin antibodies and a reduction in the level of these antibodies from 34.6 to 2.7 mg/dL. MMF may be considered as a means of immunosuppression in patients with markedly raised insulin antibodies whose diabetes cannot be controlled with insulin alone.

  17. The relationship of insulin resistance and metabolic syndrome with known breast cancer prognostic factors in postmenopausal breast cancer patients.

    PubMed

    Can, A; Alacacioglu, A; Kucukzeybek, Y; Erten, C; Cokmert, S; Demir, L; Dirican, A; Vedat Bayoglu, I; Akyol, M; Aslan, F; Oktay Tarhan, M

    2013-01-01

    The aim of this study was to investigate the effect of metabolic syndrome and insulin resistance at the time of diagnosis on the known prognostic factors of breast cancer in postmenopausal breast cancer patients. The study included 71 patients with a recent diagnosis of postmenopausal breast cancer, admitted at the Medical Oncology outpatient clinic of the Izmir Ataturk Training and Research Hospital between June 2010 and June 2011. We determined whether the patients had metabolic syndrome and insulin resistance at diagnosis, and recorded known prognostic factors, such as tumor size, axillary lymph node involvement, presence of distant metastasis, tumor grade, estrogen receptor (ER), progesterone receptor (PR), and CerbB-2 status. Among 71 patients, 25 (35%) had metabolic syndrome at the time of diagnosis, and 33 (46%) had insulin resistance with Homeostasis Model of Assessment-Insulin Resistance (HOMA-IR)>2.7. No statistically significant difference was found in the prognostic values of breast cancer, i.e. tumor size, axillary lymph node involvement, distant metastasis, tumor grade, ER, PR, and CerbB-2 status between the patients with and without metabolic syndrome. There was no statistically significant difference in the prognostic factors of breast cancer at the time of diagnosis between 33 patients with insulin resistance and 38 patients without insulin resistance. Several previous studies showed a negative relationship between metabolic syndrome and insulin resistance and prognostic factors of breast cancer in postmenopausal breast cancer patients. However, our study failed to show such a relationship. The relationship between metabolic syndrome and insulin resistance and postmenopausal breast cancer was not well demonstrated due to the small number of patients, unknown duration of the metabolic syndrome and insulin resistance, and shorter follow-up period. Further studies are required to demonstrate the effect of metabolic syndrome and insulin resistance on

  18. Insulin resistance during puberty and future fat accumulation.

    PubMed

    Travers, Sharon H; Jeffers, Barrett W; Eckel, Robert H

    2002-08-01

    Insulin resistance is a known sequela of obesity; however, the relationship of insulin resistance to future weight gain remains unclear. In several studies, insulin resistance has been associated with weight stabilization. For the most part, this relationship has been found in adults who are overweight. To evaluate the relationship of insulin resistance to future fat accumulation in pubertal children, a 3-yr prospective study was carried out. Insulin sensitivity (Si) was determined by Bergman's minimal model in 111 healthy children, aged 9.7-14.5 yr. All children were Tanner stage II or III pubertal development at baseline. Body composition was assessed by body mass index, skinfold thickness, hydrodensitometry, and bioelectric impedance analysis at baseline and annually thereafter for an additional 3 yr. A repeated-measures analysis showed that the change in percentage body fat estimated from skinfold thickness [%BF(SF)] over time changed with increasing Si (P < 0.0001). Si was divided into tertiles for each gender, with the lowest tertile representing the most insulin-resistant children. For girls, those in the lowest tertile maintained their %BF(SF) over 3 yr, whereas those girls in the middle and upper tertile had an increase in their %BF(SF). For boys, those in the lowest tertile showed a decrease in their %BF(SF), whereas those boys in the middle and upper tertile maintained their %BF(SF). These results suggest that during puberty, children who are more insulin resistant have decreased sc fat gain.

  19. Metabolic Acidosis-Induced Insulin Resistance and Cardiovascular Risk

    PubMed Central

    Souto, Gema; Donapetry, Cristóbal; Calviño, Jesús

    2011-01-01

    Abstract Microalbuminuria has been conclusively established as an independent cardiovascular risk factor, and there is evidence of an association between insulin resistance and microalbuminuria, the former preceding the latter in prospective studies. It has been demonstrated that even the slightest degree of metabolic acidosis produces insulin resistance in healthy humans. Many recent epidemiological studies link metabolic acidosis indicators with insulin resistance and systemic hypertension. The strongly acidogenic diet consumed in developed countries produces a lifetime acidotic state, exacerbated by excess body weight and aging, which may result in insulin resistance, metabolic syndrome, and type 2 diabetes, contributing to cardiovascular risk, along with genetic causes, lack of physical exercise, and other factors. Elevated fruits and vegetables consumption has been associated with lower diabetes incidence. Diseases featuring severe atheromatosis and elevated cardiovascular risk, such as diabetes mellitus and chronic kidney failure, are typically characterized by a chronic state of metabolic acidosis. Diabetic patients consume particularly acidogenic diets, and deficiency of insulin action generates ketone bodies, creating a baseline state of metabolic acidosisworsened by inadequate metabolic control, which creates a vicious circle by inducing insulin resistance. Even very slight levels of chronic kidney insufficiency are associated with increased cardiovascular risk, which may be explained at least in part by deficient acid excretory capacity of the kidney and consequent metabolic acidosis-induced insulin resistance. PMID:21352078

  20. Acylcarnitines: potential implications for skeletal muscle insulin resistance

    PubMed Central

    Aguer, Céline; McCoin, Colin S.; Knotts, Trina A.; Thrush, A. Brianne; Ono-Moore, Kikumi; McPherson, Ruth; Dent, Robert; Hwang, Daniel H.; Adams, Sean H.; Harper, Mary-Ellen

    2015-01-01

    Insulin resistance may be linked to incomplete fatty acid β-oxidation and the subsequent increase in acylcarnitine species in different tissues including skeletal muscle. It is not known if acylcarnitines participate in muscle insulin resistance or simply reflect dysregulated metabolism. The aims of this study were to determine whether acylcarnitines can elicit muscle insulin resistance and to better understand the link between incomplete muscle fatty acid β-oxidation, oxidative stress, inflammation, and insulin-resistance development. Differentiated C2C12, primary mouse, and human myotubes were treated with acylcarnitines (C4:0, C14:0, C16:0) or with palmitate with or without carnitine acyltransferase inhibition by mildronate. Treatment with C4:0, C14:0, and C16:0 acylcarnitines resulted in 20–30% decrease in insulin response at the level of Akt phosphorylation and/or glucose uptake. Mildronate reversed palmitate-induced insulin resistance concomitant with an ∼25% decrease in short-chain acylcarnitine and acetylcarnitine secretion. Although proinflammatory cytokines were not affected under these conditions, oxidative stress was increased by 2–3 times by short- or long-chain acylcarnitines. Acylcarnitine-induced oxidative stress and insulin resistance were reversed by treatment with antioxidants. Results are consistent with the conclusion that incomplete muscle fatty acid β-oxidation causes acylcarnitine accumulation and associated oxidative stress, raising the possibility that these metabolites play a role in muscle insulin resistance.—Aguer, C., McCoin, C. S., Knotts, T. A., Thrush, A. B., Ono-Moore, K., McPherson, R., Dent, R., Hwang, D. H., Adams, S. H., Harper, M.-E. Acylcarnitines: potential implications for skeletal muscle insulin resistance. PMID:25342132

  1. Contribution of insulin resistance to reduced antioxidant enzymes and vitamins in nonobese Korean children.

    PubMed

    Shin, Min-Jeong; Park, Eunju

    2006-03-01

    The prevalence of insulin resistance has been reported in nonobese, nondiabetic healthy individuals. We examined the relationship between insulin resistance and the reduced antioxidant systems of plasma lipid soluble vitamins and antioxidant enzymes in erythrocytes and to determine the contributing factors to the antioxidant systems in nonobese children. We measured blood lipid profiles, glucose, insulin concentrations, plasma antioxidant vitamins and erythrocytic antioxidant enzyme activities of 103 Korean children in the absence of obesity. Insulin resistance was estimated by homeostasis model assessment of insulin resistance (HOMA-IR). A significant inverse relationships between HOMA-IR and lipid corrected beta-carotene (r=-0.233, p<0.05), alpha-tocopherol (r=-0.370, p<0.0001) were observed. In addition, increased HOMA-IR was significantly related to the decreased activities of superoxide dismutase (r=-0.226, p<0.05) and catalase (r=-0.261, p<0.05). Stepwise multiple linear regression analyses showed that HOMA-IR was the independent factor to determine the antioxidant status such as plasma alpha-tocopherol (beta=-0.379, p<0.0001), beta-carotene (beta=-0.243, p<0.05), SOD (beta=-0.230, p<0.05), and catalase activity (beta=-0.255, p<0.05) after adjusting percent ideal body weight, waist circumference, gender, blood lipids and leptin levels in nonobese children. The reduced antioxidant status in insulin resistance state even in nonobese children suggests the importance of early nutritional intervention with features of insulin resistance.

  2. Associations of erythrocyte fatty acid patterns with insulin resistance.

    PubMed

    Bigornia, Sherman J; Lichtenstein, Alice H; Harris, William S; Tucker, Katherine L

    2016-03-01

    Synergistic or additive effects or both on cardiometabolic risk may be missed by examining individual fatty acids (FAs). A pattern analysis may be a more useful approach. In addition, it remains unclear whether erythrocyte FA composition relates to insulin resistance among Hispanics/Latinos. We derived erythrocyte FA patterns for a Puerto Rican cohort and examined their association with diet and insulin resistance in cross-sectional and prospective analyses. At baseline, principal components analysis was used to derive factor patterns with the use of 24 erythrocyte FAs from 1157 participants of the Boston Puerto Rican Health Study (aged 45-75 y). Dietary intake was assessed with a validated semiquantitative food-frequency questionnaire. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated at baseline and at the 2-y follow-up. Relations between FA patterns and HOMA-IR were analyzed in a sample of 922 participants with available data. Five FA patterns were derived, differentiated by 1) relatively high de novo lipogenesis (DNL) FAs and low n-6 (ω-6) FAs, 2) high very-long-chain saturated FAs, 3) high n-3 (ω-3) FAs, 4) high linoleic acid and low arachidonic acid, and 5) high trans FAs. The DNL pattern was positively correlated with sugar and inversely with n-6 and monounsaturated FA intakes. Only the DNL pattern was positively related to baseline HOMA-IR [adjusted geometric means (95% CIs) for quartiles 1 and 4: 1.72 (1.58, 1.87) and 2.20 (2.02, 2.39); P-trend < 0.0001]. Similar associations were observed at 2 y, after adjustment for baseline status [quartiles 1 and 4 means (95% CIs): 1.61 (1.48, 1.76) and 1.84 (1.69, 2.00); P-trend = 0.02]. These results remained consistent after the exclusion of participants with diabetes (n = 485). Our findings suggest that upregulated DNL associated with a diet high in sugar and relatively low in unsaturated FAs may adversely affect insulin sensitivity in a Hispanic/Latino cohort. © 2016 American

  3. Cognitively impaired elderly exhibit insulin resistance and no memory improvement with infused insulin.

    PubMed

    Morris, Jill K; Vidoni, Eric D; Mahnken, Jonathan D; Montgomery, Robert N; Johnson, David K; Thyfault, John P; Burns, Jeffrey M

    2016-03-01

    Insulin resistance is a risk factor for Alzheimer's disease (AD), although its role in AD etiology is unclear. We assessed insulin resistance using fasting and insulin-stimulated measures in 51 elderly subjects with no dementia (ND; n = 37) and with cognitive impairment (CI; n = 14). CI subjects exhibited either mild CI or AD. Fasting insulin resistance was measured using the homeostatic model assessment of insulin resistance (HOMA-IR). Insulin-stimulated glucose disposal was assessed using the hyperinsulinemic-euglycemic clamp to calculate glucose disposal rate into lean mass, the primary site of insulin-stimulated glucose disposal. Because insulin crosses the blood-brain barrier, we also assessed whether insulin infusion would improve verbal episodic memory compared to baseline. Different but equivalent versions of cognitive tests were administered in counterbalanced order in the basal and insulin-stimulated state. Groups did not differ in age or body mass index. Cognitively impaired subjects exhibited greater insulin resistance as measured at fasting (HOMA-IR; ND: 1.09 [1.1] vs. CI: 2.01 [2.3], p = 0.028) and during the hyperinsulinemic clamp (glucose disposal rate into lean mass; ND: 9.9 (4.5) vs. AD 7.2 (3.2), p = 0.040). Cognitively impaired subjects also exhibited higher fasting insulin compared to ND subjects, (CI: 8.7 [7.8] vs. ND: 4.2 [3.8] μU/mL; p = 0.023) and higher fasting amylin (CI: 24.1 [39.1] vs. 8.37 [14.2]; p = 0.050) with no difference in fasting glucose. Insulin infusion elicited a detrimental effect on one test of verbal episodic memory (Free and Cued Selective Reminding Test) in both groups (p < 0.0001) and no change in performance on an additional task (delayed logical memory). In this study, although insulin resistance was observed in cognitively impaired subjects compared to ND controls, insulin infusion did not improve memory. Furthermore, a significant correlation between HOMA-IR and glucose disposal rate was present only in ND

  4. Identification of individuals with insulin resistance using routine clinical measurements.

    PubMed

    Stern, Steven E; Williams, Ken; Ferrannini, Eleuterio; DeFronzo, Ralph A; Bogardus, Clifton; Stern, Michael P

    2005-02-01

    Insulin resistance is a treatable precursor of diabetes and potentially of cardiovascular disease as well. To identify insulin-resistant patients, we developed decision rules from measurements of obesity, fasting glucose, insulin, lipids, and blood pressure and family history in 2,321 (2,138 nondiabetic) individuals studied with the euglycemic insulin clamp technique at 17 European sites; San Antonio, Texas; and the Pima Indian reservation. The distribution of whole-body glucose disposal appeared to be bimodal, with an optimal insulin resistance cutoff of <28 micromol/min . kg lean body mass. Using recursive partitioning, we developed three types of classification tree models: the first, based on clinical measurements and all available laboratory determinations, had an area under the receiver operator characteristic curve (aROC) of 90.0% and generated a simple decision rule: diagnose insulin resistance if any of the following conditions are met: BMI >28.9 kg/m(2), homeostasis model assessment of insulin resistance (HOMA-IR) >4.65, or BMI >27.5 kg/m(2) and HOMA-IR >3.60. The fasting serum insulin concentrations corresponding to these HOMA-IR cut points were 20.7 and 16.3 microU/ml, respectively. This rule had a sensitivity and specificity of 84.9 and 78.7%, respectively. The second model, which included clinical measurements but no laboratory determinations, had an aROC of 85.0% and generated a decision rule that had a sensitivity and specificity of 78.7 and 79.6%, respectively. The third model, which included clinical measurements and lipid measurements but not insulin (and thus excluded HOMA-IR as well), had a similar aROC (85.1%), sensitivity (81.3%), and specificity (76.3%). Thus, insulin-resistant individuals can be identified using simple decision rules that can be tailored to specific needs.

  5. Insulin resistance, inflammation, and serum fatty acid composition.

    PubMed

    Fernández-Real, José-Manuel; Broch, Montserrat; Vendrell, Joan; Ricart, Wifredo

    2003-05-01

    Fatty acids (FAs) have been involved in the development of chronic inflammatory conditions such as insulin resistance and obesity. However, the relation among insulin resistance, obesity, inflammatory activity (circulating interleukin [IL]-6) and dietary FAs has been scarcely studied in otherwise healthy subjects. We aimed to study these interactions in 123 overweight (BMI 26.9 +/- 2.4 kg/m(2) [means +/- SD]) subjects and 109 lean (BMI 21.7 +/- 1.7 kg/m(2), P < 0.000001) subjects. IL-6 was measured by immunoassay and FA by gas liquid cromatography. The percentage of saturated FAs (r = 0.30, P = 0.01) and omega-6 FAs (r = -0.32, P = 0.001) were significantly associated with circulating IL-6, whereas the percentage of omega-3 FAs correlated negatively with C-reactive protein in overweight subjects (P = 0.04). Saturated-to-omega-3 and saturated-to-omega-6 FA ratios were significantly and positively associated with C-reactive protein (P < 0.0001) and IL-6 (P < 0.001), respectively. In contrast, none of these associations reached statistical significance in lean subjects. Those subjects in the most insulin-sensitive quintile (homeostasis model assessment value) showed a significantly higher percentage of linoleic acid (C18:2 varpi6) (P = 0.03) and a significantly lower level of araquidic (C20:0) (P = 0.04), behenic (C22:0) (P = 0.009), lignoceric (C24:0) (P = 0.02), and nervonic (C24:1 varpi9) (P = 0.001) FAs than the remaining subjects. In parallel, the most insulin-sensitive subjects showed significantly decreased C-reactive protein (P = 0.03). Serum C-reactive protein was significantly associated with percent linoleic acid and eicosapentaenoic acid in nonsmoking men (P = 0.03 and P = 0.04, respectively) and with docosahexaenoic acid in nonsmoking women (r = -0.46, P < 0.0001). We constructed a multivariant regression analysis to predict circulating IL-6. Age, BMI, waist-to-hip ratio (WHR), smoking status, and the relation of saturated to omega-6 or saturated to omega

  6. Binge Drinking Induces Whole-Body Insulin Resistance by Impairing Hypothalamic Insulin Action

    PubMed Central

    Lindtner, Claudia; Scherer, Thomas; Zielinski, Elizabeth; Filatova, Nika; Fasshauer, Martin; Tonks, Nicholas K.; Puchowicz, Michelle; Buettner, Christoph

    2013-01-01

    Individuals with a history of binge drinking have an increased risk of developing the metabolic syndrome and type 2 diabetes. Whether binge drinking impairs glucose homeostasis and insulin action is unknown. To test this, we treated Sprague-Dawley rats daily with alcohol (3 g/kg) for three consecutive days to simulate human binge drinking and found that these rats developed and exhibited insulin resistance even after blood alcohol concentrations had become undetectable. The animals were resistant to insulin for up to 54 hours after the last dose of ethanol, chiefly a result of impaired hepatic and adipose tissue insulin action. Because insulin regulates hepatic glucose production and white adipose tissue lipolysis, in part through signaling in the central nervous system, we tested whether binge drinking impaired brain control of nutrient partitioning. Rats that had consumed alcohol exhibited impaired hypothalamic insulin action, defined as the ability of insulin infused into the mediobasal hypothalamus to suppress hepatic glucose production and white adipose tissue lipolysis. Insulin signaling in the hypothalamus, as assessed by insulin receptor and AKT phosphorylation, decreased after binge drinking. Quantitative polymerase chain reaction showed increased hypothalamic inflammation and expression of protein tyrosine phosphatase 1B (PTP1B), a negative regulator of insulin signaling. Intracerebroventricular infusion of CPT-157633, a small-molecule inhibitor of PTP1B, prevented binge drinking–induced glucose intolerance. These results show that, in rats, binge drinking induces systemic insulin resistance by impairing hypothalamic insulin action and that this effect can be prevented by inhibition of brain PTP1B. PMID:23363978

  7. Fasting insulin, insulin resistance and risk of hypertension in the general population: A meta-analysis.

    PubMed

    Wang, Feng; Han, Lili; Hu, Dayi

    2017-01-01

    Studies on the association of fasting insulin concentrations or insulin resistance with subsequent risk of hypertension have yielded conflicting results. To quantitatively assess the association of fasting insulin concentrations or homeostasis model assessment insulin resistance (HOMA-IR) with incident hypertension in a general population by performing a meta-analysis. We searched the PubMed and Embase databases until August 31, 2016 for prospective observational studies investigating the elevated fasting insulin concentrations or HOMA-IR with subsequent risk of hypertension in the general population. Pooled risk ratio (RR) and 95% confidence interval (CI) of hypertension was calculated for the highest versus the lowest category of fasting insulin or HOMA-IR. Eleven studies involving 10,230 hypertension cases were identified from 55,059 participants. Meta-analysis showed that the pooled adjusted RR of hypertension was 1.54 (95% CI 1.34-1.76) for fasting insulin concentrations and 1.43 (95% CI 1.27-1.62) for HOMA-IR comparing the highest to the lowest category. Subgroup analysis results showed that the association of fasting insulin concentrations with subsequent risk of hypertension seemed more pronounced in women (RR 2.07; 95% CI 1.19-3.60) than in men (RR 1.48; 95% CI 1.17-1.88). This meta-analysis suggests that elevated fasting insulin concentrations or insulin resistance as estimated by homeostasis model assessment is independently associated with an exacerbated risk of hypertension in the general population. Early intervention of hyperinsulinemia or insulin resistance may help clinicians to identify the high risk of hypertensive population. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Insulin resistance impairs nigrostriatal dopamine function.

    PubMed

    Morris, J K; Bomhoff, G L; Gorres, B K; Davis, V A; Kim, J; Lee, P-P; Brooks, W M; Gerhardt, G A; Geiger, P C; Stanford, J A

    2011-09-01

    Clinical studies have indicated a link between Parkinson's disease (PD) and Type 2 Diabetes. Although preclinical studies have examined the effect of high-fat feeding on dopamine function in brain reward pathways, the effect of diet on neurotransmission in the nigrostriatal pathway, which is affected in PD and parkinsonism, is less clear. We hypothesized that a high-fat diet, which models early-stage Type 2 Diabetes, would disrupt nigrostriatal dopamine function in young adult Fischer 344 rats. Rats were fed a high fat diet (60% calories from fat) or a normal chow diet for 12 weeks. High fat-fed animals were insulin resistant compared to chow-fed controls. Potassium-evoked dopamine release and dopamine clearance were measured in the striatum using in vivo electrochemistry. Dopamine release was attenuated and dopamine clearance was diminished in the high-fat diet group compared to chow-fed rats. Magnetic resonance imaging indicated increased iron deposition in the substantia nigra of the high fat group. This finding was supported by alterations in the expression of several proteins involved in iron metabolism in the substantia nigra in this group compared to chow-fed animals. The diet-induced systemic and basal ganglia-specific changes may play a role in the observed impairment of nigrostriatal dopamine function. Copyright © 2011 Elsevier Inc. All rights reserved.

  9. Obesity, insulin resistance, NASH and hepatocellular carcinoma.

    PubMed

    Yu, Jun; Shen, Jiayun; Sun, Ting Ting; Zhang, Xiang; Wong, Nathalie

    2013-12-01

    Epidemiological and clinical data have clearly demonstrated that non-alcoholic steatohepatitis (NASH) predisposes risk to the development of hepatocellular carcinoma (HCC). NASH is the liver manifestation of metabolic syndrome, which constellates obesity, insulin resistance and dyslipidemia. Although the percentage of patients diagnosed annually with NASH-associated HCC is still relatively low, this number signifies a large population due to the rapidly increasing incidence of obesity and diabetes globally. Fundamental studies on lipid storage, regulation of adipose factors, inflammatory cytokine recruitments and oxidative stress have provided insights into NASH as well as metabolic syndrome. Recent evidence also indicates the significant role of genetic factors in contributing to the pathogenesis of NASH and induced hepatic malignancy. In this review, we attempt to collate current research on NASH biology that lead to our understandings on how metabolic disorders may intersect with cancer development. We also discuss study models that have supported discoveries of molecular and cellular defects, and offered a perspective on therapeutic developments. These studies have collectively increased our knowledge on the complex signaling pathways involved in NASH and cancer, and provided the foundation for improved clinical management of patients with metabolic diseases.

  10. Insulin resistant diabetes mellitus without the presence of insulin antibodies. A case report.

    PubMed

    Páv, J; Srámková, J; Matys, Z

    1976-07-01

    A case of a 26-year old woman suffering from an insulin resistant diabetes mellitus for 14 years is described. Acanthosis nigricans was diagnosed in the patient's second year and the syndrome of Stein-Leventhal at the age of 15. Diabetes could not be properly controlled either with the daily dosis of insulin as high as 1140 U or with peroral tolbutamide. Fasting serum IRI concentrations were elevated, the secretoric response to the stimulation by glucose or tolbutamide was substantial and protracted. The hypoglycemic response to the i.v. application of commercial insulin was insignificant. Serum growth hormone levels were normal. No presence of insulin antibodies in the serum was detected.

  11. [Lipid metabolism and insulin resistance--clinical aspects and pathobiochemistry].

    PubMed

    Gries, F A; Hübinger, A

    1994-01-01

    About 3 decades ago insulin resistance has been described as the pathogenetic factor leading from abnormal fat metabolism to diabetes mellitus. Within the metabolic syndrome insulin resistance is related to the upper body (android) type of obesity, hypertriglyceridaemia, hypertension, and diabetes mellitus ("deadly quartet"). It precedes the development of arterial hypertension and the metabolic disorders. The pathomechanisms leading from obesity and hypertriglyceridaemia to insulin resistance may be described by the glucose fatty acid cycle of Randle et al. According to their metabolic scheme increased supply of fatty acids results in reduced glucose oxidation. Concomittantly hepatic glucose production is increased. On the other hand insulin resistance combined with hyperinsulinaemia may lead to an elevation of VLDL-triglycerides and to a decrease of HDL-cholesterol in blood, thus creating a vicious cycle, in which elevated VLDL-triglycerides reinforce insulin resistance via the glucose fatty acid cycle. Interventions to improve insulin sensitivity and thereby lower plasma insulin should reduce obesity and hypertriglyceridaemia by dietary treatment. They usually improve promptly diabetic metabolism. New developments in pharmacological inhibition of fatty acid oxidation are discussed.

  12. Insulin Resistance Induced by Hyperinsulinemia Coincides with a Persistent Alteration at the Insulin Receptor Tyrosine Kinase Domain

    PubMed Central

    Catalano, Karyn J.; Maddux, Betty A.; Szary, Jaroslaw; Youngren, Jack F.; Goldfine, Ira D.; Schaufele, Fred

    2014-01-01

    Insulin resistance, the diminished response of target tissues to insulin, is associated with the metabolic syndrome and a predisposition towards diabetes in a growing proportion of the worldwide population. Under insulin resistant states, the cellular response of the insulin signaling pathway is diminished and the body typically responds by increasing serum insulin concentrations to maintain insulin signaling. Some evidence indicates that the increased insulin concentration may itself further dampen insulin response. If so, insulin resistance would worsen as the level of circulating insulin increases during compensation, which could contribute to the transition of insulin resistance to more severe disease. Here, we investigated the consequences of excess insulin exposure to insulin receptor (IR) activity. Cells chronically exposed to insulin show a diminished the level of IR tyrosine and serine autophosphorylation below that observed after short-term insulin exposure. The diminished IR response did not originate with IR internalization since IR amounts at the cell membrane were similar after short- and long-term insulin incubation. Förster resonance energy transfer between fluorophores attached to the IR tyrosine kinase (TK) domain showed that a change in the TK domain occurred upon prolonged, but not short-term, insulin exposure. Even though the altered ‘insulin refractory’ IR TK FRET and IR autophosphorylation levels returned to baseline (non-stimulated) levels after wash-out of the original insulin stimulus, subsequent short-term exposure to insulin caused immediate re-establishment of the insulin-refractory levels. This suggests that some cell-based ‘memory’ of chronic hyperinsulinemic exposure acts directly at the IR. An improved understanding of that memory may help define interventions to reset the IR to full insulin responsiveness and impede the progression of insulin resistance to more severe disease states. PMID:25259572

  13. B lymphocytes as emerging mediators of insulin resistance

    PubMed Central

    Winer, D A; Winer, S; Shen, L; Chng, M H Y; Engleman, E G

    2012-01-01

    Obesity is associated with chronic inflammation of various tissues including visceral adipose tissue (VAT), which contributes to insulin resistance. T cells and macrophages infiltrate VAT in obesity and orchestrate this inflammation. Recently, we made the surprising discovery that B cells are important contributors to this process. Thus, some B cells and the antibodies they produce can promote VAT-associated and systemic inflammation, leading to insulin resistance. This report will focus on the properties of these B cells, and how they contribute to insulin resistance through T-cell modulation and production of pathogenic autoantibodies. Understanding the mechanisms by which B cells contribute to insulin resistance should lead to new antibody-based diagnostics and B-cell modulating therapeutics to manage this increasingly prevalent disease. PMID:25089193

  14. Genetics of Insulin Resistance and the Metabolic Syndrome.

    PubMed

    Brown, Audrey E; Walker, Mark

    2016-08-01

    Insulin resistance and the metabolic syndrome are complex metabolic traits and key risk factors for the development of cardiovascular disease. They result from the interplay of environmental and genetic factors but the full extent of the genetic background to these conditions remains incomplete. Large-scale genome-wide association studies have helped advance the identification of common genetic variation associated with insulin resistance and the metabolic syndrome, and more recently, exome sequencing has allowed the identification of rare variants associated with the pathogenesis of these conditions. Many variants associated with insulin resistance are directly involved in glucose metabolism; however, functional studies are required to assess the contribution of other variants to the development of insulin resistance. Many genetic variants involved in the pathogenesis of the metabolic syndrome are associated with lipid metabolism.

  15. 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.

  16. Albuminuria According to Status of Autoimmunity and Insulin Sensitivity Among Youth With Type 1 and Type 2 Diabetes

    PubMed Central

    Mottl, Amy K.; Lauer, Abigail; Dabelea, Dana; Maahs, David M.; D’Agostino, Ralph B.; Dolan, Larry M.; Gilliam, Lisa K.; Lawrence, Jean M.; Rodriguez, Beatriz; Marcovina, Santica M.; Imperatore, Giuseppina; Kanakatti Shankar, Roopa; Afkarian, Maryam; Reynolds, Kristi; Liese, Angela D.; Mauer, Michael; Mayer-Davis, Elizabeth J.

    2013-01-01

    OBJECTIVE To evaluate whether etiologic diabetes type is associated with the degree of albuminuria in children with diabetes. RESEARCH DESIGN AND METHODS SEARCH is an observational, longitudinal study of children with diabetes. Youth with newly diagnosed diabetes were classified according to diabetes autoantibody (DAA) status and presence of insulin resistance. We defined insulin resistance as an insulin sensitivity score <25th percentile for the United States general youth population. DAA status was based on positivity for the 65-kD isoform of glutamate decarboxylase and insulinoma-associated protein 2 antigens. The four etiologic diabetes type groups were as follows: DAA+/insulin-sensitive (IS) (n = 1,351); DAA+/insulin-resistant (IR) (n = 438); DAA−/IR (n = 379); and DAA−/IS (n = 233). Urinary albumin:creatinine ratio (UACR) was measured from a random urine specimen. Multivariable regression analyses assessed the independent relationship between the four diabetes type groups and magnitude of UACR. RESULTS Adjusted UACR means across the four groups were as follows: DAA+/IS = 154 μg/mg; DAA+/IR = 137 μg/mg; DAA−/IR = 257 μg/mg; and DAA−/IS = 131 μg/mg (P < 0.005). Only DAA−/IR was significantly different. We performed post hoc multivariable regression analysis restricted to the two IR groups to explore the contribution of DAA status and insulin sensitivity (continuous) to the difference in UACR between the IR groups. Only insulin sensitivity was significantly associated with UACR (β = −0.54; P < 0.0001). CONCLUSIONS In youth with diabetes, the DAA−/IR group had a greater UACR than all other groups, possibly because of the greater magnitude of insulin resistance. Further exploration of the relationships between severity of insulin resistance, autoimmunity, and albuminuria in youth with diabetes is warranted. PMID:23846811

  17. IL-37 protects against obesity-induced inflammation and insulin resistance.

    PubMed

    Ballak, Dov B; van Diepen, Janna A; Moschen, Alexander R; Jansen, Henry J; Hijmans, Anneke; Groenhof, Gert-Jan; Leenders, Floris; Bufler, Philip; Boekschoten, Mark V; Müller, Michael; Kersten, Sander; Li, Suzhao; Kim, SooHyun; Eini, Hadar; Lewis, Eli C; Joosten, Leo A B; Tilg, Herbert; Netea, Mihai G; Tack, Cees J; Dinarello, Charles A; Stienstra, Rinke

    2014-09-03

    Cytokines of the IL-1 family are important modulators of obesity-induced inflammation and the development of systemic insulin resistance. Here we show that IL-1 family member IL-37, recently characterized as an anti-inflammatory cytokine, ameliorates obesity-induced inflammation and insulin resistance. Mice transgenic for human IL-37 (IL-37tg) exhibit reduced numbers of adipose tissue macrophages, increased circulating levels of adiponectin and preserved glucose tolerance and insulin sensitivity after 16 weeks of HFD. In vitro treatment of adipocytes with recombinant IL-37 reduces adipogenesis and activates AMPK signalling. In humans, elevated steady-state IL-37 adipose tissue mRNA levels are positively correlated with insulin sensitivity and a lower inflammatory status of the adipose tissue. These findings reveal IL-37 as an important anti-inflammatory modulator during obesity-induced inflammation and insulin resistance in both mice and humans, and suggest that IL-37 is a potential target for the treatment of obesity-induced insulin resistance and type 2 diabetes.

  18. Psychological insulin resistance in type 2 diabetes patients regarding oral antidiabetes treatment, subcutaneous insulin injections, or inhaled insulin.

    PubMed

    Petrak, Frank; Herpertz, Stephan; Stridde, Elmar; Pfützner, Andreas

    2013-08-01

    "Psychological insulin resistance" (PIR) is an obstacle to insulin treatment in type 2 diabetes, and patients' expectations regarding alternative ways of insulin delivery are poorly understood. PIR and beliefs regarding treatment alternatives were analyzed in patients with type 2 diabetes (n=532; mean glycated hemoglobin, 68±12 mmol/mol [8.34±1.5%]) comparing oral antidiabetes treatment, subcutaneous insulin injections, or inhaled insulin. Questionnaires were used to assess barriers to insulin treatment (BIT), generic and diabetes-specific quality of life (Short Form 36 and Problem Areas in Diabetes, German version), diabetes knowledge, locus of control (Questionnaire for the Assessment of Diabetes-Specific Locus of Control, in German), coping styles (Freiburg Questionnaire of Illness Coping, 15-Items Short Form), self-esteem (Rosenberg Self-Esteem Scale, German version), and mental disorders (Patient Health Questionnaire, German version). Patients discussed treatment optimization options with a physician and were asked to make a choice about future diabetes therapy options in a two-step treatment choice scenario. Step 1 included oral antidiabetes drugs or subcutaneous insulin injection (SCI). Step 2 included an additional treatment alternative of inhaled insulin (INH). Subgroups were analyzed according to their treatment choice. Most patients perceived their own diabetes-related behavior as active, problem-focused, internally controlled, and oriented toward their doctors' recommendations, although their diabetes knowledge was limited. In Step 1, rejection of the recommended insulin was 82%, and in Step 2, it was 57%. Fear of hypoglycemia was the most important barrier to insulin treatment. Patients choosing INH (versus SCI) scored higher regarding fear of injection, expected hardship from insulin therapy, and BIT-Sumscore. The acceptance of insulin is very low in type 2 diabetes patients. The option to inhale insulin increases the acceptability for some but

  19. Acupuncture Alters Expression of Insulin Signaling Related Molecules and Improves Insulin Resistance in OLETF Rats

    PubMed Central

    Sun, Jian

    2016-01-01

    To determine effect of acupuncture on insulin resistance in Otsuka Long-Evans Tokushima Fatty (OLETF) rats and to evaluate expression of insulin signaling components. Rats were divided into three groups: Sprague-Dawley (SD) rats, OLETF rats, and acupuncture+OLETF rats. Acupuncture was subcutaneously applied to Neiguan (PC6), Zusanli (ST36), and Sanyinjiao (SP6); in contrast, acupuncture to Shenshu (BL23) was administered perpendicularly. For Neiguan (PC6) and Zusanli (ST36), needles were connected to an electroacupuncture (EA) apparatus. Fasting blood glucose (FPG) was measured by glucose oxidase method. Plasma fasting insulin (FINS) and serum C peptide (C-P) were determined by ELISA. Protein and mRNA expressions of insulin signaling molecules were determined by Western blot and real-time RT-PCR, respectively. OLETF rats exhibit increased levels of FPG, FINS, C-P, and homeostasis model assessment-estimated insulin resistance (HOMA-IR), which were effectively decreased by acupuncture treatment. mRNA expressions of several insulin signaling related molecules IRS1, IRS2, Akt2, aPKCζ, and GLUT4 were decreased in OLETF rats compared to SD controls. Expression of these molecules was restored back to normal levels upon acupuncture administration. PI3K-p85α was increased in OLETF rats; this increase was also reversed by acupuncture treatment. Acupuncture improves insulin resistance in OLETF rats, possibly via regulating expression of key insulin signaling related molecules. PMID:27738449

  20. Vitamin D deficiency is associated with insulin resistance in nondiabetics and reduced insulin production in type 2 diabetics.

    PubMed

    Esteghamati, A; Aryan, Z; Esteghamati, Ar; Nakhjavani, M

    2015-04-01

    It is not known whether the association of serum 25-hydroxyvitamin D [25(OH)D] with glycemic measurements of individuals without diabetes is similar to those with diabetes or not. This study is aimed to investigate the association of serum 25(OH)D with glycemic markers of diabetics, nondiabetics, and prediabetics. A case-control study was conducted on age and sex matched 1,195 patients with type 2 DM, 121 prediabetics, and 209 healthy controls. Anthropometric variables, lipid profile, glycemic measurements, and serum 25(OH)D levels were recorded. Serum insulin and C-peptide levels were also measured. All glycemic measurements were compared between diabetics and nondiabetics and prediabetics at different vitamin D status. Patients with DM had lower serum 25(OH)D compared to prediabetics and healthy controls. Endogenous insulin production in response to food intake and in fasting was significantly lower in vitamin D deficient patients with DM compared to those with serum 25(OH)D>40 ng/ml. Diabetic women with serum 25(OH)D<20 ng/ml had lower beta cell function as estimated by lower HOMA-B compared to their counterparts with serum 25(OH)D>40 ng/ml. Healthy individuals with serum 25(OH)D<20 ng/ml had signs of insulin resistance as estimated by significant increase of HOMA-IR, HbA1c, and fasting plasma glucose (FPG). In addition, we found that serum 25(OH)D was inversely associated with insulin resistance. Vitamin D deficiency is associated with insulin resistance in nondiabetics, which is independent of obesity. Furthermore, vitamin D deficiency is associated with reduced insulin production in type 2 diabetics, which was mainly observed in men. Accordingly, a gender disparity also exists in association of serum 25(OH)D with glycemic measurements.

  1. Lipid-mediated muscle insulin resistance: different fat, different pathways?

    PubMed

    Ritter, Olesja; Jelenik, Tomas; Roden, Michael

    2015-08-01

    Increased dietary fat intake and lipolysis result in excessive lipid availability, which relates to impaired insulin sensitivity. Over the last years, several mechanisms possibly underlying lipid-mediated insulin resistance evolved. Lipid intermediates such as diacylglycerols (DAG) associate with changes in insulin sensitivity in many models. DAG activate novel protein kinase C (PKC) isoforms followed by inhibitory serine phosphorylation of insulin receptor substrate 1 (IRS1). Activation of Toll-like receptor 4 (TLR4) raises another lipid class, ceramides (CER), which induce pro-inflammatory pathways and lead to inhibition of Akt phosphorylation. Inhibition of glucosylceramide and ganglioside synthesis results in improved insulin sensitivity and increased activatory tyrosine phosphorylation of IRS1 in the muscle. Incomplete fat oxidation can increase acylcarnitines (ACC), which in turn stimulate pro-inflammatory pathways. This review analyzed the effects of lipid metabolites on insulin action in skeletal muscle of humans and rodents. Despite the evidence for the association of both DAG and CER with insulin resistance, its causal relevance may differ depending on the subcellular localization and the tested cohorts, e.g., athletes. Nevertheless, recent data indicate that individual lipid species and their degree of fatty acid saturation, particularly membrane and cytosolic C18:2 DAG, specifically activate PKCθ and induce both acute lipid-induced and chronic insulin resistance in humans.

  2. Association of sleep duration and insulin resistance in Taiwanese vegetarians

    PubMed Central

    2012-01-01

    Background Short sleep duration has been reported to associate with increased insulin resistance. However, no studies have investigated whether such association exists in vegetarians. The aim of this study was to investigate the association between sleep duration and insulin resistance in Taiwanese vegetarians. Methods A total of 1290 individuals were recruited from a regional hospital in south Taiwan during their regular routine physical examination. Only individuals who described themselves as Buddhist vegetarians were included in the study. Demographic information and clinical characteristics were collected and multiple logistic regression analysis was used to evaluate the association between sleep duration and insulin resistance. Results A total of 433 vegetarians were included in the study. Results from univariate logistic regression indicated that insulin resistance was significantly associated with male sex, greater waist circumference, higher triglyceride levels, lower high-density lipoprotein cholesterol levels, higher plasma creatinine levels, higher alanine transaminase levels, greater energy expenditure, and sleep duration of more than 8 hours per night. Multiple logistic regression revealed that insulin resistance was significantly and independently associated with sleep duration of more than 8 hours per night (odd ratios = 2.27, 95% confidence interval = 1.24, 4.11) after adjusting for waist circumference and levels of alanine transaminase. Conclusions Sleep duration of more than 8 hours per night is an independent risk factor associated with increased insulin resistance in vegetarians. PMID:22898005

  3. Association of sleep duration and insulin resistance in Taiwanese vegetarians.

    PubMed

    Chang, Jiunn-Kae; Koo, Malcolm; Kao, Vivia Yu-Ying; Chiang, Jui-Kun

    2012-08-16

    Short sleep duration has been reported to associate with increased insulin resistance. However, no studies have investigated whether such association exists in vegetarians. The aim of this study was to investigate the association between sleep duration and insulin resistance in Taiwanese vegetarians. A total of 1290 individuals were recruited from a regional hospital in south Taiwan during their regular routine physical examination. Only individuals who described themselves as Buddhist vegetarians were included in the study. Demographic information and clinical characteristics were collected and multiple logistic regression analysis was used to evaluate the association between sleep duration and insulin resistance. A total of 433 vegetarians were included in the study. Results from univariate logistic regression indicated that insulin resistance was significantly associated with male sex, greater waist circumference, higher triglyceride levels, lower high-density lipoprotein cholesterol levels, higher plasma creatinine levels, higher alanine transaminase levels, greater energy expenditure, and sleep duration of more than 8 hours per night. Multiple logistic regression revealed that insulin resistance was significantly and independently associated with sleep duration of more than 8 hours per night (odd ratios = 2.27, 95% confidence interval = 1.24, 4.11) after adjusting for waist circumference and levels of alanine transaminase. Sleep duration of more than 8 hours per night is an independent risk factor associated with increased insulin resistance in vegetarians.

  4. Femoral Bone Marrow Insulin Sensitivity Is Increased by Resistance Training in Elderly Female Offspring of Overweight and Obese Mothers

    PubMed Central

    Huovinen, Ville; Bucci, Marco; Lipponen, Heta; Kiviranta, Riku; Sandboge, Samuel; Raiko, Juho; Koskinen, Suvi; Koskensalo, Kalle; Eriksson, Johan G.; Parkkola, Riitta; Iozzo, Patricia; Nuutila, Pirjo

    2016-01-01

    Bone marrow insulin sensitivity may be an important factor for bone health in addition to bone mineral density especially in insulin resistant conditions. First we aimed to study if prenatal maternal obesity plays a role in determining bone marrow insulin sensitivity in elderly female offspring. Secondly we studied if a four-month individualized resistance training intervention increases bone marrow insulin sensitivity in elderly female offspring and whether this possible positive outcome is regulated by the offspring’s mother’s obesity status. 37 frail elderly females (mean age 71.9 ± 3.1 years) of which 20 were offspring of lean/normal-weight mothers (OLM, maternal BMI ≤ 26.3 kg/m2) and 17 were offspring of obese/overweight mothers (OOM, maternal BMI ≥ 28.1 kg/m2) were studied before and after a four-month individualized resistance training intervention. Nine age- and sex-matched non-frail controls (maternal BMI ≤ 26.3 kg/m2) were studied at baseline. Femoral bone marrow (FBM) and vertebral bone marrow (VBM) insulin sensitivity were measured using [18F]fluoro-2-deoxy-D-glucose positron emission tomography with computer tomography under hyperinsulinemic euglycemic clamp. We found that bone marrow insulin sensitivity was not related to maternal obesity status but FBM insulin sensitivity correlated with whole body insulin sensitivity (R = 0.487, p = 0.001). A four-month resistance training intervention increased FBM insulin sensitivity by 47% (p = 0.006) only in OOM, while VBM insulin sensitivity remained unchanged regardless of the maternal obesity status. In conclusion, FBM and VBM glucose metabolism reacts differently to a four-month resistance training intervention in elderly women according to their maternal obesity status. Trial Registration ClinicalTrials.gov NCT01931540 PMID:27669153

  5. Insulin resistance in clinical and experimental alcoholic liver disease

    PubMed Central

    Carr, Rotonya M.; Correnti, Jason

    2015-01-01

    Alcoholic liver disease (ALD) is the number one cause of liver failure worldwide; its management costs billions of health care dollars annually. Since the advent of the obesity epidemic, insulin resistance and diabetes have become common clinical findings in patients with ALD; and the development of insulin resistance predicts the progression from simple steatosis to cirrhosis in ALD patients. Both clinical and experimental data implicate the impairment of several mediators of insulin signaling in ALD, and experimental data suggest that insulin-sensitizing therapies improve liver histology. This review explores the contribution of impaired insulin signaling in ALD and summarizes the current understanding of the synergistic relationship between alcohol and nutrient excess in promoting hepatic inflammation and disease. PMID:25998863

  6. Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance

    PubMed Central

    McNay, Ewan C.; Ong, Cecilia T.; McCrimmon, Rory J.; Cresswell, James; Bogan, Jonathan S.; Sherwin, Robert S

    2010-01-01

    Insulin regulates glucose uptake and storage in peripheral tissues, and has been shown to act within the hypothalamus to acutely regulate food intake and metabolism. The machinery for transduction of insulin signaling is also present in other brain areas, particularly in the hippocampus, but a physiological role for brain insulin outside the hypothalamus has not been established. Recent studies suggest that insulin may be able to modulate cognitive functions including memory. Here we report that local delivery of insulin to the rat hippocampus enhances spatial memory, in a PI-3-kinase dependent manner, and that intrahippocampal insulin also increases local glycolytic metabolism. Selective blockade of endogenous intrahippocampal insulin signaling impairs memory performance. Further, a rodent model of type 2 diabetes mellitus produced by a high-fat diet impairs basal cognitive function and attenuates both cognitive and metabolic responses to hippocampal insulin administration. Our data demonstrate that insulin is required for optimal hippocampal memory processing. Insulin resistance within the telencephalon may underlie the cognitive deficits commonly reported to accompany type 2 diabetes. PMID:20176121

  7. Caffeine intake improves fructose-induced hypertension and insulin resistance by enhancing central insulin signaling.

    PubMed

    Yeh, Tung-Chen; Liu, Chun-Peng; Cheng, Wen-Han; Chen, Bo-Rong; Lu, Pei-Jung; Cheng, Pei-Wen; Ho, Wen-Yu; Sun, Gwo-Ching; Liou, Jau-Cheng; Tseng, Ching-Jiunn

    2014-03-01

    Recent clinical studies found that fructose intake leads to insulin resistance and hypertension. Fructose consumption promotes protein fructosylation and formation of superoxide. In a previous study, we revealed that inhibition of superoxide production in the nucleus tractus solitarii (NTS) reduces blood pressure. Caffeine displays significant antioxidant ability in protecting membranes against oxidative damage and can lower the risk of insulin resistance. However, the mechanism through which caffeine improves fructose-induced insulin resistance is unclear. The aim of this study was to investigate whether caffeine consumption can abolish superoxide generation to enhance insulin signaling in the NTS, thereby reducing blood pressure in rats with fructose-induced hypertension. Treatment with caffeine for 4 weeks decreased blood pressure, serum fasting glucose, insulin, homeostatic model assessment-insulin resistance, and triglyceride levels and increased the serum direct high-density lipoprotein level in fructose-fed rats but not in control rats. Caffeine treatment resulted in the recovery of fructose-induced decrease in nitric oxide production in the NTS. Immunoblotting and immunofluorescence analyses further showed that caffeine reduced the fructose-induced phosphorylation of insulin receptor substrate 1 (IRS1(S307)) and reversed Akt(S473) and neuronal nitric oxide synthase phosphorylation. Similarly, caffeine was able to improve insulin sensitivity and decrease insulin levels in the NTS evoked by fructose. Caffeine intake also reduced the production of superoxide and expression of receptor of advanced glycation end product in the NTS. These results suggest that caffeine may enhance insulin receptor substrate 1-phosphatidylinositol 3-kinase-Akt-neuronal nitric oxide synthase signaling to decrease blood pressure by abolishing superoxide production in the NTS.

  8. Higher Fetal Insulin Resistance in Chinese Pregnant Women with Gestational Diabetes Mellitus and Correlation with Maternal Insulin Resistance

    PubMed Central

    Wang, Qiuwei; Huang, Ruiping; Yu, Bin; Cao, Fang; Wang, Huiyan; Zhang, Ming; Wang, Xinhong; Zhang, Bin; Zhou, Hong; Zhu, Ziqiang

    2013-01-01

    Objective The aim of this study was to determine the effect of gestational diabetes mellitus (GDM) on fetal insulin resistance or β-cell function in Chinese pregnant women with GDM. Measurements Maternal fasting blood and venous cord blood samples (reflecting fetal condition) were collected in 65 well-controlled Chinese GDM mothers (only given dietary intervention) and 83 control subjects. The insulin, glucose and proinsulin concentrations of both maternal and cord blood samples were measured, and the homeostasis model assessment of insulin resistance (HOMA-IR) and the proinsulin-to-insulin ratios (an indicator of fetal β-cell function) were calculated in maternal and cord blood respectively. Results Both maternal and fetal levels of insulin, proinsulin and HOMA-IR but not proinsulin-to-insulin ratios were significantly higher in the GDM group than in the control group (maternal insulin, 24.8 vs. 15.4 µU/mL, P = 0.004, proinsulin, 23.3 vs. 16.2 pmol/L, P = 0.005, and HOMA-IR, 5.5 vs. 3.5, P = 0.041, respectively; fetal: insulin, 15.1 vs. 7.9 µU/mL, P<0.001, proinsulin, 25.8 vs. 15.1 pmol/L, P = 0.015, and HOMA-IR, 2.8 vs. 1.4, P = 0.017, respectively). Fetal HOMA-IR but not proinsulin-to-insulin ratios was significantly correlated to maternal HOMA-IR (r = 0.307, P = 0.019), in the pregnant women with GDM. Conclusions Fetal insulin resistance was higher in Chinese pregnant women with GDM than control subjects, and correlated with maternal insulin resistance. PMID:23560057

  9. Insulin resistance: Is it time for primary prevention?

    PubMed

    Mercurio, Valentina; Carlomagno, Guido; Fazio, Valeria; Fazio, Serafino

    2012-01-26

    Insulin resistance is a clinical condition characterized by a decrease in sensitivity and responsiveness to the metabolic actions of insulin, so that a given concentration of insulin produces a less-than-expected biological effect. As a result, higher levels of insulin are needed to maintain normal glucose tolerance. Hyperinsulinemia, indeed, is one of the principal characteristics of insulin resistance states. This feature is common in several pathologic conditions, such as type 2 diabetes, obesity, and dyslipidemia, and it is also a prominent component of hypertension, coronary heart disease, and atherosclerosis. The presence of endothelial dysfunction, related to insulin resistance, plays a key role in the development and progression of atherosclerosis in all of these disorders. Insulin resistance represents the earliest detectable abnormality in type 2 diabetes, and is one of the major underlying mechanisms of hypertension and cardiovascular diseases. Its early detection could be of great importance, in order to set a therapeutic attack and to counteract the higher risk of diabetes and cardiovascular diseases.

  10. Insulin resistance: The linchpin between prediabetes and cardiovascular disease.

    PubMed

    Salazar, Martin R; Carbajal, Horacio A; Espeche, Walter G; Aizpurúa, Marcelo; Leiva Sisnieguez, Carlos E; Leiva Sisnieguez, Betty C; Stavile, Rodolfo N; March, Carlos E; Reaven, Gerald M

    2016-03-01

    The aim of this study was to test the hypothesis that cardiovascular disease occurs to the greatest extent in persons with prediabetes mellitus who are also insulin resistant. In 2003, 664 non-diabetic women (n = 457) and men (n = 207), aged 52 ± 16 and 53 ± 15 years, were surveyed during a programme for cardiovascular disease prevention. Fasting plasma glucose concentrations defined participants as having normal fasting plasma glucose (fasting plasma glucose <5.6 mmol/L) or prediabetes mellitus (fasting plasma glucose ⩾ 5.6 and <7.0 mmol/L). The tertile of prediabetes mellitus subjects with the highest fasting plasma insulin concentration was classified as insulin resistant. Baseline cardiovascular disease risk factors were accentuated in prediabetes mellitus versus normal fasting glucose, particularly in prediabetes mellitus/insulin resistant. In 2012, 86% of the sample were surveyed again, and the crude incidence for cardiovascular disease was higher in subjects with prediabetes mellitus versus normal fasting glucose (13.7 vs 6.0/100 persons/10 years; age- and sex-adjusted hazard ratio = 1.88, p = 0.052). In prediabetes mellitus, the crude incidences were 22.9 versus 9.6/100 persons/10 years in insulin resistant versus non-insulin resistant persons (age- and sex-adjusted hazard ratio = 2.36, p = 0.040). In conclusion, cardiovascular disease risk was accentuated in prediabetes mellitus/insulin resistant individuals, with a relative risk approximately twice as high compared to prediabetes mellitus/non-insulin resistant subjects.

  11. 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.

  12. Crif1 Deficiency Reduces Adipose OXPHOS Capacity and Triggers Inflammation and Insulin Resistance in Mice

    PubMed Central

    Ryu, Min Jeong; Kim, Soung Jung; Kim, Yong Kyung; Choi, Min Jeong; Tadi, Surendar; Lee, Min Hee; Lee, Seong Eun; Chung, Hyo Kyun; Jung, Saet Byel; Kim, Hyun-Jin; Jo, Young Suk; Kim, Koon Soon; Lee, Sang-Hee; Kim, Jin Man; Kweon, Gi Ryang; Park, Ki Cheol; Lee, Jung Uee; Kong, Young Yun; Lee, Chul-Ho; Chung, Jongkyeong; Shong, Minho

    2013-01-01

    Impaired mitochondrial oxidative phosphorylation (OXPHOS) has been proposed as an etiological mechanism underlying insulin resistance. However, the initiating organ of OXPHOS dysfunction during the development of systemic insulin resistance has yet to be identified. To determine whether adipose OXPHOS deficiency plays an etiological role in systemic insulin resistance, the metabolic phenotype of mice with OXPHOS–deficient adipose tissue was examined. Crif1 is a protein required for the intramitochondrial production of mtDNA–encoded OXPHOS subunits; therefore, Crif1 haploinsufficient deficiency in mice results in a mild, but specific, failure of OXPHOS capacity in vivo. Although adipose-specific Crif1-haploinsufficient mice showed normal growth and development, they became insulin-resistant. Crif1-silenced adipocytes showed higher expression of chemokines, the expression of which is dependent upon stress kinases and antioxidant. Accordingly, examination of adipose tissue from Crif1-haploinsufficient mice revealed increased secretion of MCP1 and TNFα, as well as marked infiltration by macrophages. These findings indicate that the OXPHOS status of adipose tissue determines its metabolic and inflammatory responses, and may cause systemic inflammation and insulin resistance. PMID:23516375

  13. Impairment of GLP1-induced insulin secretion: role of genetic background, insulin resistance and hyperglycaemia.

    PubMed

    Herzberg-Schäfer, S; Heni, M; Stefan, N; Häring, H-U; Fritsche, A

    2012-10-01

    One major risk factor of type 2 diabetes is the impairment of glucose-induced insulin secretion which is mediated by the individual genetic background and environmental factors. In addition to impairment of glucose-induced insulin secretion, impaired glucagon-like peptide (GLP)1-induced insulin secretion has been identified to be present in subjects with diabetes and impaired glucose tolerance, but little is known about its fundamental mechanisms. The state of GLP1 resistance is probably an important mechanism explaining the reduced incretin effect observed in type 2 diabetes. In this review, we address methods that can be used for the measurement of insulin secretion in response to GLP1 in humans, and studies showing that specific diabetes risk genes are associated with resistance of the secretory function of the β-cell in response to GLP1 administration. Furthermore, we discuss other factors that are associated with impaired GLP1-induced insulin secretion, for example, insulin resistance. Finally, we provide evidence that hyperglycaemia per se, the genetic background and their interaction result in the development of GLP1 resistance of the β-cell. We speculate that the response or the non-response to therapy with GLP1 analogues and/or dipeptidyl peptidase-4 (DPP-IV) inhibitors is critically dependent on GLP1 resistance.

  14. The inflammatory status score including IL-6, TNF-α, osteopontin, fractalkine, MCP-1 and adiponectin underlies whole-body insulin resistance and hyperglycemia in type 2 diabetes mellitus.

    PubMed

    Daniele, G; Guardado Mendoza, R; Winnier, D; Fiorentino, T V; Pengou, Z; Cornell, J; Andreozzi, F; Jenkinson, C; Cersosimo, E; Federici, M; Tripathy, D; Folli, F

    2014-02-01

    A state of subclinical systemic inflammation is characteristically present in obesity/insulin resistance and type 2 diabetes mellitus (T2DM). The aim of the study was to develop an integrated measure of the circulating cytokines involved in the subclinical systemic inflammation and evaluate its relation with whole-body insulin sensitivity and glucose metabolism in T2DM. T2DM patients (n = 17, M/F 13/4, age = 55.0 ± 1.7 years, BMI = 33.5 ± 1.5 kg/m(2), HbA(1c) = 7.7 ± 0.3%) and normal glucose-tolerant (NGT) subjects (n = 15, M/F 7/8, age = 49.1 ± 2.5 years, BMI = 31.8 ± 1.2 kg/m(2), HbA(1c) = 5.6 ± 0.1%) were studied in a cross-sectional design. Whole-body insulin sensitivity was quantified by the euglycemic clamp. Beta-cell function [disposition index (DI)] was calculated using insulin and glucose values derived from an oral glucose tolerance test and the euglycemic clamp. Body fat mass was evaluated by dual-energy X-ray absorptiometry. Plasma cytokine [TNF-α, IL-6, MCP-1, osteopontin, fractalkine and adiponectin] values were divided into quintiles. A score ranging from 0 (lowest quintile) to 4 (highest quintile) was assigned. The inflammatory score (IS) was the sum of each cytokine score from which adiponectin score was subtracted in each study subject. Inflammatory cytokine levels were all higher in T2DM. IS was higher in T2DM as compared to NGT (10.0 ± 1.1 vs. 4.8 ± 0.8; p < 0.001). IS positively correlated with fasting plasma glucose (r = 0.638, p < 0.001), 1-h plasma glucose (r = 0.483, p = 0.005), 2-h plasma glucose (r = 0.611, p < 0.001) and HbA1c (r = 0.469, p = 0.007). IS was inversely correlated with insulin sensitivity (r = -0.478, p = 0.006) and DI (r = -0.523, p = 0.002). IS did not correlate with BMI and body fat mass. IS was an independent predictor of fasting plasma glucose and had a high sensibility and sensitivity to predict insulin resistance (M/I < 4). A state of subclinical inflammation defined and quantifiable by inflammatory score

  15. RELATIONSHIP OF SERUM RESISTIN WITH INSULIN RESISTANCE AND OBESITY.

    PubMed

    Zaidi, Syeda Ijlal Zehra; Shirwany, Tanvir Ali Khan

    2015-01-01

    Adipokines have been implicated in the modulation of insulin sensitivity and glucose tolerance and have thus gained importance in the study of Type 2 diabetes mellitus (T2DM). Resistin, a unique signalling molecule, is being proposed as a significant factor in the pathogenesis of obesity-related insulin resistance. However, its relevance to human diabetes mellitus remains uncertain and controversial. This study was therefore planned to compare and correlate the potential role of resistin in obese patients with T2DM and obese non-diabetic controls and also to evaluate the correlation between resistin and marker of obesity and glycaemic parameters. Fasting serum resistin, glucose and insulin were measured in forty obese diabetics (mean±SD BMI 35±5 kg/m2) and forty obese non-diabetics (mean±SD BMI 33±3 kg/m2). Insulin resistance was assessed using the HOMA-IR formula derived from fasting insulin and glucose levels. Serum resistin levels (38±8 ng/ml) were significantly higher in type 2 diabetic patients as compared with the controls. Fasting blood glucose (164±46 mg/dl), serum insulin (37±7 µU/ml) and insulin resistance (19±8), were considerably higher among the studied diabetics than in the controls. Pearson's correlation analysis revealed positive correlation between serum resistin and BMI (p=0.001) and HOMA-IR (p=0.561) in diabetic subjects. Similarly, a correlation also existed between serum resistin and BMI (p=0.016) and HOMA-IR (p=0.307) in control obese subjects. However, it was highly significant in diabetics as compared to non-diabetic controls. A significant BMI-dependent association exists between resistin and insulin resistance in patients with T2DM. It appears that resistin may play a role in the pathogenesis of obesity and insulin resistance and that both of these may contribute to the development of T2DM.

  16. Insulin resistance: an emerging link in Alzheimer's disease.

    PubMed

    Medhi, Bikash; Chakrabarty, Mrinmoy

    2013-10-01

    Relentless progression of Alzheimer's disease (AD) poses a grave situation for the biomedical community to tackle. Agents starting as hot favorites in clinical trials have failed in later stages and it is time we reconsidered our approaches to intervene the disease. Quite some interesting work in the last decade has introduced a new school of thought which factors in neuronal glycemic imbalance as a major component for the development of AD. Insulin resistance in the brain has brought forward subsequent sequelae which might work towards amyloid accretion and/or tau hyperphosphorylation. It is also pointed out that insulin works by distributing iron to neuronal tissue and an insulin resistant state throws it off gear leading to iron overloading of neurons which is ultimately detrimental. A relatively recent investigation finds the role of c-Jun-N-terminal kinase (JNK3) in AD which also seems to bear a link with insulin resistance.

  17. Role of nutrition in preventing insulin resistance in children.

    PubMed

    Blasetti, Annalisa; Franchini, Simone; Comegna, Laura; Prezioso, Giovanni; Chiarelli, Francesco

    2016-03-01

    Nutrition during prenatal, early postnatal and pubertal period is crucial for the development of insulin resistance and its consequences. During prenatal period fetal environment and nutrition seems to interfere with metabolism programming later in life. The type of dietary carbohydrates, glycemic index, protein, fat and micronutrient content in maternal nutrition could influence insulin sensitivity in the newborn. The effects of lactation on metabolism and nutritional behavior later in life have been studied. Dietary habits and quality of diet during puberty could prevent the onset of a pathological insulin resistance through an adequate distribution of macro- and micronutrients, a diet rich in fibers and vegetables and poor in saturated fats, proteins and sugars. We want to overview the latest evidences on the risk of insulin resistance later in life due to both nutritional behaviors and components during the aforementioned periods of life, following a chronological outline from fetal development to adolescence.

  18. Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance.

    PubMed

    Yang, Xiaoyong; Ongusaha, Pat P; Miles, Philip D; Havstad, Joyce C; Zhang, Fengxue; So, W Venus; Kudlow, Jeffrey E; Michell, Robert H; Olefsky, Jerrold M; Field, Seth J; Evans, Ronald M

    2008-02-21

    Glucose flux through the hexosamine biosynthetic pathway leads to the post-translational modification of cytoplasmic and nuclear proteins by O-linked beta-N-acetylglucosamine (O-GlcNAc). This tandem system serves as a nutrient sensor to couple systemic metabolic status to cellular regulation of signal transduction, transcription, and protein degradation. Here we show that O-GlcNAc transferase (OGT) harbours a previously unrecognized type of phosphoinositide-binding domain. After induction with insulin, phosphatidylinositol 3,4,5-trisphosphate recruits OGT from the nucleus to the plasma membrane, where the enzyme catalyses dynamic modification of the insulin signalling pathway by O-GlcNAc. This results in the alteration in phosphorylation of key signalling molecules and the attenuation of insulin signal transduction. Hepatic overexpression of OGT impairs the expression of insulin-responsive genes and causes insulin resistance and dyslipidaemia. These findings identify a molecular mechanism by which nutritional cues regulate insulin signalling through O-GlcNAc, and underscore the contribution of this modification to the aetiology of insulin resistance and type 2 diabetes.

  19. HSP72 protects against obesity-induced insulin resistance.

    PubMed

    Chung, Jason; Nguyen, Anh-Khoi; Henstridge, Darren C; Holmes, Anna G; Chan, M H Stanley; Mesa, Jose L; Lancaster, Graeme I; Southgate, Robert J; Bruce, Clinton R; Duffy, Stephen J; Horvath, Ibolya; Mestril, Ruben; Watt, Matthew J; Hooper, Philip L; Kingwell, Bronwyn A; Vigh, Laszlo; Hevener, Andrea; Febbraio, Mark A

    2008-02-05

    Patients with type 2 diabetes have reduced gene expression of heat shock protein (HSP) 72, which correlates with reduced insulin sensitivity. Heat therapy, which activates HSP72, improves clinical parameters in these patients. Activation of several inflammatory signaling proteins such as c-jun amino terminal kinase (JNK), inhibitor of kappaB kinase, and tumor necrosis factor-alpha, can induce insulin resistance, but HSP 72 can block the induction of these molecules in vitro. Accordingly, we examined whether activation of HSP72 can protect against the development of insulin resistance. First, we show that obese, insulin resistant humans have reduced HSP72 protein expression and increased JNK phosphorylation in skeletal muscle. We next used heat shock therapy, transgenic overexpression, and pharmacologic means to overexpress HSP72 either specifically in skeletal muscle or globally in mice. Herein, we show that regardless of the means used to achieve an elevation in HSP72 protein, protection against diet- or obesity-induced hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance was observed. This protection was tightly associated with the prevention of JNK phosphorylation. These findings identify an essential role for HSP72 in blocking inflammation and preventing insulin resistance in the context of genetic obesity or high-fat feeding.

  20. Rhus coriaria ameliorates insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM) rats.

    PubMed

    Anwer, Tarique; Sharma, Manju; Khan, Gyas; Iqbal, Muzaffar; Ali, Mohammad Sajid; Alam, Mohammad Sarfaraz; Safhi, Mohammed Mohsen; Gupta, Nakul

    2013-01-01

    We have investigated the effect of methanolic extract of Rhus coriaria (RC) on hyperinsulinemia, glucose intolerance and insulin sensitivity in non-insulin-dependent diabetes mellitus (NIDDM) rats. NIDDM was induced by single intraperitoneal injection of streptozotocin (STZ, 100 mg/kg) to 2 days old rat pups. RC (200 mg/kg and 400 mg/kg) was administered orally once a day for 5 weeks after the animals were confirmed diabetic (i.e, 90 days after STZ injection). A group of citrate control rats were also maintained which has received citrate buffer on the 2nd day of their birth. There was a significant increase in blood glucose, glycosylated hemoglobin (HbA1c) and serum insulin levels were observed in NIDDM control rats. Treatment with RC reduced the elevated levels of blood glucose, HbA1c and insulin in the NIDDM rats. An oral glucose tolerance test (OGTT) was also performed in the same groups, in which we found a significant improvement in glucose tolerance in the rats treated with RC. The insulin sensitivity was assessed for both peripheral insulin resistance and hepatic insulin resistance. RC treatment significantly improved insulin sensitivity index (K(ITT)) which was significantly decreased in NIDDM control rats. There was significant rise in homeostasis model assessment of insulin resistance (HOMA-R) in NIDDM control rats whereas RC treatment significantly prevented the rise in HOMA-R in NIDDM treated rats. Our data suggest that methanolic extract of RC significantly delayed the onset of hyperinsulinemia and glucose intolerance and improved insulin sensitivity in NIDDM rats.

  1. 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.

  2. The impact of marijuana use on glucose, insulin, and insulin resistance among US adults.

    PubMed

    Penner, Elizabeth A; Buettner, Hannah; Mittleman, Murray A

    2013-07-01

    There are limited data regarding the relationship between cannabinoids and metabolic processes. Epidemiologic studies have found lower prevalence rates of obesity and diabetes mellitus in marijuana users compared with people who have never used marijuana, suggesting a relationship between cannabinoids and peripheral metabolic processes. To date, no study has investigated the relationship between marijuana use and fasting insulin, glucose, and insulin resistance. We included 4657 adult men and women from the National Health and Nutrition Examination Survey from 2005 to 2010. Marijuana use was assessed by self-report in a private room. Fasting insulin and glucose were measured via blood samples after a 9-hour fast, and homeostasis model assessment of insulin resistance (HOMA-IR) was calculated to evaluate insulin resistance. Associations were estimated using multiple linear regression, accounting for survey design and adjusting for potential confounders. Of the participants in our study sample, 579 were current marijuana users and 1975 were past users. In multivariable adjusted models, current marijuana use was associated with 16% lower fasting insulin levels (95% confidence interval [CI], -26, -6) and 17% lower HOMA-IR (95% CI, -27, -6). We found significant associations between marijuana use and smaller waist circumferences. Among current users, we found no significant dose-response. We found that marijuana use was associated with lower levels of fasting insulin and HOMA-IR, and smaller waist circumference. Copyright © 2013 Elsevier Inc. All rights reserved.

  3. Adropin deficiency is associated with increased adiposity and insulin resistance.

    PubMed

    Ganesh Kumar, K; Zhang, Jingying; Gao, Su; Rossi, Jari; McGuinness, Owen P; Halem, Heather H; Culler, Michael D; Mynatt, Randall L; Butler, Andrew A

    2012-07-01

    Adropin is a secreted peptide that improves hepatic steatosis and glucose homeostasis when administered to diet-induced obese mice. It is not clear if adropin is a peptide hormone regulated by signals of metabolic state. Moreover, the significance of a decline in adropin expression with obesity with respect to metabolic disease is also not clear. We investigated the regulation of serum adropin by metabolic status and diet. Serum adropin levels were high in chow-fed conditions and were suppressed by fasting and diet-induced obesity (DIO). High adropin levels were observed in mice fed a high-fat low carbohydrate diet, whereas lower levels were observed in mice fed a low-fat high carbohydrate diet. To investigate the role of adropin deficiency in metabolic homeostasis, we generated adropin knockout mice (AdrKO) on the C57BL/6J background. AdrKO displayed a 50%-increase in increase in adiposity, although food intake and energy expenditure were normal. AdrKO also exhibited dyslipidemia and impaired suppression of endogenous glucose production (EndoR(a)) in hyperinsulinemic-euglycemic clamp conditions, suggesting insulin resistance. While homo- and heterozygous carriers of the null adropin allele exhibited normal DIO relative to controls, impaired glucose tolerance associated with weight gain was more severe in both groups. In summary, adropin is a peptide hormone regulated by fasting and feeding. In fed conditions, adropin levels are regulated dietary macronutrients, and increase with dietary fat content. Adropin is not required for regulating food intake, however, its functions impact on adiposity and are involved in preventing insulin resistance, dyslipidemia, and impaired glucose tolerance.

  4. Adropin Deficiency Is Associated With Increased Adiposity and Insulin Resistance

    PubMed Central

    Kumar, K. Ganesh; Zhang, Jingying; Gao, Su; Rossi, Jari; McGuinness, Owen P.; Halem, Heather H.; Culler, Michael D.; Mynatt, Randall L.; Butler, Andrew A.

    2014-01-01

    Adropin is a secreted peptide that improves hepatic steatosis and glucose homeostasis when administered to diet-induced obese mice. It is not clear if adropin is a peptide hormone regulated by signals of metabolic state. Moreover, the significance of a decline in adropin expression with obesity with respect to metabolic disease is also not clear. We investigated the regulation of serum adropin by metabolic status and diet. Serum adropin levels were high in chow-fed conditions and were suppressed by fasting and diet-induced obesity (DIO). High adropin levels were observed in mice fed a high-fat low carbohydrate diet, whereas lower levels were observed in mice fed a low-fat high carbohydrate diet. To investigate the role of adropin deficiency in metabolic homeostasis, we generated adropin knockout mice (AdrKO) on the C57BL/6J background. AdrKO displayed a 50%-increase in increase in adiposity, although food intake and energy expenditure were normal. AdrKO also exhibited dyslipidemia and impaired suppression of endogenous glucose production (EndoRa) in hyperinsulinemic–euglycemic clamp conditions, suggesting insulin resistance. While homo- and heterozygous carriers of the null adropin allele exhibited normal DIO relative to controls, impaired glucose tolerance associated with weight gain was more severe in both groups. In summary, adropin is a peptide hormone regulated by fasting and feeding. In fed conditions, adropin levels are regulated dietary macronutrients, and increase with dietary fat content. Adropin is not required for regulating food intake, however, its functions impact on adiposity and are involved in preventing insulin resistance, dyslipidemia, and impaired glucose tolerance. PMID:22318315

  5. Physical inactivity and obesity underlie the insulin resistance of aging.

    PubMed

    Amati, Francesca; Dubé, John J; Coen, Paul M; Stefanovic-Racic, Maja; Toledo, Frederico G S; Goodpaster, Bret H

    2009-08-01

    OBJECTIVE Age-associated insulin resistance may underlie the higher prevalence of type 2 diabetes in older adults. We examined a corollary hypothesis that obesity and level of chronic physical inactivity are the true causes for this ostensible effect of aging on insulin resistance. RESEARCH DESIGN AND METHODS We compared insulin sensitivity in 7 younger endurance-trained athletes, 12 older athletes, 11 younger normal-weight subjects, 10 older normal-weight subjects, 15 younger obese subjects, and 15 older obese subjects using a glucose clamp. The nonathletes were sedentary. RESULTS Insulin sensitivity was not different in younger endurance-trained athletes versus older athletes, in younger normal-weight subjects versus older normal-weight subjects, or in younger obese subjects versus older obese subjects. Regardless of age, athletes were more insulin sensitive than normal-weight sedentary subjects, who in turn were more insulin sensitive than obese subjects. CONCLUSIONS Insulin resistance may not be characteristic of aging but rather associated with obesity and physical inactivity.

  6. Mechanisms involved in cholesterol-induced neuronal insulin resistance.

    PubMed

    Taghibiglou, Changiz; Bradley, Clarrisa A; Gaertner, Tara; Li, Yuping; Wang, Yushan; Wang, Yu Tian

    2009-09-01

    Insulin receptors (IRs) are highly expressed in the central nervous system (CNS) and play an important role in normal brain functions, such as learning and memory. Due to the increasing rate of obesity in western societies and overall high fat diets, the incidents of neuronal insulin resistance is also on the rise, but the underlying mechanism is still poorly characterized. We found that cholesterol treatment produces robust insulin signaling resistance that is characterized by the marked reduction in insulin-stimulated tyrosine phosphorylation of the IR and its downstream targets insulin receptor substrate 1 (IRS1) and 2 (IRS2). Surface expression of IRs was also decreased and was correlated with an increase in facilitated receptor endocytosis. Membrane fractionation showed that after cholesterol treatment, the proportion of IRs localized in the lipid raft increased and correspondingly there was a reduction of IRs in the non-raft membrane. Interestingly, we found that IRs in the lipid rafts, unlike their counterparts in the non-raft membrane domain, were essentially unresponsive to insulin stimulation and that a high level of tyrosine phosphatase activity was associated with these raft fractions. Our results suggest that the lipid raft microdomain of the neuronal plasma membrane has a strong influence on IR signaling, and that incorporation of high levels of cholesterol may reduce IR signaling by increasing their representation in lipid rafts. The trapping of the IR in the lipid raft domain may result in its inactivation and promote its endocytosis: effects that could contribute to neuronal insulin resistance in obesity.

  7. The insulin resistance syndrome: mechanisms of clustering of cardiovascular risk.

    PubMed

    Chan, Juliana C N; Tong, Peter C Y; Critchley, Julian A J H

    2002-02-01

    For more than a decade, insulin resistance has been proposed as the key linking factor for the metabolic syndrome disease cluster of glucose intolerance, hypertension, dyslipidemia, obesity, and cardiovascular disease. Although most of the epidemiological, experimental, and clinical evidence still support the role of insulin resistance as an important component of this multifaceted syndrome, there is evidence amassing that a neurohormonal mechanism, including an endocrine role for adipocytes, probably plays a more fundamental role. This is supported by the strong associations between obesity, especially central adiposity, and all components of the metabolic syndrome, in contrast to the inconsistent relationships between blood pressure and markers of insulin resistance. However, much of the effect of visceral fat on cardiovascular risk factors is mediated through the metabolic actions of free fatty acids (FFA) on insulin resistance, thus resolving any obesity versus insulin resistance controversy. In addition to the roles of obesity and FFA in the development of insulin resistance syndrome, the high prevalence rates of this disease cluster among subjects from low socioeconomic groups as well as from developing countries have led to alternative hypotheses to better our understanding of the contributory roles of socioeconomic, in utero, and genetic factors in this syndrome. More recently, the pathogenetic roles of iron overload and liver dysfunction have also been re-examined. In this article, the various hypotheses which have been put forward to explain the diverse clinical manifestations of the metabolic or insulin resistance syndrome are summarized and put into perspective. While there is clinical and experimental evidence to support many of these independent pathways, alternative statistical methods such as factor analysis or structural equation modeling may be needed to unravel the complex nature of these interacting pathways. Finally, these hypotheses, if proven

  8. The Impact of Resveratrol Supplementation on Blood Glucose, Insulin, Insulin Resistance, Triglyceride, and Periodontal Markers in Type 2 Diabetic Patients with Chronic Periodontitis.

    PubMed

    Zare Javid, Ahmad; Hormoznejad, Razie; Yousefimanesh, Hojat Allah; Zakerkish, Mehrnoosh; Haghighi-Zadeh, Mohammad Hosein; Dehghan, Parvin; Ravanbakhsh, Maryam

    2017-01-01

    The aim of this study was to investigate the impact of resveratrol supplementation along with non-surgical periodontal treatment on blood glucose, insulin, insulin resistance, triglyceride (TG), and periodontal markers in patients with type 2 diabetes with periodontal disease. In this double-blind clinical trial study, 43 patients with diabetes with chronic periodontitis were participated. Subjects were randomly allocated to intervention and control groups. The intervention and control groups received either 480 mg/day of resveratrol or placebo capsules (two pills) for 4 weeks. Fasting blood glucose, insulin, insulin resistance (homeostasis model assessment of insulin resistance), TGs, and pocket depth were measured in all subjects' pre-intervention and post-intervention. The mean serum levels of fasting insulin and insulin resistance (homeostasis model assessment of insulin resistance) were significantly lower in the intervention group compared with control group (10.42 ± 0.28 and 10.92 ± 0.9; 3.66 ± 0.97 and 4.49 ± 1.56, respectively). There was a significant difference in the mean pocket depth between intervention and control groups (2.35 ± 0.6 and 3.38 ± 0.5, respectively) following intervention. No significant differences were observed in the mean levels of fasting blood glucose and TGs between two groups' post-intervention. It is recommended that resveratrol supplementation may be beneficial as adjuvant therapy along with non-surgical periodontal treatment in insulin resistance and improving periodontal status among patients with diabetes with periodontal disease. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  9. Hyperglycemia- and hyperinsulinemia-induced insulin resistance causes alterations in cellular bioenergetics and activation of inflammatory signaling in lymphatic muscle.

    PubMed

    Lee, Yang; Fluckey, James D; Chakraborty, Sanjukta; Muthuchamy, Mariappan

    2017-07-01

    Insulin resistance is a well-known risk factor for obesity, metabolic syndrome (MetSyn) and associated cardiovascular diseases, but its mechanisms are undefined in the lymphatics. Mesenteric lymphatic vessels from MetSyn or LPS-injected rats exhibited impaired intrinsic contractile activity and associated inflammatory changes. Hence, we hypothesized that insulin resistance in lymphatic muscle cells (LMCs) affects cell bioenergetics and signaling pathways that consequently alter contractility. LMCs were treated with different concentrations of insulin or glucose or both at various time points to determine insulin resistance. Onset of insulin resistance significantly impaired glucose uptake, mitochondrial function, oxygen consumption rates, glycolysis, lactic acid, and ATP production in LMCs. Hyperglycemia and hyperinsulinemia also impaired the PI3K/Akt while enhancing the ERK/p38MAPK/JNK pathways in LMCs. Increased NF-κB nuclear translocation and macrophage chemoattractant protein-1 and VCAM-1 levels in insulin-resistant LMCs indicated activation of inflammatory mechanisms. In addition, increased phosphorylation of myosin light chain-20, a key regulator of lymphatic muscle contraction, was observed in insulin-resistant LMCs. Therefore, our data elucidate the mechanisms of insulin resistance in LMCs and provide the first evidence that hyperglycemia and hyperinsulinemia promote insulin resistance and impair lymphatic contractile status by reducing glucose uptake, altering cellular metabolic pathways, and activating inflammatory signaling cascades.-Lee, Y., Fluckey, J. D., Chakraborty, S., Muthuchamy, M. Hyperglycemia- and hyperinsulinemia-induced insulin resistance causes alterations in cellular bioenergetics and activation of inflammatory signaling in lymphatic muscle. © FASEB.

  10. Evolutionary origins of insulin resistance: a behavioral switch hypothesis

    PubMed Central

    Watve, Milind G; Yajnik, Chittaranjan S

    2007-01-01

    Background Insulin resistance, which can lead to a number of diseases including type 2 diabetes and coronary heart disease, is believed to have evolved as an adaptation to periodic starvation. The "thrifty gene" and "thrifty phenotype" hypotheses constitute the dominant paradigm for over four decades. With an increasing understanding of the diverse effects of impairment of the insulin signaling pathway, the existing hypotheses are proving inadequate. Presentation of the hypothesis We propose a hypothesis that insulin resistance is a socio-ecological adaptation that mediates two phenotypic transitions, (i) a transition in reproductive strategy from "r" (large number of offspring with little investment in each) to "K" (smaller number of offspring with more investment in each) and (ii) a transition from "stronger to smarter" or "soldier to diplomat" i.e. from relatively more muscle dependent to brain dependent lifestyle. A common switch could have evolved for the two transitions since the appropriate environmental conditions for the two transitions are highly overlapping and interacting. Testing the hypothesis Gestational insulin resistance diverts more energy through the placenta, resulting in increased investment per offspring. On the other hand, insulin resistance is associated with reduced ovulation. The insulin signaling pathway is also related to longevity. Insulin resistance diverts more nutrients to the brain as compared to muscle. Also, hyperinsulinemia has direct positive effects on cognitive functions of the brain. The hypothesis gets support from known patterns in human clinical data and recent research on the molecular interactions in the insulin signaling pathway. Further we state many predictions of the hypothesis that can be tested experimentally or epidemiologically. Implications of the hypothesis The hypothesis can bring about a significant change in the line of treatment as well as public health policies for the control of metabolic syndrome. PMID

  11. Glycation and insulin resistance: novel mechanisms and unique targets?

    PubMed

    Song, Fei; Schmidt, Ann Marie

    2012-08-01

    Multiple biochemical, metabolic, and signal transduction pathways contribute to insulin resistance. In this review, we present evidence that the posttranslational process of protein glycation may play a role in insulin resistance. The posttranslational modifications, the advanced glycation end products (AGEs), are formed and accumulated by endogenous and exogenous mechanisms. AGEs may contribute to insulin resistance by a variety of mechanisms, including generation of tumor necrosis factor-α direct modification of the insulin molecule, thereby leading to its impaired action, generation of oxidative stress, and impairment of mitochondrial function, as examples. AGEs may stimulate signal transduction via engagement of cellular receptors, such as receptor for AGEs. AGE-receptor for AGE interaction perpetuates AGE formation and cellular stress via induction of inflammation, oxidative stress, and reduction in the expression and activity of the enzyme glyoxalase I that detoxifies the AGE precursor, methylglyoxal. Once set in motion, glycation-promoting mechanisms may stimulate ongoing AGE production and target tissue stresses that reduce insulin responsiveness. Strategies to limit AGE accumulation and action may contribute to the prevention of insulin resistance and its consequences.

  12. Serum Insulin, Glucose, Indices of Insulin Resistance, and Risk of Prostate Cancer

    PubMed Central

    Weinstein, Stephanie J.; Wright, Margaret E.; Männistö, Satu; Limburg, Paul J.; Snyder, Kirk; Virtamo, Jarmo

    2009-01-01

    Background The mitogenic and growth-stimulatory effects of insulin-like growth factors appear to play a role in prostate carcinogenesis, yet any direct association of circulating insulin levels and risk of prostate cancer remains unclear. Methods We investigated the relationship of the level of serum insulin, glucose, and surrogate indices of insulin resistance (ie, the molar ratio of insulin to glucose and the homeostasis model assessment of insulin resistance [HOMA-IR]) to the development of prostate cancer in a case–cohort study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort of Finnish men. We studied 100 case subjects with incident prostate cancer and 400 noncase subjects without prostate cancer from the larger cohort. Fasting serum was collected 5–12 years before diagnosis. We determined insulin concentrations with a double-antibody immunochemiluminometric assay and glucose concentrations with a hexokinase assay. Multivariable logistic regression models estimated relative risks as odds ratios (ORs), and all statistical tests were two-sided. Results Insulin concentrations in fasting serum that was collected on average 9.2 years before diagnosis among case subjects were 8% higher than among noncase subjects, and the molar ratio of insulin to glucose and HOMA-IR were 10% and 6% higher, respectively, but these differences were not statistically significant. Among subjects in the second through fourth insulin quartiles, compared with those in the first quartile, increased insulin levels were associated with statistically significantly increased risks of prostate cancer (OR = 1.50, 95% confidence interval [CI] = 0.75 to 3.03; OR = 1.75, 95% CI = 0.86 to 3.56; and OR = 2.55, 95% CI = 1.18 to 5.51; for the second through fourth insulin quartiles, respectively; Ptrend = .02). A similar pattern was observed with the HOMA-IR (OR = 2.10, 95% CI = 1.03 to 4.26; Ptrend = .02) for the highest vs lowest quartiles. Risk varied inconsistently with

  13. Serum insulin, glucose, indices of insulin resistance, and risk of prostate cancer.

    PubMed

    Albanes, Demetrius; Weinstein, Stephanie J; Wright, Margaret E; Männistö, Satu; Limburg, Paul J; Snyder, Kirk; Virtamo, Jarmo

    2009-09-16

    The mitogenic and growth-stimulatory effects of insulin-like growth factors appear to play a role in prostate carcinogenesis, yet any direct association of circulating insulin levels and risk of prostate cancer remains unclear. We investigated the relationship of the level of serum insulin, glucose, and surrogate indices of insulin resistance (ie, the molar ratio of insulin to glucose and the homeostasis model assessment of insulin resistance [HOMA-IR]) to the development of prostate cancer in a case-cohort study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort of Finnish men. We studied 100 case subjects with incident prostate cancer and 400 noncase subjects without prostate cancer from the larger cohort. Fasting serum was collected 5-12 years before diagnosis. We determined insulin concentrations with a double-antibody immunochemiluminometric assay and glucose concentrations with a hexokinase assay. Multivariable logistic regression models estimated relative risks as odds ratios (ORs), and all statistical tests were two-sided. Insulin concentrations in fasting serum that was collected on average 9.2 years before diagnosis among case subjects were 8% higher than among noncase subjects, and the molar ratio of insulin to glucose and HOMA-IR were 10% and 6% higher, respectively, but these differences were not statistically significant. Among subjects in the second through fourth insulin quartiles, compared with those in the first quartile, increased insulin levels were associated with statistically significantly increased risks of prostate cancer (OR = 1.50, 95% confidence interval [CI] = 0.75 to 3.03; OR = 1.75, 95% CI = 0.86 to 3.56; and OR = 2.55, 95% CI = 1.18 to 5.51; for the second through fourth insulin quartiles, respectively; P(trend) = .02). A similar pattern was observed with the HOMA-IR (OR = 2.10, 95% CI = 1.03 to 4.26; P(trend) = .02) for the highest vs lowest quartiles. Risk varied inconsistently with glucose concentration (P

  14. Peripheral Insulin Resistance and Impaired Insulin Signaling Contribute to Abnormal Glucose Metabolism in Preterm Baboons

    PubMed Central

    McGill-Vargas, Lisa L.; Gastaldelli, Amalia; Seidner, Steven R.; McCurnin, Donald C.; Leland, Michelle M.; Anzueto, Diana G.; Johnson, Marney C.; Liang, Hanyu; DeFronzo, Ralph A.; Musi, Nicolas

    2015-01-01

    Premature infants develop hyperglycemia shortly after birth, increasing their morbidity and death. Surviving infants have increased incidence of diabetes as young adults. Our understanding of the biological basis for the insulin resistance of prematurity and developmental regulation of glucose production remains fragmentary. The objective of this study was to examine maturational differences in insulin sensitivity and the insulin-signaling pathway in skeletal muscle and adipose tissue of 30 neonatal baboons using the euglycemic hyperinsulinemic clamp. Preterm baboons (67% gestation) had reduced peripheral insulin sensitivity shortly after birth (M value 12.5 ± 1.5 vs 21.8 ± 4.4 mg/kg · min in term baboons) and at 2 weeks of age (M value 12.8 ± 2.6 vs 16.3 ± 4.2, respectively). Insulin increased Akt phosphorylation, but these responses were significantly lower in preterm baboons during the first week of life (3.2-fold vs 9.8-fold). Preterm baboons had lower glucose transporter-1 protein content throughout the first 2 weeks of life (8%-12% of term). In preterm baboons, serum free fatty acids (FFAs) did not decrease in response to insulin, whereas FFAs decreased by greater than 80% in term baboons; the impaired suppression of FFAs in the preterm animals was paired with a decreased glucose transporter-4 protein content in adipose tissue. In conclusion, peripheral insulin resistance and impaired non-insulin-dependent glucose uptake play an important role in hyperglycemia of prematurity. Impaired insulin signaling (reduced Akt) contributes to the defect in insulin-stimulated glucose disposal. Counterregulatory hormones are not major contributors. PMID:25560831

  15. [Pharmacodyamic material basis of rhizoma coptidis on insulin resistance].

    PubMed

    Li, Jiachuan; Meng, Xianli; Fan, Xinjian; Lai, Xianrong; Zhang, Yi; Zeng, Yong

    2010-07-01

    To observe the impact of Rhizoma Coptidis (drug-chemical extract parts-components) on 3T3-L1 pre-adipocytes differentiation and adipocytes insulin resistance, and reveal the pharmacodyamic material basis of Rhizoma Coptidis on insulin resistance. 3T3-L1 pre-adipocytes were well cultured, and then induced to differentiate into fat cells by using dexamethasone, 3-isobutyl-1-methyl-xanthine and insulin together, and establish the insulin resistance model. Based on the experience of traditional medicine use, the adipocytes differentiation and the glucose consumption in the cell culture medium were observed independently. Aqueous extract, different chemical extract fraction and different alkaloid extract from the herb showed inhibitory effects on 3T3-L1 pre-adipocytes differentiation, especially the compound coptisine significantly inhibited the differentiation in the concentration of 16.5 micromol x L(-1), but non-alkaloid extract from the herb promoted cell differentiation significantly in the concentration of 6.0 micromol x L(-1). Each treatment group, especially jatrorrhizine hydrochloride (in the concentration of 10.5 micromol x L(-1)) significantly decreased the concentration of glucose in 3T3-L1 adipocytes culture, at the same time improved insulin resistance. These effects are similar to the role of rosiglitazone maleate. Rhizoma Coptidis significantly improved insulin resistance, prevented pre-adipocytes differentiation. Its efficacy may be the synergistic effect of various components. Meanwhile, its role in inhibiting differentiation of pre-adipocytes indicates that coptis to increasing glucose uptake dose not cause fat accumulation and weight increasing. This has some clinical significance in the insulin resistance and metabolic syndrome.

  16. Urinary Arsenic and Insulin Resistance in US Adolescents

    PubMed Central

    Peng, Qing; Harlow, Siobán D.; Park, Sung Kyun

    2015-01-01

    Chronic arsenic exposure has been associated with increased diabetes risk in adults. Insulin resistance (IR) has been proposed as a mechanism of arsenic-related diabetes. Although limited evidence in adults found no association between arsenic and IR, the association in adolescents is largely unknown. We examined the association between urinary arsenic and insulin resistance in US adolescents. Eight hundred thirty five adolescents aged 12-19 years, with complete data on urinary arsenic (total arsenic, inorganic arsenic and dimethylarsenic acid (DMA)), fasting glucose, insulin and key covariates were identified from the National Health and Nutrition Examination Survey (NHANES) cycles 2003/2004 through 2009/2010. Generalized additive mixed models accounting for intra-cluster correlation arising from the complex survey design were used to estimate the association between the updated Homeostasis Model Assessment (HOMA2)-IR and each type of arsenic. After adjusting for potential confounders, including urinary creatinine, sociodemographic factors, BMI, waist circumference, and arsenobetaine, arsenic exposure was not associated with HOMA2-IR. Interquartile range increases in total arsenic, inorganic arsenic and DMA were associated with 1.5% (95% CI: -2.0, 5.2), 1.1% (95% CI: -1.5, 3.8) and 0.25% (95% CI: -2.3, 2.9) increases in HOMA2-IR, respectively. In conclusion, despite arsenic's association with diabetes in adults and potential role in insulin resistance, our findings do not support the hypothesis that arsenic exposure at levels common in the US contributes to insulin resistance in adolescents. Whether higher doses and longer exposure duration are required for appreciable influence on insulin resistance, or that arsenic does not act through insulin resistance to induce diabetes needs further investigation.1 PMID:25845984

  17. Urinary arsenic and insulin resistance in US adolescents.

    PubMed

    Peng, Qing; Harlow, Siobán D; Park, Sung Kyun

    2015-06-01

    Chronic arsenic exposure has been associated with increased diabetes risk in adults. Insulin resistance (IR) has been proposed as a mechanism of arsenic-related diabetes. Although limited evidence in adults found no association between arsenic and IR, the association in adolescents is largely unknown. We examined the association between urinary arsenic and insulin resistance in US adolescents. Eight hundred thirty five adolescents aged 12-19 years, with complete data on urinary arsenic (total arsenic, inorganic arsenic and dimethylarsenic acid (DMA)), fasting glucose, insulin and key covariates were identified from the National Health and Nutrition Examination Survey (NHANES) cycles 2003/2004 through 2009/2010. Generalized additive mixed models accounting for intra-cluster correlation arising from the complex survey design were used to estimate the association between the updated Homeostasis Model Assessment (HOMA2)-IR and each type of arsenic. After adjusting for potential confounders, including urinary creatinine, sociodemographic factors, BMI, waist circumference, and arsenobetaine, arsenic exposure was not associated with HOMA2-IR. Interquartile range increases in total arsenic, inorganic arsenic and DMA were associated with 1.5% (95% CI: -2.0, 5.2), 1.1% (95% CI: -1.5, 3.8) and 0.25% (95% CI: -2.3, 2.9) increases in HOMA2-IR, respectively. In conclusion, despite arsenic's association with diabetes in adults and potential role in insulin resistance, our findings do not support the hypothesis that arsenic exposure at levels common in the US contributes to insulin resistance in adolescents. Whether higher doses and longer exposure duration are required for appreciable influence on insulin resistance, or that arsenic does not act through insulin resistance to induce diabetes needs further investigation.

  18. Gender Differences in Insulin Resistance, Body Composition, and Energy Balance

    PubMed Central

    Geer, Eliza B.; Shen, Wei

    2010-01-01

    Background Men and women differ substantially in regard to degrees of insulin resistance, body composition, and energy balance. Adipose tissue distribution, in particular the presence of elevated visceral and hepatic adiposity, plays a central role in the development of insulin resistance and obesity-related complications. Objective This review summarizes published data on gender differences in insulin resistance, body composition, and energy balance, to provide insight into novel gender-specific avenues of research as well as gender-tailored treatments of insulin resistance, visceral adiposity, and obesity. Methods English-language articles were identified from searches of the PubMed database through November 2008, and by reviewing the references cited in these reports. Searches included combinations of the following terms: gender, sex, insulin resistance, body composition, energy balance, and hepatic adipose tissue. Results For a given body mass index, men were reported to have more lean mass, women to have higher adiposity. Men were also found to have more visceral and hepatic adipose tissue, whereas women had more peripheral or subcutaneous adipose tissue. These differences, as well as differences in sex hormones and adipokines, may contribute to a more insulin-sensitive environment in women than in men. When normalized to kilograms of lean body mass, men and women had similar resting energy expenditure, but physical energy expenditure was more closely related to percent body fat in men than in women. Conclusion Greater amounts of visceral and hepatic adipose tissue, in conjunction with the lack of a possible protective effect of estrogen, may be related to higher insulin resistance in men compared with women. PMID:19318219

  19. Obstructive sleep apnea, insulin resistance, and steatohepatitis in severe obesity.

    PubMed

    Polotsky, Vsevolod Y; Patil, Susheel P; Savransky, Vladimir; Laffan, Alison; Fonti, Shannon; Frame, Leigh A; Steele, Kimberly E; Schweizter, Michael A; Clark, Jeanne M; Torbenson, Michael S; Schwartz, Alan R

    2009-02-01

    Obstructive sleep apnea is associated with insulin resistance and liver injury. It is unknown whether apnea contributes to insulin resistance and steatohepatitis in severe obesity. To examine whether sleep apnea and nocturnal hypoxemia predict the severity of insulin resistance, systemic inflammation, and steatohepatitis in severely obese individuals presenting for bariatric surgery. We performed sleep studies and measured fasting blood glucose, serum insulin, C-reactive protein, and liver enzymes in 90 consecutive severely obese individuals, 75 women and 15 men, without concomitant diabetes mellitus or preexistent diagnosis of sleep apnea or liver disease. Liver biopsies (n = 20) were obtained during bariatric surgery. Obstructive sleep apnea with a respiratory disturbance index greater than 5 events/hour was diagnosed in 81.1% of patients. The median respiratory disturbance index was 15 +/- 29 events/hour and the median oxygen desaturation during apneic events was 4.6 +/- 1.8%. All patients exhibited high serum levels of C-reactive protein, regardless of the severity of apnea, whereas liver enzymes were normal. Oxygen desaturation greater than 4.6% was associated with a 1.5-fold increase in insulin resistance, according to the homeostasis model assessment index. Histopathology data suggested that significant nocturnal desaturation might predispose to hepatic inflammation, hepatocyte ballooning, and liver fibrosis. Fasting blood glucose levels and steatosis scores were not affected by nocturnal hypoxia. There was no relationship between the respiratory disturbance index and insulin resistance or liver histopathology. Hypoxic stress of sleep apnea may be implicated in the development of insulin resistance and steatohepatitis in severe obesity.

  20. Effect of treatment of overt hypothyroidism on insulin resistance

    PubMed Central

    Nada, Aml Mohamed

    2013-01-01

    AIM: To investigate the impact of hypothyroidism and thyroxine therapy on insulin sensitivity in patients with overt hypothyroidism. METHODS: The study included twenty seven overtly hypothyroid and fifteen healthy euthyroid South Western Asian females. Both groups had matching age and body mass index. Physiological and pathological conditions as well as medications that may alter thyroid function, glucose homeostasis or serum lipids were ruled out. Serum thyrotropin (TSH), free tetraiodothyronine (FT4), free triiodothyronine (FT3), fasting insulin (FI), fasting plasma glucose (FPG), total cholesterol and triglycerides were measured before and six months after initiating thyroxine therapy for hypothyroid patients and once for the control group. Insulin resistance (IR) was estimated using homeostasis model assessment (HOMA-IR) and Body mass index (BMI) was calculated. RESULTS: Both study groups, hypothyroid patients and euthyroid control subjects, had matching age and body mass index (P-value 0.444, 0.607 respectively). No significant difference was found between the hypothyroid patients and the euthyroid control group regarding fasting plasma glucose, fasting insulin, insulin resistance, total cholesterol and triglycerides (P-values 0.432, 0.621, 0.883, 0.586, 0.05 respectively). In the hypothyroid patients, triglycerides showed direct correlation to TSH and inverse correlation to FT3. Similarly total cholesterol inversely correlated to FT3 but its direct correlation to TSH did not reach statistical significance. After thyroxine replacement and reaching an euthyroid state as confirmed by clinical and laboratory data, there was no significant change in fasting plasma glucose, insulin resistance or triglyceride level (P-value 0.216, 0.204, 0.175 respectively) while total cholesterol significantly decreased (P-value 0.043) and fasting insulin significantly increased (P-value 0.047). CONCLUSION: Hypothyroidism has no impact on insulin sensitivity. Correction of

  1. Effect of treatment of overt hypothyroidism on insulin resistance.

    PubMed

    Nada, Aml Mohamed

    2013-08-15

    To investigate the impact of hypothyroidism and thyroxine therapy on insulin sensitivity in patients with overt hypothyroidism. The study included twenty seven overtly hypothyroid and fifteen healthy euthyroid South Western Asian females. Both groups had matching age and body mass index. Physiological and pathological conditions as well as medications that may alter thyroid function, glucose homeostasis or serum lipids were ruled out. Serum thyrotropin (TSH), free tetraiodothyronine (FT4), free triiodothyronine (FT3), fasting insulin (FI), fasting plasma glucose (FPG), total cholesterol and triglycerides were measured before and six months after initiating thyroxine therapy for hypothyroid patients and once for the control group. Insulin resistance (IR) was estimated using homeostasis model assessment (HOMA-IR) and Body mass index (BMI) was calculated. Both study groups, hypothyroid patients and euthyroid control subjects, had matching age and body mass index (P-value 0.444, 0.607 respectively). No significant difference was found between the hypothyroid patients and the euthyroid control group regarding fasting plasma glucose, fasting insulin, insulin resistance, total cholesterol and triglycerides (P-values 0.432, 0.621, 0.883, 0.586, 0.05 respectively). In the hypothyroid patients, triglycerides showed direct correlation to TSH and inverse correlation to FT3. Similarly total cholesterol inversely correlated to FT3 but its direct correlation to TSH did not reach statistical significance. After thyroxine replacement and reaching an euthyroid state as confirmed by clinical and laboratory data, there was no significant change in fasting plasma glucose, insulin resistance or triglyceride level (P-value 0.216, 0.204, 0.175 respectively) while total cholesterol significantly decreased (P-value 0.043) and fasting insulin significantly increased (P-value 0.047). Hypothyroidism has no impact on insulin sensitivity. Correction of hypothyroidism is not associated with a

  2. Fast food, central nervous system insulin resistance, and obesity.

    PubMed

    Isganaitis, Elvira; Lustig, Robert H

    2005-12-01

    Rates of obesity and insulin resistance have climbed sharply over the past 30 years. These epidemics are temporally related to a dramatic rise in consumption of fast food; until recently, it was not known whether the fast food was driving the obesity, or vice versa. We review the unique properties of fast food that make it the ideal obesigenic foodstuff, and elucidate the mechanisms by which fast food intake contributes to obesity, emphasizing its effects on energy metabolism and on the central regulation of appetite. After examining the epidemiology of fast food consumption, obesity, and insulin resistance, we review insulin's role in the central nervous system's (CNS) regulation of energy balance, and demonstrate the role of CNS insulin resistance as a cause of leptin resistance and in the promotion of the pleasurable or "hedonic" responses to food. Finally, we analyze the characteristics of fast food, including high-energy density, high fat, high fructose, low fiber, and low dairy intake, which favor the development of CNS insulin resistance and obesity.

  3. Focal adhesion kinase negatively regulates neuronal insulin resistance.

    PubMed

    Gupta, Amit; Bisht, Bharti; Dey, Chinmoy Sankar

    2012-06-01

    Focal adhesion kinase (FAK), a non-receptor protein kinase, is known to be a phosphatidyl inositol 3-kinase (PI3K) pathway activator and thus widely implicated in regulation of cell survival and cancer. In recent years FAK has also been strongly implicated as a crucial regulator of insulin resistance in peripheral tissues like skeletal muscle and liver, where decrease in its expression/activity has been shown to lead to insulin resistance. However, in the present study we report an altogether different role of FAK in regulation of insulin/PI3K signaling in neurons, the post-mitotic cells. An aberrant increase in FAK tyrosine phosphorylation was observed in insulin resistant Neuro-2a (N2A) cells. Downregulation of FAK expression utilizing RNAi mediated gene silencing in insulin resistant N2A cells completely ameliorated the impaired insulin/PI3K signaling and glucose uptake. FAK silencing in primary cortical neurons also showed marked enhancement in glucose uptake. The results thus suggest that in neurons FAK acts as a negative regulator of insulin/PI3K signaling. Interestingly, the available literature also demonstrates cell-type specific functions of FAK in neurons. FAK that is well known for its cell survival effects has been shown to be involved in neurodegeneration. Along with these previous reports, present findings highlight a novel and critical role of FAK in neurons. Moreover, as this implicates differential regulation of insulin/PI3K pathway by FAK in peripheral tissues and neuronal cells, it strongly suggests precaution while considering FAK modulators as possible therapeutics.

  4. Insulin Signaling in Insulin Resistance States and Cancer: A Modeling Analysis.

    PubMed

    Bertuzzi, Alessandro; Conte, Federica; Mingrone, Geltrude; Papa, Federico; Salinari, Serenella; Sinisgalli, Carmela

    2016-01-01

    Insulin resistance is the common denominator of several diseases including type 2 diabetes and cancer, and investigating the mechanisms responsible for insulin signaling impairment is of primary importance. A mathematical model of the insulin signaling network (ISN) is proposed and used to investigate the dose-response curves of components of this network. Experimental data of C2C12 myoblasts with phosphatase and tensin homologue (PTEN) suppressed and data of L6 myotubes with induced insulin resistance have been analyzed by the model. We focused particularly on single and double Akt phosphorylation and pointed out insulin signaling changes related to insulin resistance. Moreover, a new characterization of the upstream signaling of the mammalian target of rapamycin complex 2 (mTORC2) is presented. As it is widely recognized that ISN proteins have a crucial role also in cell proliferation and death, the ISN model was linked to a cell population model and applied to data of a cell line of acute myeloid leukemia treated with a mammalian target of rapamycin inhibitor with antitumor activity. The analysis revealed simple relationships among the concentrations of ISN proteins and the parameters of the cell population model that characterize cell cycle progression and cell death.

  5. Insulin Signaling in Insulin Resistance States and Cancer: A Modeling Analysis

    PubMed Central

    Bertuzzi, Alessandro; Conte, Federica; Mingrone, Geltrude; Papa, Federico; Salinari, Serenella

    2016-01-01

    Insulin resistance is the common denominator of several diseases including type 2 diabetes and cancer, and investigating the mechanisms responsible for insulin signaling impairment is of primary importance. A mathematical model of the insulin signaling network (ISN) is proposed and used to investigate the dose-response curves of components of this network. Experimental data of C2C12 myoblasts with phosphatase and tensin homologue (PTEN) suppressed and data of L6 myotubes with induced insulin resistance have been analyzed by the model. We focused particularly on single and double Akt phosphorylation and pointed out insulin signaling changes related to insulin resistance. Moreover, a new characterization of the upstream signaling of the mammalian target of rapamycin complex 2 (mTORC2) is presented. As it is widely recognized that ISN proteins have a crucial role also in cell proliferation and death, the ISN model was linked to a cell population model and applied to data of a cell line of acute myeloid leukemia treated with a mammalian target of rapamycin inhibitor with antitumor activity. The analysis revealed simple relationships among the concentrations of ISN proteins and the parameters of the cell population model that characterize cell cycle progression and cell death. PMID:27149630

  6. Amelioration of insulin resistance by scopoletin in high-glucose-induced, insulin-resistant HepG2 cells.

    PubMed

    Zhang, W Y; Lee, J-J; Kim, Y; Kim, I-S; Park, J-S; Myung, C-S

    2010-12-01

    Insulin resistance plays an important role in the development of type 2 diabetes mellitus. Scopoletin, a phenolic coumarin, is reported to regulate hyperglycemia and diabetes. To examine its effect on insulin resistance, we treated high-glucose-induced, insulin-resistant HepG2 cells with scopoletin and measured phosphatidylinositol 3-kinase (PI3 K)-linked protein kinase B (Akt/PKB) phosphorylation. Scopoletin significantly stimulated the reactivation of insulin-mediated Akt/PKB phosphorylation. This effect was blocked by LY294002, a specific PI3 K inhibitor. The ability of scopoletin to activate insulin-mediated Akt/PKB was greater than that of rosiglitazone, a thiazolidinedione, and scopoletin was less adipogenic than rosiglitazone, as shown by the extent of lipid accumulation in differentiated adipocytes. Scopoletin increased the gene expression of both peroxisome proliferator-activated receptor γ2 (PPARγ2), a target receptor for rosiglitazone, and adipocyte-specific fatty acid binding protein, but not to the level induced by rosiglitazone. However, the PPARγ2 protein level was increased equally by rosiglitazone and scopoletin in differentiated adipocytes. Our results suggest that scopoletin can ameliorate insulin resistance in part by upregulating PPARγ2 expression. With its lower adipogenic property, scopoletin may be a useful candidate for managing metabolic disorders, including type 2 diabetes mellitus. © Georg Thieme Verlag KG Stuttgart · New York.

  7. Midkine, a potential link between obesity and insulin resistance.

    PubMed

    Fan, Nengguang; Sun, Haiyan; Wang, Yifei; Zhang, Lijuan; Xia, Zhenhua; Peng, Liang; Hou, Yanqiang; Shen, Weiqin; Liu, Rui; Peng, Yongde

    2014-01-01

    Obesity is associated with increased production of inflammatory mediators in adipose tissue, which contributes to chronic inflammation and insulin resistance. Midkine (MK) is a heparin-binding growth factor with potent proinflammatory activities. We aimed to test whether MK is associated with obesity and has a role in insulin resistance. It was found that MK was expressed in adipocytes and regulated by inflammatory modulators (TNF-α and rosiglitazone). In addition, a significant increase in MK levels was observed in adipose tissue of obese ob/ob mice as well as in serum of overweight/obese subjects when compared with their respective controls. In vitro studies further revealed that MK impaired insulin signaling in 3T3-L1 adipocytes, as indicated by reduced phosphorylation of Akt and IRS-1 and decreased translocation of glucose transporter 4 (GLUT4) to the plasma membrane in response to insulin stimulation. Moreover, MK activated the STAT3-suppressor of cytokine signaling 3 (SOCS3) pathway in adipocytes. Thus, MK is a novel adipocyte-secreted factor associated with obesity and inhibition of insulin signaling in adipocytes. It may provide a potential link between obesity and insulin resistance.

  8. Salt, aldosterone, and insulin resistance: impact on the cardiovascular system.

    PubMed

    Lastra, Guido; Dhuper, Sonal; Johnson, Megan S; Sowers, James R

    2010-10-01

    Hypertension and type 2 diabetes mellitus (T2DM) are powerful risk factors for cardiovascular disease (CVD) and chronic kidney disease (CKD), both of which are leading causes of morbidity and mortality worldwide. Research into the pathophysiology of CVD and CKD risk factors has identified salt sensitivity and insulin resistance as key elements underlying the relationship between hypertension and T2DM. Excess dietary salt and caloric intake, as commonly found in westernized diets, is linked not only to increased blood pressure, but also to defective insulin sensitivity and impaired glucose homeostasis. In this setting, activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS), as well as increased signaling through the mineralocorticoid receptor (MR), result in increased production of reactive oxygen species and oxidative stress, which in turn contribute to insulin resistance and impaired vascular function. In addition, insulin resistance is not limited to classic insulin-sensitive tissues such as skeletal muscle, but it also affects the cardiovascular system, where it participates in the development of CVD and CKD. Current clinical knowledge points towards an impact of salt restriction, RAAS blockade, and MR antagonism on cardiovascular and renal protection, but also on improved insulin sensitivity and glucose homeostasis.

  9. Macrophage-secreted factors induce adipocyte inflammation and insulin resistance

    SciTech Connect

    Permana, Paska A. . E-mail: Paska.Permana@med.va.gov; Menge, Christopher; Reaven, Peter D.

    2006-03-10

    Macrophage infiltration into adipose tissue increases with obesity, a condition associated with low-grade inflammation and insulin resistance. We investigated the direct effects of macrophage-secreted factors on adipocyte inflammation and insulin resistance. 3T3-L1 adipocytes incubated with media conditioned by RAW264.7 macrophages (RAW-CM) showed dramatically increased transcription of several inflammation-related genes, greater nuclear factor kappa B (NF-{kappa}B) activity, and enhanced binding of U937 monocytes. All of these effects were prevented by co-incubation with pyrrolidinedithiocarbamate, an NF-{kappa}B inhibitor. Adipocytes incubated with RAW-CM also released more non-esterified fatty acids and this increased lipolysis was not suppressed by insulin. In addition, RAW-CM treatment decreased insulin-stimulated glucose uptake in adipocytes. Taken together, these results indicate that macrophage-secreted factors induce inflammatory responses and reduce insulin responsiveness in adipocytes. These effects of macrophage-secreted factors on adipocytes may contribute significantly to the systemic inflammation and insulin resistance associated with obesity.

  10. 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

  11. Dietary iron overload induces visceral adipose tissue insulin resistance.

    PubMed

    Dongiovanni, Paola; Ruscica, Massimiliano; Rametta, Raffaela; Recalcati, Stefania; Steffani, Liliana; Gatti, Stefano; Girelli, Domenico; Cairo, Gaetano; Magni, Paolo; Fargion, Silvia; Valenti, Luca

    2013-06-01

    Increased iron stores associated with elevated levels of the iron hormone hepcidin are a frequent feature of the metabolic syndrome. The aim of this study was to assess the effect of dietary iron supplementation on insulin resistance and the role of hepcidin in C57Bl/6 male mice fed a standard or iron-enriched diet for 16 weeks. Iron supplementation increased hepatic iron and serum hepcidin fivefold and led to a 40% increase in fasting glucose due to insulin resistance, as confirmed by the insulin tolerance test, and to threefold higher levels of triglycerides. Iron supplemented mice had lower visceral adipose tissue mass estimated by epididymal fat pad, associated with iron accumulation in adipocytes. Decreased insulin signaling, evaluated by the phospho-Akt/Akt ratio, was detected in the visceral adipose tissue of iron overloaded mice, and gene expression analysis of visceral adipose tissue showed that an iron-enriched diet up-regulated iron-responsive genes and adipokines, favoring insulin resistance, whereas lipoprotein lipase was down-regulated. This resulted in hyperresistinemia and increased visceral adipose tissue expression of suppressor of cytokine signaling-3 (Socs3), a target of resistin and hepcidin implicated in insulin resistance. Acute hepcidin administration down-regulated lipoprotein lipase and up-regulated Socs3 in visceral adipose tissue. In conclusion, we characterized a model of dysmetabolic iron overload syndrome in which an iron-enriched diet induces insulin resistance and hypertriglyceridemia and affects visceral adipose tissue metabolism by a mechanism involving hepcidin up-regulation. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  12. ADIPOQ polymorphisms are associated with insulin resistance in Japanese women.

    PubMed

    Kitamoto, Aya; Kitamoto, Takuya; So, Rina; Matsuo, Tomoaki; Nakata, Yoshio; Hyogo, Hideyuki; Ochi, Hidenori; Nakamura, Takahiro; Kamohara, Seika; Miyatake, Nobuyuki; Kotani, Kazuaki; Mineo, Ikuo; Wada, Jun; Ogawa, Yuji; Yoneda, Masato; Nakajima, Atsushi; Funahashi, Tohru; Miyazaki, Shigeru; Tokunaga, Katsuto; Masuzaki, Hiroaki; Ueno, Takato; Chayama, Kazuaki; Hamaguchi, Kazuyuki; Yamada, Kentaro; Hanafusa, Toshiaki; Oikawa, Shinichi; Sakata, Toshiie; Tanaka, Kiyoji; Matsuzawa, Yuji; Hotta, Kikuko

    2015-01-01

    Visceral fat accumulation contributes to the development of insulin resistance, leading to metabolic syndrome. Adiponectin provides a link between visceral fat accumulation and insulin resistance. In addition to environmental factors, genetic factors play important roles in visceral fat accumulation and circulating adiponectin levels. Genome-wide association studies (GWASs) have identified genetic variations in the adiponectin, C1Q and collagen domain containing (ADIPOQ) gene that are associated with adiponectin levels. In this study, we investigated whether ADIPOQ single nucleotide polymorphisms (SNPs) were associated with visceral fat accumulation and insulin resistance. We measured the visceral fat area (VFA) by computed tomography (CT) and examined the presence of the insulin resistance-related phenotype (fasting plasma glucose, fasting insulin, and homeostasis model assessment-insulin resistance [HOMA-IR]) in a set of Japanese individuals (731 men and 864 women) who were genotyped for seven ADIPOQ SNPs reported by recent GWASs (namely, rs6810075, rs10937273, rs1648707, rs864265, rs182052, rs17366568, and rs6773957). SNPs associated with the phenotype (P < 0.05) were then evaluated by association analysis using a second set of the study participants (383 men and 510 women). None of the SNPs was associated with body mass index (BMI) or VFA in men or women. However, the adiponectin-decreasing alleles of rs10937273 and rs1648707 were significantly associated with HOMA-IR (P = 0.0030 and P = 0.00074, respectively) in women, independently of BMI. These SNPs were significantly associated with decreased adiponectin levels in women. Our results suggested that rs10937273 and rs1648707 may affect insulin sensitivity by regulating adiponectin production by adipose tissue in women.

  13. Insulin Resistance and Glucose Levels in Subjects with Subclinical Hypothyroidism.

    PubMed

    Khan, Sikandar Hayat; Fazal, Nadeem; Ijaz, Aamir; Manzoor, Syed Mohsin; Asif, Naveed; Rafi, Tariq; Yasir, Muhammad; Niazi, Najmusaquib Khan

    2017-06-01

    To compare insulin resistance and glycemic indicators among subjects with euthyroidism and subclinical hypothyroidism. Comparative cross-sectional study. Department of Pathology and Medicine, PNS Hafeez, Islamabad, in collaboration with the Department of Chemical Pathology and Endocrinology at the Armed Forces Institute of Pathology (AFIP), Rawalpindi, from December 2015 to September 2016. Subjects referred for executive screening of apparently healthy population (without any known history of diabetes, hypertension, heart disease or other chronic ailments), were included. Subjects were grouped as euthyroidism and subclinical hypothyroidism. Median (IQR) insulin resistance indices including fasting insulin and Homeostasis Model Assessment for Insulin Resistance in subjects with group-1 (n=176, 87%, Thyroid Stimulating Hormone: 0.5 - 3.5 mIU/L) and group-2 (n=26, 13%, Thyroid Stimulating Hormone: 3.51 - 15 mIU/L) were 7.6 (6.70) vs. 11.4 (13.72, p=0.040) and 1.77 (1.79) vs. 2.8 (3.07, p=0.071). The median differences for fasting plasma glucose were 5.0 (1.0) in group-1 vs. 5.0 (1.47) for Group-2 [p=0.618], and glycated hemoglobin was 5.60 (1.1) vs. 5.60 (1.7, p=0.824). Homeostasis Model Assessment for beta sensitivity index in paradox showed slightly higher values for group-2 [median (IQR) 86.67 (92.94)] than group-1 [111.6 (189.64, p= 0.040)]. Measures of insulin resistance including Homeostasis Model Assessment for Insulin Resistance and fasting insulin levels were significantly different between subjects with euthyroidism and having subclinical hypothyroidism.

  14. Insulin resistance and acne: a new risk factor for men?

    PubMed

    Del Prete, Michela; Mauriello, Maria Chiara; Faggiano, Antongiulio; Di Somma, Carolina; Monfrecola, Giuseppe; Fabbrocini, Gabriella; Colao, Annamaria

    2012-12-01

    The purpose of this study is to investigate the relationship between acne and insulin resistance as well as other metabolic impairment in young males. Acne is a skin disease that can be influenced by endocrine abnormalities. In females, it is associated with polycystic ovary syndrome, with peripheral insulin resistance and hyperinsulinemia, whereas few data are available in males. For investigating this, 22 young males with acne have been compared to 22 controls of comparable age and gender. Acne was scored using the global acne grading system score. Clinical as well as biochemical parameters of glucose and lipid metabolism, circulating levels of androgens, and IGF-1 were evaluated. Oral glucose tolerance test was performed and homeostasis model assessment of insulin resistance was calculated. The results thus obtained are as follows, patients had higher BMI (p = 0.003), WC (p = 0.002), WHR (p = 0.02), SBP (p = 0.0001), DBP (p = 0.001), basal (p = 0.01) and 120 min. oGTT serum insulin concentrations (p = 0.002), basal glucose concentrations (p = 0.03), HOMA-IR (p = 0.016), and lower HDL-cholesterol than controls (p = 0.001). Among the subgroup of subjects with BMI <24.9, HDL-cholesterol (p = 0.05) and 120 min. oGTT serum insulin concentrations (p = 0.009) resulted to be independent predictors of acne at multivariate analysis. In conclusion, these findings highlight a metabolic imbalance in young males affected with acne. Insulin resistance seems to play the main role for the development of acne in these subjects. Insulin resistance could represent an effective target for therapy in male acne.

  15. Lipid metabolism disturbances contribute to insulin resistance and decrease insulin sensitivity by malathion exposure in Wistar rat.

    PubMed

    Lasram, Mohamed Montassar; Bouzid, Kahena; Douib, Ines Bini; Annabi, Alya; El Elj, Naziha; El Fazaa, Saloua; Abdelmoula, Jaouida; Gharbi, Najoua

    2015-04-01

    Several studies showed that organophosphorus pesticides disturb glucose homeostasis and can increase incidence of metabolic disorders and diabetes via insulin resistance. The current study investigates the influence of malathion on glucose metabolism regulation, in vivo, during subchronic exposure. Malathion was administered orally (200 mg/kg), once a day for 28 consecutive days. Plasma glucose, insulin and Glycated hemoglobin levels were significantly increased while hepatic glycogen content was decreased in intoxicated animals compared with the control group. Furthermore, there was a significant disturbance of lipid content in subchronic treated and post-treated rats deprived of malathion for one month. In addition, we used the homeostasis model assessment (HOMA) to assess insulin resistance (HOMA-IR) and pancreatic β-cell function (HOMA-β). Our results show that malathion increases insulin resistance biomarkers and decreases insulin sensitivity indices. Statistical analysis demonstrates that there was a positive and strong significant correlation between insulin level and insulin resistance indices, HOMA-IR, HOMA-β. Similarly, a negative and significant correlation was also found between insulin level and insulin sensitivity indices. For the first time, we demonstrate that malathion induces insulin resistance in vivo using homeostasis model assessment and these changes were detectable one month after the end of exposure. To explain insulin resistance induced by malathion we focus on lipid metabolism disturbances and their interaction with many proteins involved in insulin signaling pathways.

  16. Lysophosphatidylcholine as an effector of fatty acid-induced insulin resistance[S

    PubMed Central

    Han, Myoung Sook; Lim, Yu-Mi; Quan, Wenying; Kim, Jung Ran; Chung, Kun Wook; Kang, Mira; Kim, Sunshin; Park, Sun Young; Han, Joong-Soo; Park, Shin-Young; Cheon, Hyae Gyeong; Dal Rhee, Sang; Park, Tae-Sik; Lee, Myung-Shik

    2011-01-01

    The mechanism of FFA-induced insulin resistance is not fully understood. We have searched for effector molecules(s) in FFA-induced insulin resistance. Palmitic acid (PA) but not oleic acid (OA) induced insulin resistance in L6 myotubes through C-Jun N-terminal kinase (JNK) and insulin receptor substrate 1 (IRS-1) Ser307 phosphorylation. Inhibitors of ceramide synthesis did not block insulin resistance by PA. However, inhibition of the conversion of PA to lysophosphatidylcholine (LPC) by calcium-independent phospholipase A2 (iPLA2) inhibitors, such as bromoenol lactone (BEL) or palmitoyl trifluoromethyl ketone (PACOCF3), prevented insulin resistance by PA. iPLA2 inhibitors or iPLA2 small interfering RNA (siRNA) attenuated JNK or IRS-1 Ser307 phosphorylation by PA. PA treatment increased LPC content, which was reversed by iPLA2 inhibitors or iPLA2 siRNA. The intracellular DAG level was increased by iPLA2 inhibitors, despite ameliorated insulin resistance. Pertussis toxin (PTX), which inhibits LPC action through the G-protein coupled receptor (GPCR)/Gαi, reversed insulin resistance by PA. BEL administration ameliorated insulin resistance and diabetes in db/db mice. JNK and IRS-1Ser307 phosphorylation in the liver and muscle of db/db mice was attenuated by BEL. LPC content was increased in the liver and muscle of db/db mice, which was suppressed by BEL. These findings implicate LPC as an important lipid intermediate that links saturated fatty acids to insulin resistance. PMID:21447485

  17. Vitamin B12 in obese adolescents with clinical features of insulin resistance.

    PubMed

    Ho, Mandy; Halim, Jocelyn H; Gow, Megan L; El-Haddad, Nouhad; Marzulli, Teresa; Baur, Louise A; Cowell, Chris T; Garnett, Sarah P

    2014-12-04

    Emerging evidence indicates an association between obesity, metformin use and reduced vitamin B12 status, which can have serious hematologic, neurologic and psychiatric consequences. This study aimed to examine B12 status in obese adolescents with pre-diabetes and/or clinical features of insulin resistance. Serum B12 was measured using chemiluminescence immunoassay in 103 (43 male, 60 female) obese (mean body mass index (BMI) z-score ± SD (2.36 ± 0.29)), adolescents aged 10 to 17 years, median (range) insulin sensitivity index of 1.27 (0.27 to 3.38) and 13.6% had pre-diabetes. Low B12 (<148 pmol/L) was identified in eight (7.8%) and borderline status (148 to 221 pmol/L) in an additional 25 (24.3%) adolescents. Adolescents with borderline B12 concentrations had higher BMI z-scores compared to those with normal concentrations (2.50 ± 0.22 vs. 2.32 ± 0.30, p = 0.008) or those with low B12 concentration (2.50 ± 0.22 vs. 2.27 ± 0.226, p = 0.041). In conclusion, nearly a third of obese adolescents with clinical insulin resistance had a low or borderline serum B12 status. Therefore, further investigations are warranted to explore the cause and the impact of low B12 status in obese pediatric populations.

  18. Plasma obestatin is lower at fasting and not suppressed by insulin in insulin-resistant humans.

    PubMed

    Anderwald-Stadler, Marietta; Krebs, Michael; Promintzer, Miriam; Mandl, Martina; Bischof, Martin G; Nowotny, Peter; Kästenbauer, Thomas; Luger, Anton; Prager, Rudolf; Anderwald, Christian

    2007-11-01

    Obestatin, a recently discovered 23-amino acid peptide, is involved in the regulation of appetite and body weight in antagonistic fashion to ghrelin, both deriving from a common precursor peptide. Ghrelin was shown to be associated with insulin resistance, which may also affect obestatin. We investigated the association between insulin resistance and plasma concentrations of obestatin and ghrelin in nondiabetic individuals with high (IS; n = 18, 13 females and 5 males, age 47 +/- 2 yr, BMI = 25.5 +/- 0.9 kg/m(2)) and low (IR; n = 18, 12 females and 6 males, age 45 +/- 2 yr, P = 0.49, BMI = 27.5 +/- 1.1 kg/m(2), P = 0.17) insulin-stimulated glucose disposal (M), measured by 2-h hyperinsulinemic (40 mU.min(-1).m(-2)) isoglycemic clamp tests. M(100-120 min) was higher in IS (10.7 +/- 0.7) than in IR (4.4 +/- 0.2 mg.min(-1).kg(-1), P < 10(-9)), whereas insulin-dependent suppression of free fatty acids (FFA) in plasma was reduced in IR (71 +/- 6% vs. IS: 82 +/- 5%, P < 0.02). In both groups, plasma ghrelin concentrations were comparable at fasting and similarly reduced by 24-28% during insulin infusion. IR had lower fasting plasma obestatin levels (383 +/- 26 pg/ml vs. IS: 469 +/- 23 pg/ml, P < 0.02). Clamp insulin infusion reduced plasma obestatin to approximately 81% of basal values in IS (P < 0.00002), but not in IR. Fasting plasma obestatin was correlated positively with M (r = 0.34, P = 0.04), HDL cholesterol (r = 0.45, P = 0.01), and plasma ghrelin concentrations (r = 0.80, P < 0.000001) and negatively with measures of adiposity, plasma FFA during clamp (r = -0.42, P < 0.01), and systolic blood pressure (r = -0.33, P < 0.05). In conclusion, fasting plasma concentrations of obestatin, but not of ghrelin, are reduced in insulin resistance and are positively associated with whole body insulin sensitivity in nondiabetic humans. Furthermore, plasma obestatin is reduced by insulin in insulin-sensitive but not in insulin-resistant persons.

  19. 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

  20. 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.

  1. Visceral adiposity, insulin resistance and cancer risk

    PubMed Central

    2011-01-01

    Background There is a well established link between obesity and cancer. Emerging research is characterising this relationship further and delineating the specific role of excess visceral adiposity, as opposed to simple obesity, in promoting tumorigenesis. This review summarises the evidence from an epidemiological and pathophysiological perspective. Methods Relevant medical literature was identified from searches of PubMed and references cited in appropriate articles identified. Selection of articles was based on peer review, journal and relevance. Results Numerous epidemiological studies consistently identify increased risk of developing carcinoma in the obese. Adipose tissue, particularly viscerally located fat, is metabolically active and exerts systemic endocrine effects. Putative pathophysiological mechanisms linking obesity and carcinogenesis include the paracrine effects of adipose tissue and systemic alterations associated with obesity. Systemic changes in the obese state include chronic inflammation and alterations in adipokines and sex steroids. Insulin and the insulin-like growth factor axis influence tumorigenesis and also have a complex relationship with adiposity. There is evidence to suggest that insulin and the IGF axis play an important role in mediating obesity associated malignancy. Conclusions There is much evidence to support a role for obesity in cancer progression, however further research is warranted to determine the specific effect of excess visceral adipose tissue on tumorigenesis. Investigation of the potential mechanisms underpinning the association, including the role of insulin and the IGF axis, will improve understanding of the obesity and cancer link and may uncover targets for intervention. PMID:21696633

  2. A Model of Insulin Resistance and Nonalcoholic Steatohepatitis in Rats

    PubMed Central

    Svegliati-Baroni, Gianluca; Candelaresi, Cinzia; Saccomanno, Stefania; Ferretti, Gianna; Bachetti, Tiziana; Marzioni, Marco; De Minicis, Samuele; Nobili, Liliana; Salzano, Renata; Omenetti, Alessia; Pacetti, Deborah; Sigmund, Soeren; Benedetti, Antonio; Casini, Alessandro

    2006-01-01

    Insulin resistance induces nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH). We used a high-fat, high-calorie solid diet (HFD) to create a model of insulin resistance and NASH in nongenetically modified rats and to study the relationship between visceral adipose tissue and liver. Obesity and insulin resistance occurred in HFD rats, accompanied by a progressive increase in visceral adipose tissue tumor necrosis factor (TNF)-α mRNA and in circulating free fatty acids. HFD also decreased adiponectin mRNA and peroxisome proliferator-activated receptor (PPAR)-α expression in the visceral adipose tissue and the liver, respectively, and induced hepatic insulin resistance through TNF-α-mediated c-Jun N-terminal kinase (JNK)-dependent insulin receptor substrate-1Ser307 phosphorylation. These modifications lead to hepatic steatosis accompanied by oxidative stress phenomena, necroinflammation, and hepatocyte apoptosis at 4 weeks and by pericentral fibrosis at 6 months. Supplementation of n-3 polyunsaturated fatty acid, a PPARα ligand, to HFD-treated animals restored hepatic adiponectin and PPARα expression, reduced TNF-α hepatic levels, and ameliorated fatty liver and the degree of liver injury. Thus, our model mimics the most common features of NASH in humans and provides an ideal tool to study the role of individual pathogenetic events (as for PPARα down-regulation) and to define any future experimental therapy, such as n-3 polyunsaturated fatty acid, which ameliorated the degree of liver injury. PMID:16936261

  3. Impaired activation of phosphoinositide 3-kinase by insulin in fibroblasts from patients with severe insulin resistance and pseudoacromegaly. A disorder characterized by selective postreceptor insulin resistance.

    PubMed Central

    Dib, K; Whitehead, J P; Humphreys, P J; Soos, M A; Baynes, K C; Kumar, S; Harvey, T; O'Rahilly, S

    1998-01-01

    Some patients with severe insulin resistance develop pathological tissue growth reminiscent of acromegaly. Previous studies of such patients have suggested the presence of a selective postreceptor defect of insulin signaling, resulting in the impairment of metabolic but preservation of mitogenic signaling. As the activation of phosphoinositide 3-kinase (PI 3-kinase) is considered essential for insulin's metabolic signaling, we have examined insulin-stimulated PI 3-kinase activity in anti-insulin receptor substrate (IRS)-1 immunoprecipitates from cultured dermal fibroblasts obtained from pseudoacromegalic (PA) patients and controls. At a concentration of insulin (1 nM) similar to that seen in vivo in PA patients, the activation of IRS-1-associated PI 3-kinase was reduced markedly in fibroblasts from the PA patients (32+/-7% of the activity of normal controls, P < 0.01). Genetic and biochemical studies indicated that this impairment was not secondary to a defect in the structure, expression, or activation of the insulin receptor, IRS-1, or p85alpha. Insulin stimulation of mitogenesis in PA fibroblasts, as determined by thymidine incorporation, was indistinguishable from controls, as was mitogen-activated protein kinase phosphorylation, confirming the integrity of insulin's mitogenic signaling pathways in this condition. These findings support the existence of an intrinsic defect of postreceptor insulin signaling in the PA subtype of insulin resistance, which involves impairment of the activation of PI 3-kinase. The PA tissue growth seen in such patients is likely to result from severe in vivo hyperinsulinemia activating intact mitogenic signaling pathways emanating from the insulin receptor. PMID:9486982

  4. Evaluation of leptin and insulin resistance in patients with cholelithiasis.

    PubMed

    Atamer, Aytaç; Ovünç, Ayşe Oya Kurdaş; Yeşil, Atakan; Atamer, Yildiz

    2013-08-01

    The association between insulin resistance, lipoproteins and leptin was evaluated in cholelithiasis. The study group included 55 women (68.8%) and 25 men (31.3%) with a mean age and SD of 50.56 +/- 14.28 yrs. The control group included 25 women (62.5%) and 15 men (37.5%) with a mean age of 50.93 +/- 11.73 yrs. Serum leptin levels were measured by the enzyme immunoassay method. HOMA-IR was determined by using fasting glucose and insulin levels. Insulin, total cholesterol (TC), LDL-C, HOMA-IR (p < 0.01) and leptin (p < 0.001) were significantly higher in the cholelithiasis group, compared to the controls. In patients with a HOMA-IR >2.2, age, body mass index (BMI), glucose, insulin, triglycerides (TG), TC and leptin levels were higher than in patients with a HOMA-IR < 2.2. In patients with glucose levels >100 mg/dl, mean BMI, HOMA-IR, insulin, TG, TC and leptin levels were significantly higher than in patients with glucose levels <100 mg/dl. In patients with TG levels >150 mg/dl, mean age, BMI, glucose, insulin, TC, leptin and HOMA-IR were significantly higher than in patients with TG levels < 150 mg/dl. In patients with BMI > 25 kg/m2, mean age, glucose, insulin, TG, TC, leptin, HOMA-IR were significantly higher than in patients with BMI < 25. In cholelithiasis group, there was a positive correlation between leptin and age, BMI, glucose, insulin, TG, TC, LDL-C or HOMA-IR. In conclusion, we found a positive association between increased leptin levels and abnormal lipoprotein metabolism in cholelithiasis. Cholelithiasis subjects with insulin resistance showed higher cardiometabolic risk factors than those without it.

  5. PKC-mediated modulation of L-type calcium channels may contribute to fat-induced insulin resistance.

    PubMed

    McCarty, Mark F

    2006-01-01

    and poor vitamin D status may contribute to insulin resistance, consistent with certain clinical and epidemiological findings. Magnesium, often thought of as a mild calcium antagonist, appears to have favorable effects on insulin sensitivity and risk for diabetes, and recent evidence indicates that increases of intracellular magnesium within the physiological range can diminish calcium influx through phosphorylated L-type calcium channels. It will be of interest to determine whether calcium antagonism does indeed underlie the favorable influence of good magnesium status on insulin function. A report that chromium picolinate can induce the plasmalemmal Ca2+-ATPase in smooth muscle cells, raises the possibility that modulation of calcium transport might play a role in the insulin-sensitizing efficacy of bioactive chromium.

  6. Skin pigmentation is inversely associated with insulin resistance in healthy Japanese women.

    PubMed

    Nagata, C; Konish, K; Tamura, T; Wada, K; Hayashi, M; Takeda, N; Yasuda, K

    2016-11-01

    As a low-pigment skin type is prevalent in men and women with type 1 diabetes, it is possible that skin pigmentation may be associated with insulin resistance. This study aimed to cross-sectionally examine this association in healthy women. Study participants were 792 Japanese women who attended a health examination and were not taking any medication for diabetes. Skin pigmentation on the inner upper and lower arms and forehead was measured using a Mexameter(®) skin colorimeter, a narrow-band reflective spectrophotometer. Data are expressed as a melanin index, which quantifies melanin content. Fasting blood glucose and insulin levels were also measured, and homoeostasis model assessment for insulin resistance (HOMA-IR) scores were calculated. Information on medical history and lifestyle factors were obtained by a self-administered questionnaire, while data on sun exposure were collected through interviews. Plasma 25-hydroxyvitamin D levels were measured in a subsample of women (n=464). Melanin indices at the inner upper and lower arms were significantly and inversely associated with fasting insulin levels and HOMA-IR after controlling for age, body mass index, smoking status, indicators for rater effects, cumulative sun exposure and season at the time of measurement. Additional adjustment for plasma 25-hydroxyvitamin D levels did not alter the results. These data suggest that skin pigmentation is associated with insulin resistance, and encourage future studies into the potential role of melanin and related factors in glucose homoeostasis. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  7. Interplay of overweight and insulin resistance on hypertension development.

    PubMed

    Lytsy, Per; Ingelsson, Erik; Lind, Lars; Arnlöv, Johan; Sundström, Johan

    2014-04-01

    Obesity and hypertension are associated, possibly through causal pathways involving insulin resistance and metabolic derangements. We aimed to investigate in a whites sample if overweight or obese persons without insulin resistance are at risk of developing hypertension or blood pressure progression. In a meta-analysis, using multivariable-adjusted mixed-effects logistic regression models, we investigated the risks of hypertension development and blood pressure progression by combinations of relative weight classes and presence or absence of insulin resistance (defined as highest vs. lower three quartiles using the homeostatic model assessment method) in the Uppsala Longitudinal Study of Adult Men (n = 2322) and the Prospective Investigation of the Vasculature in Uppsala Seniors studies (n = 1066). These two samples, consisting mainly of middle-aged and elderly men, provided 1846 observations for the development of hypertension in normotensive individuals and 4223 observations for progressing to a higher blood pressure stage. During a median of 10 years of follow-up, 884 (47.9%) developed hypertension and 1639 (38.8%) progressed to a higher blood pressure stage. Overweight or obese persons without insulin resistance had an increased risk of hypertension development [odds ratio (OR) 1.46, 95% confidence interval 1.14-1.88] and blood pressure progression (OR 1.32, 1.10-1.59) compared with normal-weight persons without insulin resistance. According to this study, being overweight or obese without insulin resistance increases the risk of hypertension and blood pressure progression. This adds to the evidence that overweight and obesity may be harmful per se, and that overweight and obesity without glucometabolic derangements are not benign conditions.

  8. Neurolytic celiac plexus block enhances skeletal muscle insulin signaling and attenuates insulin resistance in GK rats

    PubMed Central

    LI, JUN; CHEN, TAO; LI, KUN; YAN, HONGTAO; LI, XIAOWEI; YANG, YUN; ZHANG, YULAN; SU, BINGYIN; LI, FUXIANG

    2016-01-01

    Non-insulin-dependent diabetes mellitus (NIDDM) is associated with chronic inflammatory activity and disrupted insulin signaling, leading to insulin resistance (IR). The present study investigated the benefits of neurolytic celiac plexus block (NCPB) on IR in a rat NIDDM model. Goto-Kakizaki rats fed a high-fat, high-glucose diet to induce signs of NIDDM were randomly divided into NCPB and control groups; these received daily bilateral 0.5% lidocaine or 0.9% saline injections into the celiac plexus, respectively. Following 14 and 28 daily injections, rats were subject to oral glucose tolerance tests (OGTTs) or sacrificed for the analysis of serum free fatty acids (FFAs), serum inflammatory cytokines and skeletal muscle insulin signaling. Compared with controls, rats in the NCPB group demonstrated significantly (P<0.05) lower baseline, 60-min and 120-min OGTT values, lower 120-min serum insulin, lower IR [higher insulin sensitivity index (ISI1) and lower ISI2) and lower serum FFAs, tumor necrosis factor-α, interleukin (IL)-1β and IL-6. Conversely, NCPB rats exhibited higher basal and insulin-stimulated skeletal muscle glucose uptake and higher skeletal muscle insulin receptor substrate-1 (IRS-1) and glucose transporter type 4 expression. There were no differences between the groups in insulin receptor β (Rβ) or Akt expression; however Rβ-Y1162/Y1163 and Akt-S473 phosphorylation levels were higher and IRS-1-S307 phosphorylation were lower in NCPB rats than in the controls. These results indicate that NCPB improved insulin signaling and reduced IR, possibly by inhibiting inflammatory cytokine release. PMID:27168847

  9. Neurolytic celiac plexus block enhances skeletal muscle insulin signaling and attenuates insulin resistance in GK rats.

    PubMed

    Li, Jun; Chen, Tao; Li, Kun; Yan, Hongtao; Li, Xiaowei; Yang, Yun; Zhang, Yulan; Su, Bingyin; Li, Fuxiang

    2016-05-01

    Non-insulin-dependent diabetes mellitus (NIDDM) is associated with chronic inflammatory activity and disrupted insulin signaling, leading to insulin resistance (IR). The present study investigated the benefits of neurolytic celiac plexus block (NCPB) on IR in a rat NIDDM model. Goto-Kakizaki rats fed a high-fat, high-glucose diet to induce signs of NIDDM were randomly divided into NCPB and control groups; these received daily bilateral 0.5% lidocaine or 0.9% saline injections into the celiac plexus, respectively. Following 14 and 28 daily injections, rats were subject to oral glucose tolerance tests (OGTTs) or sacrificed for the analysis of serum free fatty acids (FFAs), serum inflammatory cytokines and skeletal muscle insulin signaling. Compared with controls, rats in the NCPB group demonstrated significantly (P<0.05) lower baseline, 60-min and 120-min OGTT values, lower 120-min serum insulin, lower IR [higher insulin sensitivity index (ISI1) and lower ISI2) and lower serum FFAs, tumor necrosis factor-α, interleukin (IL)-1β and IL-6. Conversely, NCPB rats exhibited higher basal and insulin-stimulated skeletal muscle glucose uptake and higher skeletal muscle insulin receptor substrate-1 (IRS-1) and glucose transporter type 4 expression. There were no differences between the groups in insulin receptor β (Rβ) or Akt expression; however Rβ-Y1162/Y1163 and Akt-S473 phosphorylation levels were higher and IRS-1-S307 phosphorylation were lower in NCPB rats than in the controls. These results indicate that NCPB improved insulin signaling and reduced IR, possibly by inhibiting inflammatory cytokine release.

  10. Association of oxidative status and insulin sensitivity in periparturient dairy cattle: an observational study.

    PubMed

    Abuelo, A; Hernández, J; Benedito, J L; Castillo, C

    2016-04-01

    Post-parturient insulin resistance (IR) is a common feature in all mammalian animals. However, in dairy cows, it can be exacerbated because of high milk yield, leading to excessive negative energy balance, which is related with increased disease incidence, reduced milk production and worsened reproductive performance. IR has been extensively investigated in humans suffering from diabetes mellitus. In these subjects, it is known that oxidative stress (OS) plays a causative role in the onset of IR. Although OS occurs in transitional dairy cattle, there are yet no studies that investigated the association between IR and OS in dairy cattle. Therefore, the aim of this study was to investigate whether there is a relationship between OS and IR in dairy cattle. Serum samples were taken repeatedly from 22 dairy cows from 2 months prior to the expected calving date to 2 months after calving and were analysed for markers of metabolic and redox balance. Surrogate indices of insulin sensitivity were also calculated. Generalised linear mixed models revealed an effect of the oxidative status on peripheral insulin concentration and on indices of insulin sensitivity. Hence, field trials should investigate the effectiveness of antioxidant therapy on insulin sensitivity in peripheral tissues during the transition period of dairy cattle.

  11. Sweet potato [Ipomoea batatas (L.) Lam. "Tainong 57"] starch improves insulin sensitivity in high-fructose diet-fed rats by ameliorating adipocytokine levels, pro-inflammatory status, and insulin signaling.

    PubMed

    Chen, Ya-Yen; Lai, Ming-Hoang; Hung, Hsin-Yu; Liu, Jen-Fang

    2013-01-01

    The aim of this study was to investigate the effects of low-glycemic index (GI) sweet potato starch on adipocytokines, pro-inflammatory status, and insulin signaling in the high-fructose diet-induced insulin-resistant rat. We randomly divided 24 insulin-resistant rats and 16 normal rats into two groups fed a diet containing 575 g/kg of starch: a low-GI sweet potato starch (S) or a high-GI potato starch (P). The four experimental groups were labeled as follows: insulin-resistant P (IR-P), insulin-resistant S (IR-S), normal P (N-P) and normal S (N-S). After 4 wk on the experimental diets, an intraperitoneal glucose tolerance test (IPGTT) was conducted, and the homeostasis model assessment (HOMA), adipocytokines, pro-inflammatory cytokines levels, and insulin signaling-related protein expression were measured. The homeostasis model assessment values were significantly lower in the IR-S than in the IR-P group, suggesting that insulin sensitivity was improved among sweet potato starch-fed rats. Levels of tumor necrosis factor-α, interleukin-6, resistin, and retinol binding protein-4 were significantly lower in the IR-S versus the IR-P group, indicating an improvement of pro-inflammatory status in sweet potato starch-fed rats. The sweet potato starch diet also significantly enhanced the protein expression of phospho-Tyr-insulin receptor substrate-1 and improved the translocation of glucose transporter 4 in the skeletal muscle. Our results illustrated that sweet potato starch feeding for 4 wk can improve insulin sensitivity in insulin-resistant rats, possibly by improving the adipocytokine levels, pro-inflammatory status, and insulin signaling.

  12. A novel surrogate index for hepatic insulin resistance.

    PubMed

    Vangipurapu, J; Stančáková, A; Kuulasmaa, T; Paananen, J; Kuusisto, J; Ferrannini, E; Laakso, M

    2011-03-01

    In epidemiological and genetic studies surrogate indices are needed to investigate insulin resistance in different insulin-sensitive tissues. Our objective was to develop a surrogate index for hepatic insulin resistance. A sample of 368 non-diabetic participants (age 43.0 ± 8.2 years, BMI 26.0 ± 4.0 kg/m(2); mean ± SD) whose endogenous glucose production (EGP) was measured with [6-6(2)H(2)]glucose in the fasting state and during the euglycaemic-hyperinsulinaemic clamp were included in the study. EGP multiplied by fasting plasma insulin (FPI) concentration was the reference measurement for liver insulin resistance (liver IR). Liver IR index was calculated with linear regression analysis including age, obesity indices, lipids, lipoproteins and several variables regulating glucose metabolism. The following variables were significantly associated with liver IR in multiple forward stepwise regression analysis: insulin AUC in an OGTT, fat mass, HDL-cholesterol and BMI. Liver IR index correlated significantly with EGP×FPI (r = 0.65, p < 0.001). In participants with abnormal glucose tolerance, the correlation of liver IR with EGP×FPI was slightly stronger (r = 0.69, p < 0.001) than in those with normal glucose tolerance (r = 0.62, p < 0.001). We generated a novel surrogate index for liver insulin resistance correlating strongly with EGP × FPI.

  13. Acute disruption of leptin signaling in vivo leads to increased insulin levels and insulin resistance.

    PubMed

    Levi, Jasna; Gray, Sarah L; Speck, Madeleine; Huynh, Frank K; Babich, Sandra L; Gibson, William T; Kieffer, Timothy J

    2011-09-01

    Leptin, an adipocyte-derived hormone, plays an essential role in the maintenance of normal body weight and energy expenditure, as well as glucose homeostasis. Indeed, leptin-deficient ob/ob mice are obese with profound hyperinsulinemia, insulin resistance, and often hyperglycemia. Interestingly, low doses of exogenous leptin can reverse the hyperinsulinemia and hyperglycemia in these animals without altering body weight. The hyperinsulinemia in ob/ob mice may result directly from the absence of leptin signaling in pancreatic β-cells and, in turn, contribute to both obesity and insulin resistance. Here, we acutely attenuated endogenous leptin signaling in normal mice with a polyethylene glycol (PEG)ylated mouse leptin antagonist (PEG-MLA) to determine the contribution of leptin signaling in the regulation of glucose homeostasis. PEG-MLA was either injected or continuously administered via osmotic minipumps for several days, and various metabolic parameters were assessed. PEG-MLA-treated mice had increased fasting and glucose-stimulated plasma insulin levels, decreased whole-body insulin sensitivity, elevated hepatic glucose production, and impaired insulin-mediated suppression of hepatic glucose production. Moreover, PEG-MLA treatment resulted in increased food intake and increased respiratory quotient without significantly altering energy expenditure or body composition as assessed by the lean:lipid ratio. Our findings indicate that alterations in insulin sensitivity occur before changes in the lean:lipid ratio and energy expenditure during the acute disruption of endogenous leptin signaling.

  14. D-chiro-inositol--its functional role in insulin action and its deficit in insulin resistance.

    PubMed

    Larner, Joseph

    2002-01-01

    In this review we discuss the biological significance of D-chiro-inositol, originally discovered as a component of a putative mediator of intracellular insulin action, where as a putative mediator, it accelerates the dephosphorylation of glycogen synthase and pyruvate dehydrogenase, rate limiting enzymes of non-oxidative and oxidative glucose disposal. Early studies demonstrated a linear relationship between its decreased urinary excretion and the degree of insulin resistance present. When tissue contents, including muscle, of type 2 diabetic subjects were assayed, they demonstrated a more general body deficiency. Administration of D-chiro-inositol to diabetic rats, Rhesus monkeys and now to humans accelerated glucose disposal and sensitized insulin action. A defect in vivo in the epimerization of myo-inositol to chiro-inositol in insulin sensitive tissues of the GK type 2 diabetic rat has been elucidated. Thus, administered D-chiro-inositol may act to bypass a defective normal epimerization of myo-inositol to D-chiro-inositol associated with insulin resistance and act to at least partially restore insulin sensitivity and glucose disposal.

  15. Defect in cooperativity in insulin receptors from a patient with a congenital form of extreme insulin resistance.

    PubMed Central

    Taylor, S I; Leventhal, S

    1983-01-01

    Previously, we have described a novel qualitative defect in insulin receptors from a patient with a genetic form of extreme insulin resistance (leprechaunism). Receptors from this insulin-resistant child are characterized by two abnormalities: (a) an abnormally high binding affinity for insulin, and (b) a markedly reduced sensitivity of 125I-insulin binding to alterations in pH and temperature. In this paper, we have investigated the kinetic mechanism of this abnormality in steady-state binding. The increased binding affinity for 125I-insulin results from a decrease in the dissociation rate of the hormone-receptor complex. In addition, the cooperative interactions among insulin binding sites are defective with insulin receptors from this child with leprechaunism. With insulin receptors on cultured lymphocytes from normal subjects, both negative and positive cooperativity may be observed. Porcine insulin accelerates the dissociation of the hormone-receptor complex (negative cooperativity). In contrast, certain insulin analogs such as desoctapeptide-insulin and desalanine-desasparagine-insulin retard the dissociation of the hormone-receptor complex (positive cooperativity). With insulin receptors from the leprechaun child, positive cooperativity could not be demonstrated, although negative cooperativity appeared to be normal. It seems likely that the same genetic defect may be responsible for the abnormalities in both insulin sensitivity and positive cooperativity. PMID:6345588

  16. Self-adjusting synthetic gene circuit for correcting insulin resistance

    PubMed Central

    Xue, Shuai; Charpin-El Hamri, Ghislaine; Yin, Jianli; Zulewski, Henryk; Fussenegger, Martin

    2017-01-01

    By using tools from synthetic biology, sophisticated genetic devices can be assembled to reprogram mammalian cell activities. Here, we demonstrate that a self-adjusting synthetic gene circuit can be designed to sense and reverse the insulin-resistance syndrome in different mouse models. By functionally rewiring the mitogen-activated protein kinase (MAPK) signalling pathway to produce MAPK-mediated activation of the hybrid transcription factor TetR-ELK1, we assembled a synthetic insulin-sensitive transcription-control device that self-sufficiently distinguished between physiological and increased blood insulin levels and correspondingly fine-tuned the reversible expression of therapeutic transgenes from synthetic TetR-ELK1-specific promoters. In acute experimental hyperinsulinemia, the synthetic insulin-sensing designer circuit reversed the insulin-resistance syndrome by coordinating expression of the insulin-sensitizing compound adiponectin. Engineering synthetic gene circuits to sense pathologic markers and coordinate the expression of therapeutic transgenes may provide opportunities for future gene- and cell-based treatments of multifactorial metabolic disorders. PMID:28480128

  17. Pathogenesis of selective insulin resistance in isolated hepatocytes.

    PubMed

    Cook, Joshua R; Langlet, Fanny; Kido, Yoshiaki; Accili, Domenico

    2015-05-29

    The development of insulin resistance (IR) in the liver is a key pathophysiologic event in the development of type 2 diabetes. Although insulin loses its ability to suppress glucose production, it largely retains its capacity to drive lipogenesis. This selective IR results in the characteristic hyperglycemia and dyslipidemia of type 2 diabetes. The delineation of two branched pathways of insulin receptor (InsR) signaling to glucose versus triglyceride production, one through FoxO and the other through SREBP-1c, provides a mechanism to account for this pathophysiological abnormality. We tested the complementary hypothesis that selective IR arises due to different intrinsic sensitivities of glucose production versus de novo lipogenesis to insulin as a result of cell-autonomous down-regulation of InsR number in response to chronic hyperinsulinemia. We demonstrate in mouse primary hepatocytes that chronic hyperinsulinemia abrogates insulin's inhibition of glucose production, but not its stimulation of de novo lipogenesis. Using a competitive inhibitor of InsR, we show that there is a 4-fold difference between levels of InsR inhibition required to cause resistance of glucose production versus lipogenesis to the actions of insulin. Our data support a parsimonious model in which differential InsR activation underlies the selective IR of glucose production relative to lipogenesis, but both processes require signaling through Akt1/2. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  18. [Care of insulin resistance in polycystic ovary syndrome].

    PubMed

    Hernández-Valencia, Marcelino; Hernández-Rosas, Marion; Zárate, Arturo

    2010-11-01

    Polycystic ovary syndrome (PCOS) constitutes the main cause of anovulatory sterility with a near occurrence to 7 %. The PCOS have not a constant hormonal profile, for it has been necessary the employment of approaches like those of Rotterdam to establish the presence of this dysfunction. A surprising discovery was the demonstration of the effect of the insulin on the ovary, that which modified the concept of the specificity in the action of the insulin on certain tissues, therefore a resistance stage to the action of insulin induces a compensatory hyperinsulinism to try to stimulate all the tissues, but in secondary form increases the dysfunction of the ovarian steroidogenesis. There are drugs known as "insulin sensitizers", used in the treatment of certain forms of diabetes mellitus, among those are metformin and tiazolidinediones (roziglitazone and pioglitazone), recently a compound has been used with formulation of amino acids and oligoelements (Diamel) that neutralizes the free radicals reestablishing the intracellular signs of the insulin at cellular level. It is important to guide that long term without correct the PCOS could have back effect since the insulin resistance is associates to a higher risk of increasing impaired glucose, diabetes, dyslipidemia, atherosclerosis and vascular disease. Therefore, preventive measures should be implemented that at present time are to the reach.

  19. Self-adjusting synthetic gene circuit for correcting insulin resistance.

    PubMed

    Ye, Haifeng; Xie, Mingqi; Xue, Shuai; Charpin-El Hamri, Ghislaine; Yin, Jianli; Zulewski, Henryk; Fussenegger, Martin

    2017-01-01

    By using tools from synthetic biology, sophisticated genetic devices can be assembled to reprogram mammalian cell activities. Here, we demonstrate that a self-adjusting synthetic gene circuit can be designed to sense and reverse the insulin-resistance syndrome in different mouse models. By functionally rewiring the mitogen-activated protein kinase (MAPK) signalling pathway to produce MAPK-mediated activation of the hybrid transcription factor TetR-ELK1, we assembled a synthetic insulin-sensitive transcription-control device that self-sufficiently distinguished between physiological and increased blood insulin levels and correspondingly fine-tuned the reversible expression of therapeutic transgenes from synthetic TetR-ELK1-specific promoters. In acute experimental hyperinsulinemia, the synthetic insulin-sensing designer circuit reversed the insulin-resistance syndrome by coordinating expression of the insulin-sensitizing compound adiponectin. Engineering synthetic gene circuits to sense pathologic markers and coordinate the expression of therapeutic transgenes may provide opportunities for future gene- and cell-based treatments of multifactorial metabolic disorders.

  20. 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.

  1. Dietary patterns and the insulin resistance phenotype among non-diabetic adults

    USDA-ARS?s Scientific Manuscript database

    Background: Information on the relation between dietary patterns derived by cluster analysis and insulin resistance is scarce. Objective: To compare insulin resistance phenotypes, including waist circumference, body mass index, fasting and 2-hour post-challenge insulin, insulin sensitivity index (I...

  2. Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance

    PubMed Central

    Petersen, Max C.; Madiraju, Anila K.; Gassaway, Brandon M.; Marcel, Michael; Nasiri, Ali R.; Butrico, Gina; Marcucci, Melissa J.; Zhang, Dongyan; Abulizi, Abudukadier; Zhang, Xian-Man; Philbrick, William; Hubbard, Stevan R.; Samuel, Varman T.; Rinehart, Jesse

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D), but whether NAFLD plays a causal role in the pathogenesis of T2D is uncertain. One proposed mechanism linking NAFLD to hepatic insulin resistance involves diacylglycerol-mediated (DAG-mediated) activation of protein kinase C-ε (PKCε) and the consequent inhibition of insulin receptor (INSR) kinase activity. However, the molecular mechanism underlying PKCε inhibition of INSR kinase activity is unknown. Here, we used mass spectrometry to identify the phosphorylation site Thr1160 as a PKCε substrate in the functionally critical INSR kinase activation loop. We hypothesized that Thr1160 phosphorylation impairs INSR kinase activity by destabilizing the active configuration of the INSR kinase, and our results confirmed this prediction by demonstrating severely impaired INSR kinase activity in phosphomimetic T1160E mutants. Conversely, the INSR T1160A mutant was not inhibited by PKCε in vitro. Furthermore, mice with a threonine-to-alanine mutation at the homologous residue Thr1150 (InsrT1150A mice) were protected from high fat diet–induced hepatic insulin resistance. InsrT1150A mice also displayed increased insulin signaling, suppression of hepatic glucose production, and increased hepatic glycogen synthesis compared with WT controls during hyperinsulinemic clamp studies. These data reveal a critical pathophysiological role for INSR Thr1160 phosphorylation and provide further mechanistic links between PKCε and INSR in mediating NAFLD-induced hepatic insulin resistance. PMID:27760050

  3. Psychological insulin resistance: patient beliefs and implications for diabetes management.

    PubMed

    Brod, Meryl; Kongsø, Jens Harald; Lessard, Suzanne; Christensen, Torsten L

    2009-02-01

    To define and understand patient psychological insulin resistance (PIR) and its impact on diabetes management. Systematic literature review of peer-refereed journals using the MEDLINE database, including all articles in English from 1985 to 2007. The population included patients with type 1 and type 2 diabetes, insulin naïve, and those currently using insulin. A total of 116 articles were reviewed. PIR is impacted by patients' beliefs and knowledge about diabetes and insulin, negative self-perceptions and attitudinal barriers, the fear of side effects and complications from insulin use, as well as lifestyle adaptations, restrictions required by insulin use, and social stigma. These etiological influences, both independently and in combination, constitute a patient's PIR and may result in the reluctance of patients to both initiate and intensify treatment, leading to delayed treatment initiation and compromised glucose control. PIR is complex and multifaceted. It plays an important, although often ignored, role in diabetes management. Assisting health care professionals in better understanding PIR from the patient's perspective should result in improved treatment outcomes. By tailoring treatments to patients' PIR, clinicians may be better able to help their patients begin insulin treatment sooner and improve compliance, thus facilitating target glycemic control.

  4. Allergen exposure induces adipose tissue inflammation and insulin resistance.

    PubMed

    Jung, Chien-Cheng; Tsai, Yau-Sheng; Chang, Chih-Ching; Cheng, Tsun-Jen; Chang, Ching-Wen; Liu, Ping-Yen; Chiu, Yi-Jen; Su, Huey-Jen

    2014-11-01

    This study investigates whether exposure to allergen elicits insulin resistance as a result of adipose tissue inflammation. Male C57BL/6 mice were challenged with ovalbumin (OVA) allergen for 12 weeks, and blood and adipose tissue samples were collected at 24h after the last challenge. Levels of adhesion molecules, fasting insulin, fasting glucose, and adipokines in the blood were analyzed, and fasting homeostasis model assessment was applied to determine insulin resistance (HOMA-IR). The expression of pro- and anti-inflammatory genes in dissected adipose tissues was analyzed by real-time RT-PCR. Our results showed that OVA exposure increased insulin resistance as well as resistin and E-selectin, but reduced adiponectin in the serum. Resistin level was significantly correlated with HOMA-IR. Moreover, in adipose tissues of OVA-challenged mice, the pro-inflammatory M1 genes were more abundant while the anti-inflammatory M2 genes were less than those of PBS-treated mice. The expressional changes of both M1 and M2 genes were significantly associated with serum levels of adiponectin, resistin, and E-selectin. Hematoxylin and eosin (HE) and immunohistochemistry (IHC) stain also showed that there was more obvious inflammation in OVA-challenged mice. In conclusion, the current study suggests the relationship between allergen-elicited adipose tissue inflammation and circulating inflammatory molecules, which are possible mediators for the development of insulin resistance. Therefore, we propose that allergen exposure might be one risk factor for insulin resistance. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. Gut microbiota interactions with obesity, insulin resistance and type 2 diabetes: did gut microbiote co-evolve with insulin resistance?

    PubMed

    Esteve, Eduardo; Ricart, Wifredo; Fernández-Real, Jose-Manuel

    2011-09-01

    The prevalence of obesity, insulin resistance and type 2 diabetes has steadily increased in the last decades. In addition to the genetic and environmental factors, gut microbiota may play an important role in the modulation of intermediary phenotypes leading to metabolic disease. Obesity and type 2 diabetes are associated with specific changes in gut microbiota composition. The mechanisms underlying the association of specific gut microbiota and metabolic disease include increasing energy harvest from the diet, changes in host gene expression, energy expenditure and storage, and alterations in gut permeability leading to metabolic endotoxemia, inflammation and insulin resistance. In some studies, the modifications of gut microbiota induced by antibiotics, prebiotics and probiotics led to improved inflammatory activity in parallel to amelioration of insulin sensitivity and decreased adiposity. However, these effects were mainly observed in animal models. Their extrapolation to humans awaits further studies. The fascinating role of gut microbiota on metabolic disease opens new avenues in the treatment of obesity, insulin resistance and type 2 diabetes. A co-evolutionary clue for microbiota and insulin resistance is suggested.

  6. Adipose extracellular matrix remodelling in obesity and insulin resistance.

    PubMed

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

    2016-11-01

    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. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Adipose proteome analysis: focus on mediators of insulin resistance

    PubMed Central

    Chen, Xiaoli; Hess, Sonja

    2009-01-01

    As is well known, adipose tissue is an important site for lipid metabolism and insulin-responsive glucose uptake. The recent discovery of the endocrine function of adipose tissue and the association of obesity with chronic low-grade inflammation in adipose tissue has reinforced the concept of the central role of adipose tissue in mediating obesity-linked insulin resistance and metabolic dysregulation. The study of adipose cells has provided new insights into the mechanism underlying insulin resistance as well as the therapeutic strategies for diabetes. Numerous efforts have been made in identifying key molecular regulators of insulin action and metabolism, including the utilization of advanced proteomics technology. Various proteomic approaches have been applied to identify the adipose secretome, protein-expression profiling and post-translational modifications in adipose cells in the pathological state. In this review, we summarize the recent advances in the proteomics of adipose tissue, and discuss the identified proteins that potentially play important roles in insulin resistance and diabetes. PMID:19086862

  8. Stevioside inhibits atherosclerosis by improving insulin signaling and antioxidant defense in obese insulin-resistant mice.

    PubMed

    Geeraert, B; Crombé, F; Hulsmans, M; Benhabilès, N; Geuns, J M; Holvoet, P

    2010-03-01

    Stevioside is a non-caloric natural sweetener that does not induce a glycemic response, making it attractive as sweetener to diabetics and others on carbohydrate-controlled diets. Obesity is frequently associated with insulin resistance and increased inflammation and oxidative stress. Therefore, we investigated its effects on insulin resistance, inflammation and oxidative stress related to atherosclerosis in obese insulin-resistant mice. Twelve-week-old mice were treated with stevioside (10 mg kg(-1), n=14) or placebo (n=20) for 12 weeks. Stevioside had no effect on weight and triglycerides, but lowered glucose and insulin. Stevioside treatment improved adipose tissue maturation, and increased glucose transport, insulin signaling and antioxidant defense in white visceral adipose tissues. Together, these increases were associated with a twofold increase of adiponectin. In addition, stevioside reduced plaque volume in the aortic arch by decreasing the macrophage, lipid and oxidized low-density lipoprotein (ox-LDL) content of the plaque. The higher smooth muscle cell-to-macrophage ratio was indicative for a more stable plaque phenotype. The decrease in ox-LDL in the plaque was likely due to an increase in the antioxidant defense in the vascular wall, as evidenced by increased Sod1, Sod2 and Sod3. Circulating adiponectin was associated with improved insulin signaling and antioxidant defense in both the adipose tissue and the aorta of stevioside-treated mice. Stevioside treatment was associated with improved insulin signaling and antioxidant defense in both the adipose tissue and the vascular wall, leading to inhibition of atherosclerotic plaque development and inducing plaque stabilization.

  9. Coffee, nutritional status, and renal artery resistive index.

    PubMed

    Trovato, Guglielmo M; Pirri, Clara; Martines, Giuseppe Fabio; Trovato, Francesca; Catalano, Daniela

    2010-01-01

    The relationship between nutrition and atherosclerosis is known, even dissociated from protein malnutrition. Cardiovascular impact of several nutrients is known; among them the action of coffee is still debated and cardiovascular effect of caffeine has been investigated without definite results. The aim of this study is to investigate whether coffee habits, and/or quantity of coffee consumption, have any relationship with renal resistive index (RRI), a hallmark of arterial stiffness (AS). The relationship of AS with nutritional status assessed by body composition and serum albumin, insulin resistance (assessed by HOMA), and renal function assessed by glomerular filtration rate (GFR) is concurrently investigated. This study was done with 221 consecutive patients, without diabetes, cancer, liver, renal, and heart disease, referred for clinical noninvasive assessment and nutritional counseling: 124 essential hypertensive and 97 nonhypertensive patients were eligible. Personalized Mediterranean diet, physical activity increase, and smoking withdrawal counseling were provided. By multiple linear regression, fat-free mass (FFM), HOMA (positive relationship), and number of cups of coffee/day (negative relationship) account for 17.2% of the variance to RRI. By odds ratios lower risk to increased RRI is associated with higher serum albumin, higher hemoglobin, and FFM; greater risk is associated with hypertension, insulin resistance (HOMA ≥ 3.0), and renal insufficiency (GFR ≤ 90); coffee, assessed by number of cups/day, reduces risk. Coffee use is inversely associated with RRI. Habitual coffee users have risk protection to higher RRI; lower serum albumin, insulin resistance, and renal insufficiency are associated with greater RRI.

  10. [Insulin sensitizer--anti-diabetic drugs, metformin and pioglitazone that can improve insulin resistance].

    PubMed

    Korenaga, Masaaki; Kawaguchi, Koutaro; Korenaga, Keiko; Uchida, Kouichi; Sakaida, Iso

    2006-06-01

    Nonalcoholic steatohepatitis (NASH), which is considered the hepatic manifestation of the metabolic syndrome is an increasingly cause of chronic liver disease in Japan. NASH is finally lead to liver cirrhosis and hepatocellular carcinoma as viral hepatitis, therefore, medical treatment should be considered, when NASH occurs. Treatment of patients with metabolic syndrome has been focused on the management of associated conditions such as obesity, hyperlipidemia, hypertension and hyperinsulinemia. Insulin resistance, that could accelerate liver inflammation and fibrosis by up-regulation of TNFa seems to be most important factor in many cases of NASH. The insulin-sensitizing drugs, which were biguanides (metformin) and thiazolidinediones (pioglitazone) have been shown to correct not only insulin resistance but also steatosis and inflammation in the liver. Metformin and pioglitazone might be useful drugs against NASH, however further investigations were needed.

  11. Role of PTEN in TNFα induced insulin resistance

    SciTech Connect

    Bulger, David A.; Conley, Jermaine; Conner, Spencer H.; Majumdar, Gipsy; Solomon, Solomon S.

    2015-06-05

    Aims/hypothesis: PTEN may play a reversible role in TNFα induced insulin resistance, which has been linked to obesity-associated insulin resistance (IR). Methods: Western blots for PTEN and p-Akt were performed on H-411E liver cells incubated with insulin, TNFα, and in selected experiments VO-OHpic vanadium complex in the presence and absence of PTEN siRNA. Total PTEN was compared to β-actin loading control and p-Akt was compared to total Akt. Results: Western blot and Real Time RT-PCR experiments showed increased PTEN after TNFα treatment (p = 0.04); slightly decreased PTEN after insulin treatment; and slightly increased PTEN after insulin + TNFα treatment. PTEN siRNA markedly inhibited the TNFα-induced increase in PTEN (p < 0.01) without significantly changing the p-Akt levels. The vanadium complex, exhibiting insulin-like effects, also significantly prevented the TNFα-induced increase in PTEN. Combining insulin and VO-OHpic was additive, providing both proof of concept and insight into mechanism. Discussion: The PTEN increase due to TNFα treatment was reversible by both PTEN siRNA knockdown and VO-OHpic treatment. Thus, PTEN is identified as a potential new therapeutic target for reducing IR in Type 2 DM. - Highlights: • TNFα treatment induced a significant increase in PTEN in H-411E liver cells. • PTEN siRNA knockdown prevented this effect. • VO-OHpic (vanadium complex) treatment, like insulin, decreased PTEN protein levels. • Thus, PTEN is identified as a potential therapeutic target in DM Type 2.

  12. Is Insulin Resistance a Feature of or a Primary Risk Factor for Cardiovascular Disease?

    PubMed

    Laakso, Markku

    2015-12-01

    The two major pathophysiological abnormalities in type 2 diabetes are insulin resistance and impaired insulin secretion. Insulin resistance is a general term meaning that insulin does not exert its normal effects in insulin-sensitive target tissues, such as skeletal muscle, adipose tissue, and liver, the major target tissues for insulin action in glucose metabolism. Insulin resistance (IR) promotes cardiovascular disease via multiple mechanisms, including changes in classic cardiovascular risk factors and downregulation of the insulin signaling pathways in different tissues. This review presents evidence for the association of insulin resistance with cardiovascular disease from clinical and population-based studies. The causality of the association of insulin resistance with cardiovascular disease is discussed on the basis of recent findings from the Mendelian randomization studies.

  13. 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.

  14. Delayed insulin transport across endothelium in insulin-resistant JCR:LA-cp rats.

    PubMed

    Wascher, T C; Wölkart, G; Russell, J C; Brunner, F

    2000-05-01

    Capillary endothelial cells are thought to limit the transport of insulin across the endothelium, resulting in attenuated insulin action at target sites. Whether endothelial insulin transport is altered in dysglycemic insulin-resistant states is not clear and was therefore investigated in the JCR:LA-cp corpulent male rat, which exhibits the metabolic syndrome of obesity, insulin resistance, hyperlipidemia, and hyperinsulinemia. Lean littermates that did not develop these alterations served as controls. Animals of both groups were normotensive (mean arterial pressure 136+/-2 mmHg). Hearts from obese and lean rats aged 7 (n = 6) or 18 (n = 8) weeks were perfused in vitro at 10 ml/min per gram wet wt over 51 min with Krebs-Henseleit buffer containing 0.1 or 0.5 U human insulin/l (equivalent to 0.6 and 3 nmol/l). Interstitial fluid was collected using a validated method, and interstitial insulin was determined with a radioimmunoassay. At 0.1 U/l, insulin transfer velocity was similar in both experimental groups (half-times of transfer: 11+/-0.2 min in obese and 18+/-4 min in lean rats; NS), but at 0.5 U/l, the respective half-times were 7+/-1 min in lean and 13+/-2 min in obese rats (P < 0.05). The steady-state level of insulin in the interstitium was 34+/-1% of the vascular level at 0.1 U/l and reached the vascular level (102+/-2%) at 0.5 U/l in both lean and obese rats. In rats aged 18 weeks, the half-times of insulin transfer were 31+/-2 and 14+/-l min in obese rats and 10+/-0.3 and 7+/-0.3 min in lean rats (P < 0.05). Again, interstitial steady-state levels were similar in both groups. Finally, postprandial insulin dynamics were simulated over a period of 120 min with a peak concentration of 0.8 U/l in rats aged 27 weeks (n = 4). The maximal interstitial level was 0.38+/-0.02 U/l in lean rats and 0.24+/-0.02 U/l in obese rats (P < 0.05), and a similar difference was noted throughout insulin infusion (areas under the transudate concentration-time curves: 17 and 11 U

  15. Linking mitochondrial bioenergetics to insulin resistance via redox biology.

    PubMed

    Fisher-Wellman, Kelsey H; Neufer, P Darrell

    2012-03-01

    Chronic overnutrition and physical inactivity are major risk factors for insulin resistance and type 2 diabetes. Recent research indicates that overnutrition generates an increase in hydrogen peroxide (H(2)O(2)) emission from mitochondria, serving as a release valve to relieve the reducing pressure created by fuel overload, as well as a primary signal that ultimately decreases insulin sensitivity. H(2)O(2) is a major input to cellular redox circuits that link to cysteine residues throughout the entire proteome to regulate cell function. Here we review the principles of mitochondrial bioenergetics and redox systems biology and offer new insight into how H(2)O(2) emission may be linked via redox biology to the etiology of insulin resistance. Copyright © 2011 Elsevier Ltd. All rights reserved.

  16. Linking mitochondrial bioenergetics to insulin resistance via redox biology

    PubMed Central

    Fisher-Wellman, Kelsey H.; Neufer, P. Darrell

    2012-01-01

    Chronic overnutrition and physical inactivity are major risk factors for insulin resistance and type 2 diabetes. Recent research indicates that overnutrition generates an increase in hydrogen peroxide (H2O2) emission from mitochondria, serving as a release valve to relieve the reducing pressure created by fuel overload, as well as a primary signal to ultimately decrease insulin sensitivity. H2O2 is a major input to cellular redox circuits that link to cysteine residues throughout the entire proteome to regulate cell function. Here we review the principles of mitochondrial bioenergetics and redox systems biology and offer new insight as to how H2O2 emission may be linked via redox biology to the etiology of insulin resistance. PMID:22305519

  17. Influence of magnesium on insulin resistance in obese women.

    PubMed

    Cruz, Kyria Jayanne Clímaco; de Oliveira, Ana Raquel Soares; Pinto, Denise Pereira; Morais, Jennifer Beatriz Silva; Lima, Fabiana da Silva; Colli, Célia; Torres-Leal, Francisco Leonardo; Marreiro, Dilina do Nascimento

    2014-09-01

    The present study evaluated the influence of magnesium on insulin resistance in obese women. A case-control study involving 114 women on the age between 20 and 50 years old, divided into two groups: control (eutrophic women, n = 59) and case (obese women, n = 55). The analysis of magnesium intake was carried out through the 3-day food record and also NutWin software version 1.5. The plasma, erythrocyte, and urinary magnesium concentrations were determined by flame atomic absorption spectrophotometry. The determinations of serum glucose and serum insulin were performed by enzymatic colorimetric method and chemiluminescence, respectively. The insulin resistance was assessed by homeostasis model assessment insulin resistance (HOMA-IR). The mean values of magnesium intake were lower than those recommended, without difference between groups (p > 0.05). All the patients who were evaluated showed adequate mean concentrations of magnesium in the plasma and erythrocyte. The urinary excretion of this mineral was lower than the reference values in both groups and did not show significant difference (p > 0.05). The values of serum glucose, serum insulin, and HOMA-IR were higher in obese women compared to the control group. A negative correlation was observed between erythrocyte magnesium and glycemic parameters (p < 0.05). Obese patients take in foods with low dietary magnesium content, and they show hypomagnesuria as a compensatory mechanism to keep the plasma concentration of this mineral in adequate levels. The correlation between the erythrocyte magnesium concentration and the parameters of glycemic control suggests the influence of this mineral on the index of insulin resistance in obese women.

  18. Fenretinide ameliorates insulin resistance and fatty liver in obese mice.

    PubMed

    Koh, In-uk; Jun, Hye-Seung; Choi, Joo Sun; Lim, Joo Hyun; Kim, Won Ho; Yoon, Jong Bok; Song, Jihyun

    2012-01-01

    Fenretinide (FEN), a ligand of retinol binding protein 4 (RBP4), has been suggested as a measure to reduce insulin resistance and its associated disorders such as obesity, and fatty liver by reducing serum RBP4. We investigated whether there is another possible mechanism by which fenretinide reduces insulin resistance and fatty liver in genetically obese (ob/ob) mice. Male obese mice fed a high-fat diet (45% of calories from fat) were divided into two groups (n=13 each). One (FEN) received fenretinide (20 mg/kg body weight, intraperitoneally) and the other (O) received vehicle three times weekly for 24 d. C57BL/6J mice fed a normal-fat diet (16% of calories from fat) were used as a control (C; n=13). No changes in fat weight and serum leptin level could be observed in FEN mice. Lower plasma RBP4 was observed in FEN mice compared with O mice. Fenretinide improved whole-body insulin sensitivity based on glucose and insulin tolerance tests and the homeostasis model assessment of insulin resistance. Fenretinide decreased the plasma lipid (triglyceride, cholesterol, and free-fatty acid) levels, hepatic TG level, and histological steatosis score. The mechanism by which fenretinide prevents fatty liver may be explained by an increased plasma adiponectin level, increased activation of hepatic AMP-activated protein kinase, and the expression of peroxisome proliferator-activated protein-α and peroxisomal acyl-CoA oxidase, which promote fat oxidation. FEN alleviated insulin resistance and fatty liver in obese mice and thus may act as an anti-lipidemic and anti-diabetic drug.

  19. Subchronic sleep restriction causes tissue-specific insulin resistance.

    PubMed

    Rao, Madhu N; Neylan, Thomas C; Grunfeld, Carl; Mulligan, Kathleen; Schambelan, Morris; Schwarz, Jean-Marc

    2015-04-01

    Short sleep duration is associated with an increased risk of type 2 diabetes. Subchronic sleep restriction (SR) causes insulin resistance, but the mechanisms and roles of specific tissues are unclear. The purpose of this article was to determine whether subchronic SR altered (1) hepatic insulin sensitivity, (2) peripheral insulin sensitivity, and (3) substrate utilization. This was a randomized crossover study in which 14 subjects underwent 2 admissions separated by a washout period. Each admission had 2 acclimatization nights followed by 5 nights of either SR (4 hours time in bed) or normal sleep (8 hours time in bed). MAIN OUTCOME MEASURE/METHODS: Insulin sensitivity (measured by hyperinsulinemic-euglycemic clamp) and hepatic insulin sensitivity (measured by stable isotope techniques) were measured. In addition, we assayed stress hormone (24-hour urine free cortisol, metanephrine, and normetanephrine), nonesterified fatty acid (NEFA), and β-hydroxybutyrate (β-OH butyrate) levels. Resting energy expenditure (REE) and respiratory quotient (RQ) were measured by indirect calorimetry. Compared to normal sleep, whole-body insulin sensitivity decreased by 25% (P = .008) with SR and peripheral insulin sensitivity decreased by 29% (P = .003). Whereas hepatic insulin sensitivity (endogenous glucose production) did not change significantly, percent gluconeogenesis increased (P = .03). Stress hormones increased modestly (cortisol by 21%, P = .04; metanephrine by 8%, P = .014; normetanephrine by 18%, P = .002). Fasting NEFA and β-OH butyrate levels increased substantially (62% and 55%, respectively). REE did not change (P = 0.98), but RQ decreased (0.81 ± .02 vs 0.75 ± 0.02, P = .045). Subchronic SR causes unique metabolic disturbances characterized by peripheral, but not hepatic, insulin resistance; this was associated with a robust increase in fasting NEFA levels (indicative of increased lipolysis), decreased RQ, and increased β-OH butyrate levels (indicative of whole

  20. Associations of erythrocyte fatty acid patterns with insulin resistance

    USDA-ARS?s Scientific Manuscript database

    Background: Synergistic and/or additive effects on cardiometabolic risk may be missed by examining individual fatty acids (FA). A pattern analysis may be a more useful approach. As well, it remains unclear whether erythrocyte fatty acid composition relates to insulin resistance among Hispanic/Latino...

  1. 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…

  2. Compensatory islet response to insulin resistance revealed by quantitative proteomics

    SciTech Connect

    El Ouaamari, Abdelfattah; Zhou, Jian -Ying; Liew, Chong Wee; Shirakawa, Jun; Dirice, Ercument; Gedeon, Nicholas; Kahraman, Sevim; De Jesus, Dario F.; Bhatt, Shweta; Kim, Jong -Seo; Clauss, Therese R. W.; Camp, II, David G.; Smith, Richard D.; Qian, Wei -Jun; Kulkarni, Rohit N.

    2015-07-07

    Compensatory islet response is a distinct feature of the pre-diabetic insulin resistant state in humans and rodents. To identify alterations in the islet proteome that characterize the adaptive response, we analyzed islets from five-month-old male control, high-fat diet fed (HFD) or obese ob/ob mice by LC-MS(/MS) and quantified ~1,100 islet proteins (at least two peptides) with a false discovery rate <1%. Significant alterations in abundance were observed for ~350 proteins between groups. A majority of alterations were common to both models, and the changes of a subset of ~40 proteins and 12 proteins were verified by targeted quantification using selected reaction monitoring and Western blots, respectively. The insulin resistant islets in both groups exhibited reduced expression of proteins controlling energy metabolism, oxidative phosphorylation, hormone processing, and secretory pathways. Conversely, an increased expression of molecules involved in protein synthesis and folding suggested effects in endoplasmic reticulum stress response, cell survival, and proliferation in both insulin resistant models. In conclusion, we report a unique comparison of the islet proteome that is focused on the compensatory response in two insulin resistant rodent models that are not overtly diabetic. In conclusion, these data provide a valuable resource of candidate proteins to the scientific community to undertake further studies aimed at enhancing β-cell mass in patients with diabetes. The data are available via the MassIVE repository, with accession MSV000079093.

  3. Compensatory islet response to insulin resistance revealed by quantitative proteomics

    DOE PAGES

    El Ouaamari, Abdelfattah; Zhou, Jian -Ying; Liew, Chong Wee; ...

    2015-07-07

    Compensatory islet response is a distinct feature of the pre-diabetic insulin resistant state in humans and rodents. To identify alterations in the islet proteome that characterize the adaptive response, we analyzed islets from five-month-old male control, high-fat diet fed (HFD) or obese ob/ob mice by LC-MS(/MS) and quantified ~1,100 islet proteins (at least two peptides) with a false discovery rate <1%. Significant alterations in abundance were observed for ~350 proteins between groups. A majority of alterations were common to both models, and the changes of a subset of ~40 proteins and 12 proteins were verified by targeted quantification using selectedmore » reaction monitoring and Western blots, respectively. The insulin resistant islets in both groups exhibited reduced expression of proteins controlling energy metabolism, oxidative phosphorylation, hormone processing, and secretory pathways. Conversely, an increased expression of molecules involved in protein synthesis and folding suggested effects in endoplasmic reticulum stress response, cell survival, and proliferation in both insulin resistant models. In conclusion, we report a unique comparison of the islet proteome that is focused on the compensatory response in two insulin resistant rodent models that are not overtly diabetic. In conclusion, these data provide a valuable resource of candidate proteins to the scientific community to undertake further studies aimed at enhancing β-cell mass in patients with diabetes. The data are available via the MassIVE repository, with accession MSV000079093.« less

  4. 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...

  5. Molecular mechanisms for insulin resistance in treated HIV-infection

    PubMed Central

    Hruz, Paul W.

    2010-01-01

    Identification and characterization of the molecular mechanisms contributing to the high incidence of insulin resistance in HIV infected patients treated with combined antiretroviral therapy remains a critically important goal in the quest to improve the safety of antiretroviral treatment regimens. The use of in vitro model systems together with the investigation of drug-mediated effects on glucose homeostasis in animals and healthy human volunteers has provided important insight into the contribution of individual drugs to insulin resistance and affected cellular pathways. HIV protease inhibitor mediated blockade of glucose transport and nucleoside reverse transcriptase inhibitor mediated mitochondrial toxicity have been well characterized. Together with growing understanding of mediators of insulin resistance in non-HIV metabolic syndrome, additional cellular effects including the induction of endoplasmic reticulum and oxidative stress, altered adipocytokine secretion, and lipotoxicity have been integrated into this developing picture. Further elucidation of these mechanisms provides potential for the continued development of safer antiviral drugs and targeted treatment of insulin resistance in affected patients. PMID:21663839

  6. Compensatory Islet Response to Insulin Resistance Revealed by Quantitative Proteomics

    PubMed Central

    Gedeon, Nicholas; Kahraman, Sevim; De Jesus, Dario F.; Bhatt, Shweta; Kim, Jong-Seo; Clauss, Therese RW; Camp, David G.; Smith, Richard D.; Qian, Wei-Jun; Kulkarni, Rohit N.

    2015-01-01

    Compensatory islet response is a distinct feature of the pre-diabetic insulin resistant state in humans and rodents. To identify alterations in the islet proteome that characterize the adaptive response, we analyzed islets from five-month-old male control, high-fat diet fed (HFD) or obese ob/ob mice by LC-MS(/MS) and quantified ~1,100 islet proteins (at least two peptides) with a false discovery rate <1%. Significant alterations in abundance were observed for ~350 proteins between groups. A majority of alterations were common to both models, and the changes of a subset of ~40 proteins and 12 proteins were verified by targeted quantification using selected reaction monitoring and Western blots, respectively. The insulin resistant islets in both groups exhibited reduced expression of proteins controlling energy metabolism, oxidative phosphorylation, hormone processing, and secretory pathways. Conversely, an increased expression of molecules involved in protein synthesis and folding suggested effects in endoplasmic reticulum stress response, cell survival, and proliferation in both insulin resistant models. In summary, we report a unique comparison of the islet proteome that is focused on the compensatory response in two insulin resistant rodent models that are not overtly diabetic. These data provide a valuable resource of candidate proteins to the scientific community to undertake further studies aimed at enhancing β-cell mass in patients with diabetes. The data are available via the MassIVE repository, with accession MSV000079093. PMID:26151086

  7. 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…

  8. Insulin continues to induce plasminogen activator inhibitor 1 gene expression in insulin-resistant mice and adipocytes.

    PubMed Central

    Samad, F.; Pandey, M.; Bell, P. A.; Loskutoff, D. J.

    2000-01-01

    BACKGROUND: Although the association between insulin resistance and cardiovascular risk is well established, the underlying molecular mechanisms are poorly understood. The antifibrinolytic molecule plasminogen activator inhibitor 1 (PAI-1) is a cardiovascular risk factor that is consistently elevated in insulin-resistant states such as obesity and non-insulin-dependent diabetes mellitus (NIDDM). The strong positive correlation between this elevated PAI-1 and the degree of hyperinsulinemia not only implicates insulin itself in this increase, but also suggests that PAI-1 is regulated by a pathway that does not become insulin resistant. The data in this report supports this hypothesis. MATERIALS AND METHODS: We show that insulin stimulates PAI-1 gene expression in metabolically insulin-resistant ob/ob mice and in insulin-resistant 3T3-L1 adipocytes. Moreover, we provide evidence that glucose transport and PAI-1 gene expression are mediated by different insulin signaling pathways. These observations suggest that the compensatory hyperinsulinemia that is frequently associated with insulin-resistant states, directly contribute to the elevated PAI-1. CONCLUSIONS: These results provide a potential mechanism for the abnormal increases in cardiovascular risk genes in obesity, NIDDM, and polycystic ovary disease. PMID:11055587

  9. Premature birth and insulin resistance in infancy: A prospective cohort study

    PubMed Central

    Payal, Vikas; Jora, Rakesh; Sharma, Pramod; Gupta, Pradeep Kumar; Gupta, Mukesh

    2016-01-01

    Objective: This study was done to determine the role of prematurity and other variables to predict insulin sensitivity in infancy. Subjects and Methods: In this prospective study, 36 preterm appropriate for gestational age (AGA), 11 preterm small for gestational age (SGA), and 17 term SGA included as study cohort and 36 term AGA as control cohort. Detailed anthropometry assessment was performed at birth, 3, 6, and 9 months and at 9 months, fasting plasma glucose and serum insulin was done. Insulin resistance was determined by using homeostasis model assessment version 2. Results: It is found that preterm AGA (mean difference 0.617, 95% confidence interval [CI]; 0.43–0.80, P = 0.0001), preterm SGA (mean difference 0.764, 95% CI; 0.44–1.09, P = 0.0001), and term AGA (mean difference 0.725, 95% CI; 0.49–0.96, P = 0.0001) group had significantly higher insulin resistance than control. There was no significant difference in between preterm SGA and preterm AGA (mean difference 0.147 95% CI; −0.13–0.42, P = 0.927). In multiple regression models, SGA status (β =0.505) was more significant predictor of insulin resistance index than gestational age (β = −0.481), weight-for-length (β =0.315), and ponderal index (β = −0.194). Conclusion: Preterm birth is a risk factor for the future development of insulin resistance which may develop as early as infancy. PMID:27366716

  10. The correlation of plasma omentin-1 with insulin resistance in non-obese polycystic ovary syndrome.

    PubMed

    Yang, Hai-Yan; Ma, Yan; Lu, Xin-Hong; Liang, Xing-Huan; Suo, Ying-Jun; Huang, Zhen-Xing; Lu, De-Cheng; Qin, Ying-Fen; Luo, Zuo-Jie

    2015-10-01

    Aberrant circulating adipokines are considered to be related to the pathological mechanism of polycystic ovary syndrome (PCOS). This study aims to evaluate the relationship between plasma omentin-1 levels, metabolic and hormonal parameters in the setting of non-obese Chinese women with PCOS. This was a case-controlled, cross-sectional study of 153 non-obese (BMI<25kg/m(2)) PCOS and 114 age-matched healthy non-obese control individuals. Levels of plasma omentin-1, fasting blood glucose, insulin and sexual hormones and ovary volume were analyzed in all subjects. Plasma omentin-1 levels of non-obese PCOS individuals were significantly lower than in healthy non-obese controls. Body Mass Index (BMI), homeostasis model of assessment for insulin resistance index (HOMA-IR), levels of testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), LH/FSH ratio and ovary volume (OV) were significantly higher in subjects with PCOS than controls. In the HOMA-IR stratified subgroups, PCOS individuals with insulin resistance had lower omentin-1 than those without insulin resistance after BMI adjustment. Omentin-1 was negatively correlated with BMI, HOMA-IR and fasting insulin. Multiple linear regressions revealed that BMI contributed to omentin-1 levels. Ovary volume was negatively correlated to HOMA-IR but had no correlation with omentin-1. Plasma omentin-1 concentrations were decreased in the non-obese PCOS group. Insulin resistance could further decrease plasma omentin-1 in non-obese individuals with PCOS independent of BMI status. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  11. Effects of icodextrin on insulin resistance and adipocytokine profiles in patients on peritoneal dialysis.

    PubMed

    Takeguchi, Fumihiro; Nakayama, Masaaki; Nakao, Toshiyuki

    2008-06-01

    Icodextrin peritoneal dialysis solution reportedly benefits patients suffering from metabolic derangement due to glucose load from dialysate. However, the effects of icodextrin on insulin resistance and adipocytokine profile remain unclear. Subjects comprised 14 stable patients on peritoneal dialysis for >6 months. Their mean age was 57 +/- 11 years and the mean duration of peritoneal dialysis was 49 +/- 30 months. Patients were classified into groups according to the index of insulin resistance (index of homeostasis model assessment: HOMA-IR): Group A, HOMA-IR < 2.0 (n = 7); and Group B, HOMA-IR >or= 2.0 (n = 7). Glucose peritoneal dialysis solution was subsequently switched to icodextrin once daily during the night. Changes in HOMA-IR and adipocytokine profiles were examined after three months. The glucose absorption dose tended to decrease in both groups after icodextrin introduction, with significant reductions in Group B. No changes were seen in body mass index, fluid status, peritoneal dialysis dose, residual renal function or fasting plasma glucose levels in either group. Plasma insulin levels were unchanged in Group A, but decreased significantly in Group B. The index of insulin resistance was thus unchanged in Group A (from 1.4 +/- 0.4 to 1.5 +/- 0.8) and significantly decreased in Group B (from 5.9 +/- 2.2 to 3.2 +/- 0.6; P < 0.01). Regarding plasma adipocytokine profiles, no changes were found in plasma leptin, tissue necrosis factor-alpha or total plasminogen activator inhibitor-1 levels in either group. Plasma adiponectin levels were unchanged in Group A, but significantly increased in Group B. Icodextrin solution could ameliorate insulin resistance by decreasing insulin levels due to a reduction in the glucose load and an increase in plasma adiponectin levels.

  12. Insulin Resistance Indices Are Inversely Associated With Vitamin D Binding Protein Concentrations

    PubMed Central

    Huisingh, Carrie; Alvarez, Jessica A.; Wang, Xudong; Gower, Barbara A.

    2014-01-01

    Context: We hypothesized that, similar to the coordinated homeostatic regulation of most hormones, the concentration of free and bioavailable 25-hydroxyvitamin D [25(OH)D] will be tightly controlled by total 25(OH)D and vitamin D binding protein (VDBP) and that the VDBP concentrations will be associated with insulin resistance status. Objective: Our primary objective was to investigate associations between total, free, and bioavailable 25(OH)D and VDBP. We also evaluated the relationships of VDBP with insulin resistance indices. Study Design: The study design was cross-sectional in the setting of a university children's hospital. The relative concentration of bioavailable 25(OH)D to total 25(OH)D [bioavailable 25(OH)D/total 25(OH)D was expressed as a percentage [percentage bioavailable 25(OH)D]. Results: Subjects were 47, postmenarchal, female adolescents, with a mean age of 15.8 ± 1.4 years, a mean body mass index of 23.1 ± 4.0 kg/m2. The total 25(OH)D was strongly associated with VDBP (rho = 0.57, P < .0001). At lower total 25(OH)D concentrations, the concentration of bioavailable 25(OH)D relative to total 25(OH)D was higher (23.8% vs 14.9%, P < .0001), whereas the relative concentration of free 25(OH)D was similar (P = .44). VDBP was inversely associated with fasting insulin (rho = −0.51, P = .0003) and homeostatic model assessment of basal insulin resistance (rho = −0.45, P= .002) and positively with whole-body insulin sensitivity (rho = 0.33, P = .02); these relationships persisted after adjusting for percentage fat and attenuated after adjusting for race. Conclusion: Our data suggest that VDBP concentrations are regulated by total 25(OH)D levels to maintain adequate concentrations of bioavailable 25(OH)D. VDBP concentrations are inversely associated with hyperinsulinemia and insulin resistance. PMID:24170105

  13. Role of adiponectin in insulin-resistant hypertension and atherosclerosis.

    PubMed

    Murakami, Hideyuki; Ura, Nobuyuki; Furuhashi, Masato; Higashiura, Katsuhiro; Miura, Tetsuji; Shimamoto, Kazuaki

    2003-09-01

    Insulin resistance is one of the major risk factors associated with development of hypertension and atherosclerosis. Recent studies have shown that adiponectin, an adipocyte-derived hormone, may be involved in insulin resistance and development of atherosclerosis in diabetes patients. The aim of this study was to examine adiponectin levels in patients with essential hypertension to determine the relationships between adiponectin levels and insulin sensitivity and to examine the relationship of adiponectin with pulse wave velocity (PWV) in a general population based on the results of an epidemiological survey in Japan. In a clinical study, 20 normotensives (NT) and 30 non-treated essential hypertensives (EHT) were hospitalized, and euglycemic hyperinsulinemic glucose clamp (GC) was performed to evaluate insulin sensitivity defined as M value. EHT were divided into insulin-resistant EHT (EHT-R) and insulin-nonresistant EHT (EHT-N) according to the mean -1 SD of the M value of NT as a cut-off point. Fasting plasma glucose (FPG), immunoreactive insulin (IRI), and adiponectin concentrations were measured. There were no significant differences in body mass index (BMI) or FPG among the NT, EHT-N, and EHT-R groups. The M value and adiponectin concentration in EHT-R were significantly lower than those in the NT or EHT-N. The IRI level in the EHT-R was significantly higher than those in the other groups. A positive correlation between adiponectin concentration and M value was found in all subjects, and adiponectin concentration and M value were found to be significant determinants of each other in multiple regression analysis. In an epidemiological study, we studied 391 male inhabitants of rural communities in Hokkaido, Japan. Systolic blood pressure (SBP), BMI, FPG, IRI, and adiponectin were measured in all subjects early in the morning. Homeostasis model assessment (HOMA) values were calculated as an index of insulin sensitivity, and PWV was used as an index of

  14. Roles of mitochondrial fragmentation and reactive oxygen species in mitochondrial dysfunction and myocardial insulin resistance

    SciTech Connect

    Watanabe, Tomoyuki; Saotome, Masao; Nobuhara, Mamoru; Sakamoto, Atsushi; Urushida, Tsuyoshi; Katoh, Hideki; Satoh, Hiroshi; Funaki, Makoto; Hayashi, Hideharu

    2014-05-01

    Purpose: Evidence suggests an association between aberrant mitochondrial dynamics and cardiac diseases. Because myocardial metabolic deficiency caused by insulin resistance plays a crucial role in heart disease, we investigated the role of dynamin-related protein-1 (DRP1; a mitochondrial fission protein) in the pathogenesis of myocardial insulin resistance. Methods and Results: DRP1-expressing H9c2 myocytes, which had fragmented mitochondria with mitochondrial membrane potential (ΔΨ{sub m}) depolarization, exhibited attenuated insulin signaling and 2-deoxy-D-glucose (2-DG) uptake, indicating insulin resistance. Treatment of the DRP1-expressing myocytes with Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (TMPyP) significantly improved insulin resistance and mitochondrial dysfunction. When myocytes were exposed to hydrogen peroxide (H{sub 2}O{sub 2}), they increased DRP1 expression and mitochondrial fragmentation, resulting in ΔΨ{sub m} depolarization and insulin resistance. When DRP1 was suppressed by siRNA, H{sub 2}O{sub 2}-induced mitochondrial dysfunction and insulin resistance were restored. Our results suggest that a mutual enhancement between DRP1 and reactive oxygen species could induce mitochondrial dysfunction and myocardial insulin resistance. In palmitate-induced insulin-resistant myocytes, neither DRP1-suppression nor TMPyP restored the ΔΨ{sub m} depolarization and impaired 2-DG uptake, however they improved insulin signaling. Conclusions: A mutual enhancement between DRP1 and ROS could promote mitochondrial dysfunction and inhibition of insulin signal transduction. However, other mechanisms, including lipid metabolite-induced mitochondrial dysfunction, may be involved in palmitate-induced insulin resistance. - Highlights: • DRP1 promotes mitochondrial fragmentation and insulin-resistance. • A mutual enhancement between DRP1 and ROS ipromotes insulin-resistance. • Palmitate increases DRP1 expression and induces insulin-resistance

  15. Impact of acute psychological stress on cardiovascular risk factors in face of insulin resistance.

    PubMed

    Jones, Kristian T; Shelton, Richard C; Wan, Jun; Li, Li

    2016-11-01

    Individuals with insulin resistance (IR) are at greater risk for cardiovascular disease (CVD). Psychological stress may contribute to develop CVD in IR, although mechanisms are poorly understood. Our aim was to test the hypothesis that individuals with IR have enhanced emotional and physiological responses to acute psychological stress, leading to increased CVD risk. Sixty participants were enrolled into the study, and classified into IR group (n = 31) and insulin sensitive group (n = 29) according to the Quantitative insulin sensitivity check index, which was calculated based on an oral glucose tolerance test. The Trier social stress test, a standardized experimental stress paradigm, was performed on each participant, and emotional and physiological responses were examined. Blood was collected from each subject for insulin, cytokines, and cortisol measurements. Compared with the insulin-sensitive group, individuals with IR had significantly lower ratings of energy and calm, but higher fatigue levels in response to acute stressors. Individuals with IR also showed blunted heart rate reactivity following stress. In addition, the IR status was worsened by acute psychological stress as demonstrated by further increased insulin secretion. Furthermore, individuals with IR showed significantly increased levels of leptin and interleukin-6, but decreased levels of adiponectin, at baseline, stress test, and post-stress period. Our findings in individuals with IR under acute stress would allow a better understanding of the risks for developing CVD and to tailor the interventions for better outcomes.

  16. The hepatitis C virus modulates insulin signaling pathway in vitro promoting insulin resistance.

    PubMed

    del Campo, José A; García-Valdecasas, Marta; Rojas, Lourdes; Rojas, Ángela; Romero-Gómez, Manuel

    2012-01-01

    Insulin is critical for controlling energy functions including glucose and lipid metabolism. Insulin resistance seems to interact with hepatitis C promoting fibrosis progression and impairing sustained virological response to peginterferon and ribavirin. The main aim was to elucidate the direct effect of hepatitis C virus (HCV) infection on insulin signaling both in vitro analyzing gene expression and protein abundance. Huh7.5 cells and JFH-1 viral particles were used for in vitro studies. Experiments were conducted by triplicate in control cells and infected cells. Genes and proteins involved in insulin signaling pathway were modified by HCV infection. Moreover, metformin treatment increased gene expression of PI3K, IRS1, MAP3K, AKT and PTEN more than >1.5 fold. PTP1B, encoding a tyrosin phosphatase, was found highly induced (>3 fold) in infected cells treated with metformin. However, PTP1B protein expression was reduced in metformin treated cells after JFH1 infection. Other proteins related to insulin pathway like Akt, PTEN and phosphorylated MTOR were also found down-regulated. Viral replication was inhibited in vitro by metformin. A strong effect of HCV infection on insulin pathway-related gene and protein expression was found in vitro. These results could lead to the identification of new therapeutic targets in HCV infection and its co-morbidities.

  17. On the paradox insulin resistance/insulin hypersensitivity and obesity: two tales of the same history.

    PubMed

    Guiducci, Letizia; Iervasi, Giorgio; Quinones-Galvan, Alfredo

    2014-06-01

    Insulin resistance (IR) associated with obesity represents a well-known risk factor for chronic disease. IR development may occur to hinder stressful conditions to provide an appropriate energetic supply to non-insulin-sensitive tissues. However, conditions of stress turn out to be 'maladaptive' in the long term, leading to chronic diseases. Paradoxically, insulin hypersensitivity and/or hypersecretion causing post-prandial hypoglycemia resulting in increased food intake and weight gain, can represent an event preceding obesity and IR. By performing an OGTT in obese or obese-prone individuals we observed that tardive post-prandial hypoglycemia (3h from glucose load) is not a rare event (32%); in 12% of cases it paralleled with low insulin levels, resulting in the 'true insulin hypersensitivity'. By using Matsuda-method, we confirmed the presence of insulin hypersensitivity in this group. Therefore the early recognition of this phenomenon could be useful as a predictive biomarker to identify patients prone to develop obesity and obesity related-disorders.

  18. 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

  19. Insulin resistance and gray matter volume in neurodegenerative disease.

    PubMed

    Morris, J K; Vidoni, E D; Perea, R D; Rada, R; Johnson, D K; Lyons, K; Pahwa, R; Burns, J M; Honea, R A

    2014-06-13

    The goal of this study was to compare insulin resistance in aging and aging-related neurodegenerative diseases, and to determine the relationship between insulin resistance and gray matter volume (GMV) in each cohort using an unbiased, voxel-based approach. Insulin resistance was estimated in apparently healthy elderly control (HC, n=21) and neurodegenerative disease (Alzheimer's disease (AD), n=20; Parkinson's disease (PD), n=22) groups using Homeostasis Model Assessment of Insulin Resistance 2 (HOMA2) and intravenous glucose tolerance test (IVGTT). HOMA2 and GMV were assessed within groups through General Linear Model multiple regression. We found that HOMA2 was increased in both AD and PD compared to the HC group (HC vs. AD, p=0.002, HC vs. PD, p=0.003), although only AD subjects exhibited increased fasting glucose (p=0.005). Furthermore, our voxel-based morphometry analysis revealed that HOMA2 was related to GMV in all cohorts in a region-specific manner (p<0.001, uncorrected). Significant relationships were observed in the medial prefrontal cortex (HC), medial temporal regions (AD), and parietal regions (PD). Finally, the directionality of the relationship between HOMA2 and GMV was disease-specific. Both HC and AD subjects exhibited negative relationships between HOMA2 and brain volume (increased HOMA2 associated with decreased brain volume), while a positive relationship was observed in PD. This cross-sectional study suggests that insulin resistance is increased in neurodegenerative disease, and that individuals with AD appear to have more severe metabolic dysfunction than individuals with PD or PD dementia.

  20. Rab5 activity regulates GLUT4 sorting into insulin-responsive and non-insulin-responsive endosomal compartments: a potential mechanism for development of insulin resistance.

    PubMed

    Tessneer, Kandice L; Jackson, Robert M; Griesel, Beth A; Olson, Ann Louise

    2014-09-01

    Glucose transporter isoform 4 (GLUT4) is the insulin-responsive glucose transporter mediating glucose uptake in adipose and skeletal muscle. Reduced GLUT4 translocation from intracellular storage compartments to the plasma membrane is a cause of peripheral insulin resistance. Using a chronic hyperinsulinemia (CHI)-induced cell model of insulin resistance and Rab5 mutant overexpression, we determined these manipulations altered endosomal sorting of GLUT4, thus contributing to the development of insulin resistance. We found that CHI induced insulin resistance in 3T3-L1 adipocytes by retaining GLUT4 in a Rab5-activity-dependent compartment that is unable to equilibrate with the cell surface in response to insulin. Furthermore, CHI-mediated retention of GLUT4 in this non-insulin-responsive compartment impaired filling of the transferrin receptor (TfR)-positive and TfR-negative insulin-responsive storage compartments. Our data suggest that hyperinsulinemia may inhibit GLUT4 by chronically maintaining GLUT4 in the Rab5 activity-dependent endosomal pathway and impairing formation of the TfR-negative and TfR-positive insulin-responsive GLUT4 pools. This model suggests that an early event in the development of insulin-resistant glucose transport in adipose tissue is to alter the intracellular localization of GLUT4 to a compartment that does not efficiently equilibrate with the cell surface when insulin levels are elevated for prolonged periods of time.

  1. Traumatic brain injury and obesity induce persistent central insulin resistance.

    PubMed

    Karelina, Kate; Sarac, Benjamin; Freeman, Lindsey M; Gaier, Kristopher R; Weil, Zachary M

    2016-04-01

    Traumatic brain injury (TBI)-induced impairments in cerebral energy metabolism impede tissue repair and contribute to delayed functional recovery. Moreover, the transient alteration in brain glucose utilization corresponds to a period of increased vulnerability to the negative effects of a subsequent TBI. In order to better understand the factors contributing to TBI-induced central metabolic dysfunction, we examined the effect of single and repeated TBIs on brain insulin signalling. Here we show that TBI induced acute brain insulin resistance, which resolved within 7 days following a single injury but persisted until 28 days following repeated injuries. Obesity, which causes brain insulin resistance and neuroinflammation, exacerbated the consequences of TBI. Obese mice that underwent a TBI exhibited a prolonged reduction of Akt (also known as protein kinase B) signalling, exacerbated neuroinflammation (microglial activation), learning and memory deficits, and anxiety-like behaviours. Taken together, the transient changes in brain insulin sensitivity following TBI suggest a reduced capacity of the injured brain to respond to the neuroprotective and anti-inflammatory actions of insulin and Akt signalling, and thus may be a contributing factor for the damaging neuroinflammation and long-lasting deficits that occur following TBI.

  2. Association between thyroid hormones, insulin resistance, and metabolic syndrome.

    PubMed

    Kumar, Hari K; Yadav, Raj K; Prajapati, Jayaram; Reddy, Challa V K; Raghunath, Manchala; Modi, Kirtikumar D

    2009-07-01

    To determine the association between thyroid hormones, insulin resistance, and metabolic syndrome in euthyroid women. Forty-five women with no past medical history were studied in this cross-sectional study at the Department of Endocrinology, Medwin Hospitals, Hyderabad, India, from August 2008 to September 2008. The body fat was estimated using bio-impedance method, and fasting blood sample was analyzed for total triiodothyronine (T3), total thyroxine (T4), thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), lipid profile, insulin, and glucose. The mean age of the participants was 32.6 +/= 9.6 years with a body mass index (BMI) of 29.9 +/= 3.8 kg/m2. Evidence of homeostasis model assessment index for insulin resistance (HOMA-IR) more than 3 was seen in 34 (75%) and metabolic syndrome in 29 (64%) participants. Total T3 showed a positive correlation with triglycerides, low density lipoprotein- cholesterol (LDL-C), total cholesterol, insulin, HOMA-IR and negatively with body fat. Thyroid-stimulating hormone correlated positively with BMI, insulin, HOMA-IR, LDL-C and negatively with HDL-cholesterol (p<0.05). Free triiodothyronine correlated positively with waist circumference and T4 did not correlate with metabolic syndrome parameters. Our preliminary data show an association between thyroid hormones and some components specific of the metabolic syndrome in euthyroid women. Total triiodothyronine and TSH correlated more with variables of metabolic syndrome than FT3 and T4.

  3. Is myopia another clinical manifestation of insulin resistance?

    PubMed

    Galvis, Virgilio; López-Jaramillo, Patricio; Tello, Alejandro; Castellanos-Castellanos, Yuly Andrea; Camacho, Paul Anthony; Cohen, Daniel Dylan; Gómez-Arbeláez, Diego; Merayo-Lloves, Jesús

    2016-05-01

    Myopia is a multifactorial visual refraction disease, in which the light rays from distant objects are focused in front of retina, causing blurry vision. Myopic eyes are characterized by an increased corneal curvature and/or ocular axial length. The prevalence of myopia has increased in recent decades, a trend that cannot be attributed exclusively to genetic factors. Low and middle income countries have a higher burden of refractive error, which we propose could be a consequence of a shorter exposure time to a westernized lifestyle, a phenomenon that may also explain the rapid increase in cardiometabolic diseases, such as diabetes, among those populations. We suggest that interactions between genetic, epigenetic and a rapidly changing environment are also involved in myopia onset and progression. Furthermore, we discuss several possible mechanisms by which insulin resistance may promote abnormal ocular growth and myopia to support the hypothesis that insulin resistance and hyperinsulinemia are involved in its pathogenesis, providing a link between trends in myopia and those of cardiometabolic diseases. There is evidence that insulin have direct ocular growth promoting effects as well an indirect effect via the induction of insulin-like growth factors leading to decreases insulin-like growth factor-binding protein, also implicated in ocular growth. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Anaesthesia generates neuronal insulin resistance by inducing hypothermia

    PubMed Central

    Holscher, Christian; van Aalten, Lidy; Sutherland, Calum

    2008-01-01

    Background Anaesthesia is commonly employed prior to surgical investigations and to permit icv injections in rodents. Indeed it is standard practise in many studies examining the subsequent actions of hormones and growth factors on the brain. Recent evidence that the basal activity of specific intracellular signalling proteins can be affected by anaesthesia prompted us to examine the effect of anaesthesia not only on the basal activity but also the insulin sensitivity of the major insulin signalling pathways. Results We find that urethane- and ketamine-induced anaesthesia results in rapid activation of the phosphatidylinositol (PI) 3-kinase-protein kinase B (PKB) signalling pathway in the brain, increases tau phosphorylation while at the same time reducing basal activity of the Ras-ERK pathway. Subsequent injection of insulin does not alter the activity of either the PI 3-kinase or ERK signalling pathways, indicating a degree of neuronal molecular insulin resistance. However, if body temperature is maintained during anaesthesia then there is no alteration in the basal activity of these signalling molecules. Subsequent response of both pathways to insulin injection is restored. Conclusion The data is consistent with a hypothermia related alteration in neuronal signalling following anaesthesia, and emphasises the importance of maintaining the body temperature of rodents when monitoring insulin (or growth factor/neurotrophic agent) action in the brain of anesthetised rodents. PMID:18844978

  5. Intrinsic Frequency and the Single Wave Biopsy: Implications for Insulin Resistance.

    PubMed

    Petrasek, Danny; Pahlevan, Niema M; Tavallali, Peyman; Rinderknecht, Derek G; Gharib, Morteza

    2015-07-16

    Insulin resistance is the hallmark of classical type II diabetes. In addition, insulin resistance plays a central role in metabolic syndrome, which astonishingly affects 1 out of 3 adults in North America. The insulin resistance state can precede the manifestation of diabetes and hypertension by years. Insulin resistance is correlated with a low-grade inflammatory condition, thought to be induced by obesity as well as other conditions. Currently, the methods to measure and monitor insulin resistance, such as the homeostatic model assessment and the euglycemic insulin clamp, can be impractical, expensive, and invasive. Abundant evidence exists that relates increased pulse pressure, pulse wave velocity (PWV), and vascular dysfunction with insulin resistance. We introduce a potential method of assessing insulin resistance that relies on a novel signal-processing algorithm, the intrinsic frequency method (IFM). The method requires a single pulse pressure wave, thus the term " wave biopsy."

  6. Cellular mechanisms of insulin resistance: role of stress-regulated serine kinases and insulin receptor substrates (IRS) serine phosphorylation.

    PubMed

    Tanti, Jean-François; Jager, Jennifer

    2009-12-01

    Insulin receptor substrates (IRS) serine phosphorylation is a time-controlled physiological feedback mechanism in insulin signaling that is hijacked by metabolic and inflammatory stresses to promote insulin resistance. Kinases, including IKKbeta, JNK, ERK, mTOR, and S6K, activated by the inducers of insulin resistance induce uncontrolled IRS serine phosphorylation. Studies with genetically modified mice reveal that these kinases integrate signals from metabolic and inflammatory stresses in adipose tissue, liver, and hypothalamus leading to peripheral and central insulin resistance. Moreover, IKKbeta/NF-kappaB and JNK1 pathways in myeloid cells represent a core mechanism involved in inflammation linked to obesity. These kinases are thus potential drug targets against insulin resistance and the targeting of the IKKbeta/NF-kappaB or the JNK pathway may evolve into future diabetes medication.

  7. Insulin resistance in chronic kidney disease: a systematic review.

    PubMed

    Spoto, Belinda; Pisano, Anna; Zoccali, Carmine

    2016-12-01

    Insulin resistance (IR) is an early metabolic alteration in chronic kidney disease (CKD) patients, being apparent when the glomerular filtration rate is still within the normal range and becoming almost universal in those who reach the end stage of kidney failure. The skeletal muscle represents the primary site of IR in CKD, and alterations at sites beyond the insulin receptor are recognized as the main defect underlying IR in this condition. Estimates of IR based on fasting insulin concentration are easier and faster but may not be adequate in patients with CKD because renal insufficiency reduces insulin catabolism. The hyperinsulinemic euglycemic clamp is the gold standard for the assessment of insulin sensitivity because this technique allows a direct measure of skeletal muscle sensitivity to insulin. The etiology of IR in CKD is multifactorial in nature and may be secondary to disturbances that are prominent in renal diseases, including physical inactivity, chronic inflammation, oxidative stress, vitamin D deficiency, metabolic acidosis, anemia, adipokine derangement, and altered gut microbiome. IR contributes to the progression of renal disease by worsening renal hemodynamics by various mechanisms, including activation of the sympathetic nervous system, sodium retention, and downregulation of the natriuretic peptide system. IR has been solidly associated with intermediate mechanisms leading to cardiovascular (CV) disease in CKD including left ventricular hypertrophy, vascular dysfunction, and atherosclerosis. However, it remains unclear whether IR is an independent predictor of mortality and CV complications in CKD. Because IR is a modifiable risk factor and its reduction may lower CV morbidity and mortality, unveiling the molecular mechanisms responsible for the pathogenesis of CKD-related insulin resistance is of importance for the identification of novel therapeutic targets aimed at reducing the high CV risk of this condition.

  8. Intensive insulin treatment induces insulin resistance in diabetic rats by impairing glucose metabolism-related mechanisms in muscle and liver.

    PubMed

    Okamoto, Maristela Mitiko; Anhê, Gabriel Forato; Sabino-Silva, Robinson; Marques, Milano Felipe dos Santos Ferreira; Freitas, Helayne Soares; Mori, Rosana Cristina Tieko; Melo, Karla Fabiana S; Machado, Ubiratan Fabres

    2011-10-01

    Insulin replacement is the only effective therapy to manage hyperglycemia in type 1 diabetes mellitus (T1DM). Nevertheless, intensive insulin therapy has inadvertently led to insulin resistance. This study investigates mechanisms involved in the insulin resistance induced by hyperinsulinization. Wistar rats were rendered diabetic by alloxan injection, and 2 weeks later received saline or different doses of neutral protamine Hagedorn insulin (1.5, 3, 6, and 9 U/day) over 7 days. Insulinopenic-untreated rats and 6U- and 9U-treated rats developed insulin resistance, whereas 3U-treated rats revealed the highest grade of insulin sensitivity, but did not achieve good glycemic control as 6U- and 9U-treated rats did. This insulin sensitivity profile was in agreement with glucose transporter 4 expression and translocation in skeletal muscle, and insulin signaling, phosphoenolpyruvate carboxykinase/glucose-6-phosphatase expression and glycogen storage in the liver. Under the expectation that insulin resistance develops in hyperinsulinized diabetic patients, we believe insulin sensitizer approaches should be considered in treating T1DM.

  9. A novel botanical formula prevents diabetes by improving insulin resistance.

    PubMed

    Kan, Juntao; Velliquette, Rodney A; Grann, Kerry; Burns, Charlie R; Scholten, Jeff; Tian, Feng; Zhang, Qi; Gui, Min

    2017-07-05

    Type 2 diabetes mellitus (T2DM) is a major risk factor for cardiovascular disease, and the prevalence has increased significantly in recent decades to epidemic proportions in China. Individually, fenugreek (Trigonella foenum graecum) seed, mulberry (Morus alba L.) leaf and American ginseng (Panax quinquefolius) root can improve glycemia in various animal models and humans with impaired glucose metabolism and T2DM. The aim of this study was to design an optimized botanical formula containing these herbal extracts as a nutritional strategy for the prevention of insulin resistance and T2DM. Cell-free α-amylase and α-glucosidase enzyme assays were used to determine inhibitory potential of extracts. Glucose uptake was examined in differentiated human adipocytes using radiolabeled 2-deoxyglucose. Male Sprague Dawley rats were divided and glycemia balanced into 5 groups: two controls (naïve and model) and three doses of the botanical test formula containing standardized fenugreek seed, mulberry leaf and American ginseng extracts (42.33, 84.66 and 169.33 mg/kg BW). Insulin resistance and T2DM was induced by feeding animals a high fat diet and with an alloxan injection. Glucose tolerance was examined by measuring serum glucose levels following an oral glucose load. Fenugreek seed and mulberry leaf dose dependently inhibited α-amylase (IC50 = 73.2 μg/mL) and α-glucosidase (IC50 = 111.8 ng/mL), respectively. All three botanical extracts improved insulin sensitivity and glucose uptake in human adipocytes, which lead to the design of an optimized botanical test formula. In a rat model of insulin resistance and T2DM, the optimized botanical test formula improved fasting serum glucose levels, fasting insulin resistance and the development of impaired glucose tolerance. The reduction in epididymal adipose tissue GLUT4 and PDK1 expression induced by high fat diet and alloxan was blunted by the botanical test formula. A novel botanical formula containing standardized

  10. 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

  11. 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.

  12. Saliva as a non-invasive diagnostic tool for inflammation and insulin-resistance.

    PubMed

    Desai, Gauri S; Mathews, Suresh T

    2014-12-15

    Saliva has been progressively studied as a non-invasive and relatively stress-free diagnostic alternative to blood. Currently, saliva testing is used for clinical assessment of hormonal perturbations, detection of HIV antibodies, DNA analysis, alcohol screening, and drug testing. Recently, there has been increasing interest in evaluating the diagnostic potential of saliva in obesity, inflammation, and insulin-resistance. Current literature has demonstrated elevated levels of inflammatory biomarkers including C-reactive protein, tumor necrosis factor-α, interleukin-6, and interferon-γ in saliva of obese/overweight children and adults. Salivary antioxidant status has also been studied as a measure of oxidative stress in individuals with type 2 diabetes. Further, several studies have demonstrated correlations of salivary markers of stress and insulin resistance including cortisol, insulin, adiponectin, and resistin with serum concentrations. These findings suggest the potential diagnostic value of saliva in health screening and risk stratification studies, particularly in the pediatric population, with implications for inflammatory, metabolic and cardiovascular conditions. However, additional studies are required to standardize saliva collection and storage procedures, validate analytical techniques for biomarker detection, and establish reference ranges for routine clinical use. The purpose of this review is to summarize and evaluate recent advancements in using saliva as a diagnostic tool for inflammation and insulin-resistance.

  13. Serum Magnesium Concentrations in the Canadian Population and Associations with Diabetes, Glycemic Regulation, and Insulin Resistance.

    PubMed

    Bertinato, Jesse; Wang, Kuan Chiao; Hayward, Stephen

    2017-03-17

    Total serum magnesium (Mg) concentration (SMC) is commonly used to assess Mg status. This study reports current SMCs of Canadians and their associations with demographic factors, diabetes, and measures of glycemic control and insulin resistance using results from the Canadian Health Measures Survey cycle 3 (2012-2013). Associations were examined in adults aged 20-79 years using linear mixed models. Mean SMCs and percentile distributions for 11 sex-age groups between 3 and 79 years (n = 5561) are reported. SMCs were normally distributed and differences (p < 0.05) among sex and age groups were small. Between 9.5% and 16.6% of adult sex-age groups had a SMC below the lower cut-off of a population-based reference interval (0.75-0.955 mmol·L(-1)) established in the United States population as part of the NHANES I conducted in 1971-1974. Having diabetes was associated with 0.04 to 0.07 mmol·L(-1) lower SMC compared to not having diabetes in the various models. Body mass index, glycated hemoglobin, serum glucose and insulin concentrations, and homeostatic model assessment of insulin resistance were negatively associated with SMC. This is the first study to report SMCs in a nationally representative sample of the Canadian population. A substantial proportion of Canadians are hypomagnesaemic in relation to a population-based reference interval, and SMC was negatively associated with diabetes and indices of glycemic control and insulin resistance.

  14. Spirulina protects against rosiglitazone induced osteoporosis in insulin resistance rats.

    PubMed

    Gupta, Sumeet; Hrishikeshvan, H J; Sehajpal, Prabodh K

    2010-01-01

    The study was undertaken to assess the protective effect of Spirulina fusiformis extract against Rosiglitazone induced osteoporosis and pharmacodynamic effects of Rosiglitazone with Spirulina in treating hyperglycemia and hyperlipidemia of insulin resistance rat. For this aim, 30 Wistar albino rats were equally divided into five groups as control (C), diabetes mellitus (DM), diabetes mellitus+Rosiglitazone (DM+R), diabetes mellitus+Spirulina (DM+S), and diabetes mellitus+Rosiglitazone+Spirulina (DM+R+S). Serum glucose, triglyceride, HDL, LDL and insulin concentrations were estimated by routine standard methods in blood samples collected on 21th day. Integrity of the bone surface was examined by scanning electronic microscopy, and bone strength was measured by micro-hardness test on 45th day. A significant decrease in total bone mineral density was observed in group DM+R rats (p<0.05). The number and depth of resorptive pits on surface of the bone in Rosiglitazone treated rats improved clearly with Spirulina administration. The intactness and integrity of the bone surface as well as the bone strength improved due to the high content of calcium and phosphorous in Spirulina. Besides, chromium and gamma-linoleic acid in Spirulina helped to decrease the fasting serum glucose, HDL, LDL and triglycerides levels in insulin resistance rats. These findings suggest that combination therapy of Rosiglitazone with Spirulina reduced the risk of osteoporosis in insulin resistance rats. Additionally, Spirulina complemented the antihyperglycemic and antilipidemic activity of Rosiglitazone. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

  15. Insulin induces a shift in lipid and primary carbon metabolites in a model of fasting-induced insulin resistance.

    USDA-ARS?s Scientific Manuscript database

    Peripheral insulin resistance shifts metabolic fuel use away from carbohydrates, and towards lipids, and is most commonly associated with Type 2 diabetes mellitus. However, regulated insulin resistance is an evolved mechanism to preserve glucose for the brain in conditions of high demand or carbohy...

  16. Liver enzymes are associated with hepatic insulin resistance, insulin secretion, and glucagon concentration in healthy men and women.

    PubMed

    Bonnet, Fabrice; Ducluzeau, Pierre-Henri; Gastaldelli, Amalia; Laville, Martine; Anderwald, Christian H; Konrad, Thomas; Mari, Andrea; Balkau, Beverley

    2011-06-01

    The pathophysiological mechanisms to explain the association between risk of type 2 diabetes and elevated concentrations of γ-glutamyltransferase (GGT) and alanineaminotransferase (ALT) remain poorly characterized. We explored the association of liver enzymes with peripheral and hepatic insulin resistance, insulin secretion, insulin clearance, and glucagon concentration. We studied 1,309 nondiabetic individuals from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study; all had a euglycemic-hyperinsulinemic clamp and an oral glucose tolerance test (OGTT) with assessment of insulin secretion and hepatic insulin extraction. The hepatic insulin resistance index was calculated in 393 individuals. In both men and women, plasma concentrations of GGT and ALT were inversely related with insulin sensitivity (M/I) (all P < 0.01). Likewise, the hepatic insulin resistance index was positively correlated with both GGT (r = 0.37, P < 0.0001, men; r = 0.36, P < 0.0001, women) and ALT (r = 0.25, P = 0.0005, men; r = 0.18, P = 0.01, women). These associations persisted in multivariable models. Increased GGT and ALT were significantly associated with higher insulin secretion rates and with both reduced endogenous clearance of insulin and hepatic insulin extraction during the OGTT (P = 0.0005 in men; P = 0.003 in women). Plasma fasting glucagon levels increased over ALT quartiles (men, quartile 4 vs. quartile 1 11.2 ± 5.1 vs. 9.3 ± 3.8 pmol/L, respectively, P = 0.0002; women, 9.0 ± 4.3 vs. 7.6 ± 3.1, P = 0.001). In healthy individuals, increased GGT and ALT were biomarkers of both systemic and hepatic insulin resistance with concomitant increased insulin secretion and decreased hepatic insulin clearance. The novel finding of a positive correlation between ALT and fasting glucagon level concentrations warrants confirmation in type 2 diabetes.

  17. JNK and IKKβ phosphorylation is reduced by glucocorticoids in adipose tissue from insulin-resistant rats.

    PubMed

    Motta, Katia; Barbosa, Amanda Marreiro; Bobinski, Franciane; Boschero, Antonio Carlos; Rafacho, Alex

    2015-01-01

    Peripheral insulin resistance (IR) is one of the main side effects caused by glucocorticoid (GC)-based therapies, and the molecular mechanisms of GC-induced IR are not yet fully elucidated. Thus, we aimed to investigate the effects of dexamethasone treatment on the main components of insulin and inflammatory signaling in the adipose tissue of rats. Male Wistar rats received daily injections of dexamethasone (1mg/kg body weight (b.w.), intraperitoneally (i.p.)) for 5 days (DEX), whereas control rats received saline (CTL). The metabolic status was investigated, and the epididymal fat fragments were collected for lipolysis and western blot analyses. The DEX rats became hyperglycemic, hyperinsulinemic, insulin resistant and glucose intolerant, compared with the CTL rats (P<0.05). The basal glycerol release in the fat fragments was 1.5-fold higher in the DEX rats (P<0.05). The phosphorylation of protein kinase B (PKB) at ser(473) decreased by 44%, whereas, the phosphorylation of insulin receptor substrate (IRS)-1 at ser(307) increased by 93% in the adipose tissue of the DEX rats after an oral bolus of glucose (P<0.05). The basal phosphorylation of c-jun-N-terminal kinase (JNK) and inhibitor of nuclear factor kappa-B (IKKβ) proteins was reduced by 46% and 58%, respectively, in the adipose tissue of the DEX rats (P<0.05). This was paralleled with a significant reduction (47%) in the glucocorticoid receptor (GR) protein content in the adipose tissue of the DEX rats (P<0.05). The insulin-resistant status of rats induced by dexamethasone administration have PKB and IRS-1 activity attenuated in epididymal fat without increases in the phosphorylation of the proinflammatory signals JNK and IKKβ. Copyright © 2014 Elsevier Ltd. All rights reserved.

  18. Psychological insulin resistance in geriatric patients with diabetes mellitus.

    PubMed

    Bahrmann, Anke; Abel, Amelie; Zeyfang, Andrej; Petrak, Frank; Kubiak, Thomas; Hummel, Jana; Oster, Peter; Bahrmann, Philipp

    2014-03-01

    To determine the extent to which geriatric patients with diabetes mellitus experience psychological insulin resistance (PIR). A total of 67 unselected geriatric patients with diabetes (mean age 82.8±6.7 years, diabetes duration 12.2 [0.04-47.2] years, 70.1% female) were recruited in a geriatric care center of a university hospital. A comprehensive geriatric assessment (CGA) was performed including WHO-5, Hospital Anxiety and Depression Scale (HADS), Mini Mental State Examination (MMSE) and Barthel-Index. We assessed PIR using the Barriers of Insulin Treatment Questionnaire (BIT) and the Insulin Treatment Appraisal Scale in a face-to-face interview. Insulin-naïve patients (INP) showed higher PIR scores than patients already on insulin therapy (BIT-sum score: 4.3±1.4 vs. 3.2±1.0; p<0.001). INP reported in the BIT increased fear of injection and self-testing (2.4±2.4 vs. 1.3±0.8; p=0.016), expect disadvantages from insulin treatment (2.7±1.6 vs. 1.9±1.4; p=0.04), and fear of stigmatization by insulin injection (5.2±2.3 vs. 3.6±2.6; p=0.008). Fear of hypoglycemia, however, did not differ significantly (6.3±2.8 vs. 5.1±3.1; p=0.11). Depression was not shown to be a barrier to insulin therapy. INP with diabetes have a significantly more negative attitude toward insulin therapy in comparison to patients already on insulin. Systematic assessment of barriers of insulin therapy, individualized diabetes treatment plans and information of patients may help to overcome such negative attitudes, leading to quicker initiation of therapy, improved adherence to treatment and a better quality of life. Copyright © 2013 Elsevier Ireland Ltd. 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. Circulating betatrophin levels are increased in patients with type 2 diabetes and associated with insulin resistance.

    PubMed

    Chen, Xi; Lu, Puhan; He, Wentao; Zhang, Jianhua; Liu, Lei; Yang, Yan; Liu, Zhelong; Xie, Junhui; Shao, Shiying; Du, Tingting; Su, Xianghui; Zhou, Xinrong; Hu, Shuhong; Yuan, Gang; Zhang, Muxun; Zhang, Hong; Liu, Liegang; Wang, Daowen; Yu, Xuefeng

    2015-01-01

    Betatrophin has recently attracted increasing interests as a potential β-cell regenerative therapy in diabetes. However, differences in betatrophin profiles in patients with type 2 diabetes mellitus (T2DM) remain unclear. The objective of the study was to examine circulating betatrophin levels in subjects with different glucose tolerance status and its correlation with insulin resistance. Serum betatrophin levels were measured using an ELISA in age-, sex-, body mass index-, and blood lipid-matched subjects with normal glucose tolerance (n = 137), isolated impaired fasting glucose (n = 69), isolated impaired glucose tolerance (n = 120), and newly diagnosed T2DM (n = 112) from the Risk Evaluation of Cancers in Chinese Diabetic Individuals: A Longitudinal study. Serum betatrophin levels were elevated in patients with T2DM compared with subjects with normal glucose tolerance, isolated impaired fasting glucose, or isolated impaired glucose tolerance (798.6 ± 42.5 vs 692.7 ± 29.0, P < .05, vs 682.7 ± 43.0, P < .05, vs 646.8 ± 34.3 pg/mL, P < .01). Betatrophin levels positively correlated with the index of homeostasis model assessment of insulin resistance (partial r = 0.11); inversely correlated with quantitative insulin sensitivity check index (partial r = -0.11), the Gutt insulin sensitivity index (partial r = -0.12), and the Matsuda insulin sensitivity index (partial r = -0.11) after controlling for age, sex, body mass index, and blood lipid in all participants (all values of P < .05). Circulating betatrophin levels are increased in patients with T2DM and associated with indexes of insulin resistance.

  2. Concentrations of chromium, selenium, and copper in the hair of viscerally obese adults are associated with insulin resistance.

    PubMed

    Kim, Ha-Na; Song, Sang-Wook

    2014-05-01

    Visceral adiposity is linked to the development of insulin resistance, which is a condition that may contribute to metabolic abnormalities and cardiovascular disease. Various minerals play essential roles in different metabolic functions in the body. Thus, the relationships between mineral concentrations in the hair and insulin resistance were analyzed in 144 Korean adults (71 viscerally obese subjects and 73 normal control subjects) in this cross-sectional study. Visceral obesity was measured using a bioelectrical impedance analysis (BIA), and insulin resistance levels were assessed using the homeostasis model assessment insulin resistance (HOMA-IR) index. The viscerally obese group exhibited significantly higher levels of serum glucose (96.5 vs 91.0 mg/dL, P = 0.023), insulin concentration (4.78 vs 2.98 μIU/mL, P = 0.003), and the HOMA-IR index (1.18 vs 0.64, P = 0.003) compared with the normal control group. After adjusting for age and sex, there was a positive correlation between copper levels in the hair and the HOMA-IR index in the viscerally obese group (r = 0.241, P = 0.046) whereas chromium and selenium levels in the hair were negatively correlated with the HOMA-IR index (r = -0.256, P = 0.034, and r = -0.251, P = 0.038, respectively). Thus, chromium and selenium levels in the hair of viscerally obese adults were inversely associated with insulin resistance, whereas copper levels in the hair were positively associated with insulin resistance. This suggests that the mineral status of viscerally obese adults might play a role in the development of insulin resistance.

  3. Insulin resistance: a chicken that has come to roost.

    PubMed

    Reaven, G M

    1999-11-18

    Insulin-mediated glucose disposal varies approximately 10-fold in apparently healthy human beings. Insulin (I)-resistant individuals can remain glucose tolerant if the pancreas compensates for this defect by secreting large amounts of I. Type 2 diabetes develops when I-resistant persons cannot sustain this state of compensatory hyperinsulinemia (increases I). However, the ability of increases I to prevent decompensation of glucose tolerance is a mixed blessing, and the combination of I resistance and increases I predisposes such individuals to develop a series of abnormalities that increase risk of coronary heart disease (CHD). Given the health-related consequences of I resistance and increases I, it has been suggested that a "thrifty" genotype exists that favored evolutionary survival by enhancing I secretion and thereby promoting energy accumulation. An alternative view is that conservation of muscle mass was necessary for survival, and that muscle I resistance was the "thrifty" genotype. This latter hypothesis is more consistent with current data, and there is evidence of a genetic basis for I resistance. In either case, there is little question as to the importance of I resistance and related abnormalities in diseases of Western civilization. However, the strength of the association between I resistance and its consequences varies in magnitude, and it is necessary to emphasize that development of a clinical end-point will vary as a function of (1) degree of I resistance; (2) "closeness" of I resistance to the end-point; and (3) the ability to compensate for the effects of I resistance. I resistance is a physiological characteristic, genetically determined, that helped primitive humans to survive. It is greatly aggravated by obesity and physical inactivity, and represents a modern scourge.

  4. Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus

    PubMed Central

    Tangvarasittichai, Surapon

    2015-01-01

    Oxidative stress is increased in metabolic syndrome and type 2 diabetes mellitus (T2DM) and this appears to underlie the development of cardiovascular disease, T2DM and diabetic complications. Increased oxidative stress appears to be a deleterious factor leading to insulin resistance, dyslipidemia, β-cell dysfunction, impaired glucose tolerance and ultimately leading to T2DM. Chronic oxidative stress, hyperglycemia and dyslipidemia are particularly dangerous for β-cells from lowest levels of antioxidant, have high oxidative energy requirements, decrease the gene expression of key β-cell genes and induce cell death. If β-cell functioning is impaired, it results in an under production of insulin, impairs glucose stimulated insulin secretion, fasting hyperglycemia and eventually the development of T2DM. PMID:25897356

  5. Induction of heat shock proteins may combat insulin resistance.

    PubMed

    McCarty, Mark F

    2006-01-01

    The molecular mechanism responsible for obesity-associated insulin resistance has been partially clarified: increased fatty acid levels in muscle fibers promote diacylglycerol synthesis, which activates certain isoforms of protein kinase C (PKC). This in turn triggers a kinase cascade which activates both IkappaB kinase-beta (IKK-beta) and c-Jun N-terminal kinase (JNK), each of which can phosphorylate a key serine residue in IRS-1, rendering it a poor substrate for the activated insulin receptor. Heat shock proteins Hsp27 and Hsp72 have the potential to prevent the activation of IKK-beta and JNK, respectively; this suggests that induction of heat shock proteins may blunt the adverse impact of fat overexposure on insulin function. Indeed, bimoclomol--a heat shock protein co-inducer being developed for treatment of diabetic neuropathy--and lipoic acid--suspected to be a heat shock protein inducer--have each demonstrated favorable effects on the insulin sensitivity of obese rodents, and parenteral lipoic acid is reported to improve the insulin sensitivity of type 2 diabetics. Moreover, there is reason to believe that heat shock protein induction may have a favorable impact on the microvascular complications of diabetes, and on the increased risk for macrovascular disease associated with diabetes and insulin resistance syndrome. Heat shock protein induction may also have potential for preventing or treating neurodegenerative disorders, controlling inflammation, and possibly even slowing the aging process. The possible complementarity of bimoclomol and lipoic acid for heat shock protein induction should be assessed, and further efforts to identify well-tolerated agents active in this regard are warranted.

  6. Cellular insulin resistance disrupts leptin-mediated control of neuronal signaling and transcription.

    PubMed

    Nazarians-Armavil, Anaies; Menchella, Jonathan A; Belsham, Denise D

    2013-06-01

    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.

  7. Effects of Dietary n-3 Fatty Acids on Hepatic and Peripheral Insulin Sensitivity in Insulin-Resistant Humans

    PubMed Central

    Lalia, Antigoni Z.; Johnson, Matthew L.; Jensen, Michael D.; Hames, Kazanna C.; Port, John D.

    2015-01-01

    OBJECTIVE Dietary n-3 polyunsaturated fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), prevent insulin resistance and stimulate mitochondrial biogenesis in rodents, but the findings of translational studies in humans are thus far ambiguous. The aim of this study was to evaluate the influence of EPA and DHA on insulin sensitivity, insulin secretion, and muscle mitochondrial function in insulin-resistant, nondiabetic humans using a robust study design and gold-standard measurements. RESEARCH DESIGN AND METHODS Thirty-one insulin-resistant adults received 3.9 g/day EPA+DHA or placebo for 6 months in a randomized double-blind study. Hyperinsulinemic-euglycemic clamp with somatostatin was used to assess hepatic and peripheral insulin sensitivity. Postprandial glucose disposal and insulin secretion were measured after a meal. Measurements were performed at baseline and after 6 months of treatment. Abdominal fat distribution was evaluated by MRI. Muscle oxidative capacity was measured in isolated mitochondria using high-resolution respirometry and noninvasively by magnetic resonance spectroscopy. RESULTS Compared with placebo, EPA+DHA did not alter peripheral insulin sensitivity, postprandial glucose disposal, or insulin secretion. Hepatic insulin sensitivity, determined from the suppression of endogenous glucose production by insulin, exhibited a small but significant improvement with EPA+DHA compared with placebo. Muscle mitochondrial function was unchanged by EPA+DHA or placebo. CONCLUSIONS This study demonstrates that dietary EPA+DHA does not improve peripheral glucose disposal, insulin secretion, or skeletal muscle mitochondrial function in insulin-resistant nondiabetic humans. There was a modest improvement in hepatic insulin sensitivity with EPA+DHA, but this was not associated with any improvements in clinically meaningful outcomes. PMID:25852206

  8. Improving insulin resistance in obese youth: choose your measures wisely.

    PubMed

    Shaibi, Gabriel Q; Davis, Jaimie N; Weigensberg, Marc J; Goran, Michael I

    2011-06-01

    The purpose of this investigation was to compare the homeostasis model assessment of insulin resistance (HOMA-IR) to more direct measures of insulin action before and after lifestyle interventions in obese Latino youth. Eleven obese Latino boys (age 15.1 ± 1.6 years, body mass index (BMI) percentile 97.3 ± 3.5%) and twenty obese Latina girls (age 14.7 ± 1.8 years, BMI percentile 96.6 ± 3.6%) participated in two distinct lifestyle interventions. Boys participated in a 16-week exercise intervention and girls participated in a 12-week nutrition education program. Insulin sensitivity was determined by the frequently sampled intravenous glucose tolerance test (FSIVGTT) in boys and by a 3-hour oral glucose tolerance test with multiple sampling calculations for the whole-body insulin sensitivity index (WBISI) in girls. HOMA-IR was measured for both groups. HOMA-IR was correlated at baseline to the FSIVGTT (r = -0.57, p = 0.07) and the WBISI (r = -0.78, p<0.01) and at follow-up (FSIVGTT: r = -0.81, p<0.003; WBISI: r = -0.71, p = 0.001). Post-intervention, insulin sensitivity increased 45% in the boys and 34% in the girls; however, these improvements were not reflected by significant changes in HOMA-IR. Improvements in insulin sensitivity following an intervention measured either by the FSIVGTT or an OGTT were not detected by HOMA-IR. Researchers and clinicians should exercise caution in relying on fasting indices, such as HOMA-IR, to determine the impact of lifestyle interventions on insulin sensitivity in overweight youth.

  9. Exercise training reduces insulin resistance in postmyocardial infarction rats

    PubMed Central

    Wang, Youhua; Tian, Zhenjun; Zang, Weijin; Jiang, Hongke; Li, Youyou; Wang, Shengpeng; Chen, Shengfeng

    2015-01-01

    Myocardial infarction (MI) induces cardiac dysfunction and insulin resistance (IR). This study examines the effects of MI-related IR on vasorelaxation and its underlying mechanisms, with a specific focus on the role of exercise in reversing the impaired vasorelaxation. Adult male Sprague–Dawley rats were divided into three groups: Sham, MI, and MI+Exercise. MI+Exercise rats were subjected to 8 weeks of treadmill training. Cardiac contraction, myocardial and arterial structure, vasorelaxation, levels of inflammatory cytokines, expression of eNOS and TNF-α, and activation of PI3K/Akt/eNOS and p38 mitogen-activated protein kinase (p38 MAPK) were determined in aortas. MI significantly impaired endothelial structure and vasodilation (P < 0.05–0.01), as indicated by decreased arterial vasorelaxation to ACh and insulin. MI also attenuated the myocardial contractile response, decreased aortic PI3K/Akt/eNOS expression and phosphorylation by insulin, and increased IL-1β, IL-6, and TNF-α expression and p38 MAPK activity (P < 0.05–0.01). Exercise improved insulin sensitivity in aortas, facilitated myocardial contractile response and arterial vasorelaxation to ACh and insulin, and increased arterial PI3K/Akt/eNOS activity. Moreover, exercise markedly reversed increased p38 MAPK activity and normalized inflammatory cytokines in post-MI arteries. Inhibition of PI3K with LY-294002, and eNOS with L-NAME significantly blocked arterial vasorelaxation and PI3K/Akt/eNOS phosphorylation in response to insulin. In conclusion, these results demonstrate that endothelial dysfunction in response to insulin plays an important role in MI-related IR. The reversal of IR by exercise is most likely associated with normalizing inflammatory cytokines, increasing the activation of PI3K/Akt/eNOS, and reducing the activation of p38 MAPK. PMID:25907785

  10. Myeloid cell-restricted insulin receptor deficiency protects against obesity-induced inflammation and systemic insulin resistance.

    PubMed

    Mauer, Jan; Chaurasia, Bhagirath; Plum, Leona; Quast, Thomas; Hampel, Brigitte; Blüher, Matthias; Kolanus, Waldemar; Kahn, C Ronald; Brüning, Jens C

    2010-05-06

    A major component of obesity-related insulin resistance is the establishment of a chronic inflammatory state with invasion of white adipose tissue by mononuclear cells. This results in the release of pro-inflammatory cytokines, which in turn leads to insulin resistance in target tissues such as skeletal muscle and liver. To determine the role of insulin action in macrophages and monocytes in obesity-associated insulin resistance, we conditionally inactivated the insulin receptor (IR) gene in myeloid lineage cells in mice (IR(Deltamyel)-mice). While these animals exhibit unaltered glucose metabolism on a normal diet, they are protected from the development of obesity-associated insulin resistance upon high fat feeding. Euglycemic, hyperinsulinemic clamp studies demonstrate that this results from decreased basal hepatic glucose production and from increased insulin-stimulated glucose disposal in skeletal muscle. Furthermore, IR(Deltamyel)-mice exhibit decreased concentrations of circulating tumor necrosis factor (TNF) alpha and thus reduced c-Jun N-terminal kinase (JNK) activity in skeletal muscle upon high fat feeding, reflecting a dramatic reduction of the chronic and systemic low-grade inflammatory state associated with obesity. This is paralleled by a reduced accumulation of macrophages in white adipose tissue due to a pronounced impairment of matrix metalloproteinase (MMP) 9 expression and activity in these cells. These data indicate that insulin action in myeloid cells plays an unexpected, critical role in the regulation of macrophage invasion into white adipose tissue and in the development of obesity-associated insulin resistance.

  11. Exosomal biomarkers of brain insulin resistance associated with regional atrophy in Alzheimer's disease.

    PubMed

    Mullins, Roger J; Mustapic, Maja; Goetzl, Edward J; Kapogiannis, Dimitrios

    2017-04-01

    Brain insulin resistance (IR), which depends on insulin-receptor-substrate-1 (IRS-1) phosphorylation, is characteristic of Alzheimer's disease (AD). Previously, we demonstrated higher pSer312-IRS-1 (ineffective insulin signaling) and lower p-panTyr-IRS-1 (effective insulin signaling) in neural origin-enriched plasma exosomes of AD patients vs.

  12. Fucosterol activates the insulin signaling pathway in insulin resistant HepG2 cells via inhibiting PTP1B.

    PubMed

    Jung, Hyun Ah; Bhakta, Himanshu Kumar; Min, Byung-Sun; Choi, Jae Sue

    2016-10-01

    Insulin resistance is a characteristic feature of type 2 diabetes mellitus (T2DM) and is characterized by defects in insulin signaling. This study investigated the modulatory effects of fucosterol on the insulin signaling pathway in insulin-resistant HepG2 cells by inhibiting protein tyrosine phosphatase 1B (PTP1B). In addition, molecular docking simulation studies were performed to predict binding energies, the specific binding site of fucosterol to PTP1B, and to identify interacting residues using Autodock 4.2 software. Glucose uptake was determined using a fluorescent D-glucose analogue and the glucose tracer 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxyglucose, and the signaling pathway was detected by Western blot analysis. We found that fucosterol enhanced insulin-provoked glucose uptake and conjointly decreased PTP1B expression level in insulin-resistant HepG2 cells. Moreover, fucosterol significantly reduced insulin-stimulated serine (Ser307) phosphorylation of insulin receptor substrate 1 (IRS1) and increased phosphorylation of Akt, phosphatidylinositol-3-kinase, and extracellular signal- regulated kinase 1 at concentrations of 12.5, 25, and 50 µM in insulin-resistant HepG2 cells. Fucosterol inhibited caspase-3 activation and nuclear factor kappa B in insulin-resistant hepatocytes. These results suggest that fucosterol stimulates glucose uptake and improves insulin resistance by downregulating expression of PTP1B and activating the insulin signaling pathway. Thus, fucosterol has potential for development as an anti-diabetic agent.

  13. Peroxynitrite mediates muscle insulin resistance in mice via nitration of IRbeta/IRS-1 and Akt

    SciTech Connect

    Zhou Jun; Huang Kaixun

    2009-11-15

    Accumulating evidence suggests that peroxynitrite (ONOO{sup -}) is involved in the pathogenesis of insulin resistance. In the current study, we investigated whether insulin resistance in vivo could be mediated by nitration of proteins involved in the early steps of the insulin signal transduction pathway. Exogenous peroxynitrite donated by 3-morpholinosydnonimine hydrochloride (SIN-1) induced in vivo nitration of the insulin receptor beta subunit (IRbeta), insulin receptor substrate (IRS)-1, and protein kinase B/Akt (Akt) in skeletal muscle of mice and dramatically reduced whole-body insulin sensitivity and muscle insulin signaling. Moreover, in high-fat diet (HFD)-fed insulin-resistant mice, we observed enhanced nitration of IRbeta and IRS-1 in skeletal muscle, in parallel with impaired whole-body insulin sensitivity and muscle insulin signaling. Reversal of nitration of these proteins by treatment with the peroxynitrite decomposition catalyst FeTPPS yielded an improvement in whole-body insulin sensitivity and muscle insulin signaling in HFD-fed mice. Taken together, these findings provide new mechanistic insights for the involvement of peroxynitrite in the development of insulin resistance and suggest that nitration of proteins involved in the early steps of insulin signal transduction is a novel molecular mechanism of HFD-induced muscle insulin resistance.

  14. Role of leptin and adiponectin in insulin resistance.

    PubMed

    Yadav, Amita; Kataria, Megha A; Saini, Vandana; Yadav, Anil

    2013-02-18

    Adipose tissue is a major source of energy for the human body. It is also a source of major adipocytokines adiponectin and leptin. Insulin resistance is a condition in which insulin action is impaired in adipose tissue and is more strongly linked to intra-abdominal fat than to fat in other depots. The expression of adiponectin decreases with increase in the adiposity. Adiponectin mediates insulin-sensitizing effect through binding to its receptors AdipoR1 and AdipoR2, leading to activation of adenosine monophosphate dependent kinase (AMPK), PPAR-α, and presumably other yet-unknown signalling pathways. Weight loss significantly elevates plasma adiponectin levels. Reduction of adiponectin has been associated with insulin resistance, dyslipidemia, and atherosclerosis in humans. The other major adipokine is leptin. Leptin levels increase in obesity and subcutaneous fat has been a major determinant of circulating leptin levels. The leptin signal is transmitted by the Janus kinase, signal transducer and activator of transcription ((JAK-STAT) pathway. The net action of leptin is to inhibit appetite, stimulate thermogenesis, enhance fatty acid oxidation, decrease glucose, and reduce body weight and fat.

  15. Importance of insulin resistance to vascular repair and regeneration.

    PubMed

    Cubbon, Richard M; Mercer, Ben N; Sengupta, Anshuman; Kearney, Mark T

    2013-07-01

    Metabolic insulin resistance is apparent across a spectrum of clinical disorders, including obesity and diabetes, and is characterized by an adverse clustering of cardiovascular risk factors related to abnormal cellular responses to insulin. These disorders are becoming increasingly prevalent and represent a major global public health concern because of their association with significant increases in atherosclerosis-related mortality. Endogenous repair mechanisms are thought to retard the development of vascular disease, and a growing evidence base supports the adverse impact of the insulin-resistant phenotype upon indices of vascular repair. Beyond the impact of systemic metabolic changes, emerging data from murine studies also provide support for abnormal insulin signaling at the level of vascular cells in retarding vascular repair. Interrelated pathophysiological factors, including reduced nitric oxide bioavailability, oxidative stress, altered growth factor activity, and abnormal intracellular signaling, are likely to act in conjunction to impede vascular repair while also driving vascular damage. Understanding of these processes is shaping novel therapeutic paradigms that aim to promote vascular repair and regeneration, either by recruiting endogenous mechanisms or by the administration of cell-based therapies.

  16. [The effect of nerobol and ecdysterone on insulin-dependent processes linked normally and in insulin resistance].

    PubMed

    Kosovskiĭ, M I; Syrov, V N; Mirakhmedov, M M; Katkova, S P; Khushbaktova, Z A

    1989-01-01

    The effect of substances with anabolic activity (metandienone and ecdysterone phytoecdysteroid) on the manifestation of insulin effects was studied on a model of insulin resistance in rats induced by injections of hydrocortisone or by insulin insufficiency caused by alloxan. The sensitivity of the body to i. v. infusion of insulin and the reactivity of isolated fatty tissue to the hormone were increased after administration of these substances to test animals. The above effects of steroids were determined by nonspecific synthesis of total proteins in cells rather than by an increase in insulin secretion.

  17. [Implication of MAP kinases in obesity-induced inflammation and insulin resistance].

    PubMed

    Ceppo, Franck; Jager, Jennifer; Berthou, Flavien; Giorgetti-Peraldi, Sophie; Cormont, Mireille; Bost, Fréderic; Tanti, Jean-François

    2014-01-01

    Insulin resistance is often associated with obesity and is a major risk factor for development of type 2 diabetes as well as cardiovascular and hepatic diseases. Insulin resistance may also increase the incidence or the aggressiveness of some cancers. Insulin resistance occurs owing to defects in insulin signaling in target tissues of this hormone. During the last ten years, it became evident that the chronic low-grade inflammatory state that develops during obesity plays an important role in insulin resistance development. Indeed, inflammatory cytokines activate several signaling pathways that impinge on the insulin signaling pathway. Among them, this review will focus on the implication of the MAP kinases JNK and ERK1/2 signaling in the development of insulin signaling alterations and will discuss the possibility to target these pathways in order to fight insulin resistance. © Société de Biologie, 2014.

  18. Insulin, glucose, insulin resistance, and incident colorectal cancer in male smokers.

    PubMed

    Limburg, Paul J; Stolzenberg-Solomon, Rachael Z; Vierkant, Robert A; Roberts, Katherine; Sellers, Thomas A; Taylor, Philip R; Virtamo, Jarmo; Cerhan, James R; Albanes, Demetrius

    2006-12-01

    Hyperinsulinemia is a putative colorectal cancer (CRC) risk factor. Insulin resistance (IR) commonly precedes hyperinsulinemia and can be quantitatively measured by using the homeostasis model assessment-insulin resistance (HOMA-IR) index. To date, few studies have directly examined serum insulin as an indicator of CRC risk, and none have reported associations on the basis of HOMA-IR. We performed a case-cohort study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study (n=29,133). Baseline exposure and fasting serum biomarker data were available for 134 incident CRC case and 399 non-case subjects. HOMA-IR was derived as fasting insulin x fasting glucose/22.5. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by using age-adjusted and multivariable-adjusted Cox proportional hazards regression models. Median (interquartile range) values for serum insulin, glucose, and HOMA-IR were 4.1 (2.9-7.2) mIU/L, 101 (94-108) mg/dL, and 0.99 (0.69-1.98) for case subjects and 4.1 (2.7-6.1) mIU/L, 99 (93-107) mg/dL, and 1.02 (0.69-1.53) for non-case subjects, respectively. On the basis of comparison of the highest versus lowest quartiles for each biomarker, insulin (HR, 1.84; 95% CI, 1.03-3.30) and HOMA-IR (HR, 1.85; 95% CI, 1.06-3.24) were significantly associated with incident CRC, whereas glucose was marginally associated with incident CRC (HR, 1.70; 95% CI, 0.92-3.13) in age-adjusted risk models. However, trends across biomarker quartiles were somewhat inconsistent (P trend=.12, .04, and .12, respectively), and multivariable adjustment generally attenuated the observed risk estimates. Data from this prospective study of male smokers provide limited support for hyperinsulinemia, hyperglycemia, and/or insulin resistance as CRC risk factors.

  19. [Effect of 17β-estradiol on bioenergetic processes in the heart mitochondria of ovariectomized rats with insulin resistance].

    PubMed

    Gorbenko, N I; Borikov, A Y; Ivanova, O V; Taran, E V; Zvyagina, T S

    2014-01-01

    Тhe bioenergetic processes in the heart mitochondria of Wistar rats with fructose-induced insulin resistance was investigated in female animals with different estrogen status. Respiration studies on isolated heart mitochondria by the polarographic method revealed that estrogen deficiency reduced complex IV activity, while its combination with high-fructose diet induced additional disturbances in the coupling of respiration and oxidative phosphorylation at the level of complex I of the electron transport chain. Exogenous 17b-estradiol inhibited the development of mitochondrial dysfunction in cardiomyocytes of ovariectomized rats with insulin resistance.

  20. Insulin Resistance in Young Obese Subjects and Its Relation to Smoking (A Pilot Study).

    PubMed

    Juneja, Aarzoo; Dwivedi, Shridhar; Srivastava, D K; Chandra, Kailash

    2017-03-01

    Insulin resistance is a condition in which cells fail to respond to the normal actions of insulin. Dietary fat, obesity and smoking have been attributed to increase insulin resistance. However, the prevalence of insulin resistance in young obese subjects and its relation to smoking is not well established. This study comprising seventy-five healthy young adults was undertaken to find insulin resistance in obese smokers and non smokers both. Present study showed an overall prevalence of raised homeostatic model assessment of insulin resistance in 14.7 % otherwise healthy young subjects (20-30 years age group). Non-smokers did not show any significant correlation between insulin resistance and body mass index at either stage (normal, pre-obese as well as obese). Smokers also did not show any significant difference of insulin resistance in normal and pre-obese stages. However, marked increase in homeostatic model assessment of insulin resistance was observed in obese smokers. Homeostatic model assessment of insulin resistance showed a linear trend in relation to body mass index and its values were found to be higher in smokers. Obesity combined with smoking demonstrated statistically significant increase in homeostatic model assessment of insulin resistance.

  1. Insulin resistance in postmenopausal women: concurrent effects of hormone replacement therapy and coffee.

    PubMed

    Catalano, D; Trovato, G M; Spadaro, D; Martines, G F; Garufi, G; Tonzuso, A; Grasso, D; Sciacchitano, S G

    2008-10-01

    In postmenopausal women, an increase in insulin resistance is associated with an increased risk of diabetes, cardiovascular disease and breast cancer. Hormone replacement therapy (HRT) can reduce insulin resistance and coffee use is reported to decrease the incidence of diabetes. The aim of our study was to assess possible concurrent effects of HRT and espresso coffee intake on insulin resistance and on interdependent nutritional and clinical features. A total of 478 healthy postmenopausal, non-diabetic women (aged 54.5 +/- 4.2 years) were studied: 360 had been on HRT for at least 2 years and 118 were not treated. Insulin resistance was assessed by a conventional homeostasis model (HOMA-IR). Insulin resistance is directly related to body mass index (p < 0.0001), and not with age and blood pressure; hypertensive menopausal women have a slightly higher body mass index but the same degree of insulin resistance as normotensive women. Women on HRT show lower insulin resistance, but not lower prevalence of arterial hypertension. Coffee use is associated with a decrease in insulin resistance in non-obese women receiving HRT, but not in other subsets. The combination of coffee consumption and HRT could lower insulin resistance in postmenopausal women. In overweight women, greater insulin sensitivity is associated with intake of espresso coffee and not with HRT; in normal weight women, only HRT is associated with lower insulin resistance.

  2. [Obesity, inflammation and insulin resistance: which role for adipokines].

    PubMed

    Antuna-Puente, Barbara; Feve, Bruno; Fellahi, Soraya; Bastard, Jean-Philippe

    2007-01-01

    Adipose tissue is now recognized as an endocrine organ involved in regulating physiologic and pathologic processes including inflammation. It synthesizes and secretes hormones such as leptin and adiponectin. It can secrete other products namely adipokines including cytokines and chemokines. The release of adipokines by either adipocytes or adipose tissue-infiltrated macrophages leads to a chronic sub-inflammatory state that likely plays a major role in cardiovascular complications linked to obesity and insulin resistance.

  3. The importance of palmitoleic acid to adipocyte insulin resistance and whole-body insulin sensitivity in type 1 diabetes.

    PubMed

    Bergman, Bryan C; Howard, David; Schauer, Irene E; Maahs, David M; Snell-Bergeon, Janet K; Clement, Timothy W; Eckel, Robert H; Perreault, Leigh; Rewers, Marian

    2013-01-01

    Type 1 diabetes is an insulin-resistant state, but it is less clear which tissues are affected. Our previous report implicated skeletal muscle and liver insulin resistance in people with type 1 diabetes, but this occurred independently of generalized, visceral, or ectopic fat. The aim of the study was to measure adipose tissue insulin sensitivity and plasma triglyceride composition in individuals with type 1 diabetes after overnight insulin infusion to lower fasting glucose. Fifty subjects (25 individuals with type 1 diabetes and 25 controls without) were studied. After 3 d of dietary control and overnight insulin infusion, we performed a three-stage hyperinsulinemic/euglycemic clamp infusing insulin at 4, 8, and 40 mU/m(2) · min. Infusions of [1,1,2,3,3-(2)H(2)]glycerol and [1-(13)C]palmitate were used to quantify lipid metabolism. Basal glycerol and palmitate rates of appearance were similar between groups, decreased more in control subjects during the first two stages of the clamp, and similarly suppressed during the highest i