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Sample records for affect insulin resistance

  1. Diabetes prevention: Reproductive age women affected by insulin resistance.

    PubMed

    Rezai, Shadi; LoBue, Stephen; Henderson, Cassandra E

    2016-07-01

    In the United States, 29.1 million people are affected by diabetes, of which 95% have type 2 diabetes. There has been a fivefold increase in type 2 diabetes in the latter half of the 20th century, an increase strongly linked to the obesity epidemic in the United States. In addition, insulin resistance affects 86 million Americans, or more than one-third of the adult population, as manifested by impaired fasting glucose tolerance with random glucose values ranging from ⩾100 to <126 mg/dL. In all, 90% of those affected by impaired fasting glucose tolerance or pre-diabetes are unaware of their metabolic derangement. Although impaired fasting glucose tolerance increases one's risk of developing type 2 diabetes, once identified, application of lifestyle changes by affected individuals may avoid or delay the onset of type 2 diabetes. For reproductive age women who are found to have impaired fasting glucose tolerance, lifestyle changes may be an effective tool to diminish the reproductive health consequences of insulin resistance related diseases. PMID:27638898

  2. Insulin Signaling And Insulin Resistance

    PubMed Central

    Beale, Elmus G.

    2013-01-01

    Insulin resistance or its sequelae may be the common etiology of maladies associated with metabolic syndrome (e.g., 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. PMID:23111650

  3. 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

  4. The β2 Adrenergic Receptor Gln27Glu Polymorphism Affects Insulin Resistance in Patients with Heart Failure

    PubMed Central

    Vardeny, Orly; Detry, Michelle A.; Moran, John J.M.; Johnson, Maryl R.; Sweitzer, Nancy K.

    2009-01-01

    Insulin resistance is prevalent in heart failure (HF) patients, and beta2 adrenergic receptors (β2-AR) are involved in glucose homeostasis. We hypothesized that β2-AR Gln27Glu and Arg16Gly polymorphisms affect insulin resistance in HF patients and explored if effects of β2-AR polymorphisms on glucose handling are modified by choice of beta blocker. We studied 30 non-diabetic adults with HF and a history of systolic dysfunction, 15 on metoprolol succinate and 15 on carvedilol. We measured fasting glucose, insulin, and insulin resistance, and determined β2-AR genotypes at codons 27 and 16. The cohort was insulin resistant with a mean HOMA-IR score of 3.4 (95%CI 2.3-4.5, normal value=1.0). Patients with the Glu27Glu genotype exhibited higher insulin and HOMA-IR compared to individuals carrying a Gln allele (p=0.019). Patients taking carvedilol demonstrated lower insulin resistance if also carrying a wild type allele at codon 27 (fasting insulin 9.8±10.5 versus 20.5±2.1 for variant, p=0.072, HOMA-IR 2.4±2.7 versus 5.1±0.6, p=0.074, respectively); those on metoprolol succinate had high insulin resistance irrespective of genotype. The β2-AR Glu27Glu genotype may be associated with higher insulin concentrations and insulin resistance in patients with HF. Future studies are needed to confirm whether treatment with carvedilol may be associated with decreased insulin and insulin resistance in β2-AR codon 27 Gln carriers. PMID:19034036

  5. 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.

  6. Renal Lipotoxicity-Associated Inflammation and Insulin Resistance Affects Actin Cytoskeleton Organization in Podocytes

    PubMed Central

    Vivas, Yurena; Velasco, Ismael; Yeo, Tet-Kin; Chen, Sheldon; Medina-Gomez, Gema

    2015-01-01

    In the last few decades a change in lifestyle has led to an alarming increase in the prevalence of obesity and obesity-associated complications. Obese patients are at increased risk of developing hypertension, heart disease, insulin resistance (IR), dyslipidemia, type 2 diabetes and renal disease. The excess calories are stored as triglycerides in adipose tissue, but also may accumulate ectopically in other organs, including the kidney, which contributes to the damage through a toxic process named lipotoxicity. Recently, the evidence suggests that renal lipid accumulation leads to glomerular damage and, more specifically, produces dysfunction in podocytes, key cells that compose and maintain the glomerular filtration barrier. Our aim was to analyze the early mechanisms underlying the development of renal disease associated with the process of lipotoxicity in podocytes. Our results show that treatment of podocytes with palmitic acid produced intracellular accumulation of lipid droplets and abnormal glucose and lipid metabolism. This was accompanied by the development of inflammation, oxidative stress and endoplasmic reticulum stress and insulin resistance. We found specific rearrangements of the actin cytoskeleton and slit diaphragm proteins (Nephrin, P-Cadherin, Vimentin) associated with this insulin resistance in palmitic-treated podocytes. We conclude that lipotoxicity accelerates glomerular disease through lipid accumulation and inflammation. Moreover, saturated fatty acids specifically promote insulin resistance by disturbing the cytoarchitecture of podocytes. These data suggest that renal lipid metabolism and cytoskeleton rearrangements may serve as a target for specific therapies aimed at slowing the progression of podocyte failure during metabolic syndrome. PMID:26545114

  7. Renal Lipotoxicity-Associated Inflammation and Insulin Resistance Affects Actin Cytoskeleton Organization in Podocytes.

    PubMed

    Martínez-García, Cristina; Izquierdo-Lahuerta, Adriana; Vivas, Yurena; Velasco, Ismael; Yeo, Tet-Kin; Chen, Sheldon; Medina-Gomez, Gema

    2015-01-01

    In the last few decades a change in lifestyle has led to an alarming increase in the prevalence of obesity and obesity-associated complications. Obese patients are at increased risk of developing hypertension, heart disease, insulin resistance (IR), dyslipidemia, type 2 diabetes and renal disease. The excess calories are stored as triglycerides in adipose tissue, but also may accumulate ectopically in other organs, including the kidney, which contributes to the damage through a toxic process named lipotoxicity. Recently, the evidence suggests that renal lipid accumulation leads to glomerular damage and, more specifically, produces dysfunction in podocytes, key cells that compose and maintain the glomerular filtration barrier. Our aim was to analyze the early mechanisms underlying the development of renal disease associated with the process of lipotoxicity in podocytes. Our results show that treatment of podocytes with palmitic acid produced intracellular accumulation of lipid droplets and abnormal glucose and lipid metabolism. This was accompanied by the development of inflammation, oxidative stress and endoplasmic reticulum stress and insulin resistance. We found specific rearrangements of the actin cytoskeleton and slit diaphragm proteins (Nephrin, P-Cadherin, Vimentin) associated with this insulin resistance in palmitic-treated podocytes. We conclude that lipotoxicity accelerates glomerular disease through lipid accumulation and inflammation. Moreover, saturated fatty acids specifically promote insulin resistance by disturbing the cytoarchitecture of podocytes. These data suggest that renal lipid metabolism and cytoskeleton rearrangements may serve as a target for specific therapies aimed at slowing the progression of podocyte failure during metabolic syndrome. PMID:26545114

  8. Treating insulin resistance: future prospects.

    PubMed

    Bailey, Clifford J

    2007-03-01

    Insulin resistance typically reflects multiple defects of insulin receptor and post-receptor signalling that impair a diverse range of metabolic and vascular actions. Many potential intervention targets and compounds with therapeutic activity have been described. Proof of principle for a non-peptide insulin mimetic has been demonstrated by specific activation of the intracellular B-subunit of the insulin receptor. Potentiation of insulin action has been achieved with agents that enhance phosphorylation and prolong the tyrosine kinase activity of the insulin receptor and its protein substrates after activation by insulin. These include inhibitors of phosphatases and serine kinases that normally prevent or terminate tyrosine kinase signalling. Additional approaches involve increasing the activity of phosphatidylinositol 3-kinase and other downstream components of the insulin signalling pathways. Experimental interventions to remove signalling defects caused by cytokines, certain adipocyte hormones, excess fatty acids, glucotoxicity and negative feedback by distal signalling steps have also indicated therapeutic possibilities. Several hormones, metabolic enzymes, minerals, co-factors and transcription co-activators have shown insulin-sensitising potential. Since insulin resistance affects many metabolic and cardiovascular diseases, it provides an opportunity for simultaneous therapeutic attack on a broad front.

  9. Circulating leptin and osteoprotegerin levels affect insulin resistance in healthy premenopausal obese women.

    PubMed

    Ugur-Altun, Betul; Altun, Armagan

    2007-11-01

    We investigated the relationship between circulating leptin and osteoprotegerin (OPG) levels and insulin resistance assessed by HOMA-IR in premenopausal obese and normal weight women. Thirty four obese women (age 31 +/- 8 years) (BMI 35 +/- 4 kg/m(2)) with 19 healthy controls (age 31 +/- 7 years) (BMI <25 kg/m(2)) (BMI 21 +/- 2 kg/m(2)) were included in the study. Women were healthy and had no osteoporosis. Circulating leptin levels were significantly higher in obese women (17.11 +/- 2.05 ng/mL vs. 8.38 +/- 4.71 ng/mL, p <0.0001) and decreased OPG levels were found (14.7 +/- 7.15 pg/mL vs. 19.17 +/- 6.37 pg/mL, p = 0.03). Leptin showed a positive correlation with BMI (r = 0.851, p <0.0001), waist-to-hip ratio (r = 0.692, p <0.0001), fasting insulin (r = 0.441, p <0.001), HOMA-IR (r = 0.412, p = 0.002), fibrinogen (r = 0.387, p = 0.004), uric acid (r = 0.293, p = 0.033), hematocrit (r = 0.394, p = 0.003), systolic (r = 0.504, p <0.0001), and diastolic blood pressure (r = 0.363, p = 0.008). OPG showed a negative correlation with insulin (r = -0.341, p = 0.013) and HOMA-IR (r = -0.324, p = 0.018). In obese women group, the regression equation of HOMA-IR was (HOMA-IR = [0.095 x leptin]-[0.051 x OPG] + 1.71). However, there was no relation between leptin and OPG levels. In conclusion, circulating leptin and OPG levels were related to insulin resistance in premenopausal obese women. However, leptin had no interference in OPG in premenopausal women. PMID:17923273

  10. All about Insulin Resistance

    MedlinePlus

    ... news is that cutting calories, being active, and losing weight can reverse insulin resistance and lower your ... you’ll lose weight. Studies have shown that losing even 7% of your weight, may help. For ...

  11. Insulin Resistance and Obesity Affect Lipid Profile in the Salivary Glands

    PubMed Central

    Matczuk, Jan; Zalewska, Anna; Łukaszuk, Bartłomiej; Knaś, Małgorzata; Maciejczyk, Mateusz; Garbowska, Marta; Ziembicka, Dominika M.; Waszkiel, Danuta; Chabowski, Adrian; Żendzian-Piotrowska, Małgorzata

    2016-01-01

    In today's world wrong nutritional habits together with a low level of physical activity have given rise to the development of obesity and its comorbidity, insulin resistance. More specifically, many researches indicate that lipids are vitally involved in the onset of a peripheral tissue (e.g., skeletal muscle, heart, and liver) insulin resistance. Moreover, it seems that diabetes can also induce changes in respect of lipid composition of both the salivary glands and saliva. However, judging by the number of research articles, the salivary glands lipid profile still has not been sufficiently explored. In the current study we aim to assess the changes in the main lipid fractions, namely, triacylglycerols, phospholipids, free fatty acids, and diacylglycerols, in the parotid and the submandibular salivary glands of rats exposed to a 5-week high fat diet regimen. We observed that the high caloric fat diet caused a significant change in the salivary glands lipid composition, especially with respect to PH and TG, but not DAG or FFAs, classes. The observed reduction in PH concentration is an interesting phenomenon frequently signifying the atrophy and malfunctions in the saliva secreting organs. On the other hand, the increased accumulation of TG in the glands may be an important clinical manifestation of metabolic syndrome and type 2 diabetes mellitus. PMID:27471733

  12. Insulin Resistance and Obesity Affect Lipid Profile in the Salivary Glands.

    PubMed

    Matczuk, Jan; Zalewska, Anna; Łukaszuk, Bartłomiej; Knaś, Małgorzata; Maciejczyk, Mateusz; Garbowska, Marta; Ziembicka, Dominika M; Waszkiel, Danuta; Chabowski, Adrian; Żendzian-Piotrowska, Małgorzata; Kurek, Krzysztof

    2016-01-01

    In today's world wrong nutritional habits together with a low level of physical activity have given rise to the development of obesity and its comorbidity, insulin resistance. More specifically, many researches indicate that lipids are vitally involved in the onset of a peripheral tissue (e.g., skeletal muscle, heart, and liver) insulin resistance. Moreover, it seems that diabetes can also induce changes in respect of lipid composition of both the salivary glands and saliva. However, judging by the number of research articles, the salivary glands lipid profile still has not been sufficiently explored. In the current study we aim to assess the changes in the main lipid fractions, namely, triacylglycerols, phospholipids, free fatty acids, and diacylglycerols, in the parotid and the submandibular salivary glands of rats exposed to a 5-week high fat diet regimen. We observed that the high caloric fat diet caused a significant change in the salivary glands lipid composition, especially with respect to PH and TG, but not DAG or FFAs, classes. The observed reduction in PH concentration is an interesting phenomenon frequently signifying the atrophy and malfunctions in the saliva secreting organs. On the other hand, the increased accumulation of TG in the glands may be an important clinical manifestation of metabolic syndrome and type 2 diabetes mellitus. PMID:27471733

  13. Insulin Resistance of Puberty.

    PubMed

    Kelsey, Megan M; Zeitler, Philip S

    2016-07-01

    Puberty is a time of considerable metabolic and hormonal change. Notably, puberty is associated with a marked decrease in insulin sensitivity, on par with that seen during pregnancy. In otherwise healthy youth, there is a nadir in insulin sensitivity in mid-puberty, and then it recovers at puberty completion. However, there is evidence that insulin resistance (IR) does not resolve in youth who are obese going into puberty and may result in increased cardiometabolic risk. Little is known about the underlying pathophysiology of IR in puberty, and how it might contribute to increased disease risk (e.g., type 2 diabetes). In this review, we have outlined what is known about the IR in puberty in terms of pattern, potential underlying mechanisms and other mediating factors. We also outline other potentially related metabolic changes that occur during puberty, and effects of underlying insulin resistant states (e.g., obesity) on pubertal changes in insulin sensitivity. PMID:27179965

  14. Chemokine-like receptor 1 deficiency does not affect the development of insulin resistance and nonalcoholic fatty liver disease in mice.

    PubMed

    Gruben, Nanda; Aparicio Vergara, Marcela; Kloosterhuis, Niels J; van der Molen, Henk; Stoelwinder, Stefan; Youssef, Sameh; de Bruin, Alain; Delsing, Dianne J; Kuivenhoven, Jan Albert; van de Sluis, Bart; Hofker, Marten H; Koonen, Debby P Y

    2014-01-01

    The adipokine chemerin and its receptor, chemokine-like receptor 1 (Cmklr1), are associated with insulin resistance and nonalcoholic fatty liver disease (NAFLD), which covers a broad spectrum of liver diseases, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). It is possible that chemerin and/or Cmklr1 exert their effects on these disorders through inflammation, but so far the data have been controversial. To gain further insight into this matter, we studied the effect of whole-body Cmklr1 deficiency on insulin resistance and NAFLD. In view of the primary role of macrophages in hepatic inflammation, we also transplanted bone marrow from Cmklr1 knock-out (Cmklr1-/-) mice and wild type (WT) mice into low-density lipoprotein receptor knock-out (Ldlr-/-) mice, a mouse model for NASH. All mice were fed a high fat, high cholesterol diet containing 21% fat from milk butter and 0.2% cholesterol for 12 weeks. Insulin resistance was assessed by an oral glucose tolerance test, an insulin tolerance test, and by measurement of plasma glucose and insulin levels. Liver pathology was determined by measuring hepatic inflammation, fibrosis, lipid accumulation and the NAFLD activity score (NAS). Whole-body Cmklr1 deficiency did not affect body weight gain or food intake. In addition, we observed no differences between WT and Cmklr1-/- mice for hepatic inflammatory and fibrotic gene expression, immune cell infiltration, lipid accumulation or NAS. In line with this, we detected no differences in insulin resistance. In concordance with whole-body Cmklr1 deficiency, the absence of Cmklr1 in bone marrow-derived cells in Ldlr-/- mice did not affect their insulin resistance or liver pathology. Our results indicate that Cmklr1 is not involved in the pathogenesis of insulin resistance or NAFLD. Thus, we recommend that the associations reported between Cmklr1 and insulin resistance or NAFLD should be interpreted with caution.

  15. Myeloid Heme Oxygenase-1 Haploinsufficiency Reduces High Fat Diet-Induced Insulin Resistance by Affecting Adipose Macrophage Infiltration in Mice

    PubMed Central

    Huang, Jun-Yuan; Chiang, Ming-Tsai; Yet, Shaw-Fang; Chau, Lee-Young

    2012-01-01

    Increased adipose tissue macrophages contribute to obesity-induced metabolic syndrome. Heme oxygenase-1 (HO-1) is a stress-inducible enzyme with potent anti-inflammatory and proangiogenic activities in macrophages. However, the role of macrophage HO-1 on obesity-induced adipose inflammation and metabolic syndrome remains unclear. Here we show that high-fat diet (HFD) feeding in C57BL/6J mice induced HO-1 expression in the visceral adipose tissue, particularly the stromal vascular fraction. When the irradiated C57BL/6J mice reconstituted with wild-type or HO-1+/− bone marrow were fed with HFD for over 24 weeks, the HO-1+/− chimeras were protected from HFD-induced insulin resistance and this was associated with reduced adipose macrophage infiltration and angiogenesis, suggesting that HO-1 affects myeloid cell migration toward adipose tissue during obesity. In vivo and in vitro migration assays revealed that HO-1+/− macrophages exhibited an impaired migration response. Chemoattractant-induced phosphorylation of p38 and focal adhesion kinase (FAK) declined faster in HO-1+/− macrophages. Further experiments demonstrated that carbon monoxide and bilirubin, the byproducts derived from heme degradation by HO-1, enhanced macrophage migration by increasing phosphorylation of p38 and FAK, respectively. These data disclose a novel role of hematopoietic cell HO-1 in promoting adipose macrophage infiltration and the development of insulin resistance during obesity. PMID:22761690

  16. Extreme Air Pollution Conditions Adversely Affect Blood Pressure and Insulin Resistance: The Air Pollution and Cardiometabolic Disease Study.

    PubMed

    Brook, Robert D; Sun, Zhichao; Brook, Jeffrey R; Zhao, Xiaoyi; Ruan, Yanping; Yan, Jianhua; Mukherjee, Bhramar; Rao, Xiaoquan; Duan, Fengkui; Sun, Lixian; Liang, Ruijuan; Lian, Hui; Zhang, Shuyang; Fang, Quan; Gu, Dongfeng; Sun, Qinghua; Fan, Zhongjie; Rajagopalan, Sanjay

    2016-01-01

    Mounting evidence supports that fine particulate matter adversely affects cardiometabolic diseases particularly in susceptible individuals; however, health effects induced by the extreme concentrations within megacities in Asia are not well described. We enrolled 65 nonsmoking adults with metabolic syndrome and insulin resistance in the Beijing metropolitan area into a panel study of 4 repeated visits across 4 seasons since 2012. Daily ambient fine particulate matter and personal black carbon levels ranged from 9.0 to 552.5 µg/m(3) and 0.2 to 24.5 µg/m(3), respectively, with extreme levels observed during January 2013. Cumulative fine particulate matter exposure windows across the prior 1 to 7 days were significantly associated with systolic blood pressure elevations ranging from 2.0 (95% confidence interval, 0.3-3.7) to 2.7 (0.6-4.8) mm Hg per SD increase (67.2 µg/m(3)), whereas cumulative black carbon exposure during the previous 2 to 5 days were significantly associated with ranges in elevations in diastolic blood pressure from 1.3 (0.0-2.5) to 1.7 (0.3-3.2) mm Hg per SD increase (3.6 µg/m(3)). Both black carbon and fine particulate matter were significantly associated with worsening insulin resistance (0.18 [0.01-0.36] and 0.22 [0.04-0.39] unit increase per SD increase of personal-level black carbon and 0.18 [0.02-0.34] and 0.22 [0.08-0.36] unit increase per SD increase of ambient fine particulate matter on lag days 4 and 5). These results provide important global public health warnings that air pollution may pose a risk to cardiometabolic health even at the extremely high concentrations faced by billions of people in the developing world today. PMID:26573709

  17. Extreme Air Pollution Conditions Adversely Affect Blood Pressure and Insulin Resistance: The Air Pollution and Cardiometabolic Disease Study.

    PubMed

    Brook, Robert D; Sun, Zhichao; Brook, Jeffrey R; Zhao, Xiaoyi; Ruan, Yanping; Yan, Jianhua; Mukherjee, Bhramar; Rao, Xiaoquan; Duan, Fengkui; Sun, Lixian; Liang, Ruijuan; Lian, Hui; Zhang, Shuyang; Fang, Quan; Gu, Dongfeng; Sun, Qinghua; Fan, Zhongjie; Rajagopalan, Sanjay

    2016-01-01

    Mounting evidence supports that fine particulate matter adversely affects cardiometabolic diseases particularly in susceptible individuals; however, health effects induced by the extreme concentrations within megacities in Asia are not well described. We enrolled 65 nonsmoking adults with metabolic syndrome and insulin resistance in the Beijing metropolitan area into a panel study of 4 repeated visits across 4 seasons since 2012. Daily ambient fine particulate matter and personal black carbon levels ranged from 9.0 to 552.5 µg/m(3) and 0.2 to 24.5 µg/m(3), respectively, with extreme levels observed during January 2013. Cumulative fine particulate matter exposure windows across the prior 1 to 7 days were significantly associated with systolic blood pressure elevations ranging from 2.0 (95% confidence interval, 0.3-3.7) to 2.7 (0.6-4.8) mm Hg per SD increase (67.2 µg/m(3)), whereas cumulative black carbon exposure during the previous 2 to 5 days were significantly associated with ranges in elevations in diastolic blood pressure from 1.3 (0.0-2.5) to 1.7 (0.3-3.2) mm Hg per SD increase (3.6 µg/m(3)). Both black carbon and fine particulate matter were significantly associated with worsening insulin resistance (0.18 [0.01-0.36] and 0.22 [0.04-0.39] unit increase per SD increase of personal-level black carbon and 0.18 [0.02-0.34] and 0.22 [0.08-0.36] unit increase per SD increase of ambient fine particulate matter on lag days 4 and 5). These results provide important global public health warnings that air pollution may pose a risk to cardiometabolic health even at the extremely high concentrations faced by billions of people in the developing world today.

  18. 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

  19. A gene expression signature for insulin resistance.

    PubMed

    Konstantopoulos, Nicky; Foletta, Victoria C; Segal, David H; Shields, Katherine A; Sanigorski, Andrew; Windmill, Kelly; Swinton, Courtney; Connor, Tim; Wanyonyi, Stephen; Dyer, Thomas D; Fahey, Richard P; Watt, Rose A; Curran, Joanne E; Molero, Juan-Carlos; Krippner, Guy; Collier, Greg R; James, David E; Blangero, John; Jowett, Jeremy B; Walder, Ken R

    2011-02-11

    Insulin resistance is a heterogeneous disorder caused by a range of genetic and environmental factors, and we hypothesize that its etiology varies considerably between individuals. This heterogeneity provides significant challenges to the development of effective therapeutic regimes for long-term management of type 2 diabetes. We describe a novel strategy, using large-scale gene expression profiling, to develop a gene expression signature (GES) that reflects the overall state of insulin resistance in cells and patients. The GES was developed from 3T3-L1 adipocytes that were made "insulin resistant" by treatment with tumor necrosis factor-α (TNF-α) and then reversed with aspirin and troglitazone ("resensitized"). The GES consisted of five genes whose expression levels best discriminated between the insulin-resistant and insulin-resensitized states. We then used this GES to screen a compound library for agents that affected the GES genes in 3T3-L1 adipocytes in a way that most closely resembled the changes seen when insulin resistance was successfully reversed with aspirin and troglitazone. This screen identified both known and new insulin-sensitizing compounds including nonsteroidal anti-inflammatory agents, β-adrenergic antagonists, β-lactams, and sodium channel blockers. We tested the biological relevance of this GES in participants in the San Antonio Family Heart Study (n = 1,240) and showed that patients with the lowest GES scores were more insulin resistant (according to HOMA_IR and fasting plasma insulin levels; P < 0.001). These findings show that GES technology can be used for both the discovery of insulin-sensitizing compounds and the characterization of patients into subtypes of insulin resistance according to GES scores, opening the possibility of developing a personalized medicine approach to type 2 diabetes.

  20. How does acupuncture affect insulin sensitivity in women with polycystic ovary syndrome and insulin resistance? Study protocol of a prospective pilot study

    PubMed Central

    Zheng, Yanhua; Stener-Victorin, Elisabet; Ng, Ernest H Y; Li, Juan; Wu, Xiaoke; Ma, Hongxia

    2015-01-01

    Introduction Hyperinsulinaemia and insulin resistance (IR) are key features of polycystic ovary syndrome (PCOS) and metabolic syndrome. The effect of 5 weeks of acupuncture treatment has been investigated in a completed prospective pilot trial (Clinicaltrials.gov: NCT01457209), and acupuncture with electrical stimulation applied to insulin-resistant rats with dihydrotestosterone-induced PCOS was shown to improve insulin sensitivity. Therefore, we now aim to conduct a prospective pilot study to evaluate whether using the same acupuncture treatment protocol given over a longer period of time (6 months) than in the previous pilot trial will improve insulin sensitivity in women with PCOS and IR. Our hypothesis is that acupuncture with combined manual and low-frequency electrical stimulation of the needles will improve insulin sensitivity in women with PCOS and IR. Methods/analysis This is a prospective pilot trial. A total of 112 women with PCOS and IR will be recruited and categorised according to their body mass index (BMI) as normal weight (BMI=18.5−23 kg/m2) or as overweight/obese (BMI>23 kg/m2). Acupuncture will be applied three times per week for 6 months at 30 min per treatment. The primary outcome will be the change in insulin sensitivity before and after 6 months of acupuncture treatment, as measured by an oral glucose tolerance test. Ethics/dissemination Ethical approval of this study has been granted from the ethics committee of the First Affiliated Hospital of Guangzhou Medical University (No. 2013039). Written and informed consent will be obtained from each patient before any study procedure is performed, according to good clinical practice. The results of this trial will be disseminated in a peer-reviewed journal and presented at international congresses. Trial registration numbers NCT02026323 and ChiCTR-OCH-13003921. PMID:25941189

  1. 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

  2. The APOE -219G/T and +113G/C polymorphisms affect insulin resistance among Turks.

    PubMed

    Komurcu-Bayrak, Evrim; Onat, Altan; Yuzbasiogullari, Berna; Mononen, Nina; Laaksonen, Reijo; Kähönen, Mika; Hergenc, Gulay; Lehtimäki, Terho; Erginel-Unaltuna, Nihan

    2011-05-01

    The -219G/T (rs405509) and +113G/C (rs440446) polymorphisms within the regulatory region of the apolipoprotein E (APOE) gene have been related to the transcriptional activity of the gene. We examined the effect of the stated polymorphisms and their construct haplotypes with the APOE ɛ2/ɛ3/ɛ4 polymorphism on lipid levels and insulin resistance in the Turkish Adult Risk Factor Study. Randomly selected 1774 adults (mean age, 55.0 ± 11.7 years; 51.2% women) participating in the population-based Turkish Adult Risk Factor Study were cross-sectionally analyzed for the -219G/T, +113G/C, and ɛ2/ɛ3/ɛ4 polymorphisms as well as their haplotypes. Insulin resistance was defined as the 70th percentile in the sample (>2.51) of the homeostatic model assessment (HOMA). The frequencies of the -219T and +113C alleles were 0.477 and 0.423, respectively; and those of haplotype 1 (GGɛ3) and haplotype 2 (TCɛ3) were 44.1% and 41.9%, respectively. The -219G/T and +113G/C genotypes (both P < .04) and diplotypes of haplotype 2 (TCɛ3) (P < .014) were inversely related to serum fasting insulin and the HOMA index, even after controlling for 8 relevant covariates, but not to serum lipids. Within the APOE3 group, haplotype 2 (TC-/TC+) heterozygotes had an odds ratio of 0.66 (95% confidence interval, 0.42-0.99) for HOMA of insulin resistance after adjusting for 8 covariates. APOE promoter polymorphisms and their diplotypes are independently related with serum fasting insulin levels and HOMA index among Turks.

  3. Lipid signals and insulin resistance.

    PubMed

    Zhang, Chongben; Klett, Eric L; Coleman, Rosalind A

    2013-12-01

    The metabolic syndrome, a cluster of metabolic derangements that include obesity, glucose intolerance, dyslipidemia and hypertension, is a major risk factor for cardiovascular disease. Insulin resistance has been proposed to be the common feature that links obesity to the metabolic syndrome, but the mechanism remains obscure. Although the excess content of triacylglycerol in muscle and liver is highly associated with insulin resistance in these tissues, triacylglycerol itself is not causal but merely a marker. Thus, attention has turned to the accumulation of cellular lipids known to have signaling roles. This review will discuss recent progress in understanding how glycerolipids and related lipid intermediates may impair insulin signaling. PMID:24533033

  4. Lipid signals and insulin resistance.

    PubMed

    Zhang, Chongben; Klett, Eric L; Coleman, Rosalind A

    2013-12-01

    The metabolic syndrome, a cluster of metabolic derangements that include obesity, glucose intolerance, dyslipidemia and hypertension, is a major risk factor for cardiovascular disease. Insulin resistance has been proposed to be the common feature that links obesity to the metabolic syndrome, but the mechanism remains obscure. Although the excess content of triacylglycerol in muscle and liver is highly associated with insulin resistance in these tissues, triacylglycerol itself is not causal but merely a marker. Thus, attention has turned to the accumulation of cellular lipids known to have signaling roles. This review will discuss recent progress in understanding how glycerolipids and related lipid intermediates may impair insulin signaling.

  5. Alteration of JNK-1 Signaling in Skeletal Muscle Fails to Affect Glucose Homeostasis and Obesity-Associated Insulin Resistance in Mice

    PubMed Central

    Spohn, Gabriele; Brönneke, Hella S.; Schmidt-Supprian, Marc; Wunderlich, F. Thomas

    2013-01-01

    Obesity and associated metabolic disturbances, such as increased circulating fatty acids cause prolonged low grade activation of inflammatory signaling pathways in liver, skeletal muscle, adipose tissue and even in the CNS. Activation of inflammatory pathways in turn impairs insulin signaling, ultimately leading to obesity-associated type 2 diabetes mellitus. Conventional JNK-1 knock out mice are protected from high fat diet-induced insulin resistance, characterizing JNK-1-inhibition as a potential approach to improve glucose metabolism in obese patients. However, the cell type-specific role of elevated JNK-1 signaling as present during the course of obesity has not been fully elucidated yet. To investigate the functional contribution of altered JNK-1 activation in skeletal muscle, we have generated a ROSA26 insertion mouse strain allowing for Cre-activatable expression of a JNK-1 constitutive active construct (JNKC). To examine the consequence of skeletal muscle-restricted JNK-1 overactivation in the development of insulin resistance and glucose metabolism, JNKC mice were crossed to Mck-Cre mice yielding JNKSM-C mice. However, despite increased muscle-specific JNK activation, energy homeostasis and glucose metabolism in JNKSM-C mice remained largely unaltered compared to controls. In line with these findings, obese mice with skeletal muscle specific disruption of JNK-1, did not affect energy and glucose homeostasis. These experiments indicate that JNK-1 activation in skeletal muscle does not account for the major effects on diet-induced, JNK-1-mediated deterioration of insulin action and points towards a so far underappreciated role of JNK-1 in other tissues than skeletal muscle during the development of obesity-associated insulin resistance. PMID:23349837

  6. 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. PMID:18765680

  7. Insulin Resistance and Prediabetes

    MedlinePlus

    ... to be used in most health care providers' offices. The clamp is a research tool used by scientists to learn more about glucose metabolism. Research has shown that if blood tests indicate prediabetes, insulin ... care provider's office or commercial facility and sending the sample to ...

  8. Obesity genes and insulin resistance

    PubMed Central

    Belkina, Anna C.; Denis, Gerald V.

    2011-01-01

    Purpose of review The exploding prevalence of insulin resistance and Type 2 diabetes (T2D) linked to obesity has become an alarming public health concern. Worldwide, approximately 171 million people suffer from obesity-induced diabetes and public health authorities expect this situation to deteriorate rapidly. An interesting clinical population of ‘metabolically healthy but obese’ (MHO) cases is relatively protected from T2D and its associated cardiovascular risk. The molecular basis for this protection is not well understood but is likely to involve reduced inflammatory responses. The inflammatory cells and pathways that respond to overnutrition are the primary subject matter for this review. Recent findings The chance discovery of a genetic mutation in the Brd2 gene, which is located in the class II major histocompatibility complex and makes mice enormously fat but protects them from diabetes, offers revolutionary new insights into the cellular mechanisms that link obesity to insulin resistance and T2D. These Brd2-hypomorphic mice have reduced inflammation in fat that is normally associated with insulin resistance, and resemble MHO patients, suggesting novel therapeutic pathways for obese patients at risk for T2D. Summary Deeper understanding of the functional links between genes that control inflammatory responses to diet-induced obesity is crucial to the development of therapies for obese, insulin-resistant patients. PMID:20585247

  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. Mitochondrial efficiency and insulin resistance.

    PubMed

    Crescenzo, Raffaella; Bianco, Francesca; Mazzoli, Arianna; Giacco, Antonia; Liverini, Giovanna; Iossa, Susanna

    2014-01-01

    Insulin resistance, "a relative impairment in the ability of insulin to exert its effects on glucose, protein and lipid metabolism in target tissues," has many detrimental effects on metabolism and is strongly correlated to deposition of lipids in non-adipose tissues. Mitochondria are the main cellular sites devoted to ATP production and fatty acid oxidation. Therefore, a role for mitochondrial dysfunction in the onset of skeletal muscle insulin resistance has been proposed and many studies have dealt with possible alteration in mitochondrial function in obesity and diabetes, both in humans and animal models. Data reporting evidence of mitochondrial dysfunction in type two diabetes mellitus are numerous, even though the issue that this reduced mitochondrial function is causal in the development of the disease is not yet solved, also because a variety of parameters have been used in the studies carried out on this subject. By assessing the alterations in mitochondrial efficiency as well as the impact of this parameter on metabolic homeostasis of skeletal muscle cells, we have obtained results that allow us to suggest that an increase in mitochondrial efficiency precedes and therefore can contribute to the development of high-fat-induced insulin resistance in skeletal muscle. PMID:25601841

  11. Insulin Resistance Alters Islet Morphology in Nondiabetic Humans

    PubMed Central

    Mezza, Teresa; Muscogiuri, Giovanna; Sorice, Gian Pio; Clemente, Gennaro; Hu, Jiang; Pontecorvi, Alfredo; Holst, Jens J.; Giaccari, Andrea; Kulkarni, Rohit N.

    2014-01-01

    Type 2 diabetes is characterized by poor glucose uptake in metabolic tissues and manifests when insulin secretion fails to cope with worsening insulin resistance. In addition to its effects on skeletal muscle, liver, and adipose tissue metabolism, it is evident that insulin resistance also affects pancreatic β-cells. To directly examine the alterations that occur in islet morphology as part of an adaptive mechanism to insulin resistance, we evaluated pancreas samples obtained during pancreatoduodenectomy from nondiabetic subjects who were insulin-resistant or insulin-sensitive. We also compared insulin sensitivity, insulin secretion, and incretin levels between the two groups. We report an increased islet size and an elevated number of β- and α-cells that resulted in an altered β-cell–to–α-cell area in the insulin- resistant group. Our data in this series of studies suggest that neogenesis from duct cells and transdifferentiation of α-cells are potential contributors to the β-cell compensatory response to insulin resistance in the absence of overt diabetes. PMID:24215793

  12. Mitochondrial dysfunction and insulin resistance: an update

    PubMed Central

    Montgomery, Magdalene K; Turner, Nigel

    2014-01-01

    Mitochondrial dysfunction has been implicated in the development of insulin resistance (IR); however, a large variety of association and intervention studies as well as genetic manipulations in rodents have reported contrasting results. Indeed, even 39 years after the first publication describing a relationship between IR and diminished mitochondrial function, it is still unclear whether a direct relationship exists, and more importantly if changes in mitochondrial capacity are a cause or consequence of IR. This review will take a journey through the past and summarise the debate about the occurrence of mitochondrial dysfunction and its possible role in causing decreased insulin action in obesity and type 2 diabetes. Evidence is presented from studies in various human populations, as well as rodents with genetic manipulations of pathways known to affect mitochondrial function and insulin action. Finally, we have discussed whether mitochondria are a potential target for the treatment of IR. PMID:25385852

  13. The evolutionary benefit of insulin resistance.

    PubMed

    Soeters, Maarten R; Soeters, Peter B

    2012-12-01

    Insulin resistance is perceived as deleterious, associated with conditions as the metabolic syndrome, type 2 diabetes mellitus and critical illness. However, insulin resistance is evolutionarily well preserved and its persistence suggests that it benefits survival. Insulin resistance is important in various states such as starvation, immune activation, growth and cancer, to spare glucose for different biosynthetic purposes such as the production of NADPH, nucleotides in the pentose phosphate pathway and oxaloacetate for anaplerosis. In these conditions, total glucose oxidation by the tricarboxylic acid cycle is actually low and energy demands are largely met by fatty acid and ketone body oxidation. This beneficial role of insulin resistance has consequences for treatment and research. Insulin resistance should be investigated at the cellular, tissue and whole organism level. The metabolic pathways discussed here, should be integrated in the accepted and valid mechanistic events of insulin resistance before interfering with them to promote insulin sensitivity at any cost.

  14. 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

  15. 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. PMID:27252163

  16. Dietary sardine protein lowers insulin resistance, leptin and TNF-α and beneficially affects adipose tissue oxidative stress in rats with fructose-induced metabolic syndrome.

    PubMed

    Madani, Zohra; Louchami, Karim; Sener, Abdullah; Malaisse, Willy J; Ait Yahia, Dalila

    2012-02-01

    The present study aims at exploring the effects of sardine protein on insulin resistance, plasma lipid profile, as well as oxidative and inflammatory status in rats with fructose-induced metabolic syndrome. Rats were fed sardine protein (S) or casein (C) diets supplemented or not with high-fructose (HF) for 2 months. Rats fed the HF diets had greater body weight and adiposity and lower food intake as compared to control rats. Increased plasma glucose, insulin, HbA1C, triacylglycerols, free fatty acids and impaired glucose tolerance and insulin resistance was observed in HF-fed rats. Moreover, a decline in adipose tissues antioxidant status and a rise in lipid peroxidation and plasma TNF-α and fibrinogen were noted. Rats fed sardine protein diets exhibited lower food intake and fat mass than those fed casein diets. Sardine protein diets diminished plasma insulin and insulin resistance. Plasma triacylglycerol and free fatty acids were also lower, while those of α-tocopherol, taurine and calcium were enhanced as compared to casein diets. Moreover, S-HF diet significantly decreased plasma glucose and HbA1C. Sardine protein consumption lowered hydroperoxide levels in perirenal and brown adipose tissues. The S-HF diet, as compared to C-HF diet decreased epididymal hydroperoxides. Feeding sardine protein diets decreased brown adipose tissue carbonyls and increased glutathione peroxidase activity. Perirenal and epididymal superoxide dismutase and catalase activities and brown catalase activity were significantly greater in S-HF group than in C-HF group. Sardine protein diets also prevented hyperleptinemia and reduced inflammatory status in comparison with rats fed casein diets. Taken together, these results support the beneficial effect of sardine protein in fructose-induced metabolic syndrome on such variables as hyperglycemia, insulin resistance, hyperlipidemia and oxidative and inflammatory status, suggesting the possible use of sardine protein as a protective

  17. Insulin resistance, polycystic ovary syndrome and metformin.

    PubMed

    Pugeat, M; Ducluzeau, P H

    1999-01-01

    Polycystic ovary syndrome (PCOS) is the most common disorder of ovarian function in premenopausal women. PCOS is characterised by chronic anovulation and androgen excess with clinical manifestation of irregular menstrual cycles, hirsutism and/or acne. Insulin resistance with resultant hyperinsulinaemia, irrespective of excess weight or frank obesity, has been reported in patients with PCOS, and, as insulin has a direct effect on ovarian androgen production in vitro, insulin resistance may play a crucial role in the physiopathology of PCOS. Although the molecular mechanism(s) of insulin resistance in PCOS is unclear, excessive insulin-independent serine phosphorylation of the beta subunit of the insulin receptor, as reported in some patients with PCOS, has been put forward as a new mechanism for insulin resistance. Insulin-sensitising agents have recently been investigated for their role in the short term treatment of insulin resistance in PCOS. Controlled studies have shown that metformin administration, by promoting bodyweight loss, can decrease fasting and stimulated plasma insulin levels. However, other studies have shown metformin 500 mg 3 times daily to decrease insulin secretion and to reduce ovarian production of 17alpha-hydroxyprogesterone with recovery of spontaneous or clomifene-induced ovulation, independently of weight loss. These findings suggest a new indication for metformin and present insulin-sensitising agents as a novel approach in the treatment of ovarian hyperandrogenism and abnormal ovulation in PCOS. They also suggest that long term administration of metformin might be helpful in treating insulin resistance, thus reducing risks of type 2 (non-insulin-dependent) diabetes and cardiovascular disease in these patients.

  18. Cardiovascular manifestations of insulin resistance.

    PubMed

    Chahwala, Veer; Arora, Rohit

    2009-01-01

    Data from the Centers for Disease Control and Prevention indicate that the prevalence of diabetes is increasing steadily and is coupled with a rise in obesity. Studies such as the Nurses' Health Study show that even slight glucose abnormalities, namely insulin resistance, increase the risk of myocardial infarctions, strokes, other cardiovascular disease, and mortality. Insulin resistance was found to accelerate atherosclerosis, inflammation, the onset of diabetes, cardiovascular disease, obesity, hypertension, chronic kidney disease, and dyslipidemia. Adiponectin was found to have potent antiinflammatory and antiatherosclerotic effects. Similarly, studies indicate that peroxisome proliferators-activated receptor agonists have the potential to treat obesity, diabetes, and atherosclerosis. From a preventive standpoint, it was shown that intensive glucose control reduces long-term cardiovascular risk. This intensive control approach included the use of thiazolidinediones (TZDs; troglitazone, pioglitazone, and rosiglitazone), which were demonstrated to have vascular and nonglycemic effects beyond glucose-lowering. A drawback of using TZDs is peripheral fluid retention. The DREAM study showed that participants with impaired fasting glucose or impaired glucose tolerance who are free from cardiovascular disease benefited significantly from taking 8 mg rosiglitazone per day. The ADOPT study provided evidence that rosiglitazone is more efficient at controlling glycemic loss and maintaining low glycosylated hemoglobin levels than metformin and glyburide. Data from the CHICAGO study indicate that the progression of carotid artery intima-media thickness, a marker of atherosclerosis and a surrogate end point for cardiovascular disease, was slowed more with pioglitazone than glimepiride in a racially diverse population of men and women with diabetes mellitus type 2. Overall, investigators have shifted from a focus on hyperglycemia to a multifactorial approach to risk management

  19. Liver fat and SHBG affect insulin resistance in midlife women: The Study of Women’s Health Across the Nation (SWAN)

    PubMed Central

    Kavanagh, Kylie; Espeland, Mark A.; Sutton-Tyrrell, Kim; Barinas-Mitchell, Emma; El Khoudary, Samar R.; Wildman, Rachel P.

    2012-01-01

    The liver is an insulin-responsive organ that contributes significantly to both whole body insulin sensitivity and availability of sex steroids through the production of sex hormone binding globulin (SHBG). Our objective was to explore whether lower SHBG was associated with ectopic liver fat and mediated its effect on insulin resistance in The Study of Women’s Health Across the Nation (SWAN). A subset of midlife African American and Caucasian women from SWAN (n=208; 50.9±0.18 yrs; 71% Caucasian) had computed tomography scans to quantify visceral, subcutaneous and liver fat. Blood samples were collected and assayed for hormonal and metabolic markers. The cohort, while overweight, was generally healthy, and both liver fat and SHBG were unaffected by menopausal stage or race. Both higher liver fat and lower SHBG levels were significantly associated with higher insulin concentrations after adjustment for adiposity (r=−0.25, p<0.001 and r=−0.18, p=0.01). SHBG and liver fat had additive effects on insulin concentrations such that women with the lowest SHBG and the highest fat levels had the highest values (interaction p=0.09). The association between SHBG and insulin was more apparent among women with fattier livers. SHBG and liver fat appear to have independent effects on insulin levels as adjustment for each other did not diminish the strength of either association (p=0.023 and 0.001 respectively). These results confirmed the strong independent associations between increased liver fat and decreased SHBG with increased metabolic risk in midlife women. Further these data underscore the need for additional research into the role of liver fat in modifying SHBG’s influence on insulin levels. PMID:23784907

  20. Insulin resistance and diabetes in HIV infection.

    PubMed

    Das, Satyajit

    2011-09-01

    Insulin resistance is an important and under recognized consequence of HIV treatment. Different studies have yielded widely varying estimates of the prevalence of impaired glucose metabolism in people on highly active antiretroviral therapy (HAART). The risk increases further with hepatitis C co infection. Although Protease inhibitors (PIs) are the main drug class implicated in insulin resistance, some studies have shown an association of increased risk of diabetes with cumulative exposure of nucleoside reverse transcriptase inhibitors (NRTIs). The effect of switching to other antiretrovirals has not been fully determined and the long-term consequences of insulin resistance in this population are not known. Treatment of established diabetes mellitus should generally follow existing guidelines. It is therefore reasonable to recommend general measures to increase insulin sensitivity in all patients infected with HIV, such as regular aerobic exercise and weight reduction for overweight persons. The present review article has the information of some recent patents regarding the insulin resistance in HIV infection. PMID:21824074

  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. Insulin resistance and muscle insulin receptor substrate‐1 serine hyperphosphorylation

    PubMed Central

    Stuart, Charles A.; Howell, Mary E. A.; Cartwright, Brian M.; McCurry, Melanie P.; Lee, Michelle L.; Ramsey, Michael W.; Stone, Michael H.

    2014-01-01

    Abstract Insulin resistance in metabolic syndrome subjects is profound in spite of muscle insulin receptor and insulin‐responsive glucose transporter (GLUT4) expression being nearly normal. Insulin receptor tyrosine kinase phosphorylation of insulin receptor substrate‐1 (IRS‐1) at Tyr896 is a necessary step in insulin stimulation of translocation of GLUT4 to the cell surface. Serine phosphorylation of IRS‐1 by some kinases diminishes insulin action in mice. We evaluated the phosphorylation status of muscle IRS‐1 in 33 subjects with the metabolic syndrome and seventeen lean controls. Each underwent euglycemic insulin clamps and a thigh muscle biopsy before and after 8 weeks of either strength or endurance training. Muscle IRS‐1 phosphorylation at six sites was quantified by immunoblots. Metabolic syndrome muscle IRS‐1 had excess phosphorylation at Ser337 and Ser636 but not at Ser307, Ser789, or Ser1101. Ser337 is a target for phosphorylation by glycogen synthase kinase 3 (GSK3) and Ser636 is phosphorylated by c‐Jun N‐terminal kinase 1 (JNK1). Exercise training without weight loss did not change the IRS‐1 serine phosphorylation. These data suggest that baseline hyperphosphorylation of at least two key serines within muscle IRS‐1 diminishes the transmission of the insulin signal and thereby decreases the insulin‐stimulated translocation of GLUT4. Excess fasting phosphorylation of muscle IRS‐1 at Ser636 may be a major cause of the insulin resistance seen in obesity and might prevent improvement in insulin responsiveness when exercise training is not accompanied by weight loss. PMID:25472611

  3. 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.

  4. Mechanisms Linking Inflammation to Insulin Resistance.

    PubMed

    Chen, Li; Chen, Rui; Wang, Hua; Liang, Fengxia

    2015-01-01

    Obesity is now widespread around the world. Obesity-associated chronic low-grade inflammation is responsible for the decrease of insulin sensitivity, which makes obesity a major risk factor for insulin resistance and related diseases such as type 2 diabetes mellitus and metabolic syndromes. The state of low-grade inflammation is caused by overnutrition which leads to lipid accumulation in adipocytes. Obesity might increase the expression of some inflammatory cytokines and activate several signaling pathways, both of which are involved in the pathogenesis of insulin resistance by interfering with insulin signaling and action. It has been suggested that specific factors and signaling pathways are often correlated with each other; therefore, both of the fluctuation of cytokines and the status of relevant signaling pathways should be considered during studies analyzing inflammation-related insulin resistance. In this paper, we discuss how these factors and signaling pathways contribute to insulin resistance and the therapeutic promise targeting inflammation in insulin resistance based on the latest experimental studies. PMID:26136779

  5. Insulin resistance: regression and clustering.

    PubMed

    Yoon, Sangho; Assimes, Themistocles L; Quertermous, Thomas; Hsiao, Chin-Fu; Chuang, Lee-Ming; Hwu, Chii-Min; Rajaratnam, Bala; Olshen, Richard A

    2014-01-01

    In this paper we try to define insulin resistance (IR) precisely for a group of Chinese women. Our definition deliberately does not depend upon body mass index (BMI) or age, although in other studies, with particular random effects models quite different from models used here, BMI accounts for a large part of the variability in IR. We accomplish our goal through application of Gauss mixture vector quantization (GMVQ), a technique for clustering that was developed for application to lossy data compression. Defining data come from measurements that play major roles in medical practice. A precise statement of what the data are is in Section 1. Their family structures are described in detail. They concern levels of lipids and the results of an oral glucose tolerance test (OGTT). We apply GMVQ to residuals obtained from regressions of outcomes of an OGTT and lipids on functions of age and BMI that are inferred from the data. A bootstrap procedure developed for our family data supplemented by insights from other approaches leads us to believe that two clusters are appropriate for defining IR precisely. One cluster consists of women who are IR, and the other of women who seem not to be. Genes and other features are used to predict cluster membership. We argue that prediction with "main effects" is not satisfactory, but prediction that includes interactions may be. PMID:24887437

  6. 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

  7. The Epoxyeicosatrienoic Acid Pathway Enhances Hepatic Insulin Signaling and is Repressed in Insulin-Resistant Mouse Liver.

    PubMed

    Schäfer, Alexander; Neschen, Susanne; Kahle, Melanie; Sarioglu, Hakan; Gaisbauer, Tobias; Imhof, Axel; Adamski, Jerzy; Hauck, Stefanie M; Ueffing, Marius

    2015-10-01

    Although it is widely accepted that ectopic lipid accumulation in the liver is associated with hepatic insulin resistance, the underlying molecular mechanisms have not been well characterized.Here we employed time resolved quantitative proteomic profiling of mice fed a high fat diet to determine which pathways were affected during the transition of the liver to an insulin-resistant state. We identified several metabolic pathways underlying altered protein expression. In order to test the functional impact of a critical subset of these alterations, we focused on the epoxyeicosatrienoic acid (EET) eicosanoid pathway, whose deregulation coincided with the onset of hepatic insulin resistance. These results suggested that EETs may be positive modulators of hepatic insulin signaling. Analyzing EET activity in primary hepatocytes, we found that EETs enhance insulin signaling on the level of Akt. In contrast, EETs did not influence insulin receptor or insulin receptor substrate-1 phosphorylation. This effect was mediated through the eicosanoids, as overexpression of the deregulated enzymes in absence of arachidonic acid had no impact on insulin signaling. The stimulation of insulin signaling by EETs and depression of the pathway in insulin resistant liver suggest a likely role in hepatic insulin resistance. Our findings support therapeutic potential for inhibiting EET degradation.

  8. Insulin Resistance, Brain Atrophy, and Cognitive Performance in Late Middle–Aged Adults

    PubMed Central

    Willette, Auriel A.; Xu, Guofan; Johnson, Sterling C.; Birdsill, Alex C.; Jonaitis, Erin M.; Sager, Mark A.; Hermann, Bruce P.; La Rue, Asenath; Asthana, Sanjay; Bendlin, Barbara B.

    2013-01-01

    OBJECTIVE Insulin resistance dysregulates glucose uptake and other functions in brain areas affected by Alzheimer disease. Insulin resistance may play a role in Alzheimer disease etiopathogenesis. This longitudinal study examined whether insulin resistance among late middle–aged, cognitively healthy individuals was associated with 1) less gray matter in Alzheimer disease–sensitive brain regions and 2) worse cognitive performance. RESEARCH DESIGN AND METHODS Homeostasis model assessment of insulin resistance, gray matter volume, and the Rey Auditory Verbal Learning Test (RAVLT) were acquired in 372 participants at baseline and a consecutive subset of 121 individuals ~4 years later. Voxel-based morphometry and tensor-based morphometry were used, respectively, to test the association of insulin resistance with baseline brain volume and progressive gray matter atrophy. RESULTS Higher insulin resistance predicted less gray matter at baseline and 4 years later in medial temporal lobe, prefrontal cortices, precuneus, and other parietal gyri. A region-of-interest analysis, independent of the voxel-wise analyses, confirmed that higher insulin resistance was related to medial temporal lobe atrophy. Atrophy itself corresponded to cognitive deficits in the RAVLT. Temporal lobe atrophy that was predicted by higher insulin resistance significantly mediated worse RAVLT encoding performance. CONCLUSIONS These results suggest that insulin resistance in an asymptomatic, late middle–aged cohort is associated with progressive atrophy in regions affected by early Alzheimer disease. Insulin resistance may also affect the ability to encode episodic information by negatively influencing gray matter volume in medial temporal lobe. PMID:23069842

  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. PMID:21304221

  10. [Smoking, insulin resistance and type 2 diabetes].

    PubMed

    Magis, D; Geronooz, I; Scheen, A J

    2002-09-01

    Smoking is a major risk factor for cardiovascular disease. It is associated with endothelial dysfunction and lipid disorders similar to those found in the insulin resistance syndrome. Studies have thus tried to demonstrate a relationship between smoking and insulin resistance, and between smoking and type 2 diabetes mellitus. Even if their results may sometimes differ, smoking does seem to be associated with an impaired insulin sensitivity that is proportional to tobacco consumption. Nicotine replacement therapies seem also to generate a certain, though lower, degree of insulin resistance. If there is no major weight gain after smoking cessation, the latter is accompanied by a progressive return to normal insulin sensitivity. Several large epidemiological studies recently demonstrated that smoking could increase the risk of type 2 diabetes mellitus, with a relative risk between 1.5 and 3.0. Finally, among type 2 diabetic patients, smoking has a harmful effect on metabolic control and long-term complications of the disease, at least partially by increasing the components of the insulin resistance syndrome. All these observations represent further argument to promote smoking cessation in the general population, and more particularly in individuals at risk to develop type 2 diabetes, as well as in the diabetic population. PMID:12440345

  11. 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…

  12. [CHANGES IN LIFESTYLE FACTORS AFFECT THE LEVELS OF NEUROPEPTIDES, INVOLVED IN THE CONTROL OF EATING BEHAVIOR, INSULIN RESISTANCE AND LEVEL OF CHRONIC SYSTEMIC INFLAMMATION IN YOUNG OVERWEIGHT PERSONS].

    PubMed

    Shevchenko, Yu; Mamontova, T; Baranova, A; Vesnina, L; Kaidashev, I

    2015-11-01

    The continuous rise of overweight and obesity is a major concern for present and future healthcare management. The aim of our study was to evaluate the influence of lifestyle changes on central regulatory mechanisms of maintaining energy homeostasis, insulin resistance and chronic systemic inflammation in 18-25 year old overweight patients. The anthropometric measurements were done for each patient, including body weight, height, waist circumference (WC), hip circumference (HC), waist to hip ratio, and body mass index (BMI). Patients were divided into two groups according to their BMI. 20 males and 21 females with BMI > 25 kg/m2 were included in the first, study, group. The second, control, group consisted of 16 males and 11 females with BMI - 18.5 - 24.9 kg/m 2. Lipid profile, fasting glucose and insulin levels, HOMA-IR, TNF-α, ceruloplasmin, neuropeptides Agouti-related protein - AgRP and kokain- and amphetamine-mediated transcript - CART were examined at the beginning of the study (Day 1) and after 10 week treatment period (Day 70). During the 10 week treatment period, people in the study group underwent physical exercise programs of 40-60 minute duration three times per week, and brisk walking during the remaining days. The mean calorie expenditure during the exercise was 500 kcal/day. Each patient in the study group was given balanced, healthy diet with 20% calorie restriction from baseline diet. Our study reveled that negative energy balance caused a statistically significant decrease in AgRP, reduction of visceral fat stores, increase of HDL, reduction of TNF-α and dissolution of insulin resistance signs. Significant but not statistically significant reduction of CART level was observed after increased physical activity program and calorie restriction diet, which might play an important role in the mechanism of decreasing weight. However, further investigations are required in order to determine its place in body weight regulation. PMID:26656551

  13. 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.

  14. 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. PMID:20631738

  15. Insulin resistance in cirrhosis: prolonged reduction of hyperinsulinemia normalizes insulin sensitivity.

    PubMed

    Petrides, A S; Stanley, T; Matthews, D E; Vogt, C; Bush, A J; Lambeth, H

    1998-07-01

    Insulin resistance is present in nearly all patients with cirrhosis, but its etiology remains unknown. Chronic hyperinsulinemia has been suspected as a potential candidate, and we therefore tested the hypothesis that, in cirrhosis, prolonged reduction of the hyperinsulinemia restores insulin sensitivity. Whole-body insulin sensitivity (euglycemic insulin-clamp technique), glucose turnover (6,6-2H2-glucose isotope dilution), glucose oxidation (indirect calorimetry), non-oxidative glucose disposal, and fractional glycogen synthase activity in muscle (biopsies) were measured in eight clinically stable patients with cirrhosis before and at the end of a 4-day continuous subcutaneous infusion of the somatostatin-analogue octreotide (200 microg/24 h) designed to continuously reduce plasma insulin levels. Baseline data were compared with results obtained in healthy individuals matched for sex, age, and weight (n = 8). During the baseline (pre-octreotide) study, patients demonstrated a significant decrease in insulin-mediated glucose uptake compared with controls (5.75 +/- 0.21 vs. 7.98 +/- 0.84 mg/kg/min; P < .03), which was entirely accounted for by an impairment in non-oxidative glucose disposal (P < .04). Four-day infusion of octreotide to cirrhotic patients: 1) reduced postabsorptive and meal-stimulated plasma insulin levels by approximately 35% to 45% without significantly affecting glucose tolerance; 2) did not significantly alter plasma free fatty acids (FFA), growth hormone, and glucagon levels in the postabsorptive state and during the meal test; 3) normalized insulin-mediated whole-body glucose disposal (7.63 +/- 0.72 mg/kg/min post-octreotide; P = not significant vs. control). Restoration of insulin-mediated glucose utilization was entirely caused by normalization of non-oxidative glucose disposal; 4) was associated with a considerably more pronounced stimulation by insulin of the fractional glycogen synthase in muscle compared with pre-octreotide results

  16. 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. PMID:27650286

  17. 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. PMID:26991531

  18. The Importance of Palmitoleic Acid to Adipocyte Insulin Resistance and Whole-Body Insulin Sensitivity in Type 1 Diabetes

    PubMed Central

    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

    Context: 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. Objective: 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. Design, Patients, and Methods: 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/m2 · min. Infusions of [1,1,2,3,3-2H2]glycerol and [1-13C]palmitate were used to quantify lipid metabolism. Results: 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 insulin dose. The concentration of insulin required for 50% inhibition of lipolysis was twice as high in individuals with type 1 diabetes. Plasma triglyceride saturation was similar between groups, but palmitoleic acid in plasma triglyceride was inversely related to adipocyte insulin sensitivity. Unesterified palmitoleic acid in plasma was positively related to insulin sensitivity in controls, but not in individuals with type 1 diabetes. Conclusions: Adipose tissue insulin resistance is a significant feature of type 1 diabetes. Palmitoleic acid is not related to insulin sensitivity in type 1 diabetes, as it was in controls, suggesting a novel mechanism for insulin resistance in this population. PMID:23150678

  19. Excess exposure to insulin is the primary cause of insulin resistance and its associated atherosclerosis.

    PubMed

    Cao, Wenhong; Ning, Jie; Yang, Xuefeng; Liu, Zhenqi

    2011-11-01

    The main goal of this review is to provide more specific and effective targets for prevention and treatment of insulin resistance and associated atherosclerosis. Modern technologies and medicine have vastly improved human health and prolonged the average life span of humans primarily by eliminating various premature deaths and infectious diseases. The modern technologies have also provided us abundant food and convenient transportation tools such as cars. As a result, more people are becoming overfed and sedentary. People are generally ingesting more calories than their bodies' need, leading to the so-called "positive energy imbalance", which is inseparable from the development of insulin resistance and its associated atherosclerosis. A direct consequence of insulin resistance is hyperinsulinemia. The current general view is that insulin is not functional properly in the presence of insulin resistance. Thus, the role of insulin itself in the development of insulin resistance and associated atherosclerosis has not been recognized. We have recently observed that the basal level of insulin signaling is increased in the presence of insulin resistance and hyperinsulinemia. In this review, we will explain how the increased basal insulin signaling contributes to the development of insulin resistance and associated atherosclerosis. We will first explain how insulin causes insulin resistance through two arbitrary stages (before and after the presence of obvious insulin resistance), and, then, explain how the excess exposure to insulin and the relative insulin insufficiency contributes to the atherosclerotic diseases. We propose that blockade of the excess insulin signaling is a viable approach to prevent and/or reverse insulin resistance and its associated atherosclerosis.

  20. 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

  1. [Cytokines, endothelial dysfunction, and insulin resistance].

    PubMed

    de Carvalho, Maria Helena C; Colaço, André Luiz; Fortes, Zuleica Bruno

    2006-04-01

    Endothelial dysfunction is associated with several vascular conditions as atherosclerosis, hypertension, hyperlipidemia and diabetes mellitus. In all these conditions insulin resistance (IR) is present. Cytokines are low molecular weight proteins with several endocrine and metabolic functions that participate of inflammation and immune response. Several of these cytokines are independent risk factors for cerebrovascular and coronary artery disease. The major sources of cytokines (adipokines) are the visceral and subcutaneous adipose tissues. Thus, increased adipose tissue mass is associated with alteration in adipokine production as over expression of tumor necrosis factor alpha, interleukin 6, plasminogen activator inhibitor 1, and under expression of adiponectin in adipocite tissue. The pro-inflammatory status associated with these changes provides a potential link between IR and endothelial dysfunction, the early stage in the atherosclerotic process, in obese individuals, and type 2 diabetic patients. Reduction of adipose tissue mass through weight reduction in association with exercise reduces TNF-alpha, IL-6, and PAI-1, increases adiponectin, and is associated with improved insulin sensitivity and endothelial function. This review will focus on the evidence for regulation of endothelial function by insulin and the adypokines such as adyponectin, leptin, resistin, IL-6 and TNF-alpha. Interaction between insulin signaling and adypokines will be discussed, as well as the concept that aberrant adypokine secretion in IR and/or obesity impairs endothelial function and contributes further to reduce insulin sensitivity.

  2. Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in humans and mice.

    PubMed

    Foti, Daniela; Chiefari, Eusebio; Fedele, Monica; Iuliano, Rodolfo; Brunetti, Leonardo; Paonessa, Francesco; Manfioletti, Guidalberto; Barbetti, Fabrizio; Brunetti, Arturo; Croce, Carlo M; Fusco, Alfredo; Brunetti, Antonio

    2005-07-01

    Type 2 diabetes mellitus is a widespread disease, affecting millions of people globally. Although genetics and environmental factors seem to have a role, the cause of this metabolic disorder is largely unknown. Here we report a genetic flaw that markedly reduced the intracellular expression of the high mobility group A1 (HMGA1) protein, and adversely affected insulin receptor expression in cells and tissues from four subjects with insulin resistance and type 2 diabetes. Restoration of HMGA1 protein expression in subjects' cells enhanced INSR gene transcription, and restored cell-surface insulin receptor protein expression and insulin-binding capacity. Loss of Hmga1 expression, induced in mice by disrupting the Hmga1 gene, considerably decreased insulin receptor expression in the major targets of insulin action, largely impaired insulin signaling and severely reduced insulin secretion, causing a phenotype characteristic of human type 2 diabetes. PMID:15924147

  3. Obesity, insulin resistance, and microvessel density.

    PubMed

    Frisbee, Jefferson C

    2007-01-01

    The growing incidence and prevalence of the overweight/obese condition across developed economies worldwide has an enormous impact on increasing the risk for the development of impaired glycemic control or insulin resistance and ultimately peripheral vascular disease (PVD) in afflicted individuals. This places an enormous economic and social burden on these societies, in terms of additional health care costs and lost productivity and through a reduction in the quality of life of the individual owing, in part, to the progressive PVD. Characterized by an inability of the vascular systems to adequately perfuse tissues and organs relative to their metabolic demand, PVD is in part a function of a structural remodeling of the microvascular networks such that the density of microvessel and capillaries within tissues is reduced below that under normal conditions, with the potential for profound negative impacts on the processes of mass transport and exchange. The review discusses the severity of the obesity "epidemic" from the perspective of PVD and the effects of the development of the obese, insulin-resistant condition on tissue/organ microvessel density. Additional material is reviewed that addresses ameliorative treatments, primarily exercise training, on blunting microvessel loss in the obese, insulin-resistant individual, and on potential mechanistic contributors that warrant considerable future investigation.

  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. Acute Psychological Stress Results in the Rapid Development of Insulin Resistance

    PubMed Central

    Li, Li; Li, Xiaohua; Zhou, Wenjun; Messina, Joseph L.

    2013-01-01

    In recent years, the roles of chronic stress and depression as an independent risk factor for decreased insulin sensitivity and the development of diabetes have been increasingly recognized. However, an understanding and the mechanisms linking insulin resistance and acute psychological stress are very limited. We hypothesized that acute psychological stress may cause the development of insulin resistance, which may be a risk factor in developing type 2 diabetes. We tested the hypothesis in a well-established mouse model using 180 episodes of inescapable foot shock (IES), followed by a behavioral escape test. In this study, mice that received IES treatment were tested for acute insulin resistance by measuring glucose metabolism and insulin signaling. When compared to normal and sham mice, mice that were exposed to IES resulting in escape failure (defined as IES with behavioral escape failure) displayed elevated blood glucose levels in both glucose tolerance and insulin tolerance tests. Furthermore, mice with IES exposure and behavioral escape failure exhibited impaired hepatic insulin signaling via the insulin-induced insulin receptor/insulin receptor substrate 1/Akt pathway, without affecting similar pathways in skeletal muscle, adipose tissue and brain. Additionally, a rise in murine growth-related oncogene KC/GRO was associated with impaired glucose metabolism in IES mice, suggesting a mechanism by which psychological stress by IES may influence glucose metabolism. The present results indicate that psychological stress induced by IES can acutely alter hepatic responsiveness to insulin and affect whole-body glucose metabolism. PMID:23444388

  6. Molecular characterization of insulin resistance and glycolytic metabolism in the rat uterus

    PubMed Central

    Zhang, Yuehui; Sun, Xue; Sun, Xiaoyan; Meng, Fanci; Hu, Min; Li, Xin; Li, Wei; Wu, Xiao-Ke; Brännström, Mats; Shao, Ruijin; Billig, Håkan

    2016-01-01

    Peripheral insulin resistance and hyperandrogenism are the primary features of polycystic ovary syndrome (PCOS). However, how insulin resistance and hyperandrogenism affect uterine function and contribute to the pathogenesis of PCOS are open questions. We treated rats with insulin alone or in combination with human chorionic gonadotropin (hCG) and showed that peripheral insulin resistance and hyperandrogenism alter uterine morphology, cell phenotype, and cell function, especially in glandular epithelial cells. These defects are associated with an aberration in the PI3K/Akt signaling pathway that is used as an indicator for the onset of insulin resistance in classical metabolic tissues. Concomitantly, increased GSK3β (Ser-9) phosphorylation and decreased ERK1/2 phosphorylation in rats treated with insulin and hCG were also observed. We also profiled the expression of glucose transporter (Glut) isoform genes in the uterus under conditions of insulin resistance and/or hyperandrogenism. Finally, we determined the expression pattern of glycolytic enzymes and intermediates during insulin resistance and hyperandrogenism in the uterus. These findings suggest that the PI3K/Akt and MAPK/ERK signaling pathways play a role in the onset of uterine insulin resistance, and they also suggest that changes in specific Glut isoform expression and alterations to glycolytic metabolism contribute to the endometrial dysfunction observed in PCOS patients. PMID:27461373

  7. Molecular characterization of insulin resistance and glycolytic metabolism in the rat uterus.

    PubMed

    Zhang, Yuehui; Sun, Xue; Sun, Xiaoyan; Meng, Fanci; Hu, Min; Li, Xin; Li, Wei; Wu, Xiao-Ke; Brännström, Mats; Shao, Ruijin; Billig, Håkan

    2016-01-01

    Peripheral insulin resistance and hyperandrogenism are the primary features of polycystic ovary syndrome (PCOS). However, how insulin resistance and hyperandrogenism affect uterine function and contribute to the pathogenesis of PCOS are open questions. We treated rats with insulin alone or in combination with human chorionic gonadotropin (hCG) and showed that peripheral insulin resistance and hyperandrogenism alter uterine morphology, cell phenotype, and cell function, especially in glandular epithelial cells. These defects are associated with an aberration in the PI3K/Akt signaling pathway that is used as an indicator for the onset of insulin resistance in classical metabolic tissues. Concomitantly, increased GSK3β (Ser-9) phosphorylation and decreased ERK1/2 phosphorylation in rats treated with insulin and hCG were also observed. We also profiled the expression of glucose transporter (Glut) isoform genes in the uterus under conditions of insulin resistance and/or hyperandrogenism. Finally, we determined the expression pattern of glycolytic enzymes and intermediates during insulin resistance and hyperandrogenism in the uterus. These findings suggest that the PI3K/Akt and MAPK/ERK signaling pathways play a role in the onset of uterine insulin resistance, and they also suggest that changes in specific Glut isoform expression and alterations to glycolytic metabolism contribute to the endometrial dysfunction observed in PCOS patients. PMID:27461373

  8. 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

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

    PubMed

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

    2013-11-01

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

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

    PubMed

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

    2013-11-01

    Insulin resistance is a hallmark of obesity, the cardiorenal metabolic syndrome and type 2 diabetes mellitus (T2DM). The progression of insulin resistance increases the risk for cardiovascular disease (CVD). The significance of insulin resistance is underscored by the alarming rise in the prevalence of obesity and its associated comorbidities in the Unites States and worldwide over the last 40-50 years. The incidence of obesity is also on the rise in adolescents. Furthermore, premenopausal women have lower CVD risk compared to men, but this protection is lost in the setting of obesity and insulin resistance. Although systemic and cardiovascular insulin resistance is associated with impaired insulin metabolic signaling and cardiovascular dysfunction, the mechanisms underlying insulin resistance and cardiovascular dysfunction remain poorly understood. Recent studies show that insulin resistance in obesity and diabetes is linked to a metabolic inflammatory response, a state of systemic and tissue specific chronic low grade inflammation. Evidence is also emerging that there is polarization of macrophages and lymphocytes towards a pro-inflammatory phenotype that contributes to progression of insulin resistance in obesity, cardiorenal metabolic syndrome and diabetes. In this review, we provide new insights into factors, such as, the renin-angiotensin-aldosterone system, sympathetic activation and incretin modulators (e.g., DPP-4) and immune responses that mediate this inflammatory state in obesity and other conditions characterized by insulin resistance. PMID:23932846

  11. FACTORS AFFECTING THE DEPOSITION OF AEROSOLIZED INSULIN

    EPA Science Inventory

    Abstract
    Background
    The inhalation of insulin for absorption into the bloodstream via the lung seems to be a promising technique for the treatment of diabetes mellitus. A fundamental issue to be resolved in the development of such insulin aerosol delivery systems is their...

  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. 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

  14. [Comparison of biosynthetic human insulin and purified pork insulin. Studies in insulin-resistant obese patients using the insulin suppression test].

    PubMed

    Richard, J L; Rodier, M; Cavalie, G; Lachkar, H; Orsetti, A; Monnier, L; Mirouze, J

    1986-02-01

    An insulin suppression test performed in random order with either biosynthetic human insulin or purified pork insulin was used to compare biological activity of these two insulins in obese patients suffering from varying degrees of glucose intolerance. Blood glucose curve, steady-state blood glucose levels, insulin sensitivity indices and steady-state plasma insulin levels were identical during the two sets of tests. Furthermore endogenous insulin and glucagon secretion were similarly suppressed. The insulin suppression test is a simple and rapid procedure to compare the biological activity of fast-acting insulins. Our results confirm the insulin-resistance in obesity and clearly show that biosynthetic human and porcine insulins have similar biological potency.

  15. Deletion of exon 3 of the insulin receptor gene in a kindred with a familial form of insulin resistance

    SciTech Connect

    Wertheimer, E.; Barbetti, F.; Accili, D.; Taylor, S.I.; Litvin, Y.; Ebstein, R.P.; Bennet, E.R.

    1994-05-01

    Molecular scanning techniques, such as denaturing gradient gel electrophoresis (DGGE), greatly facilitate screening candidate genes for mutations. The authors have used DGGE to screen for mutations in the insulin receptor gene in a family in which four of five daughters were affected by type A insulin resistance in association with acanthosis nigricans and hyperandrogenism. DGGE did not detect mutations in any of the 22 exons of the insulin receptor gene. Nevertheless, Southern blot analysis suggested that there was a deletion of exon 3 in the other paternal allele of the insulin receptor gene. Analysis of the father`s cDNA confirmed that exon 3 was deleted from mRNA molecules derived from one of his two alleles of the insulin receptor gene. Furthermore, the father was found to be hemizygous for a polymorphic sequence (GAC{sup Asp} at codon 234) in exon 3 that was not inherited by any of the five daughters. Instead, all five daughters inherited the paternal allele with the deletion mutation. They did not detect mutations in the mother`s insulin receptor gene. Furthermore, the clinical syndrome did not segregate with either of the mother`s two alleles of the insulin receptor gene. Although the youngest daughter inherited the mutant allele from her father, she was not clinically affected. The explanation for the incomplete penetrance is not known. These results emphasize the importance of specifically searching for deletion mutations when screening candidate genes for mutations. Furthermore, the existence of apparently asymptomatic carriers of mutations in the insulin receptor gene, such as the father in the present study, suggests that the prevalence of mutations in the insulin receptor gene may be higher than would be predicted on the basis of the observed prevalence of patients with extreme insulin resistance. 34 refs., 6 figs., 1 tab.

  16. Metabolomic Response of Skeletal Muscle to Aerobic Exercise Training in Insulin Resistant Type 1 Diabetic Rats

    PubMed Central

    Dotzert, Michelle S.; Murray, Michael R.; McDonald, Matthew W.; Olver, T. Dylan; Velenosi, Thomas J.; Hennop, Anzel; Noble, Earl G.; Urquhart, Brad L.; Melling, C. W. James

    2016-01-01

    The etiology of insulin resistance in Type 1 Diabetes (T1D) is unknown, however it affects approximately 20% of T1D patients. Intramyocellular lipids (IMCL) have been identified as a mechanism of insulin resistance. We examined skeletal muscle of T1D rats to determine if alterations in lipid metabolism were evident and whether aerobic exercise training improves IMCL and insulin resistance. To do so, 48 male Sprague-Dawley rats were divided into control (C), sedentary diabetes (D) and diabetes exercise (DX) groups. Following multiple low-dose Streptozotocin (STZ) injections (20 mg/kg), glycemia (9–15 mM) was maintained using insulin treatment. DX were treadmill trained at high intensity (~75% V02max; 5days/week) for 10 weeks. The results demonstrate that D exhibited insulin resistance compared with C and DX, indicated by decreased glucose infusion rate during a hyperinsulinemic-euglycemic clamp (p < 0.05). There were no differences between C and DX, suggesting that exercise improved insulin resistance (p < 0.05). Metabolomics analysis revealed a significant shift in lipid metabolism whereby notable fatty acid metabolites (arachidonic acid, palmitic acid and several polyunsaturated fatty acids) were significantly elevated in D compared to C and DX. Based on the intermediates observed, insulin resistance in T1D is characterized by an insulin-desensitizing intramyocellular fatty acid metabolite profile that is ameliorated with exercise training. PMID:27197730

  17. 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

  18. 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. PMID:24358272

  19. Obesity and insulin resistance in resistant hypertension: implications for the kidney.

    PubMed

    Rao, Akhilesh; Pandya, Vishwam; Whaley-Connell, Adam

    2015-05-01

    There is recognition that the obesity epidemic contributes substantially to the increasing incidence of CKD and resistant hypertension (HTN). The mechanisms by which obesity promotes resistance are an area of active interest and intense investigation. It is thought that increases in visceral adiposity lead to a proinflammatory, pro-oxidative milieu that promote resistance to the metabolic actions of insulin. This resistance to insulin at the level of skeletal muscle tissue impairs glucose disposal/utilization through actions on the endothelium that include vascular rarefaction, reductions in vascular relaxation, and vascular remodeling. Insulin resistance derived from increased adipose tissue and obesity has system-wide implications for other tissue beds such as the kidney that affects blood pressure regulation. The additional autocrine and paracrine activities of adipose tissue contribute to inappropriate activation of the renin-angiotensin-aldosterone system and the sympathetic nervous system that promote kidney microvascular remodeling, stiffness, and sodium (Na(+)) retention that in turn promote HTN and in the CKD patient, resistance. In this review, we will summarize the important mechanisms that link obesity to CKD as they relate to resistant HTN.

  20. Acylcarnitines: potential implications for skeletal muscle insulin resistance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  1. Severe Injury Is Associated With Insulin Resistance, Endoplasmic Reticulum Stress Response, and Unfolded Protein Response

    PubMed Central

    Jeschke, Marc G.; Finnerty, Celeste C.; Herndon, David N.; Song, Juquan; Boehning, Darren; Tompkins, Ronald G.; Baker, Henry V.; Gauglitz, Gerd G.

    2012-01-01

    Objective We determined whether postburn hyperglycemia and insulin resistance are associated with endoplasmic reticulum (ER) stress/unfolded protein response (UPR) activation leading to impaired insulin receptor signaling. Background Inflammation and cellular stress, hallmarks of severely burned and critically ill patients, have been causally linked to insulin resistance in type 2 diabetes via induction of ER stress and the UPR. Methods Twenty severely burned pediatric patients were compared with 36 nonburned children. Clinical markers, protein, and GeneChip analysis were used to identify transcriptional changes in ER stress and UPR and insulin resistance–related signaling cascades in peripheral blood leukocytes, fat, and muscle at admission and up to 466 days postburn. Results Burn-induced inflammatory and stress responses are accompanied by profound insulin resistance and hyperglycemia. Genomic and protein analysis revealed that burn injury was associated with alterations in the signaling pathways that affect insulin resistance, ER/sarcoplasmic reticulum stress, inflammation, and cell growth/apoptosis up to 466 days postburn. Conclusion Burn-induced insulin resistance is associated with persistent ER/sarcoplasmic reticulum stress/UPR and subsequent suppressed insulin receptor signaling over a prolonged period of time. PMID:22241293

  2. Role of exercise training in the prevention and treatment of insulin resistance and non-insulin-dependent diabetes mellitus.

    PubMed

    Ivy, J L

    1997-11-01

    the insulin response to a glucose challenge without affecting glucose tolerance, and to increase the rate of glucose clearance during a euglycaemic clamp. Muscle glucose uptake is equal to the product of the arteriovenous glucose difference and the rate of glucose delivery or muscle blood flow. While it has been known for many years that insulin will accelerate blood glucose extraction by insulin-sensitive peripheral tissues, recent evidence suggests that it can also acutely vasodilate skeletal muscle and increase muscle blood flow in a dose-dependent manner. A reduced ability of insulin to stimulate muscle blood flow is a characteristic of insulin-resistant obese individuals and individuals with NIDDM. Exercise training, however, has been found to help alleviate this problem, and substantially improve the control of insulin over blood glucose. Improvements in insulin resistance and glucose tolerance with exercise training are highly related to an increased skeletal muscle insulin action. This increased insulin action is associated with an increase in the insulin-regulatable glucose transporters, GLUT4, and enzymes responsible for the phosphorylation, storage and oxidation of glucose. Changes in muscle morphology may also be important following training. With exercise training there is an increase in the conversion of fast twitch glycolytic IIb fibres to fast twitch oxidative IIa fibres, as well as an increase in capillary density. IIa fibres have a greater capillary density and are more insulin-sensitive and -responsive than IIb fibres. Evidence has been provided that morphological changes in muscle, particularly the capillary density of the muscle, are associated with changes in fasting insulin levels and glucose tolerance. Furthermore, significant correlations between glucose clearance, muscle capillary density and fibre type have been found in humans during a euglycaemic clamp. Exercise training may also improve control over hepatic glucose production by increasin

  3. Mechanisms of human insulin resistance and thiazolidinedione-mediated insulin sensitization

    PubMed Central

    Sears, D. D.; Hsiao, G.; Hsiao, A.; Yu, J. G.; Courtney, C. H.; Ofrecio, J. M.; Chapman, J.; Subramaniam, S.

    2009-01-01

    Cellular and tissue defects associated with insulin resistance are coincident with transcriptional abnormalities and are improved after insulin sensitization with thiazolidinedione (TZD) PPARγ ligands. We characterized 72 human subjects by relating their clinical phenotypes with functional pathway alterations. We transcriptionally profiled 364 biopsies harvested before and after hyperinsulinemic-euglycemic clamp studies, at baseline and after 3-month TZD treatment. We have identified molecular and functional characteristics of insulin resistant subjects and distinctions between TZD treatment responder and nonresponder subjects. Insulin resistant subjects exhibited alterations in skeletal muscle (e.g., glycolytic flux and intramuscular adipocytes) and adipose tissue (e.g., mitochondrial metabolism and inflammation) that improved relative to TZD-induced insulin sensitization. Pre-TZD treatment expression of MLXIP in muscle and HLA-DRB1 in adipose tissue from insulin resistant subjects was linearly predictive of post-TZD insulin sensitization. We have uniquely characterized coordinated cellular and tissue functional pathways that are characteristic of insulin resistance, TZD-induced insulin sensitization, and potential TZD responsiveness. PMID:19841271

  4. 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

  5. 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

  6. 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.

  7. Fasting glucose insulin ratio: a useful measure of insulin resistance in girls with premature adrenarche.

    PubMed

    Vuguin, P; Saenger, P; Dimartino-Nardi, J

    2001-10-01

    The purpose of this study was to determine whether the fasting glucose/insulin ratio is a useful screening test for insulin resistance in prepubertal girls with premature adrenarche. The glucose/insulin ratio was compared with the insulin sensitivity index calculated from the frequently sampled iv glucose tolerance test with tolbutamide using the minimal model computer program. Thirty-three prepubertal girls (22 Caribbean Hispanic and 11 African American; mean age, 6.8 yr; bone age, 8 yr) were studied. All underwent a 60-min ACTH stimulation test. The fasting glucose/insulin ratio was also compared with IGF-binding protein-1 and ACTH-stimulated androgen levels. Insulin sensitivity correlated significantly with the glucose/insulin ratio (0.76; P < 0.001), fasting insulin (0.75; P < 0.001), and IGF-binding protein-1 (0.59; P < 0.005). Stepwise regression analysis with the insulin sensitivity index as the dependent variable showed that the fasting glucose/insulin ratio was significantly predictive of the insulin sensitivity index (P < 0.002). When viewed as a screening test, setting a value of the fasting glucose/insulin ratio of less than 7 as abnormal and of less than 5.7 x 10(-4) min/microU.ml for the insulin sensitivity index as evidence of insulin resistance (normal prepubertal insulin sensitivity index, >5.7 x 10(-4) min/microU.ml), the sensitivity of the fasting glucose/insulin ratio was 87%, and the specificity was 89%. Furthermore, those girls with a low glucose/insulin ratio (<7) had higher body mass index, fasting insulin, free T, and ACTH-stimulated 17-hydroxypregnenolone and lower fasting IGF-binding protein-1 and SHBG than those girls with a glucose/insulin ratio greater than 7. The fasting glucose/insulin ratio is a useful screening test for insulin resistance in prepubertal Caribbean Hispanic and African American girls with premature adrenarche.

  8. [Alcohol, steatohepatitis, insulin resistance and hepatitis C].

    PubMed

    Couzigou, P; Mathurin, P; Serfaty, L; Cacoub, P; Moussalli, J; Pialoux, G; Chossegros, P; Cattan, L; Pol, S

    2008-03-01

    Patients with chronic hepatitis C have frequently other morbidities, either because they are frequent in the general population (metabolic syndrome) and/or because the route of contamination (chronic alcohol consumption succeeding to drug abuse). These co-morbidities have a harmfull impact on fibrosis progression during the natural history of HCV infection and reduce the efficacy of antiviral treatments. Thus, it is crucial to diagnose early and treat these different diseases which may be combined. They are the metabolic syndrome and/or chronic alcohol consumption resulting in insuline resistance, infection by the human immune deficiency virus or by the hepatitis B virus as well as chronic tobacco use or excessive consumption of cannabis. An optimal is based on a multidisciplinary approach to reduce fibrosis progression and improve the efficiency of antiviral therapies. However, the hepatologist has to come back to a global care, which is mandatory at the individual level as well as for the public health. PMID:18675184

  9. Muscle-specific vascular endothelial growth factor deletion induces muscle capillary rarefaction creating muscle insulin resistance.

    PubMed

    Bonner, Jeffrey S; Lantier, Louise; Hasenour, Clinton M; James, Freyja D; Bracy, Deanna P; Wasserman, David H

    2013-02-01

    Muscle insulin resistance is associated with a reduction in vascular endothelial growth factor (VEGF) action and muscle capillary density. We tested the hypothesis that muscle capillary rarefaction critically contributes to the etiology of muscle insulin resistance in chow-fed mice with skeletal and cardiac muscle VEGF deletion (mVEGF(-/-)) and wild-type littermates (mVEGF(+/+)) on a C57BL/6 background. The mVEGF(-/-) mice had an ~60% and ~50% decrease in capillaries in skeletal and cardiac muscle, respectively. The mVEGF(-/-) mice had augmented fasting glucose turnover. Insulin-stimulated whole-body glucose disappearance was blunted in mVEGF(-/-) mice. The reduced peripheral glucose utilization during insulin stimulation was due to diminished in vivo cardiac and skeletal muscle insulin action and signaling. The decreased insulin-stimulated muscle glucose uptake was independent of defects in insulin action at the myocyte, suggesting that the impairment in insulin-stimulated muscle glucose uptake was due to poor muscle perfusion. The deletion of VEGF in cardiac muscle did not affect cardiac output. These studies emphasize the importance for novel therapeutic approaches that target the vasculature in the treatment of insulin-resistant muscle. PMID:23002035

  10. Heterozygous caveolin-3 mice show increased susceptibility to palmitate-induced insulin resistance.

    PubMed

    Talukder, M A Hassan; Preda, Marilena; Ryzhova, Larisa; Prudovsky, Igor; Pinz, Ilka M

    2016-03-01

    Insulin resistance and diabetes are comorbidities of obesity and affect one in 10 adults in the United States. Despite the high prevalence, the mechanisms of cardiac insulin resistance in obesity are still unclear. We test the hypothesis that the insulin receptor localizes to caveolae and is regulated through binding to caveolin-3 (CAV3). We further test whether haploinsufficiency forCAV3 increases the susceptibility to high-fat-induced insulin resistance. We used in vivo and in vitro studies to determine the effect of palmitate exposure on global insulin resistance, contractile performance of the heart in vivo, glucose uptake in the heart, and on cellular signaling downstream of theIR We show that haploinsufficiency forCAV3 increases susceptibility to palmitate-induced global insulin resistance and causes cardiomyopathy. On the basis of fluorescence energy transfer (FRET) experiments, we show thatCAV3 andIRdirectly interact in cardiomyocytes. Palmitate impairs insulin signaling by a decrease in insulin-stimulated phosphorylation of Akt that corresponds to an 87% decrease in insulin-stimulated glucose uptake inHL-1 cardiomyocytes. Despite loss of Akt phosphorylation and lower glucose uptake, palmitate increased insulin-independent serine phosphorylation ofIRS-1 by 35%. In addition, we found lipid induced downregulation ofCD36, the fatty acid transporter associated with caveolae. This may explain the problem the diabetic heart is facing with the simultaneous impairment of glucose uptake and lipid transport. Thus, these findings suggest that loss ofCAV3 interferes with downstream insulin signaling and lipid uptake, implicatingCAV3 as a regulator of theIRand regulator of lipid uptake in the heart. PMID:27033451

  11. Failure of Homeostatic Model Assessment of Insulin Resistance to Detect Marked Diet-Induced Insulin Resistance in Dogs

    PubMed Central

    Ader, Marilyn; Stefanovski, Darko; Richey, Joyce M.; Kim, Stella P.; Kolka, Cathryn M.; Ionut, Viorica; Kabir, Morvarid; Bergman, Richard N.

    2014-01-01

    Accurate quantification of insulin resistance is essential for determining efficacy of treatments to reduce diabetes risk. Gold-standard methods to assess resistance are available (e.g., hyperinsulinemic clamp or minimal model), but surrogate indices based solely on fasting values have attractive simplicity. One such surrogate, the homeostatic model assessment of insulin resistance (HOMA-IR), is widely applied despite known inaccuracies in characterizing resistance across groups. Of greater significance is whether HOMA-IR can detect changes in insulin sensitivity induced by an intervention. We tested the ability of HOMA-IR to detect high-fat diet–induced insulin resistance in 36 healthy canines using clamp and minimal model analysis of the intravenous glucose tolerance test (IVGTT) to document progression of resistance. The influence of pancreatic function on HOMA-IR accuracy was assessed using the acute insulin response during the IVGTT (AIRG). Diet-induced resistance was confirmed by both clamp and minimal model (P < 0.0001), and measures were correlated with each other (P = 0.001). In striking contrast, HOMA-IR ([fasting insulin (μU/mL) × fasting glucose (mmol)]/22.5) did not detect reduced sensitivity induced by fat feeding (P = 0.22). In fact, 13 of 36 animals showed an artifactual decrease in HOMA-IR (i.e., increased sensitivity). The ability of HOMA-IR to detect diet-induced resistance was particularly limited under conditions when insulin secretory function (AIRG) is less than robust. In conclusion, HOMA-IR is of limited utility for detecting diet-induced deterioration of insulin sensitivity quantified by glucose clamp or minimal model. Caution should be exercised when using HOMA-IR to detect insulin resistance when pancreatic function is compromised. It is necessary to use other accurate indices to detect longitudinal changes in insulin resistance with any confidence. PMID:24353184

  12. 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

  13. 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

  14. The Renin Angiotensin Aldosterone System and Insulin Resistance in Humans

    PubMed Central

    Underwood, Patricia C

    2012-01-01

    Alterations in the renin angiotensin aldosterone system (RAAS) contribute to the underlying pathophysiology of insulin resistance in humans; however, individual differences in the treatment response of insulin resistance to RAAS blockade persist. Thus, understanding inter-individual differences in the relationship between the RAAS and insulin resistance may provide insights into improved personalized treatments and improved outcomes. The effects of the systemic RAAS on blood pressure regulation and glucose metabolism have been studied extensively; however, recent discoveries on the influence of local tissue RAAS in the skeletal muscle, heart, vasculature, adipocytes, and pancreas have led to an improved understanding of how activated tissue RAAS influences the development of insulin resistance and diabetes in humans. Angiotensin II (ANGII) is the predominant RAAS component contributing to insulin resistance; however, other players such as aldosterone, renin, and ACE2 are also involved. This review examines the role of local ANGII activity on insulin resistance development in skeletal muscle, adipocytes, and pancreas, followed by a discussion of the other RAAS components implicated in insulin resistance, including ACE2, Ang1-7, renin, and aldosterone. PMID:23242734

  15. Adipocyte Metrnl Antagonizes Insulin Resistance Through PPARγ Signaling.

    PubMed

    Li, Zhi-Yong; Song, Jie; Zheng, Si-Li; Fan, Mao-Bing; Guan, Yun-Feng; Qu, Yi; Xu, Jian; Wang, Pei; Miao, Chao-Yu

    2015-12-01

    Adipokines play important roles in metabolic homeostasis and disease. We have recently identified a novel adipokine Metrnl, also known as Subfatin, for its high expression in subcutaneous fat. Here, we demonstrate a prodifferentiation action of Metrnl in white adipocytes. Adipocyte-specific knockout of Metrnl exacerbates insulin resistance induced by high-fat diet (HFD), whereas adipocyte-specific transgenic overexpression of Metrnl prevents insulin resistance induced by HFD or leptin deletion. Body weight and adipose content are not changed by adipocyte Metrnl. Consistently, no correlation is found between serum Metrnl level and BMI in humans. Metrnl promotes white adipocyte differentiation, expandability, and lipid metabolism and inhibits adipose inflammation to form functional fat, which contributes to its activity against insulin resistance. The insulin sensitization of Metrnl is blocked by PPARγ inhibitors or knockdown. However, Metrnl does not drive white adipose browning. Acute intravenous injection of recombinant Metrnl has no hypoglycemic effect, and 1-week intravenous administration of Metrnl is unable to rescue insulin resistance exacerbated by adipocyte Metrnl deficiency. Our results suggest adipocyte Metrnl controls insulin sensitivity at least via its local autocrine/paracrine action through the PPARγ pathway. Adipocyte Metrnl is an inherent insulin sensitizer and may become a therapeutic target for insulin resistance. PMID:26307585

  16. Hypertension Management and Microvascular Insulin Resistance in Diabetes

    PubMed Central

    Ko, Seung-Hyun; Cao, Wenhong; Liu, Zhenqi

    2011-01-01

    Type 2 diabetes is in essence a vascular disease and is frequently associated with hypertension, macrovascular events, and microvascular complications. Microvascular dysfunction, including impaired recruitment and capillary rarefaction, has been implicated in the pathogenesis of diabetic complications. Microvascular insulin resistance and renin-angiotensin system upregulation are present in diabetes, and each contributes to the development of hypertension and microvascular dysfunction. In the insulin-sensitive state, insulin increases microvascular perfusion by increasing endothelial nitric oxide production, but this effect is abolished by insulin resistance. Angiotensin II, acting via the type 1 receptors, induces inflammation and oxidative stress, leading to impaired insulin signaling, reduced nitric oxide availability, and vasoconstriction. Conversely, it acts on the type 2 receptors to cause vasodilatation. Because substrate and hormonal exchanges occur in the microvasculature, antihypertensive agents targeted to improve microvascular insulin sensitivity and function may have beneficial effects beyond their capacity to lower blood pressure in patients with diabetes. PMID:20582734

  17. Joint effect of insulin signalling genes on cardiovascular events and on whole body and endothelial insulin resistance

    PubMed Central

    Bacci, Simonetta; Prudente, Sabrina; Copetti, Massimiliano; Spoto, Belinda; Rizza, Stefano; Baratta, Roberto; Di Pietro, Natalia; Morini, Eleonora; Di Paola, Rosa; Testa, Alessandra; Mallamaci, Francesca; Tripepi, Giovanni; Zhang, Yuan-Yuan; Mercuri, Luana; Di Silvestre, Sara; Lauro, Renato; Malatino, Lorenzo; Consoli, Agostino; Pellegrini, Fabio; Pandolfi, Assunta; Frittitta, Lucia; Zoccali, Carmine; Federici, Massimo; Doria, Alessandro; Trischitta, Vincenzo

    2012-01-01

    Objective Insulin resistance (IR) and cardiovascular disease (CVD) share a common soil. We investigated the combined role of single nucleotide polymorphisms (SNPs) affecting insulin signaling (ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; TRIB3 Q84R, rs2295490) on CVD, age at myocardial infarction (MI), in vivo insulin sensitivity and in vitro insulin-stimulated nitric oxide synthase (NOS) activity. Design and Setting 1. We first studied, incident cardiovascular events (a composite endpoint comprising myocardial infarction -MI-, stroke and cardiovascular death) in 733 patients (2,186 person-years, 175 events). 2. In a replication attempt, age at MI was tested in 331 individuals. 3. OGTT-derived insulin sensitivity index (ISI) was assessed in 829 individuals with fasting glucose < 126 mg/dl. 4. NOS activity was measured in 40 strains of human vein endothelial cells (HUVECs). Results 1. Risk variants jointly predicted cardiovascular events (HR=1.181; p=0.0009) and, when added to clinical risk factors, significantly improved survival C-statistics; they also allowed a significantly correct reclassification (by net reclassification index) in the whole sample (135/733 individuals) and, even more, in obese patients (116/204 individuals). 2. Risk variants were jointly associated with age at MI (p=0.006). 3. A significant association was also observed with ISI (p=0.02). 4. Finally, risk variants were jointly associated with insulin-stimulated NOS activity in HUVECs (p=0.009). Conclusions Insulin signaling genes variants jointly affect cardiovascular disease, very likely by promoting whole body and endothelium-specific insulin resistance. Further studies are needed to address whether their genotyping help identify very high-risk patients who need specific and/or more aggressive preventive strategies. PMID:23107043

  18. [Childhhood obesity, insulin resistance and increased cardiovascular risk].

    PubMed

    Carlone, Angela; Venditti, Chiara; Cipolloni, Laura; Zampetti, Simona; Spoletini, Marialuisa; Capizzi, Marco; Leto, Gaetano; Buzzetti, Raffaella

    2012-10-01

    Excess fat is one of the major risk factors for insulin resistance predisposing to the development of cardiovascular diseases in western countries. We know that obese patients are strongly at risk of cardiovascular diseases, like myocardial infarction or stroke. These diseases are the most frequent cause of death in the adult population, representing a social and economic problem. Today there are not available and useful markers for screening and diagnosis of insulin- resistance in young people. "Easy-to-detect" clinical markers must be found to identify young subjects at risk of cardiovascular diseases. Very interesting the relationship between wrist circumference, its bone composition and insulin resistance. PMID:23114400

  19. Plasminogen activator inhibitor 1 and insulin levels in various insulin resistance states.

    PubMed

    Scelles, V; Raccah, D; Alessi, M C; Vialle, J M; Juhan-Vague, I; Vague, P

    1992-01-01

    Among obese insulin resistant subjects plasminogen activator inhibitor 1 (PAI 1) levels are closely associated with fasting insulin levels in cross sectional as well as intervention studies. Insulin concentration by itself does not seem to modulate PAI 1 levels at least in acute conditions. PAI 1 levels could be more directly related to the insulin resistant state than to hyperinsulinaemia. To elucidate further this phenomenon we compared insulin, triglyceride and PAI 1 levels in twenty control subjects and in three groups of patients presenting insulin resistance 14 obese subjects, 6 patients with Cushing disease and 7 with acromegaly. None of the tested subjects was diabetic. Fasting insulin levels were elevated in obese (21.4 +/- 8.0) hypercortisolic (20.3 +/- 11.0) and acromegalic patients (16.1 +/- 5.0) compared to controls (9.2 +/- 3.0 microU/ml, m +/- SD). PAI activity and PAI 1 antigen levels were elevated in the obese group only (34.3 +/- 13.0 for PAI 1 activity) and not in the others: 10.2 +/- 10.0, 7.0 +/- 4.6 I U/l for hypercortisolic and acromegalic patients respectively (normal controls 9.7 +/- 5.4). Triglyceride levels were also elevated among obese subjects 2.2 +/- 1.3 vs 1.1 +/- 0.4 mM/l in the controls; they were slightly higher than normal but not significantly in the hypercortisolic (1.5 +/- 0.6) and acromegalic (1.43 +/- 0.6 mM/l) patients. The mechanism of insulin resistance is different in the three conditions studied here. This may explain why elevated PAI 1 concentration are restricted to the common form of insulin resistance as seen in obese subjects. Therefore insulin resistant state per se is not associated with elevated PAI 1 levels.

  20. 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

  1. p-Cresyl sulfate promotes insulin resistance associated with CKD.

    PubMed

    Koppe, Laetitia; Pillon, Nicolas J; Vella, Roxane E; Croze, Marine L; Pelletier, Caroline C; Chambert, Stéphane; Massy, Ziad; Glorieux, Griet; Vanholder, Raymond; Dugenet, Yann; Soula, Hédi A; Fouque, Denis; Soulage, Christophe O

    2013-01-01

    The mechanisms underlying the insulin resistance that frequently accompanies CKD are poorly understood, but the retention of renally excreted compounds may play a role. One such compound is p-cresyl sulfate (PCS), a protein-bound uremic toxin that originates from tyrosine metabolism by intestinal microbes. Here, we sought to determine whether PCS contributes to CKD-associated insulin resistance. Administering PCS to mice with normal kidney function for 4 weeks triggered insulin resistance, loss of fat mass, and ectopic redistribution of lipid in muscle and liver, mimicking features associated with CKD. Mice treated with PCS exhibited altered insulin signaling in skeletal muscle through ERK1/2 activation. In addition, exposing C2C12 myotubes to concentrations of PCS observed in CKD caused insulin resistance through direct activation of ERK1/2. Subtotal nephrectomy led to insulin resistance and dyslipidemia in mice, and treatment with the prebiotic arabino-xylo-oligosaccharide, which reduced serum PCS by decreasing intestinal production of p-cresol, prevented these metabolic derangements. Taken together, these data suggest that PCS contributes to insulin resistance and that targeting PCS may be a therapeutic strategy in CKD. PMID:23274953

  2. 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

  3. Liver Sinusoidal Endothelial Cells Link Hyperinsulinemia to Hepatic Insulin Resistance

    PubMed Central

    Tsuchiya, Kyoichiro; Accili, Domenico

    2013-01-01

    Insulin signaling in vascular endothelial cells (ECs) is critical to maintain endothelial function but also to mediate insulin action on peripheral glucose disposal. However, gene knockout studies have reached disparate conclusions. Thus, insulin receptor inactivation in ECs does not impair insulin action, whereas inactivation of Irs2 does. Previously, we have shown that endothelial ablation of the three Foxo genes protects mice from atherosclerosis. Interestingly, here we show that mice lacking FoxO isoforms in ECs develop hepatic insulin resistance through excessive generation of nitric oxide (NO) that impairs insulin action in hepatocytes via tyrosine nitration of insulin receptors. Coculture experiments demonstrate that NO produced in liver sinusoidal ECs impairs insulin’s ability to suppress glucose production in hepatocytes. The effects of liver sinusoidal ECs can be mimicked by NO donors and can be reversed by NO inhibitors in vivo and ex vivo. The findings are consistent with a model in which excessive, rather than reduced, insulin signaling in ECs predisposes to systemic insulin resistance, prompting a reevaluation of current approaches to insulin sensitization. PMID:23349480

  4. Cardiac Aging and Insulin Resistance: Could Insulin/Insulin-Like Growth Factor (IGF) Signaling be used as a Therapeutic Target?

    PubMed Central

    Boudina, Sihem

    2013-01-01

    Intrinsic cardiac aging is an independent risk factor for cardiovascular disease and is associated with structural and functional changes that impede cardiac responses to stress and to cardio-protective mechanisms. Although systemic insulin resistance and the associated risk factors exacerbate cardiac aging, cardiac-specific insulin resistance without confounding systemic alterations, could prevent cardiac aging. Thus, strategies aimed to reduce insulin/insulin-like growth factor (IGF) signaling in the heart prevent cardiac aging in lower organisms and in mammals but the mechanisms underlying this protection are not fully understood. In this review, we describe the impact of aging on the cardiovascular system and discuss the mounting evidence that reduced insulin/IGF signaling in the heart could alleviate age-associated alterations and preserve cardiac performance. PMID:23448491

  5. A peroxiredoxin, PRDX-2, is required for insulin secretion and insulin/IIS-dependent regulation of stress resistance and longevity.

    PubMed

    Oláhová, Monika; Veal, Elizabeth A

    2015-08-01

    Peroxiredoxins (Prx) are abundant thiol peroxidases with a conserved anti-ageing role. In contrast to most animals, the nematode worm, Caenorhabditis elegans, encodes a single cytosolic 2-Cys Prx, PRDX-2, rendering it an excellent model for examining how peroxiredoxins affect animal physiology and ageing. Our previous work revealed that, although PRDX-2 protects against the toxicity of peroxides, enigmatically, prdx-2-mutant animals are hyper-resistant to other forms of oxidative stress. Here, we have investigated the basis for this increased resistance. Mammalian FOXO and Nrf2 transcription factors directly promote the expression of a range of detoxification enzymes. We show that the FOXO orthologue, DAF-16, and the Nrf2 orthologue, SKN-1, are required for the increased stress resistance of prdx-2-mutant worms. Our data suggest that PRDX-2 is required for normal levels of insulin secretion and hence the inhibition of DAF-16 and SKN-1 by insulin/IGF-1-like signalling (IIS) under nutrient-rich conditions. Intriguingly, loss of PRDX-2 increases DAF-16 and SKN-1 activities sufficiently to increase arsenite resistance without initiating other IIS-inhibited processes. Together, these data suggest that loss of peroxiredoxin function may increase stress resistance by reducing insulin secretion, but that further changes in insulin signalling are required for the reprogramming of development and fat metabolism. In addition, we reveal that the temperature-dependent prolongevity function of PRDX-2 is required for the extended lifespan associated with several pathways, including further reductions in IIS.

  6. A peroxiredoxin, PRDX-2, is required for insulin secretion and insulin/IIS-dependent regulation of stress resistance and longevity

    PubMed Central

    Oláhová, Monika; Veal, Elizabeth A

    2015-01-01

    Peroxiredoxins (Prx) are abundant thiol peroxidases with a conserved anti-ageing role. In contrast to most animals, the nematode worm, Caenorhabditis elegans, encodes a single cytosolic 2-Cys Prx, PRDX-2, rendering it an excellent model for examining how peroxiredoxins affect animal physiology and ageing. Our previous work revealed that, although PRDX-2 protects against the toxicity of peroxides, enigmatically, prdx-2-mutant animals are hyper-resistant to other forms of oxidative stress. Here, we have investigated the basis for this increased resistance. Mammalian FOXO and Nrf2 transcription factors directly promote the expression of a range of detoxification enzymes. We show that the FOXO orthologue, DAF-16, and the Nrf2 orthologue, SKN-1, are required for the increased stress resistance of prdx-2-mutant worms. Our data suggest that PRDX-2 is required for normal levels of insulin secretion and hence the inhibition of DAF-16 and SKN-1 by insulin/IGF-1-like signalling (IIS) under nutrient-rich conditions. Intriguingly, loss of PRDX-2 increases DAF-16 and SKN-1 activities sufficiently to increase arsenite resistance without initiating other IIS-inhibited processes. Together, these data suggest that loss of peroxiredoxin function may increase stress resistance by reducing insulin secretion, but that further changes in insulin signalling are required for the reprogramming of development and fat metabolism. In addition, we reveal that the temperature-dependent prolongevity function of PRDX-2 is required for the extended lifespan associated with several pathways, including further reductions in IIS. PMID:25808059

  7. Insulin resistance in SD rats chronically treated with ethanol

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We have previously demonstrated that hepatic insulin signaling is disrupted in Sprague-Dawley (SD) rats fed EtOH-containing diets by total enteral nutrition (TEN). To determine if whole body insulin resistance could be demonstrated in the TEN model, we conducted euglycemic-hyperinsulinemic clamp st...

  8. Astragalus polysaccharides affect insulin resistance by regulating the hepatic SIRT1-PGC-1α/PPARα-FGF21 signaling pathway in male Sprague Dawley rats undergoing catch-up growth.

    PubMed

    Gu, Chengying; Zeng, Yipeng; Tang, Zhaosheng; Wang, Chaoxun; He, Yanju; Feng, Xinge; Zhou, Ligang

    2015-11-01

    The present study investigated the effects of Astragalus polysaccharides (APS) on insulin resistance by modulation of hepatic sirtuin 1 (SIRT1)‑peroxisome proliferator‑activated receptor (PPAR)‑γ coactivator (PGC)‑1α/PPARα‑fibroblast growth factor (FGF)21, and glucose and lipid metabolism. Thirty male Sprague Dawley rats were divided into three groups: A normal control group, a catch‑up growth group and an APS‑treated (APS-G) group. The latter two groups underwent food restriction for 4 weeks, prior to being provided with a high fat diet, which was available ad libitum. The APS‑G group was orally treated with APS for 8 weeks, whereas the other groups were administered saline. Body weight was measured and an oral glucose tolerance test (OGTT) was conducted after 8 weeks. The plasma glucose and insulin levels obtained from the OGTT were assayed, and hepatic morphology was observed by light and transmission electron microscopy. In addition, the mRNA expression levels of PGC‑1α/PPARα, and the protein expression levels of SIRT1, FGF21 and nuclear factor‑κB were quantified in the liver and serum. APS treatment suppressed abnormal glycolipid metabolism and insulin resistance following 8 weeks of catch‑up growth by improving hepatic SIRT1‑PPARα‑FGF21 intracellular signaling and reducing chronic inflammation, and by partially attenuating hepatic steatosis. The suppressive effects of APS on liver acetylation and glycolipid metabolism‑associated molecules contributed to the observed suppression of insulin resistance. However, the mechanism underlying the effects of APS on insulin resistance requires further research in order to be elucidated. Rapid and long‑term treatment with APS may provide a novel, safe and effective therapeutic strategy for type 2 diabetes. PMID:26323321

  9. 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

  10. Metabolic Syndrome: Insulin Resistance and Prediabetes.

    PubMed

    Mayans, Laura

    2015-08-01

    Metabolic syndrome is a cluster of conditions that synergistically increase the risk of cardiovascular disease, type 2 diabetes, and premature mortality. The components are abdominal obesity, impaired glucose metabolism, dyslipidemia, and hypertension. Prediabetes, which is a combination of excess body fat and insulin resistance, is considered an underlying etiology of metabolic syndrome. Prediabetes manifests as impaired fasting glucose and/or impaired glucose tolerance. Impaired fasting glucose is defined as a fasting blood glucose level of 100 to 125 mg/dL; impaired glucose tolerance requires a blood glucose level of 140 to 199 mg/dL 2 hours after a 75-g oral intake of glucose. In patients with prediabetes, the rate of progression to diabetes within 3 years can be decreased by approximately 58% with lifestyle modifications. These include weight loss through exercise (30 minutes or more of moderate physical activity on most, preferably all, days of the week) and dietary modifications. Recommended diets are high in fruits, vegetables, whole grains, and fish. Consumption of sweetened beverages, including diet soda, should be avoided. For patients who do not achieve goals with lifestyle modifications, metformin can be considered. Weight loss drugs and bariatric surgery are appropriate for select patients. Hypertension and dyslipidemia should be managed according to current guidelines. PMID:26280340

  11. 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

  12. Insulin Secretory Capacity and Insulin Resistance in Korean Type 2 Diabetes Mellitus Patients

    PubMed Central

    2016-01-01

    It is well known that many Korean patients with type 2 diabetes mellitus (T2DM) were non-obese and had decreased insulin secretion in past. However, during the past three decades, lifestyles in Korea have been westernized. As a result, the prevalence of obesity, the main cause of diabetes has increased. Thus, there is still a question as to whether the main pathophysiology of current Korean T2DM is insulin resistance or an insulin secretion defect. Because various anti-diabetes medications having different mechanisms of action are currently used as therapeutics, it is important to understand which of these factors is the main physiology in the development of diabetes in Koreans. In this review, we review changes in obesity prevalence, insulin resistance and insulin secretion defects in Korean T2DM during three decades. PMID:27546870

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

    PubMed

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

    2010-05-01

    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.

  14. 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

  15. 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.

  16. 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

  17. Role of Ceramide in Apoptosis and Development of Insulin Resistance.

    PubMed

    Kuzmenko, D I; Klimentyeva, T K

    2016-09-01

    This review presents data on the functional biochemistry of ceramide, one of the key sphingolipids with properties of a secondary messenger. Molecular mechanisms of the involvement of ceramide in apoptosis in pancreatic β-cells and its role in the formation of insulin resistance in pathogenesis of type 2 diabetes are reviewed. One of the main predispositions for the development of insulin resistance and diabetes is obesity, which is associated with ectopic fat deposition and significant increase in intracellular concentrations of cytotoxic ceramides. A possible approach to the restoration of tissue sensitivity to insulin in type 2 diabetes based on selective reduction of the content of cytotoxic ceramides is discussed. PMID:27682164

  18. 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.

  19. Garlic extract attenuates brain mitochondrial dysfunction and cognitive deficit in obese-insulin resistant rats.

    PubMed

    Pintana, Hiranya; Sripetchwandee, Jirapas; Supakul, Luerat; Apaijai, Nattayaporn; Chattipakorn, Nipon; Chattipakorn, Siriporn

    2014-12-01

    Oxidative stress in the obese-insulin resistant condition has been shown to affect cognitive as well as brain mitochondrial functions. Garlic extract has exerted a potent antioxidant effect. However, the effects of garlic extract on the brain of obese-insulin resistant rats have never been investigated. We hypothesized that garlic extract improves cognitive function and brain mitochondrial function in obese-insulin resistant rats induced by long-term high-fat diet (HFD) consumption. Male Wistar rats were fed either normal diet or HFD for 16 weeks (n = 24/group). At week 12, rats in each dietary group received either vehicle or garlic extract (250 and 500 mg·kg(-1)·day(-1)) for 28 days. Learning and memory behaviors, metabolic parameters, and brain mitochondrial function were determined at the end of treatment. HFD led to increased body weight, visceral fat, plasma insulin, cholesterol, and malondialdehyde (MDA) levels, indicating the development of insulin resistance. Furthermore, HFD rats had cognitive deficit and brain mitochondrial dysfunction. HFD rats treated with both doses of garlic extract had decreased body weight, visceral fat, plasma cholesterol, and MDA levels. Garlic extract also improved cognitive function and brain mitochondrial function, which were impaired in obese-insulin resistant rats caused by HFD consumption.

  20. Increased insulin resistance and insulin secretion in nondiabetic African-Americans and Hispanics compared with non-Hispanic whites. The Insulin Resistance Atherosclerosis Study.

    PubMed

    Haffner, S M; D'Agostino, R; Saad, M F; Rewers, M; Mykkänen, L; Selby, J; Howard, G; Savage, P J; Hamman, R F; Wagenknecht, L E

    1996-06-01

    The etiology of NIDDM is still controversial, with both insulin resistance and decreased insulin secretion postulated as potential important factors. African-Americans and Hispanics have a two- to threefold excess risk of developing NIDDM compared with non-Hispanic whites. Yet little is known concerning the prevalence of insulin resistance and secretion defects in minorities, especially in African-Americans in population-based studies. Fasting and 2-h post-glucose load glucose and insulin levels, insulin-mediated glucose disposal (insulin sensitivity index) (S(I)), glucose effectiveness (S(G)), and first-phase insulin response (acute insulin response [AIR]) were determined in nondiabetic African-Americans (n= 288), Hispanics (n= 363), and non-Hispanic whites (n= 435) as part of the Insulin Resistance Atherosclerosis Study. Subjects received a standard 2-h oral glucose tolerance test on the first day and an insulin-modified frequently sampled intravenous glucose tolerance test on the second day. African-Americans and Hispanics were more obese than non-Hispanic whites. Both African-Americans and Hispanics had higher fasting and 2-h insulin concentrations and AIR but lower S(I) than non-Hispanic whites. No ethnic difference was observed in S(G). After further adjustments for obesity, body fat distribution, and behavioral factors, African-Americans continued to have higher fasting and 2-h insulin levels and AIR, but lower S(I) than non-Hispanic whites. In contrast, after adjustment for these covariates, no significant ethnic differences in S(I) or fasting insulin levels were observed between Hispanics and non-Hispanic whites. Hispanics continued to have higher 2-h insulin levels and AIRs than those in non-Hispanic whites. In this report, the association between S(I) and upper body adiposity (waist-to-hip, ratio) was similar in each ethnic group. Both nondiabetic African-Americans and Hispanics have increased insulin resistance and higher AIR than nondiabetic non

  1. Impaired translocation of GLUT4 results in insulin resistance of atrophic soleus muscle.

    PubMed

    Xu, Peng-Tao; Song, Zhen; Zhang, Wen-Cheng; Jiao, Bo; Yu, Zhi-Bin

    2015-01-01

    Whether or not the atrophic skeletal muscle induces insulin resistance and its mechanisms are not resolved now. The antigravity soleus muscle showed a progressive atrophy in 1-week, 2-week, and 4-week tail-suspended rats. Hyperinsulinemic-euglycemic clamp showed that the steady-state glucose infusion rate was lower in 4-week tail-suspended rats than that in the control rats. The glucose uptake rates under insulin- or contraction-stimulation were significantly decreased in 4-week unloaded soleus muscle. The key protein expressions of IRS-1, PI3K, and Akt on the insulin-dependent pathway and of AMPK, ERK, and p38 on the insulin-independent pathway were unchanged in unloaded soleus muscle. The unchanged phosphorylation of Akt and p38 suggested that the activity of two signal pathways was not altered in unloaded soleus muscle. The AS160 and GLUT4 expression on the common downstream pathway also was not changed in unloaded soleus muscle. But the GLUT4 translocation to sarcolemma was inhibited during insulin stimulation in unloaded soleus muscle. The above results suggest that hindlimb unloading in tail-suspended rat induces atrophy in antigravity soleus muscle. The impaired GLUT4 translocation to sarcolemma under insulin stimulation may mediate insulin resistance in unloaded soleus muscle and further affect the insulin sensitivity of whole body in tail-suspended rats.

  2. 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.

  3. The gut microbiota, obesity and insulin resistance.

    PubMed

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

    2013-02-01

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

  4. Leptin Deficiency Causes Insulin Resistance Induced by Uncontrolled Diabetes

    PubMed Central

    German, Jonathan P.; Wisse, Brent E.; Thaler, Joshua P.; Oh-I, Shinsuke; Sarruf, David A.; Ogimoto, Kayoko; Kaiyala, Karl J.; Fischer, Jonathan D.; Matsen, Miles E.; Taborsky, Gerald J.; Schwartz, Michael W.; Morton, Gregory J.

    2010-01-01

    OBJECTIVE Depletion of body fat stores during uncontrolled, insulin-deficient diabetes (uDM) results in markedly reduced plasma leptin levels. This study investigated the role of leptin deficiency in the genesis of severe insulin resistance and related metabolic and neuroendocrine derangements induced by uDM. RESEARCH DESIGN AND METHODS Adult male Wistar rats remained nondiabetic or were injected with the β-cell toxin, streptozotocin (STZ) to induce uDM and subsequently underwent subcutaneous implantation of an osmotic minipump containing either vehicle or leptin at a dose (150 μg/kg/day) designed to replace leptin at nondiabetic plasma levels. To control for leptin effects on food intake, another group of STZ-injected animals were pair fed to the intake of those receiving leptin. Food intake, body weight, and blood glucose levels were measured daily, with body composition and indirect calorimetry performed on day 11, and an insulin tolerance test to measure insulin sensitivity performed on day 16. Plasma hormone and substrate levels, hepatic gluconeogenic gene expression, and measures of tissue insulin signal transduction were also measured. RESULTS Physiologic leptin replacement prevented insulin resistance in uDM via a mechanism unrelated to changes in food intake or body weight. This effect was associated with reduced total body fat and hepatic triglyceride content, preservation of lean mass, and improved insulin signal transduction via the insulin receptor substrate–phosphatidylinositol-3-hydroxy kinase pathway in the liver, but not in skeletal muscle or adipose tissue. Although physiologic leptin replacement lowered blood glucose levels only slightly, it fully normalized elevated plasma glucagon and corticosterone levels and reversed the increased hepatic expression of gluconeogenic enzymes characteristic of rats with uDM. CONCLUSIONS We conclude that leptin deficiency plays a key role in the pathogenesis of severe insulin resistance and related endocrine

  5. Assessment of insulin resistance in normoglycemic young adults.

    PubMed

    Preethi, B L; Jaisri, G; Kumar, K M Prasanna; Sharma, Rajeev

    2011-01-01

    Detection of Insulin resistance (IR) in normoglycemic young subjects before the onset of Impaired Glucose Tolerance (IGT) is of importance as it affords implementation of preventive measures in such high risk subject. Very few studies have specifically evaluated for the presence of IR in younger age group with normal glucose tolerance. The gold standard for investigating and quantifying insulin resistance is the "hyperinsulinemic euglycemic clamp," the complicated nature of the "clamp" technique, alternatives have been sought to simplify the measurement of insulin resistance. The oral glucose tolerance test (OGTT) is one of the most commonly used methods to evaluate whole body glucose tolerance in vivo. IR & IS values of HOMA-IR, ISI 0-120, QUICKIE mathematical models derived from OGTT have been shown to produce equivalent results as in Euglycemic clamp technique we hypothesized that normoglycemic young adult who are siblings of type II diabetics (SD) probably have higher IR values than the siblings of non diabetics as they are genetically predisposed. In this study 79 normal young adult volunteers, 40 subjects with family history of diabetes (SD) and 39 subjects without family history of diabetes (SND), in the age range of 18 to 25 years were evaluated for Insulin resistance. Standard (75 g) OGTT was performed on all the study subjects after an overnight fast. Fasting (basal), 30, 120 min venous plasma glucose & Corresponding specific insulin concentration was determined by radioimmuno assay (RIA) using a human specific antibody RIA kit. In each subject, the degree of insulin resistance was estimated by various parameters of Insulin resistance & sensitivity that were calculated using physiological mathematical models like HOMA-IR, ISI0-120, IGI, QUICKIE and their formulas derived from OGTT. The mean age of the study population was 19.01 (18 to 25 years), Male: 33 (41.3%) and Female: 47 (58.8%). The normoglycemic subjects were categorized as Siblings of Diabetics

  6. Glycation & Insulin Resistance: Novel Mechanisms and Unique Targets?

    PubMed Central

    Song, Fei; Schmidt, Ann Marie

    2012-01-01

    Objectives Multiple biochemical, metabolic and signal transduction pathways contribute to insulin resistance. In this review, we present the evidence that the post-translational process of protein glycation may play role in insulin resistance. The post-translational modifications, the advanced glycation endproducts (AGEs), are formed and accumulate by endogenous and exogenous mechanisms. Methods and Results AGEs may contribute to insulin resistance by a variety of mechanisms, including generation of tumor necrosis factor-alpha, 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 RAGE, or receptor for AGE. AGE-RAGE 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, or MG. Conclusions 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 prevention of insulin resistance and its consequences. PMID:22815341

  7. Peripheral insulin resistance and impaired insulin signaling contribute to abnormal glucose metabolism in preterm baboons.

    PubMed

    Blanco, Cynthia L; 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

    2015-03-01

    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.

  8. Consumption of low-fat dairy foods for 6 months improves insulin resistance without adversely affecting lipids or bodyweight in healthy adults: a randomized free-living cross-over study

    PubMed Central

    2013-01-01

    Background Given the highly debated role of dairy food consumption in modulating biomarkers of metabolic syndrome, this study was conducted to examine the influence of long-term (6 month) dairy consumption on metabolic parameters in healthy volunteers under free-living conditions without energy restriction. Methods Twenty-three healthy subjects completed a randomized, crossover trial of 12 months. Participants consumed their habitual diets and were randomly assigned to one of two treatment groups: a high dairy supplemented group instructed to consume 4 servings of dairy per day (HD); or a low dairy supplemented group limited to no more than 2 servings of dairy per day (LD). Baseline, midpoint, and endpoint metabolic responses were examined. Results Endpoint measurements of body weight and composition, energy expenditure, blood pressure, blood glucose, and blood lipid and lipoprotein responses did not differ (p > 0.05) between the LD and HD groups. HD consumption improved (p < 0.05) plasma insulin (-9%) and insulin resistance (-11%, p = 0.03) as estimated by HOMA-IR compared with the LD group. Conclusions Study results suggest that high dairy consumption (4 servings/d) may improve insulin resistance without negatively impacting bodyweight or lipid status under free-living conditions. Trial registration Trial registration: NCT01761955 PMID:23638799

  9. Hyperinsulinemia improves ischemic LV function in insulin resistant subjects

    PubMed Central

    2010-01-01

    Background Glucose is a more efficient substrate for ATP production than free fatty acid (FFA). Insulin resistance (IR) results in higher FFA concentrations and impaired myocardial glucose use, potentially worsening ischemia. We hypothesized that metabolic manipulation with a hyperinsulinemic euglycemic clamp (HEC) would affect a greater improvement in left ventricular (LV) performance during dobutamine stress echo (DSE) in subjects with IR. Methods 24 subjects with normal LV function and coronary disease (CAD) awaiting revascularization underwent 2 DSEs. Prior to one DSEs they underwent an HEC, where a primed infusion of insulin (rate 43 mU/m 2/min) was co-administered with 20% dextrose at variable rates to maintain euglycemia. At steady-state the DSE was performed and images of the LV were acquired with tissue Doppler at each stage for offline analysis. Segmental peak systolic velocities (Vs) were recorded, as well as LV ejection fraction (EF). Subjects were then divided into two groups based on their insulin sensitivity during the HEC. Results HEC changed the metabolic environment, suppressing FFAs and thereby increasing glucose use. This resulted in improved LV performance at peak stress, measured by EF (IS group mean difference 5.3 (95% CI 2.5-8) %, p = 0.002; IR group mean difference 8.7 (95% CI 5.8-11.6) %, p < 0.0001) and peak V s in ischemic segments (IS group mean improvement 0.7(95% CI 0.07-1.58) cm/s, p = 0.07; IR group mean improvement 1.0 (95% CI 0.54-1.5) cm/s, p < 0.0001) , that was greater in the subjects with IR. Conclusions Increased myocardial glucose use induced by HEC improves LV function under stress in subjects with CAD and IR. Cardiac metabolic manipulation in subjects with IR is a promising target for future therapy. PMID:20576156

  10. 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

  11. 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.

  12. Insulin resistance in uremia: Insulin receptor kinase activity in liver and muscle from chronic uremic rats

    SciTech Connect

    Cecchin, F.; Ittoop, O.; Sinha, M.K.; Caro, J.F. )

    1988-04-01

    The authors have studied the structure and function of the partially purified insulin receptors from liver and skeletal muscle in a rat model of severe chronic uremia. {sup 125}I-insulin binding was higher in the liver from uremic rats when compared with ad libitum- and pair-fed controls. Furthermore, the ability of insulin to stimulate the autophosphorylation of the {beta}-subunit and insulin receptor kinase activity using Glu{sup 80}, Tyr{sup 20} as exogenous phosphoacceptor was increased in the liver of the uremic animals. The structural characteristics of the receptors, as determined by electrophoretic mobilities of affinity labeled {alpha}-subunit and the phosphorylated {beta}-subunit, were normal in uremia. {sup 125}I-insulin binding and insulin receptor kinase activity were similar in the skeletal muscle from uremic and pair- and ad libitum-fed animals. Thus the data are supportive of the hypothesis that in liver and muscle of chronic uremic rats, insulin resistance is due to a defect(s) distal to the insulin receptor kinase.

  13. 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

  14. Role of PTEN in TNF Induced Insulin Resistance

    PubMed Central

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

    2015-01-01

    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. PMID:25918024

  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. 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.

  17. Transgenic mice with muscle-specific insulin resistance develop increased adiposity, impaired glucose tolerance, and dyslipidemia.

    PubMed

    Moller, D E; Chang, P Y; Yaspelkis, B B; Flier, J S; Wallberg-Henriksson, H; Ivy, J L

    1996-06-01

    Impaired skeletal muscle insulin receptor function is a feature of common forms of insulin resistance, including obesity and noninsulin-dependent diabetes mellitus. However, the extent to which this defect accounts for impaired muscle glucose disposal or altered in vivo glucose homeostasis remains to be established. We recently showed that transgenic mice that overexpress dominant-negative insulin receptors specifically in striated muscle have a severe defect in muscle insulin receptor-mediated signaling and modest hyperinsulinemia. Here we performed hindlimb perfusion studies to determine the impact of this defect on muscle glucose uptake and metabolism. Maximal rates of insulin-stimulated muscle 3-O-methylglucose transport were reduced by 32-40% in transgenic mice with proportional defects involving total hindlimb [14C]glucose uptake, lactate production, and muscle glycogen synthesis. To address the hypothesis that muscle insulin resistance could promote an increase in the accretion of body fat, carcass analysis was performed using two independent lines of transgenic mice. Although body weights were normal, transgenic mice had a 22-38% increase in body fat, with a reciprocal decrease (10-15%) in body protein. Mean gonadal fat pad weight was also increased in transgenic mice. Skeletal muscle histology and fiber type distribution were not affected. To determine whether muscle-specific insulin resistance was sufficient to cause impaired glucose tolerance, oral glucose tolerance tests were performed with 6-month-old transgenic and control mice. Fasting glucose levels were increased by 25%, and peak values were 22-40% higher in transgenic mice. Transgenic mice also had a 37% decrease in plasma lactate levels and modest increases in levels of plasma triglycerides and FFA (29% and 15%, respectively). We conclude that 1) severe defects in muscle insulin receptor function result in impaired insulin-stimulated glucose uptake and metabolism in this tissue; 2) muscle

  18. Exercise reduces cellular stress related to skeletal muscle insulin resistance.

    PubMed

    de Matos, Mariana Aguiar; Ottone, Vinícius de Oliveira; Duarte, Tamiris Campos; Sampaio, Pâmela Fiche da Matta; Costa, Karine Beatriz; Fonseca, Cheyenne Alves; Neves, Miguel Pontes Correa; Schneider, Suzanne Maria; Moseley, Pope; Coimbra, Cândido Celso; Magalhães, Flávio de Castro; Rocha-Vieira, Etel; Amorim, Fabiano Trigueiro

    2014-03-01

    This study sought to evaluate the effects of a single session of exercise on the expression of Hsp70, of c-jun N-terminal kinase (JNK), and insulin receptor substrate 1 serine 612 (IRS(ser612)) phosphorylation in the skeletal muscle of obese and obese insulin-resistant patients. Twenty-seven volunteers were divided into three experimental groups (eutrophic insulin-sensitive, obese insulin-sensitive, and obese insulin-resistant) according to their body mass index and the presence of insulin resistance. The volunteers performed 60 min of aerobic exercise on a cycle ergometer at 60 % of peak oxygen consumption. M. vastus lateralis samples were obtained before and after exercise. The protein expressions were evaluated by Western blot. Our findings show that compared with paired eutrophic controls, obese subjects have higher basal levels of p-JNK (100 ± 23 % vs. 227 ± 67 %, p = 0.03) and p-IRS-1(ser612) (100 ± 23 % vs. 340 ± 67 %, p < 0.001) and reduced HSP70 (100 ± 16 % vs. 63 ± 12 %, p < 0.001). The presence of insulin resistance results in a further increase in p-JNK (460 ± 107 %, p < 0.001) and a decrease in Hsp70 (46 ± 5 %, p = 0.006), but p-IRS-1(ser612) levels did not differ from obese subjects (312 ± 73 %, p > 0.05). Exercise reduced p-JNK in obese insulin-resistant subjects (328 ± 33 %, p = 0.001), but not in controls or obese subjects. Furthermore, exercise reduced p-IRS-1(ser612) for both obese (122 ± 44 %) and obese insulin-resistant (185 ± 36 %) subjects. A main effect of exercise was observed in HSP70 (p = 0.007). We demonstrated that a single session of exercise promotes changes that characterize a reduction in cellular stress that may contribute to exercise-induced increase in insulin sensitivity.

  19. 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.

  20. Atorvastatin ameliorates endothelium-specific insulin resistance induced by high glucose combined with high insulin.

    PubMed

    Yang, Ou; Li, Jinliang; Chen, Haiyan; Li, Jie; Kong, Jian

    2016-09-01

    The aim of the present study was to establish an endothelial cell model of endothelium-specific insulin resistance to evaluate the effect of atorvastatin on insulin resistance-associated endothelial dysfunction and to identify the potential pathway responsible for its action. Cultured human umbilical vein endothelial cells (HUVECs) were pretreated with different concentrations of glucose with, or without, 10‑5 M insulin for 24 h, following which the cells were treated with atorvastatin. The tyrosine phosphorylation of insulin receptor (IR) and insulin receptor substrate-1 (IRS‑1), the production of nitric oxide (NO), the activity and phosphorylation level of endothelial NO synthase (eNOS) on serine1177, and the mRNA levels of endothelin‑1 (ET‑1) were assessed during the experimental procedure. Treatment of the HUVECs with 30 mM glucose and 10‑5 M insulin for 24 h impaired insulin signaling, with reductions in the tyrosine phosphorylation of IR and protein expression of IRS‑1 by almost 75 and 65%, respectively. This, in turn, decreased the activity and phosphorylation of eNOS on serine1177, and reduced the production of NO by almost 80%. By contrast, the mRNA levels of ET‑1 were upregulated. All these changes were ameliorated by atorvastatin. Taken together, these results demonstrated that high concentrations of glucose and insulin impaired insulin signaling leading to endothelial dysfunction, and that atorvastatin ameliorated these changes, acting primarily through the phosphatidylinositol 3-kinase/Akt/eNOS signaling pathway. PMID:27484094

  1. Inflammation and Oxidative Stress: The Molecular Connectivity between Insulin Resistance, Obesity, and Alzheimer's Disease

    PubMed Central

    Verdile, Giuseppe; Keane, Kevin N.; Cruzat, Vinicius F.; Medic, Sandra; Sabale, Miheer; Rowles, Joanne; Wijesekara, Nadeeja; Martins, Ralph N.; Fraser, Paul E.; Newsholme, Philip

    2015-01-01

    Type 2 diabetes (T2DM), Alzheimer's disease (AD), and insulin resistance are age-related conditions and increased prevalence is of public concern. Recent research has provided evidence that insulin resistance and impaired insulin signalling may be a contributory factor to the progression of diabetes, dementia, and other neurological disorders. Alzheimer's disease (AD) is the most common subtype of dementia. Reduced release (for T2DM) and decreased action of insulin are central to the development and progression of both T2DM and AD. A literature search was conducted to identify molecular commonalities between obesity, diabetes, and AD. Insulin resistance affects many tissues and organs, either through impaired insulin signalling or through aberrant changes in both glucose and lipid (cholesterol and triacylglycerol) metabolism and concentrations in the blood. Although epidemiological and biological evidence has highlighted an increased incidence of cognitive decline and AD in patients with T2DM, the common molecular basis of cell and tissue dysfunction is rapidly gaining recognition. As a cause or consequence, the chronic inflammatory response and oxidative stress associated with T2DM, amyloid-β (Aβ) protein accumulation, and mitochondrial dysfunction link T2DM and AD. PMID:26693205

  2. 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

  3. 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

  4. TWEAK prevents TNF-α-induced insulin resistance through PP2A activation in human adipocytes.

    PubMed

    Vázquez-Carballo, Ana; Ceperuelo-Mallafré, Victòria; Chacón, Matilde R; Maymó-Masip, Elsa; Lorenzo, Margarita; Porras, Almudena; Vendrell, Joan; Fernández-Veledo, Sonia

    2013-07-01

    Visceral fat is strongly associated with insulin resistance. Obesity-associated adipose tissue inflammation and inflammatory cytokine production are considered key mediators of insulin signaling inhibition. TWEAK is a relatively new member of the TNF cytokine superfamily, which can exist as full length membrane-associated (mTWEAK) and soluble (sTWEAK) isoforms. Although TWEAK has been shown to have important functions in chronic inflammatory diseases its physiological role in adipose tissue remains unresolved. In this study, we explore the molecular mechanisms involved in the modulation of TNF-α-induced effects on insulin sensitivity by sTWEAK in a human visceral adipose cell line and also in primary human adipocytes obtained from visceral fat depots. Our data reveal that sTWEAK ameliorates TNF-α-induced insulin resistance on glucose uptake, GLUT4 translocation and insulin signaling without affecting other metabolic effects of TNF-α such as lipolysis or apoptotis. Co-immunoprecipitation experiments in adipose cells revealed that pretreatment with sTWEAK specifically inhibits TRAF2 association with TNFR1, but not with TNFR2, which mediates insulin resistance. However, sTWEAK does not affect other downstream molecules activated by TNF-α, such as TAK1. Rather, sTWEAK abolishes the stimulatory effect of TNF-α on JNK1/2, which is directly involved in the development of insulin resistance. This is associated with an increase in PP2A activity upon sTWEAK treatment. Silencing of the PP2A catalytic subunit gene overcomes the dephosphorylation effect of sTWEAK on JNK1/2, pointing to PP2A as a relevant mediator of sTWEAK-induced JNK inactivation. Overall, our data reveal a protective role of TWEAK in glucose homeostasis and identify PP2A as a new driver in the modulation of TNF-α signaling by sTWEAK.

  5. 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. PMID:11900279

  6. Adiponectin Dysregulation and Insulin Resistance in Type 1 Diabetes

    PubMed Central

    Snell-Bergeon, Janet K.; Erickson, Christopher; Schauer, Irene E.; Bergman, Bryan C.; Rewers, Marian; Maahs, David M.

    2012-01-01

    Context: Type 1 diabetes (T1D) is associated with insulin resistance despite elevated levels of the insulin-sensitizing protein adiponectin. Whether the expected positive correlation between adiponectin and insulin sensitivity is preserved in a T1D population is unknown. Objective: We measured the correlation between total and high-molecular-weight (HMW) adiponectin and insulin sensitivity in T1D patients and nondiabetic controls and identified determinants of adiponectin levels in patients with T1D. Design and Participants: Fasting total and HMW adiponectin were measured in 86 subjects from the Coronary Artery Calcification in T1D (CACTI) cohort (39 T1D, 47 nondiabetic; age 45 ± 8 yr; 55% female). The association of adiponectin levels with insulin sensitivity was analyzed. Setting: The study was conducted at an academic research institute. Methods: Fasting total and HMW adiponectin were measured by RIA and ELISA, respectively. Insulin sensitivity was measured by a hyperinsulinemic-euglycemic clamp. Multivariate linear regression was used to identify determinants of adiponectin levels. Results: Adiponectin levels positively correlated with insulin sensitivity in both subject groups (total adiponectin, r = 0.33 P < 0.05 for T1D, r = 0.29 P < 0.05 controls), but insulin sensitivity was lower in T1D subjects at any given level of total or HMW adiponectin. Adiponectin levels were independently associated with age, gender, and trunk fat, but these variables did not account for increased adiponectin in patients with T1D. Conclusion: Adiponectin levels are positively correlated with insulin sensitivity in T1D patients. However, T1D patients have decreased insulin sensitivity compared with controls at every level of adiponectin, suggesting an important adaptive change of adiponectin set point. PMID:22278421

  7. FFA-induced hepatic insulin resistance in vivo is mediated by PKCδ, NADPH oxidase, and oxidative stress.

    PubMed

    Pereira, Sandra; Park, Edward; Mori, Yusaku; Haber, C Andrew; Han, Ping; Uchida, Toyoyoshi; Stavar, Laura; Oprescu, Andrei I; Koulajian, Khajag; Ivovic, Alexander; Yu, Zhiwen; Li, Deling; Bowman, Thomas A; Dewald, Jay; El-Benna, Jamel; Brindley, David N; Gutierrez-Juarez, Roger; Lam, Tony K T; Najjar, Sonia M; McKay, Robert A; Bhanot, Sanjay; Fantus, I George; Giacca, Adria

    2014-07-01

    Fat-induced hepatic insulin resistance plays a key role in the pathogenesis of type 2 diabetes in obese individuals. Although PKC and inflammatory pathways have been implicated in fat-induced hepatic insulin resistance, the sequence of events leading to impaired insulin signaling is unknown. We used Wistar rats to investigate whether PKCδ and oxidative stress play causal roles in this process and whether this occurs via IKKβ- and JNK-dependent pathways. Rats received a 7-h infusion of Intralipid plus heparin (IH) to elevate circulating free fatty acids (FFA). During the last 2 h of the infusion, a hyperinsulinemic-euglycemic clamp with tracer was performed to assess hepatic and peripheral insulin sensitivity. An antioxidant, N-acetyl-L-cysteine (NAC), prevented IH-induced hepatic insulin resistance in parallel with prevention of decreased IκBα content, increased JNK phosphorylation (markers of IKKβ and JNK activation, respectively), increased serine phosphorylation of IRS-1 and IRS-2, and impaired insulin signaling in the liver without affecting IH-induced hepatic PKCδ activation. Furthermore, an antisense oligonucleotide against PKCδ prevented IH-induced phosphorylation of p47(phox) (marker of NADPH oxidase activation) and hepatic insulin resistance. Apocynin, an NADPH oxidase inhibitor, prevented IH-induced hepatic and peripheral insulin resistance similarly to NAC. These results demonstrate that PKCδ, NADPH oxidase, and oxidative stress play a causal role in FFA-induced hepatic insulin resistance in vivo and suggest that the pathway of FFA-induced hepatic insulin resistance is FFA → PKCδ → NADPH oxidase and oxidative stress → IKKβ/JNK → impaired hepatic insulin signaling.

  8. 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

    2014-08-01

    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.

  9. 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

    2014-08-01

    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. PMID:25100064

  10. 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.

  11. 4-Hydroxyisoleucine improves insulin resistance in HepG2 cells by decreasing TNF-α and regulating the expression of insulin signal transduction proteins

    PubMed Central

    GAO, FENG; JIAN, LIUMENG; ZAFAR, MOHAMMAD ISHRAQ; DU, WEN; CAI, QIN; SHAFQAT, RAJA ADEEL; LU, FURONG

    2015-01-01

    Previous studies have indicated that 4-hydroxy-isoleucine (4-HIL) improves insulin resistance, however, the underlying mechanisms remain to be elucidated. In the present study, the molecular mechanisms underlying how 4-HIL improves insulin resistance in hepatocytes were examined. HepG2 cells were co-cultured with insulin and a high glucose concentration to obtain insulin-resistant (IR) HepG2 cells. Insulin sensitivity was determined by measuring the glucose uptake rate. The IR HepG2 cells were treated with different concentrations of 4-HIL to determine its effect on IR Hep2 cells. The levels of tumor necrosis factor-α (TNF-α) were measured by an enzyme-linked immunosorbent assay and protein levels of TNF-α converting enzyme (TACE)/tissue inhibitor of metalloproteinase 3 (TIMP3), insulin receptor substrate (IRS)-1, IRS-2, phosphorylated (p)-IRS-1 (Ser307) and glucose transporter type 4 (GLUT4) were measured by western blot analysis. The results of the present study demonstrated that insulin-induced glucose uptake was reduced in IR HepG2 cells; however, this reduction was reversed by 4-HIL in a dose-dependent manner. 4-HIL achieved this effect by downregulating the expression of TNF-α and TACE, and upregulating the expression of TIMP3 in IR HepG2 cells. In addition, 4-HIL increased the expression of the insulin transduction regulators IRS-1 and GLUT4, and decreased the expression of p-IRS-1 (Ser307), without affecting the expression of IRS-2. The present study suggests that 4-HIL improved insulin resistance in HepG2 cells by the following mechanisms: 4-HIL reduced TNF-α levels by affecting the protein expression of the TACE/TIMP3 system and 4-HIL stimulated the expression of IRS-1 and GLUT4, but inhibited the expression of p-IRS-1 (Ser307). PMID:26352439

  12. Effect of a β-Hydroxyphosphonate Analogue of ʟ-Carnitine on Insulin-Sensitive and Insulin-Resistant 3T3-L1 Adipocytes.

    PubMed

    Avalos-Soriano, Anaguiven; De la Cruz-Cordero, Ricardo; López-Martínez, Francisco Josue; Rosado, Jorge L; Duarte-Vázquez, Miguel Ángel; Garcia-Gasca, Teresa

    2015-01-01

    This study investigated the effect of a β-x200B;hydroxyphosphonate analog of ʟ-carnitine (L-CA) (CAS number: 1220955-x200B;20-3, Component: 1221068-91-2, C12H29NO4PI), (3-Hexanaminium, 1-(dimethoxyphosphinyl)-2-hydroxy-N,N,N,5-x200B;tetramethy-iodide (1:1), (2R, 3S)) on parameters related with type-2 diabetes in an in vitro model. Nontoxic concentrations of L-CA were assayed and compared to commercial ʟ-carnitine effects. L-CA did not affect adipogenesis in normal cells, but an increment of TG accumulation was observed on insulin-resistant adipocytes (80%) when compared with resistant control. L-CA also stimulated glucose analog 2-NBDG uptakes on insulin-resistant adipocytes in a similar way as insulin when compared to insulin-resistant cells. Our results show that the L-CA promoted insulin-like responses on insulin-resistant adipocytes without appreciable pro-adipogenic effect in sensitive adipocytes. PMID:26160659

  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. PMID:24064339

  14. Skeletal muscle insulin resistance is fundamental to the cardiometabolic syndrome.

    PubMed

    Nistala, Ravi; Stump, Craig S

    2006-01-01

    The cardiometabolic syndrome is associated with insulin resistance and a dysregulation of glucose and lipid metabolism that occurs in multiple tissues. Of these, skeletal muscle is the most abundant insulin-sensitive tissue, handling > 40% of the postprandial glucose uptake, while consuming 20% of the body's energy. The inability to efficiently take up and store fuel, and to transition from fat to glucose as the primary source of fuel during times of plenty (increased insulin), has been termed metabolic inflexibility. This resistance to insulin is thought to be a major contributor to the whole-body metabolic dysregulation that leads to increased cardiovascular risk. Recent investigation has identified specific defects in postinsulin receptor signaling in skeletal muscle from resistant humans and animals. Potential mechanisms contributing to this reduced insulin signaling and action include decreases in mitochondrial oxidative capacity, increased intramuscular lipid accumulation, increased reactive oxygen species generation, and up-regulated inflammatory pathways. Future research is focused on understanding these and other potential mechanisms to identify therapeutic targets for reducing cardiometabolic syndrome risk. PMID:17675899

  15. Sildenafil Reduces Insulin-Resistance in Human Endothelial Cells

    PubMed Central

    Mammi, Caterina; Pastore, Donatella; Lombardo, Marco F.; Ferrelli, Francesca; Caprio, Massimiliano; Consoli, Claudia; Tesauro, Manfredi; Gatta, Lucia; Fini, Massimo; Federici, Massimo; Sbraccia, Paolo; Donadel, Giulia; Bellia, Alfonso; Rosano, Giuseppe M.; Fabbri, Andrea; Lauro, Davide

    2011-01-01

    Background The efficacy of Phosphodiesterase 5 (PDE5) inhibitors to re-establish endothelial function is reduced in diabetic patients. Recent evidences suggest that therapy with PDE5 inhibitors, i.e. sildenafil, may increase the expression of nitric oxide synthase (NOS) proteins in the heart and cardiomyocytes. In this study we analyzed the effect of sildenafil on endothelial cells in insulin resistance conditions in vitro. Methodology/Principal Findings Human umbilical vein endothelial cells (HUVECs) were treated with insulin in presence of glucose 30 mM (HG) and glucosamine 10 mM (Gluc-N) with or without sildenafil. Insulin increased the expression of PDE5 and eNOS mRNA assayed by Real time-PCR. Cytofluorimetric analysis showed that sildenafil significantly increased NO production in basal condition. This effect was partially inhibited by the PI3K inhibitor LY 294002 and completely inhibited by the NOS inhibitor L-NAME. Akt-1 and eNOS activation was reduced in conditions mimicking insulin resistance and completely restored by sildenafil treatment. Conversely sildenafil treatment can counteract this noxious effect by increasing NO production through eNOS activation and reducing oxidative stress induced by hyperglycaemia and glucosamine. Conclusions/Significance These data indicate that sildenafil might improve NOS activity of endothelial cells in insulin resistance conditions and suggest the potential therapeutic use of sildenafil for improving vascular function in diabetic patients. PMID:21297971

  16. Insulin Resistance Induces Posttranslational Hepatic Sortilin 1 Degradation in Mice*

    PubMed Central

    Li, Jibiao; Matye, David J.; Li, Tiangang

    2015-01-01

    Insulin promotes hepatic apolipoprotein B100 (apoB100) degradation, whereas insulin resistance is a major cause of hepatic apoB100/triglyceride overproduction in type 2 diabetes. The cellular trafficking receptor sortilin 1 (Sort1) was recently identified to transport apoB100 to the lysosome for degradation in the liver and thus regulate plasma cholesterol and triglyceride levels. Genetic variation of SORT1 was strongly associated with cardiovascular disease risk in humans. The major goal of this study is to investigate the effect and molecular mechanism of insulin regulation of Sort1. Results showed that insulin induced Sort1 protein, but not mRNA, in AML12 cells. Treatment of PI3K or AKT inhibitors decreased Sort1 protein, whereas expression of constitutively active AKT induced Sort1 protein in AML12 cells. Consistently, hepatic Sort1 was down-regulated in diabetic mice, which was partially restored after the administration of the insulin sensitizer metformin. LC-MS/MS analysis further revealed that serine phosphorylation of Sort1 protein was required for insulin induction of Sort1 in a casein kinase 2-dependent manner and that inhibition of PI3K signaling or prevention of Sort1 phosphorylation accelerated proteasome-dependent Sort1 degradation. Administration of a PI3K inhibitor to mice decreased hepatic Sort1 protein and increased plasma cholesterol and triglyceride levels. Adenovirus-mediated overexpression of Sort1 in the liver prevented PI3K inhibitor-induced Sort1 down-regulation and decreased plasma triglyceride but had no effect on plasma cholesterol in mice. This study identified Sort1 as a novel target of insulin signaling and suggests that Sort1 may play a role in altered hepatic apoB100 metabolism in insulin-resistant conditions. PMID:25805502

  17. 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.

  18. 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

  19. Obesity, insulin resistance, and skeletal muscle nitric oxide synthase

    PubMed Central

    Kraus, Raymond M.; Houmard, Joseph A.; Kraus, William E.; Tanner, Charles J.; Pierce, Joseph R.; Choi, Myung Dong

    2012-01-01

    The molecular mechanisms responsible for impaired insulin action have yet to be fully identified. Rodent models demonstrate a strong relationship between insulin resistance and an elevation in skeletal muscle inducible nitric oxide synthase (iNOS) expression; the purpose of this investigation was to explore this potential relationship in humans. Sedentary men and women were recruited to participate (means ± SE: nonobese, body mass index = 25.5 ± 0.3 kg/m2, n = 13; obese, body mass index = 36.6 ± 0.4 kg/m2, n = 14). Insulin sensitivity was measured using an intravenous glucose tolerance test with the subsequent modeling of an insulin sensitivity index (SI). Skeletal muscle was obtained from the vastus lateralis, and iNOS, endothelial nitric oxide synthase (eNOS), and neuronal nitric oxide synthase (nNOS) content were determined by Western blot. SI was significantly lower in the obese compared with the nonobese group (∼43%; P < 0.05), yet skeletal muscle iNOS protein expression was not different between nonobese and obese groups. Skeletal muscle eNOS protein was significantly higher in the nonobese than the obese group, and skeletal muscle nNOS protein tended to be higher (P = 0.054) in the obese compared with the nonobese group. Alternative analysis based on SI (high and low tertile) indicated that the most insulin-resistant group did not have significantly more skeletal muscle iNOS protein than the most insulin-sensitive group. In conclusion, human insulin resistance does not appear to be associated with an elevation in skeletal muscle iNOS protein in middle-aged individuals under fasting conditions. PMID:22797309

  20. Subchronic Sleep Restriction Causes Tissue-Specific Insulin Resistance

    PubMed Central

    Neylan, Thomas C.; Grunfeld, Carl; Mulligan, Kathleen; Schambelan, Morris; Schwarz, Jean-Marc

    2015-01-01

    Context: 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. Objective: The purpose of this article was to determine whether subchronic SR altered (1) hepatic insulin sensitivity, (2) peripheral insulin sensitivity, and (3) substrate utilization. Design: 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. Results: 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). Conclusion: 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

  1. Vitamin D insufficiency and insulin resistance in obese adolescents.

    PubMed

    Peterson, Catherine A; Tosh, Aneesh K; Belenchia, Anthony M

    2014-12-01

    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

  2. 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

  3. 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.

  4. Colonic Macrophages "Remote Control" Adipose Tissue Inflammation and Insulin Resistance.

    PubMed

    Biswas, Subhra K; Bonecchi, Raffaella

    2016-08-01

    The early events linking diet-induced adipose tissue inflammation and insulin resistance remain poorly understood. In this issue of Cell Metabolism, Kawano et al. (2016) show that infiltration of colonic pro-inflammatory macrophages orchestrated by the intestinal CCL2/CCR2 axis kick-starts this process during high-fat-diet feeding. PMID:27508866

  5. 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.

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

    DOE PAGES

    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; et al

    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

  7. Associations of erythrocyte fatty acid patterns with insulin resistance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  8. [Second Consensus of the Chilean Society of Endocrinology and Diabetes about insulin resistance].

    PubMed

    Pollak, Felipe; Araya, Verónica; Lanas, Alejandra; Sapunar, Jorge; Arrese, Marco; Aylwin, Carmen Gloria; Bezanilla, Carmen Gloria; Carrasco, Elena; Carrasco, Fernando; Codner, Ethel; Díaz, Erik; Durruty, Pilar; Galgani, José; García, Hernán; Lahsen, Rodolfo; Liberman, Claudio; López, Gloria; Maíz, Alberto; Mujica, Verónica; Poniachik, Jaime; Sir, Teresa; Soto, Néstor; Valderas, Juan; Villaseca, Paulina; Zavala, Carlos

    2015-05-01

    Insulin resistance is a prevalent condition commonly associated with unhealthy lifestyles. It affects several metabolic pathways, increasing risk of abnormalities at different organ levels. Thus, diverse medical specialties should be involved in its diagnosis and treatment. With the purpose of unifying criteria about this condition, a scientific-based consensus was elaborated. A questionnaire including the most important topics such as cardio-metabolic risk, non-alcoholic fatty liver disease and polycystic ovary syndrome, was designed and sent to national experts. When no agreement among them was achieved, the Delphi methodology was applied. The main conclusions reached are that clinical findings are critical for the diagnosis of insulin resistance, not being necessary blood testing. Acquisition of a healthy lifestyle is the most important therapeutic tool. Insulin-sensitizing drugs should be prescribed to individuals at high risk of disease according to clinically validated outcomes. There are specific recommendations for pregnant women, children, adolescents and older people. PMID:26203576

  9. [Second Consensus of the Chilean Society of Endocrinology and Diabetes about insulin resistance].

    PubMed

    Pollak, Felipe; Araya, Verónica; Lanas, Alejandra; Sapunar, Jorge; Arrese, Marco; Aylwin, Carmen Gloria; Bezanilla, Carmen Gloria; Carrasco, Elena; Carrasco, Fernando; Codner, Ethel; Díaz, Erik; Durruty, Pilar; Galgani, José; García, Hernán; Lahsen, Rodolfo; Liberman, Claudio; López, Gloria; Maíz, Alberto; Mujica, Verónica; Poniachik, Jaime; Sir, Teresa; Soto, Néstor; Valderas, Juan; Villaseca, Paulina; Zavala, Carlos

    2015-05-01

    Insulin resistance is a prevalent condition commonly associated with unhealthy lifestyles. It affects several metabolic pathways, increasing risk of abnormalities at different organ levels. Thus, diverse medical specialties should be involved in its diagnosis and treatment. With the purpose of unifying criteria about this condition, a scientific-based consensus was elaborated. A questionnaire including the most important topics such as cardio-metabolic risk, non-alcoholic fatty liver disease and polycystic ovary syndrome, was designed and sent to national experts. When no agreement among them was achieved, the Delphi methodology was applied. The main conclusions reached are that clinical findings are critical for the diagnosis of insulin resistance, not being necessary blood testing. Acquisition of a healthy lifestyle is the most important therapeutic tool. Insulin-sensitizing drugs should be prescribed to individuals at high risk of disease according to clinically validated outcomes. There are specific recommendations for pregnant women, children, adolescents and older people.

  10. The effect of oral metformin on insulin sensitivity in insulin-resistant ponies.

    PubMed

    Tinworth, Kellie D; Boston, Ray C; Harris, Patricia A; Sillence, Martin N; Raidal, Sharanne L; Noble, Glenys K

    2012-01-01

    Metformin may be an effective therapeutic option for insulin-resistant (I-R) horses/ponies because, in humans, it reportedly enhances insulin sensitivity (SI) of peripheral tissues without stimulating insulin secretion. To determine the effect of metformin on insulin and glucose dynamics in I-R ponies, six ponies were studied in a cross-over design by Minimal Model analysis of a frequently-sampled intravenous glucose tolerance test (FSIGT). Metformin was administered at 15 mg/kg bodyweight (BW), orally, twice-daily, for 21 days to the metformin-treated group. The control group received a placebo. A FSIGT was conducted before and after treatment. The Minimal Model of glucose and insulin dynamics rendered indices describing SI, glucose effectiveness (Sg), acute insulin response to glucose (AIRg) and the disposition index (DI). The body condition score (BCS), BW and cresty neck score (CNS) were also assessed. There was no significant change in SI, Sg, AIRg, DI, BW, BCS or CNS in response to metformin, or over time in the control group. There were no measurable benefits of metformin on SI, consistent with recent work showing that the bioavailability of metformin in horses is poor, and chronic dosing may not achieve therapeutic blood concentrations. Alternatively, metformin may only be effective in obese ponies losing weight or with hyperglycaemia.

  11. 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

  12. Possible Involvement of Insulin Resistance in the Progression of Cancer Cachexia in Mice.

    PubMed

    Ohsawa, Masahiro; Murakami, Tomoyasu; Kume, Kazuhiko

    2016-01-01

    Malnutrition is a common problem among cancer patients, affecting up to 85% of patients with certain cancers. In severe cases, malnutrition can progress to cachexia, a specific form of malnutrition characterized by loss of lean body mass and muscle wasting. Although this muscle wasting might be a product of enhanced protein degradation, the precise mechanisms of cancer cachexia are not fully elucidated. Based on basic and clinical research, glucose intolerance and insulin resistance have been postulated to be associated with cancer cachexia. Since insulin in the skeletal muscle inhibits protein degradation and promotes protein synthesis, insulin resistance could be a possible cause of cancer cachexia. Therefore, we investigated the involvement of insulin resistance in the development of cancer cachexia in tumor-bearing mice. The signaling protein in the insulin cascade was attenuated in the skeletal muscle and hypothalamus from tumor-bearing mice. We identified Chrysanthemum morifolium RAMAT., known as Kikuka, as a peroxisome proliferator-activated receptor γ (PPARγ) ligand. Treatment with Kikuka attenuates the skeletal muscle changes in tumor-bearing mice. These results suggest that this natural PPARγ activator might be an attractive candidate for the treatment of cancer cachexia. In the symposium, we presented the PPARγ activator-induced improvement of cancer cachexia. PMID:27150920

  13. Crosstalk between exercise and galanin system alleviates insulin resistance.

    PubMed

    Fang, Penghua; He, Biao; Shi, Mingyi; Zhu, Yan; Bo, Ping; Zhang, Zhenwen

    2015-12-01

    Studies have demonstrated that aerobic exercise can enhance insulin sensitivity, however, the precise mechanism for this outcome is not entirely identified. Emerging evidences point out that exercise can upregulate galanin protein and mRNA expression, resulting in improvement of insulin sensitivity via an increase in translocation of glucose transporter 4 and subsequent glucose uptake in myocytes and adipocytes of healthy and type 2 diabetic rats, which may be blocked by galanin antagonist. In return, galanin can exert the exercise-protective roles to prevent excessive movement of skeletal muscle and to accelerate exercise trauma repair in exercise-relative tissues. Studies also implicated that combination of aerobic exercise and activation of galanin system may make more significant improvement in insulin sensitivity than that of either one did. These suggest that galanin system is essential for physical activity to alleviate insulin resistance, namely, the beneficial effect of physical activity on glucose uptake is at least partly mediated by galanin system. Besides, co-treatment with galanin and exercise is an effective therapeutic strategy for reducing insulin resistance.

  14. 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. PMID:27063082

  15. 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. PMID:26833850

  16. Pancreatic digestive enzyme blockade in the small intestine prevents insulin resistance in hemorrhagic shock.

    PubMed

    DeLano, Frank A; Schmid-Schönbein, Geert W

    2014-01-01

    Hemorrhagic shock is associated with metabolic defects, including hyperglycemia and insulin resistance, but the mechanisms are unknown. We recently demonstrated that reduction of the extracellular domain of the insulin receptor by degrading proteases may lead to a reduced ability to maintain normal plasma glucose values. In shock, transfer of digestive enzymes from the lumen of the intestine into the systemic circulation after breakdown of the intestinal mucosal barrier causes inflammation and organ dysfunction. Suppression of the digestive enzymes in the lumen of the intestine with protease inhibitors is effective in reducing the level of the inflammatory reactions. To determine the degree to which blockade of digestive enzymes affects insulin resistance in shock, rats were exposed to acute hemorrhagic shock (mean arterial pressure of 30 mmHg for 2 h) at which time all shed blood volume was returned. Digestive proteases in the intestine were blocked with a serine protease inhibitor (tranexamic acid in polyethylene glycol and physiological electrolyte solution), and the density of the insulin receptor was measured with immunohistochemistry in the mesentery microcirculation. The untreated rat without enzyme blockade had significantly attenuated levels of insulin receptor density as compared with control and treated rats. Blockade of the digestive proteases after 60 min of hypotension in the lumen of the small intestine led to a lesser decrease in insulin receptor density compared with controls without protease blockade. Glucose tolerance test indicates a significant increase in plasma glucose levels 2 h after hemorrhagic shock, which are reduced to control values in the presence of protease inhibition in the lumen of the intestine. The transient reduction of the plasma glucose levels after an insulin bolus is significantly attenuated after shock but is restored when digestive enzymes in the lumen of the intestine are blocked. These results suggest that in

  17. 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.

  18. Skeletal muscle fatty acid handling in insulin resistant men.

    PubMed

    van Hees, Anneke M J; Jans, Anneke; Hul, Gabby B; Roche, Helen M; Saris, Wim H M; Blaak, Ellen E

    2011-07-01

    Disturbances in skeletal muscle lipid metabolism may precede or contribute to the development of whole body insulin resistance. In this study, we examined fasting and postprandial skeletal muscle fatty acid (FA) handling in insulin resistant (IR) men. Thirty men with the metabolic syndrome (MetS) (National Cholesterol Education Program-Adult Treatment Panel III) were included in this sub-study to the LIPGENE study, and divided in two groups (IR and control) based on the median of insulin sensitivity (S(I) = 2.06 (mU/l(-1))·min(-1)·10(-4)). Fasting and postprandial skeletal muscle FA handling were examined by combining the forearm balance technique with stable isotopes of palmitate. [(2)H(2)]-palmitate was infused intravenously to label endogenous triacylglycerol (TAG) and free FAs (FFAs) in the circulation and [U-(13)C]-palmitate was incorporated in a high-fat mixed meal (2.6 MJ, 61 E% fat) to label chylomicron-TAG. Muscle biopsies were taken to determine muscle TAG, diacylglycerol (DAG), FFA, and phospholipid (PL) content, their fractional synthetic rates (FSRs) and degree of saturation, as well as messenger RNA (mRNA) expression of genes involved in lipid metabolism. In the first 2 h after meal consumption, forearm muscle [(2)H(2)]-labeled TAG extraction was higher in IR vs. control (P = 0.05). Fasting percentage saturation of muscle DAG was higher in IR vs. control (P = 0.016). No differences were observed for intramuscular TAG, DAG, FFA, and PL content, FSR, and muscle mRNA expression. In conclusion, increased muscle (hepatically derived) TAG extraction during postprandial conditions and increased saturation of intramuscular DAG are associated with insulin resistance, suggesting that disturbances in skeletal muscle FA handling could play a role in the development of whole body insulin resistance and type 2 diabetes. PMID:21331063

  19. Hyperhomocysteinemia, Insulin Resistance and High HS- CRP Levels in Prehypertension

    PubMed Central

    Talikoti, Prashanth; Hamide, Abdoul

    2014-01-01

    Background: Pre-hypertension refers to blood pressure in the range of 120 to 139 mm of Hg / 80 to 89 mm of Hg and its prevalence is increasing in India. Previous studies have documented the increase in homocysteine, C-reactive protein and insulin resistance and their role in the development of hypertension. In recent years much attention has been focused on subjects with prehypertension, as the risk for development of cardiovascular disease is higher in these subjects compared to those with normal blood pressure. Objectives: To evaluate the serum homocysteine, hs-CRP level and insulin resistance in subjects with prehypertension. Materials and Methods: Sixty prehypertensives and 32 normotensives were recruited according to Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of blood pressure (JNC 7) guidelines. Serum homocysteine, vitamin B12, folate, insulin, hs-CRP and lipid profile were analysed. Independent t-test was carried out to compare two groups and pearson correlation analyses were carried out between various parameters with systolic blood pressure (SBP) and diastolic blood pressure (DBP). Results: Cardiovascular risk factors like serum homocysteine, insulin resistance and inflammatory marker hs-CRP were significantly increased in prehypertensives. Total cholesterol, TG, LDL-C and VLDL-C were significantly increased when compared to normotensives. Serum homocysteine correlated positively and vitamin B12 and folate negatively with Systolic Blood Pressure. Conclusion: The present study concludes that the established cardiovascular risk factors, homocysteine, insulin resistance, and hs-CRP which have roles in the etiopathogenesis of hypertension, were elevated in subjects with prehypertension. Thus, early detection and life style modification may reduce the risk or delay the onset of hypertension and other cardiovascular complications. PMID:25302190

  20. 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

  1. 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

  2. Biological effects of THC and a lipophilic cannabis extract on normal and insulin resistant 3T3-L1 adipocytes.

    PubMed

    Gallant, M; Odei-Addo, F; Frost, C L; Levendal, R-A

    2009-10-01

    Type 2 diabetes, a chronic disease, affects about 150 million people world wide. It is characterized by insulin resistance of peripheral tissues such as liver, skeletal muscle, and fat. Insulin resistance is associated with elevated levels of tumor necrosis factor alpha (TNF-alpha), which in turn inhibits insulin receptor tyrosine kinase autophosphorylation. It has been reported that cannabis is used in the treatment of diabetes. A few reports indicate that smoking cannabis can lower blood glucose in diabetics. Delta(9)-tetrahydrocannabinol (THC) is the primary psychoactive component of cannabis. This study aimed to determine the effect of a lipophilic cannabis extract on adipogenesis, using 3T3-L1 cells, and to measure its effect on insulin sensitivity in insulin resistant adipocytes. Cells were cultured in Dulbecco's modified eagle medium (DMEM) with 10% fetal bovine serum (FBS) and differentiated over a 3 day period for all studies. In the adipogenesis studies, differentiated cells were exposed to the extract in the presence and absence of insulin. Lipid content and glucose uptake was subsequently measured. Insulin-induced glucose uptake increased, while the rate of adipogenesis decreased with increasing THC concentration. Insulin-resistance was induced using TNF-alpha, exposed to the extract and insulin-induced glucose uptake measured. Insulin-induced glucose was increased in these cells after exposure to the extract. Semiquantitative real time polymerase chain reaction (RT-PCR) was performed after ribonucleic acid (RNA) extraction to evaluate the effects of the extract on glucose transporter isotype 4 (GLUT-4), insulin receptor substrate-1 (IRS-1) and IRS-2 gene expression. PMID:19345076

  3. Severe insulin resistance alters metabolism in mesenchymal progenitor cells.

    PubMed

    Balhara, Bharti; Burkart, Alison; Topcu, Vehap; Lee, Youn-Kyoung; Cowan, Chad; Kahn, C Ronald; Patti, Mary-Elizabeth

    2015-06-01

    Donohue syndrome (DS) is characterized by severe insulin resistance due to mutations in the insulin receptor (INSR) gene. To identify molecular defects contributing to metabolic dysregulation in DS in the undifferentiated state, we generated mesenchymal progenitor cells (MPCs) from induced pluripotent stem cells derived from a 4-week-old female with DS and a healthy newborn male (control). INSR mRNA and protein were significantly reduced in DS MPC (for β-subunit, 64% and 89% reduction, respectively, P < .05), but IGF1R mRNA and protein did not differ vs control. Insulin-stimulated phosphorylation of INSR or the downstream substrates insulin receptor substrate 1 and protein kinase B did not differ, but ERK phosphorylation tended to be reduced in DS (32% decrease, P = .07). By contrast, IGF-1 and insulin-stimulated insulin-like growth factor 1 (IGF-1) receptor phosphorylation were increased in DS (IGF-1, 8.5- vs 4.5-fold increase; INS, 11- vs 6-fold; P < .05). DS MPC tended to have higher oxygen consumption in both the basal state (87% higher, P =.09) and in response to the uncoupler carbonyl cyanide-p-triflouromethoxyphenylhydrazone (2-fold increase, P =.06). Although mitochondrial DNA or mass did not differ, oxidative phosphorylation protein complexes III and V were increased in DS (by 37% and 6%, respectively; P < .05). Extracellular acidification also tended to increase in DS (91% increase, P = .07), with parallel significant increases in lactate secretion (34% higher at 4 h, P < .05). In summary, DS MPC maintain signaling downstream of the INSR, suggesting that IGF-1R signaling may partly compensate for INSR mutations. However, alterations in receptor expression and pathway-specific defects in insulin signaling, even in undifferentiated cells, can alter cellular oxidative metabolism, potentially via transcriptional mechanisms. PMID:25811318

  4. Association Between Chilli Food Habits with Iron Status and Insulin Resistance in a Chinese Population

    PubMed Central

    Wang, Rui; Xiao, Cheng

    2014-01-01

    Abstract Some studies have indicated that the consumption of chilli-containing foods can influence iron absorption and affect serum insulin and glucose concentrations, which may help to alleviate diabetes or prediabetes. The objective of this study was to explore the relationship between chilli food habits with iron status and insulin resistance in the Chinese population. Fasting blood samples, anthropometric data, and chilli food habit data collected from 8433 adults (aged 18 to 99), in 2009, as part of the China Health and Nutrition Survey, a large-scale longitudinal, household-based survey in China. Chilli food habits were assessed using chilli food eating frequencies (no eating, sometimes eating, often eating, and usually eating) and chilli food types (a little bit hot, moderately hot, and very hot). Fasting serum ferritin, insulin, and fasting plasma glucose were also measured. The homeostasis model assessment of insulin resistance (HOMA-IR) was used to estimate insulin resistance. Compared with the chilli-eating group, the no eating group had higher HOMA-IR levels for both men and women (P<.05). There were significant differences in HOMA-IR (P<.05) for both men and women and in ferritin (P<.001) for women according to different chilli food types. However, there was no significant difference in the ferritin level and HOMA-IR components for different chilli food eating frequencies in both sex groups. Chilli food habits, especially the different hotness levels of chilli food, were associated with iron status and insulin resistance in the Chinese population. Additional studies are needed to elucidate mechanisms of action and to establish causal inference. PMID:24479485

  5. 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.

  6. Effect of metformin on insulin-resistant endothelial cell function

    PubMed Central

    CHEN, HAIYAN; LI, JIE; YANG, OU; KONG, JIAN; LIN, GUANGZHU

    2015-01-01

    The aim of the present study was to investigate the effect of metformin on the function of insulin-resistant (IR) endothelial cells. A model of IR endothelial cells was established by incubating cells with 30 mM glucose, 1 μM dexamethasone and various concentrations of insulin. The nitric oxide (NO) content of the endothelial cells was determined by measuring the rate of nitroreductase production; the endothelin (ET) concentration was examined by enzyme-linked immunosorbent assay; and the expression levels of endothelial nitric oxide synthase (eNOS) were detected using western blotting. The optimal conditions for inducing insulin resistance in endothelial cells were a combination treatment of 10−4 mmol/l insulin, 30 mM glucose and 1 μM dexamethasone for 48 h. Notably, metformin administration significantly increased the NO content and reduced the ET-1 concentration in the IR cells compared with the non-treated control cells (P<0.05); furthermore, metformin significantly increased the intracellular eNOS protein expression in IR endothelial cells compared with the non-treated control cells (P<0.05), with an optimal metformin concentration of 10−3 mmol/l. Thus, the present study identified that metformin improves the function of IR endothelial cells, possibly through promoting eNOS protein expression and increasing the NO content. PMID:25663871

  7. The Impact of Organokines on Insulin Resistance, Inflammation, and Atherosclerosis

    PubMed Central

    2016-01-01

    Immoderate energy intake, a sedentary lifestyle, and aging have contributed to the increased prevalence of obesity, sarcopenia, metabolic syndrome, type 2 diabetes, and cardiovascular disease. There is an urgent need for the development of novel pharmacological interventions that can target excessive fat accumulation and decreased muscle mass and/or strength. Adipokines, bioactive molecules derived from adipose tissue, are involved in the regulation of appetite and satiety, inflammation, energy expenditure, insulin resistance and secretion, glucose and lipid metabolism, and atherosclerosis. Recently, there is emerging evidence that skeletal muscle and the liver also function as endocrine organs that secrete myokines and hepatokines, respectively. Novel discoveries and research into these organokines (adipokines, myokines, and hepatokines) may lead to the development of promising biomarkers and therapeutics for cardiometabolic disease. In this review, I summarize recent data on these organokines and focus on the role of adipokines, myokines, and hepatokines in the regulation of insulin resistance, inflammation, and atherosclerosis. PMID:26996418

  8. 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

  9. Abdominal Obesity and Insulin Resistance in People Exposed to Moderate-to-High Levels of Dioxin

    PubMed Central

    Chang, Jung-Wei; Chen, Hsiu-Ling; Su, Huey-Jen; Lee, Ching-Chang

    2016-01-01

    Obesity, a risk factor for developing metabolic complications, is a major public health problem. Abdominal obesity is strongly accompanied by a cluster of metabolic abnormalities characterized by insulin resistance. The link between persistent organic pollutants (POPs) and insulin resistance has been investigated in animal and epidemiological studies. We aimed to examine whether insulin resistance is greater in people with abdominal obesity (AO) and concomitant exposure to serum dioxins (PCDD/Fs). We conducted a cross-sectional descriptive study of 2876 participants living near a PCDD/Fs contaminated area. Seventeen 2,3,7,8-substituted PCDD/Fs congeners were measured, and then the associations between the main predictor variable, serum TEQDF-1998, abdominal obesity (AO), dependent variables, and insulin resistance were examined. Twelve of the 17 congeners, widely distributed among PCDDs, and PCDFs, had trends for associations with abdominal adiposity. In men, the highest quintiles of 1,2,3,7,8-PeCDF; 1,2,3,7,8-PeCDD; 2,3,7,8-TCDD; 2,3,7,8-TCDF; and 2,3,4,7,8-PeCDF had the top five adjusted odds ratios (AORs) + 95% confidence intervals (CIs):[4.2; 2.7–6.4], [3.6; 2.3–5.7], [3.2; 2.1–5.0], [3.0; 2.0–4.5], and [2.9; 1.9–4.7], respectively. In women, the highest quintiles of 1,2,3,4,7,8,9-HpCDF; 1,2,3,6,7,8-HxCDF; and 1,2,3,4,6,7,8-HpCDF had the top three AORs + 95% CIs:[3.0; 1.9–4.7], [2.0; 1.3–3.1], and [1.9; 1.3–2.9], respectively. After confounding factors had been adjusted for, men, but not women, with higher serum TEQDF-1998 levels or abdominal obesity had a significantly (Ptrend < 0.001) greater risk for abnormal insulin resistance. The groups with the highest joint serum TEQDF-1998 and abdominal obesity levels were associated with elevated insulin resistance at 5.0 times the odds of the groups with the lowest joint levels (AOR 5.23; 95% CI: 3.53–7.77). We hypothesize that serum TEQDF-1998 and abdominal obesity affect the association with

  10. Intracellular lipid accumulation in liver and muscle and the insulin resistance syndrome.

    PubMed

    Lara-Castro, Cristina; Garvey, W Timothy

    2008-12-01

    This article emphasizes intrahepatocellular and intramyocellular lipid accumulation as components of the insulin resistance syndrome. It examines the mechanisms responsible for the interrelationships among ectopic fat deposition, insulin resistance, and associated metabolic traits. These relationships are complex and vary according to diet, exercise, weight loss, and racial identity. Overall, there is a high degree of association of both intrahepatocellular and intramyocellular lipids with insulin resistance and associated cardiometabolic risk factors. It concludes that further research is necessary to determine the orchestrated roles of adipose and nonadipose tissue compartments in the regulation of insulin sensitivity, and mechanisms explaining racial differences in the insulin resistance syndrome-trait cluster.

  11. Insulin resistance and autonomic function in traumatic lower limb amputees.

    PubMed

    Peles, E; Akselrod, S; Goldstein, D S; Nitzan, H; Azaria, M; Almog, S; Dolphin, D; Halkin, H; Modan, M

    1995-10-01

    This study examined plasma insulin response to oral glucose load and autonomic nervous system activity in male lower limb amputees (n = 52) aged 50-65 years, compared to matched controls (n = 53). The groups had similar body mass index, blood pressure and plasma lipid levels. The amputees had higher mean fasting plasma insulin levels (18.4 +/- 9.7 (SD) versus 13.7 +/- 5.1 mU/l, p = 0.005) and during an oral glucose tolerance test (OGTT) (1 h levels 88.1 +/- 45.3 versus 62.1 +/- 42.7, p = 0.016) with similar plasma glucose levels, indicating insulin resistance. At baseline with the subjects supine, there were no group differences in low- or high-frequency power of heart rate variability or in plasma levels of norepinephrine (NE) or epinephrine (EPI). In response to orthostasis, the groups had similarly increased plasma NE levels. During the OGTT, amputees had significantly larger increments in low-frequency power than did controls (2.2 +/- 1.3 versus 1.6 +/- 0.9 (beats/min)2 respectively, p < 0.01) and plasma NE levels increased significantly in amputees (1595 +/- 849 versus 1941 +/- 986 pM, p = 0.0008) but not in controls. At 1 h after glucose administration, plasma EPI levels were decreased significantly from baseline in both groups; at both 1 and 2 h after glucose administration, plasma EPI levels were higher in the amputees than controls. Amputees appear to have a combination of enhanced sympathoneural responsiveness and attenuated suppression of adrenomedullary secretion during glucose challenge. As catecholamines antagonize insulin effects, one possible explanation for insulin resistance in amputees is hyperglycaemia-induced sympathoneural activation and a failure of hyperglycaemia to decrease adrenomedullary secretion.

  12. Toona Sinensis ameliorates insulin resistance via AMPK and PPARγ pathways.

    PubMed

    Liu, Hung-Wen; Huang, Wen-Cheng; Yu, Wen-Jen; Chang, Sue-Joan

    2015-06-01

    Toona Sinensis leaf (TSL) extract with a beneficial effect for managing hyperglycemia has been reported, however the underlying mechanism by which TSL extract acts as an insulin sensitizer remains uncertain, especially in peripheral tissues. TSL 95% ethanol extract exhibited the highest transactivity of PPARγ and contained the highest amounts of natural PPARγ ligands including palmitic acid, linoleic acid, and α-linolenic acid among different TSL ethanol extracts (0, 10, 50, 70, and 95%). The efficacy and the mechanism of TSL ethanol extract (95%) mediated anti-diabetic effects were examined by both in vivo and in vitro models in this study. An improved whole-body insulin sensitivity was observed in high-fat diet-fed (HFD) mice after 14 weeks of TSL treatment, as evidenced by a faster rate of plasma glucose clearing. The improved insulin sensitivity was through direct stimulation of PPARγ and adiponectin expression in adipose tissues of HFD mice. In addition to the PPARγ pathway, TSL stimulated glucose uptake via directly inducing AMPKα but not AS160 activation in C2C12 myotubes under palmitate-induced insulin resistance. TSL successfully induced sirtuin 1 and restored PGC1α, but failed to restore mitochondrial electron transport complexes I, III, IV and V in mRNA levels. Loss of the mitochondrial membrane potential coupled with AMPK activation suggests that TSL acts as a mitochondrial inhibitor to stimulate AMPK-mediated glucose uptake. This study demonstrated that TSL stimulated glucose uptake via AMPK activation in skeletal muscles and promoted PPARγ and normalized adiponectin expression in adipose tissues, thereby ameliorating insulin resistance.

  13. Bariatric Surgery in Morbidly Obese Insulin Resistant Humans Normalises Insulin Signalling but Not Insulin-Stimulated Glucose Disposal

    PubMed Central

    de Berker, David A. R.; May, Margaret T.; Hers, Ingeborg; Dayan, Colin M.; Andrews, Robert C.; Tavaré, Jeremy M.

    2015-01-01

    Aims Weight-loss after bariatric surgery improves insulin sensitivity, but the underlying molecular mechanism is not clear. To ascertain the effect of bariatric surgery on insulin signalling, we examined glucose disposal and Akt activation in morbidly obese volunteers before and after Roux-en-Y gastric bypass surgery (RYGB), and compared this to lean volunteers. Materials and Methods The hyperinsulinaemic euglycaemic clamp, at five infusion rates, was used to determine glucose disposal rates (GDR) in eight morbidly obese (body mass index, BMI=47.3±2.2 kg/m2) patients, before and after RYGB, and in eight lean volunteers (BMI=20.7±0.7 kg/m2). Biopsies of brachioradialis muscle, taken at fasting and insulin concentrations that induced half-maximal (GDR50) and maximal (GDR100) GDR in each subject, were used to examine the phosphorylation of Akt-Thr308, Akt-473, and pras40, in vivo biomarkers for Akt activity. Results Pre-operatively, insulin-stimulated GDR was lower in the obese compared to the lean individuals (P<0.001). Weight-loss of 29.9±4 kg after surgery significantly improved GDR50 (P=0.004) but not GDR100 (P=0.3). These subjects still remained significantly more insulin resistant than the lean individuals (p<0.001). Weight loss increased insulin-stimulated skeletal muscle Akt-Thr308 and Akt-Ser473 phosphorylation, P=0.02 and P=0.03 respectively (MANCOVA), and Akt activity towards the substrate PRAS40 (P=0.003, MANCOVA), and in contrast to GDR, were fully normalised after the surgery (obese vs lean, P=0.6, P=0.35, P=0.46, respectively). Conclusions Our data show that although Akt activity substantially improved after surgery, it did not lead to a full restoration of insulin-stimulated glucose disposal. This suggests that a major defect downstream of, or parallel to, Akt signalling remains after significant weight-loss. PMID:25876175

  14. Exercise ameliorates insulin resistance via Ca2+ signals distinct from those of insulin for GLUT4 translocation in skeletal muscles.

    PubMed

    Park, Dae-Ryoung; Park, Kwang-Hyun; Kim, Byung-Ju; Yoon, Chung-Su; Kim, Uh-Hyun

    2015-04-01

    Muscle contraction and insulin induce glucose uptake in skeletal muscle through GLUT4 membrane translocation. Beneficial effects of exercise on glucose homeostasis in insulin-resistant individuals are known to be due to their distinct mechanism between contraction and insulin action on glucose uptake in skeletal muscle. However, the underlying mechanisms are not clear. Here we show that in skeletal muscle, distinct Ca(2+) second messengers regulate GLUT4 translocation by contraction and insulin treatment; d-myo-inositol 1,4,5-trisphosphate/nicotinic acid adenine dinucleotide phosphate (NAADP) and cyclic ADP-ribose/NAADP are main players for insulin- and contraction-induced glucose uptake, respectively. Different patterns of phosphorylation of AMPK and Ca(2+)/calmodulin-dependent protein kinase II were shown in electrical stimuli (ES)- and insulin-induced glucose uptake pathways. ES-induced Ca(2+) signals and glucose uptake are dependent on glycolysis, which influences formation of NAD(P)-derived signaling messengers, whereas insulin-induced signals are not. High-fat diet (HFD) induced a defect in only insulin-mediated, but not ES-mediated, Ca(2+) signaling for glucose uptake, which is related to a specifically lower NAADP formation. Exercise decreases blood glucose levels in HFD-induced insulin resistance mice via NAADP formation. Thus we conclude that different usage of Ca(2+) signaling in contraction/insulin-stimulated glucose uptake in skeletal muscle may account for the mechanism by which exercise ameliorates glucose homeostasis in individuals with type 2 diabetes.

  15. Ameliorative Effect of Allopurinol on Vascular Complications of Insulin Resistance

    PubMed Central

    El-Bassossy, Hany M.; Elberry, Ahmed A.; Azhar, Ahmad; Ghareib, Salah A.; Alahdal, Abdulrahman M.

    2015-01-01

    The aim of the current study was to evaluate the possible protective effect of allopurinol (Allo) on experimentally induced insulin resistance (IR) and vascular complications. Rats were divided into four groups: control, IR, allopurinol-treated IR (IR-Allo), and allopurinol-treated control (Allo). IR was induced by adding fructose and high fat, high salt diet for 12 weeks. The results showed that Allo has alleviated the increased level of TNF-α and the systolic, diastolic, mean, and notch pressure observed in IR with no change in pulse pressure. In addition, Allo decreased the heart rate in the treated group compared to IR rats. On the other hand, it has no effect on increased levels of insulin, glucose, fructosamine, or body weight gain compared to IR group, while it increased significantly the insulin level and body weight without hyperglycemia in the control group. Moreover, Allo treatment ameliorated increased level of 4HNE, Ang II, and Ang R1. In conclusion, the results of the current study show that Allo has a protective effect on vascular complications of IR which may be attributed to the effect of Allo on decreasing the TNF-α, 4HNE, Ang II, and Ang R1 as well as increasing the level of insulin secretion. PMID:25785277

  16. Genetic Forms of Severe Insulin Resistance: What Endocrinologists Should Know

    PubMed Central

    Parker, Victoria E. R.; Semple, Robert K.

    2015-01-01

    Insulin resistance” is a widely used clinical term. It is usually defined as a state characterised by reduced glucose-lowering activity of insulin, but is also sometimes used as a shorthand label for a clinical syndrome encompassing major pathologies such as type 2 diabetes, polycystic ovary syndrome, fatty liver disease, and atherosclerosis. Nevertheless the precise cellular origins of insulin resistance (IR), the causal links among these phenomena, and the mechanisms underlying them, remain poorly understood or contentious. Prevalent IR usually results from a genetic predisposition interacting with acquired obesity, however even in some lean individuals very severe degrees of IR are seen. It is important to identify these people as they often harbour identifiable single gene defects, and they may benefit from molecular diagnosis, genetic counselling, and sometimes tailored therapies. Observation of people with known single gene defects also offers the opportunity to make inferences about the mechanistic links between IR and common pathologies. We now summarise the currently known monogenic forms of severe IR, with an emphasis on practical aspects of their recognition, diagnosis and management. In particular, we draw distinctions among the biochemical subphenotypes of IR that arise from primary adipose tissue dysfunction or from primary insulin signalling defects, and discuss the implications of this dichotomy for management. PMID:23857978

  17. 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

  18. Mitochondrial involvement in skeletal muscle insulin resistance: A case of imbalanced bioenergetics.

    PubMed

    Affourtit, Charles

    2016-10-01

    Skeletal muscle insulin resistance in obesity associates with mitochondrial dysfunction, but the causality of this association is controversial. This review evaluates mitochondrial models of nutrient-induced muscle insulin resistance. It transpires that all models predict that insulin resistance arises as a result of imbalanced cellular bioenergetics. The nature and precise origin of the proposed insulin-numbing molecules differ between models but all species only accumulate when metabolic fuel supply outweighs energy demand. This observation suggests that mitochondrial deficiency in muscle insulin resistance is not merely owing to intrinsic functional defects, but could instead be an adaptation to nutrient-induced changes in energy expenditure. Such adaptive effects are likely because muscle ATP supply is fully driven by energy demand. This market-economic control of myocellular bioenergetics offers a mechanism by which insulin-signalling deficiency can cause apparent mitochondrial dysfunction, as insulin resistance lowers skeletal muscle anabolism and thus dampens ATP demand and, consequently, oxidative ATP synthesis. PMID:27473535

  19. Perfluorooctanoic acid exposure for 28 days affects glucose homeostasis and induces insulin hypersensitivity in mice

    NASA Astrophysics Data System (ADS)

    Yan, Shengmin; Zhang, Hongxia; Zheng, Fei; Sheng, Nan; Guo, Xuejiang; Dai, Jiayin

    2015-06-01

    Perfluoroalkyl acids (PFAAs) are widely used in many applications due to their unique physical and chemical characteristics. Because of the increasing prevalence of metabolic syndromes, including obesity, dyslipidemia and insulin resistance, concern has arisen about the roles of environmental pollutants in such diseases. Earlier epidemiologic studies showed a potential association between perfluorooctanoic acid (PFOA) and glucose metabolism, but how PFOA influences glucose homeostasis is still unknown. Here, we report on the modulation of the phosphatidylinositol 3-kinase-serine/threonine protein kinase (PI3K-AKT) signaling pathway in the livers of mice after 28 d of exposure to PFOA. Compared with normal mice, PFOA exposure significantly decreased the expression of the phosphatase and tensin homologue (PTEN) protein and affected the PI3K-AKT signaling pathway in the liver. Tolerance tests further indicated that PFOA exposure induced higher insulin sensitivity and glucose tolerance in mice. Biochemical analysis revealed that PFOA exposure reduced hepatic glycogen synthesis, which might be attributed to gluconeogenesis inhibition. The levels of several circulating proteins were altered after PFOA exposure, including proteins potentially related to diabetes and liver disease. Our results suggest that PFOA affected glucose metabolism and induced insulin hypersensitivity in mice.

  20. The relationship between rosacea and insulin resistance and metabolic syndrome.

    PubMed

    Akin Belli, Asli; Ozbas Gok, Seyran; Akbaba, Gulhan; Etgu, Fatma; Dogan, Gursoy

    2016-06-01

    Rosacea is a chronic inflammatory skin disease affecting the face. A positive correlation has been found between rosacea and cardiovascular diseases. We sought to investigate the relation between rosacea and metabolic syndrome (MS) and insulin resistance (IR). Between January and June 2015, a case-control study including 47 age-, gender-, and body mass index (BMI)-matched rosacea patients and 50 controls was conducted. Demographic data, clinical features of rosacea patients, anthropometric measures, laboratory findings, blood pressure levels, BMI, smoking history, alcohol consumption, sports life, family history of cardiovascular disease, and presence of MS and IR were recorded. Forty-seven rosacea patients (12 men and 35 women; age range: 35-68 years) and 50 controls (11 men and 39 women; age range: 38-78 years) were included in our study. Of 47 rosacea patients, 24 had erythematotelangiectatic type, 22 had papulopustular type, and one had phymatous type. Whereas the rate of IR was significantly higher in the rosacea group, there was no significant difference in the rate of MS between rosacea and the control group (p = 0.009 and p = 0.186, respectively). In addition, the rosacea group had significantly higher fasting blood glucose, total cholesterol, and systolic and diastolic blood pressure levels (p<0.05). Mean levels of LDL, triglyceride, total cholesterol and CRP were significantly higher than in the control group (p<0.05). Our findings suggest that there is a relationship between rosacea and IR and some parameters of cardiovascular risk factors. We recommend investigation of IR in rosacea patients. PMID:27328660

  1. [Simvastatin's effect on insulin resistance in rats with diabetes mellitus].

    PubMed

    Iskakova, S; Zharmakhanova, G; Bekmukhambetov, Y; Dworacka, M; Dworacki, G

    2015-05-01

    The aim of this experimental study was to estimate the effect of Simvastatin on glycemic variability-related insulin resistance in the course of diabetes mellitus (DM) in rats. Fifty seven male Wistar rats were divided into four groups: I - rats with diabetes mellitus and glycemic variability treated with Simvastatin (20 mg/kg body weight, intragastral during 8 weeks); II - placebo-treated rats with DM and glycemic variability; III - placebo treated rats with DM and IV - nondiabetic control rats. DM was induced by feeding rats with high-fat diet (61%) during five weeks and low-dose of Streptozotocin (30 mg/kg, intraperitoneally). Daily glucose excursions were stimulated by feeding animals twice a day. We measured fasting blood glucose, glycated hemoglobin (HbA1c), insulin and HOMAIR was calculated. Higher insulin resistance in diabetic rats is related to greater daily glycemic variability. In our study was installed significant increasing HOMAIR in diabetics rats with glycemic excursions comparison with the control. Our results showed that the simvastatin-treatment decreases the indices glycemic variability and HOMA in diabetic rats with glycemic excursions.

  2. REGULATION OF OBESITY AND INSULIN RESISTANCE BY NITRIC OXIDE

    PubMed Central

    Sansbury, Brian E.; Hill, Bradford G.

    2014-01-01

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

  3. Genetic and environmental influences on insulin levels and the insulin resistance syndrome: an analysis of women twins.

    PubMed

    Mayer, E J; Newman, B; Austin, M A; Zhang, D; Quesenberry, C P; Edwards, K; Selby, J V

    1996-02-15

    Multiple factors may determine insulin resistance and the insulin resistance syndrome. The contributions of genes and environment to the distribution of fasting insulin levels and to the associations of fasting insulin with elements of the syndrome were evaluated in the second examination of the Kaiser Permanente Women Twins Study (Oakland, California, 1989-1990). Subjects included 556 white women (165 monozygous twin pairs, 113 dizygous pairs; 455 women with normal glucose tolerance, 75 with impaired glucose tolerance, and 26 with non-insulin-dependent diabetes by World Health Organization criteria). The intraclass correlation coefficients for log fasting insulin for monozygous and dizygous twin pairs were 0.64 and 0.40, respectively. After adjustment for age, behavioral factors, and body mass index, the estimated classic heritability was 0.53 (p = 0.003). Commingling analysis of fasting insulin indicated the presence of four distributions (p < 0.001), consistent with at least one, and perhaps two, genes influencing this trait. In an unmatched multiple regression model among women from monozygous twin pairs only, log fasting insulin was independently associated with body mass index (p < 0.0001), waist/hip ratio (p = 0.02), and glucose intolerance (p = 0.04), but not with triglycerides, high density lipoprotein cholesterol, or hypertension. After removal of genetic influences by analysis of monozygous intrapair differences, only body mass index (p < 0.0001) remained independently related to fasting insulin. The authors conclude that, in addition to significant genetic influences on fasting insulin, environmental or behavioral factors (particularly nongenetic variation in obesity) are important determinants of fasting insulin and the insulin resistance syndrome.

  4. Insulin resistance and hypothyroidism: a complex relationship in non-alcoholic fatty liver disease.

    PubMed

    Misra, Sanjukta; Singh, Bratati

    2013-05-01

    An association of non-alcoholic fatty liver disease with insulin resistant metabolic syndrome and hypothyroidism has been suggested. Aim of the present study was to explore the above association and also to establish the correlation between hypothyroidism and insulin resistance in patients with nonalcoholic fatty liver disease. Study group comprised 40 cases of non-alcoholic fatty liver disease and 30 healthy controls. Serum samples were analysed for fasting glucose, insulin, lipid profile and thyroid hormones. Insulin resistance was assessed by homeostatic model of assessment calculation. Nonalcoholic fatty liver disease patients demonstrated significantly higher insulin resistance, TSH values and significantly lower FT4 values as compared to controls, which illustrates the prevalence of insulin resistance and hypothyroidism in patients. A significant positive correlation between TSH and Insulin resistance (r = 0.87, p < 0.001) and a significant negative correlation between FT4 and insulin resistance (r = -0.14, p < 0.001) were established in the cases. Moreover TSH was significantly related to low density lipoprotein cholesterol, independent of insulin resistance. There have been some doubts over the clinical correlation between insulin resistance and hypothyroidism to delineate increased risk of cardiovascular disease. So earlier detection and treatment of risk factors may have a significant impact on progression of non-alcoholic fatty liver disease. PMID:24765691

  5. Hypoglycemic effects and mechanisms of electroacupuncture on insulin resistance.

    PubMed

    Yin, Jieyun; Kuang, Jian; Chandalia, Manisha; Tuvdendorj, Demidmaa; Tumurbaatar, Batbayar; Abate, Nicola; Chen, Jiande D Z

    2014-08-01

    The aim of this study was to investigate effects and mechanisms of electroacupuncture (EA) on blood glucose and insulin sensitivity in mice fed a high-fat diet. Both wild-type (WT) and adipose ectonucleotide pyrophosphate phosphodiesterase (ENPP1) transgenic (TG) mice were fed a high-fat diet for 12 wk; for each mouse, an intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (ITT) were performed with or without EA at abdomen or auricular areas. A high-fat diet-induced insulin resistance in both WT and TG mice. In the WT mice, EA at 3 Hz and 15 Hz, but not at 1 Hz or 100 Hz, via CV4+CV12 significantly reduced postprandial glucose levels; EA at 3 Hz was most potent. The glucose level was reduced by 61.7% at 60 min and 74.5% at 120 min with EA at 3 Hz (all P < 0.001 vs. control). Similar hypoglycemic effect was noted in the TG mice. On the contrary, EA at auricular points increased postprandial glucose level (P < 0.03). 4). EA at 3 Hz via CV4+CV12 significantly enhanced the decrease of blood glucose after insulin injection, suggesting improvement of insulin sensitivity. Plasma free fatty acid was significantly suppressed by 42.5% at 15 min and 50.8% at 30 min with EA (P < 0.01) in both WT and TG mice. EA improves glucose tolerance in both WT and TG mice fed a high-fat diet, and the effect is associated with stimulation parameters and acupoints and is probably attributed to the reduction of free fatty acid. PMID:24848362

  6. Pioglitazone Improves Cognitive Function via Increasing Insulin Sensitivity and Strengthening Antioxidant Defense System in Fructose-Drinking Insulin Resistance Rats

    PubMed Central

    Yin, Qing-Qing; Pei, Jin-Jing; Xu, Song; Luo, Ding-Zhen; Dong, Si-Qing; Sun, Meng-Han; You, Li; Sun, Zhi-Jian; Liu, Xue-Ping

    2013-01-01

    Insulin resistance (IR) links Alzheimer’s disease (AD) with oxidative damage, cholinergic deficit, and cognitive impairment. Peroxisome proliferator-activated receptor γ (PPARγ) agonist pioglitazone previously used to treat type 2 diabetes mellitus (T2DM) has also been demonstrated to be effective in anti-inflammatory reaction and anti-oxidative stress in the animal models of AD and other neuroinflammatory diseases. Here, we investigated the effect of pioglitazone on learning and memory impairment and the molecular events that may cause it in fructose-drinking insulin resistance rats. We found that long-term fructose-drinking causes insulin resistance, oxidative stress, down-regulated activity of cholinergic system, and cognitive deficit, which could be ameliorated by pioglitazone administration. The results from the present study provide experimental evidence for using pioglitazone in the treatment of brain damage caused by insulin resistance. PMID:23527159

  7. Cocoa-rich diet ameliorates hepatic insulin resistance by modulating insulin signaling and glucose homeostasis in Zucker diabetic fatty rats.

    PubMed

    Cordero-Herrera, Isabel; Martín, María Ángeles; Escrivá, Fernando; Álvarez, Carmen; Goya, Luis; Ramos, Sonia

    2015-07-01

    Insulin resistance is the primary characteristic of type 2 diabetes and results from insulin signaling defects. Cocoa has been shown to exert anti-diabetic effects by lowering glucose levels. However, the molecular mechanisms responsible for this preventive activity and whether cocoa exerts potential beneficial effects on the insulin signaling pathway in the liver remain largely unknown. Thus, in this study, the potential anti-diabetic properties of cocoa on glucose homeostasis and insulin signaling were evaluated in type 2 diabetic Zucker diabetic fatty (ZDF) rats. Male ZDF rats were fed a control or cocoa-rich diet (10%), and Zucker lean animals received the control diet. ZDF rats supplemented with cocoa (ZDF-Co) showed a significant decrease in body weight gain, glucose and insulin levels, as well as an improved glucose tolerance and insulin resistance. Cocoa-rich diet further ameliorated the hepatic insulin resistance by abolishing the increased serine-phosphorylated levels of the insulin receptor substrate 1 and preventing the inactivation of the glycogen synthase kinase 3/glycogen synthase pathway in the liver of cocoa-fed ZDF rats. The anti-hyperglycemic effect of cocoa appeared to be at least mediated through the decreased levels of hepatic phosphoenolpyruvate carboxykinase and increased values of glucokinase and glucose transporter 2 in the liver of ZDF-Co rats. Moreover, cocoa-rich diet suppressed c-Jun N-terminal kinase and p38 activation caused by insulin resistance. These findings suggest that cocoa has the potential to alleviate both hyperglycemia and hepatic insulin resistance in type 2 diabetic ZDF rats.

  8. Oral carbohydrate loading with 18% carbohydrate beverage alleviates insulin resistance.

    PubMed

    Tamura, Takahiko; Yatabe, Tomoaki; Kitagawa, Hiroyuki; Yamashita, Koichi; Hanazaki, Kazuhiro; Yokoyama, Masataka

    2013-01-01

    Preoperative 12.6% oral carbohydrate loading is an element of the Enhanced Recovery After Surgery (ERAS) protocol aimed at alleviating postoperative insulin resistance; however, in Japan, beverages with 18% carbohydrate content are generally used for preoperative carbohydrate loading. We investigated the effect of 18% carbohydrate loading on alleviating insulin resistance. Six healthy volunteers participated in this crossover-randomized study and were segregated into 2 groups: volunteers in the carbohydrate-loading group (group A) who fasted from after 9 pm and ingested 375 mL of a beverage containing 18% carbohydrate (ArginaidWaterTM; Nestle, Tokyo, Japan) between 9 pm and 12 pm, and 250 mL of the same liquid at 6:30 am. Volunteers in control group (group B) drank only water. At 8:30 am, a hyperinsulinemic normoglycemic clamp was initiated. Glucose infusion rate (GIR) and levels of ketone bodies and cytokines (IL-1β, IL-6, and TNF-α) before clamping were evaluated. p<0.05 was considered statistically significant. Levels of blood glucose, insulin, and cytokines at the start of the clamp were similar in both the groups. The GIR in group A was significantly higher than that in group B (11.5±2.4 vs 6.2±2.2 mg/kg/min, p=0.005), while blood ketone body levels were significantly lower in group A (22±4 vs 124±119 μmol/L, p=0.04). Preoperative 18% carbohydrate loading could prevent the decrease in insulin sensitivity and suppress catabolism in healthy volunteers. Thus, carbohydrate loading with a beverage with 18% carbohydrate content might contribute to improvements in perioperative management. PMID:23353610

  9. Skin Tags and Acanthosis Nigricans in Patients with Hepatitis C Infection in Relation to Insulin Resistance and Insulin Like Growth Factor-1 Levels

    PubMed Central

    El Safoury, Omar Soliman; Shaker, Olfat G; Fawzy, May Mohsen

    2012-01-01

    Background: Skin tags (ST) are papillomas commonly found in the neck, axillae of middle-aged and elderly people Aim: Insulin and insulin-like growth factor (IGF-1) levels are affected by hepatitis C virus (HCV) infection and both of them may be implicated in the etiopathogenesis of ST and acanthosis nigricans (AN) through their proliferative and differentiating properties. So, the aim of this work was to evaluate the impact of HCV infection on ST and AN through the estimation of insulin resistance and IGF-1. Materials and Methods: Participants were arranged into four groups: (ST +ve / HCV +ve) 23 subjects, (ST+ / HCV -ve) 19 subjects, (HCV -ve / ST-ve) 20 subjects and (ST-ve /HCV +ve) 22 subjects. Age, ST size, color, number, AN, fasting glucose, fasting insulin, insulin resistance, IGF-1, HCV-antibodies (Ab) were recorded. Results: The mean number of ST in Group 1 was half the number of ST in Group 2 (11.0±9.3 / 22.3±14.0) (P=0.005). The difference in insulin resistance between the same groups was non-significant (13.1±10.6 / 9.0±5.5) (P=0.441) while the difference in IGF-1 was statistically significant (218.6±46.2 /285.4±32.8) (P=0.002). The multivariate logistic regression for the variables revealed that insulin resistance is the only factor affecting the occurrence of ST (OR=1.096, P=0.023). Multivariate regression analysis for the variables showed that HCV was borderline but not a significant factor affecting the number of ST (Beta=-0.409, P=0.053). The number of patients with AN was doubled in Group 2 in comparison to Group 1 but this was non significant 3(13%) / 6(32%) (P=0.2800). Conclusion: HCV is associated with a significant decrease in the ST number and in the serum level of IGF-1 together with an obvious decrease in the occurrence of AN. Our results may point to the entrant effect of insulin resistance and IGF-1 in ST and AN development. The current study suggests the evaluation of IGF-1-lowering agents in the control of ST and AN especially in

  10. Tumor necrosis factor-alpha and ceramides in insulin resistance.

    PubMed

    Brindley, D N; Wang, C N; Mei, J; Xu, J; Hanna, A N

    1999-01-01

    The present studies tested the hypothesis that some effects of tumor necrosis factor-alpha (TNF-alpha) are mediated by activation of sphingomyelinases and the production of ceramides. Differentiated 3T3-L1 adipocytes were incubated with short-chain ceramide analogs, (C2- and C6-ceramides: N-acetyl- and N-hexanoyl-sphingosines, respectively), and this treatment increased 2-deoxyglucose uptake in the absence of insulin progressively from 2-24 h. This effect was inhibited by blocking the activations of mitogen-activated protein kinase, phosphatidylinositol 3-kinase (PI 3-kinase), and ribosomal S6 kinase which mediated an increase in GLUT1 concentrations. Long-term increases in PI 3-kinase activity associated with insulin receptor substrate-1 (IRS-1) increased the proportion of GLUT1 and GLUT4 in plasma membranes. These events explain the increases in noninsulin-dependent glucose uptake and incorporation of this glucose into the fatty acid and glycerol moieties of triacylglycerol. The mechanisms by which TNF-alpha and ceramides increase PI 3-kinase activity were investigated further by using rat2 fibroblasts. Incubation for 20 min with TNF-alpha, bacterial sphingomyelinase, or C2-ceramides increased PI 3-kinase activity by about fivefold, and this effect depended upon a stimulation of tyrosine kinase activity and an increase in Ras-GTP. This demonstrates the existence of a novel signaling pathway for TNF-alpha that could contribute to the effects of this cytokine in stimulating basal glucose uptake. By contrast, treating the 3T3-L1 adipocytes for 2-24 h with C2-ceramide diminished insulin-stimulated glucose uptake by decreasing the insulin-induced translocation of GLUT1 and GLUT4 to plasma membranes. This inhibition was observed when there was no increase in basal glucose uptake, and it occurred downstream of PI 3-kinase. Our work provides further mechanisms whereby TNF-alpha and ceramides produce insulin resistance and decrease the effectiveness of insulin in

  11. Experimental alcohol-related peripheral neuropathy: role of insulin/IGF resistance.

    PubMed

    Nguyen, Van Anh; Le, Tran; Tong, Ming; Mellion, Michelle; Gilchrist, James; de la Monte, Suzanne M

    2012-08-01

    The mechanisms of alcohol-related peripheral neuropathy (ALPN) are poorly understood. We hypothesize that, like alcohol-related liver and brain degeneration, ALPN may be mediated by combined effects of insulin/IGF resistance and oxidative stress. Adult male Long Evans rats were chronically pair-fed with diets containing 0% or 37% ethanol (caloric), and subjected to nerve conduction studies. Chronic ethanol feeding slowed nerve conduction in the tibial (p = 0.0021) motor nerve, and not plantar sensory nerve, but it did not affect amplitude. Histological studies of the sciatic nerve revealed reduced nerve fiber diameters with increased regenerative sprouts, and denervation myopathy in ethanol-fed rats. qRT-PCR analysis demonstrated reduced mRNA levels of insulin, IGF-1, and IGF-2 polypeptides, IGF-1 receptor, and IRS2, and ELISAs revealed reduced immunoreactivity for insulin and IGF-1 receptors, IRS-1, IRS-4, myelin-associated glycoprotein, and tau in sciatic nerves of ethanol-fed rats (all p < 0.05 or better). The findings suggest that ALPN is characterized by (1) slowed conduction velocity with demyelination, and a small component of axonal degeneration; (2) impaired trophic factor signaling due to insulin and IGF resistance; and (3) degeneration of myelin and axonal cytoskeletal proteins. Therefore, ALPN is likely mediated by molecular and signal transduction abnormalities similar to those identified in alcoholic liver and brain degeneration.

  12. Reconceptualizing resistance: sociology and the affective dimension of resistance.

    PubMed

    Hynes, Maria

    2013-12-01

    This paper re-examines the sociological study of resistance in light of growing interest in the concept of affect. Recent claims that we are witness to an 'affective turn' and calls for a 'new sociological empiricism' sensitive to affect indicate an emerging paradigm shift in sociology. Yet, mainstream sociological study of resistance tends to have been largely unaffected by this shift. To this end, this paper presents a case for the significance of affect as a lens by which to approach the study of resistance. My claim is not simply that the forms of actions we would normally recognize as resistance have an affective dimension. Rather, it is that the theory of affect broadens 'resistance' beyond the purview of the two dominant modes of analysis in sociology; namely, the study of macropolitical forms, on the one hand, and the micropolitics of everyday resistance on the other. This broadened perspective challenges the persistent assumption that ideological forms of power and resistance are the most pertinent to the contemporary world, suggesting that much power and resistance today is of a more affective nature. In making this argument, it is a Deleuzian reading of affect that is pursued, which opens up to a level of analysis beyond the common understanding of affect as emotion. I argue that an affective approach to resistance would pay attention to those barely perceptible transitions in power and mobilizations of bodily potential that operate below the conscious perceptions and subjective emotions of social actors. These affective transitions constitute a new site at which both power and resistance operate.

  13. [EXPRESSION OF GENES, WHICH CONTROL GLUCOSE METABOLISM, IN BLOOD CELLS OF THE OBESE BOYS WITH INSULIN RESISTANCE].

    PubMed

    Tiazhka, O V; Minchenko, D O; Davydov, V V; Moliavko, O S; Budreiko, O A; Kulieshova, D K; Minchenko, O H

    2015-01-01

    We studied the expression of genes, which responsible for glucose metabolism, in the blood of obese boys with and without of insulin resistance as well as in normal (control) individuals. It was shown that the expression level of PFKFB3 gene is increased, PFKFB1 and INSIG2--is decreased, but HK2 gene--significantly does not change in the blood cells of obese boys with normal insulin sensitivity as compared to control group. Insulin resistance in obese boys leads to up-regulation of INSIG2 gene expression as well as to down-regulation of PFKFB1, PFKFB3, and HK2 genes in the blood.cells as compared to obese patients with normal insulin sensitivity. Results of this study provide evidence that obesity affects the expression of the subset of glucose metabolism-related genes in the blood cells and that insulin resistance in obesity is associated with changes in the expression level of PFKFB1, PFKFB3, HK2, and INSIG2 genes, which contribute to the development of insulin resistance as well as glucose intolerance. PMID:26827442

  14. Valproic acid reduces insulin-resistance, fat deposition and FOXO1-mediated gluconeogenesis in type-2 diabetic rat.

    PubMed

    Khan, Sabbir; Kumar, Sandeep; Jena, Gopabandhu

    2016-06-01

    Recent evidences highlighted the role of histone deacetylases (HDACs) in insulin-resistance, gluconeogenesis and islet function. HDACs can modulate the expression of various genes, which directly or indirectly affect glucose metabolism. This study was aimed to evaluate the role of valproic acid (VPA) on fat deposition, insulin-resistance and gluconeogenesis in type-2 diabetic rat. Diabetes was developed in Sprague-Dawley rats by the combination of high-fat diet and low dose streptozotocin. VPA at the doses of 150 and 300 mg/kg/day and metformin (positive control) 150 mg/kg twice daily for 10 weeks were administered by oral gavage. Insulin-resistance, dyslipidemia and glycemia were evaluated by biochemical estimations, while fat accumulation and structural alteration were assessed by histopathology. Protein expression and insulin signaling were evaluated by western blot and immunohistochemistry. VPA treatment significantly reduced the plasma glucose, HbA1c, insulin-resistance, fat deposition in brown adipose tissue, white adipose tissue and liver, which are comparable to metformin treatment. Further, VPA inhibited the gluconeogenesis and glucagon expression as well as restored the histopathological alterations in pancreas and liver. Our findings provide new insights on the anti-diabetic role of VPA in type-2 diabetes mellitus by the modulation of insulin signaling and forkhead box protein O1 (FOXO1)-mediated gluconeogenesis. Since VPA is a well established clinical drug, the detailed molecular mechanisms of the present findings can be further investigated for possible clinical use.

  15. Mechanisms of insulin resistance in human obesity: evidence for receptor and postreceptor defects.

    PubMed Central

    Kolterman, O G; Insel, J; Saekow, M; Olefsky, J M

    1980-01-01

    To assess the mechanisms of the insulin resistance in human obesity, we have determined, using a modification of the euglycemic glucose clamp technique, the shape of the in vivo insulin-glucose disposal dose-response curves in 7 control and 13 obese human subjects. Each subject had at least three euglycemic studies performed at insulin infusion rates of 15, 40, 120, 240, or 1,200 mU/M2/min. The glucose disposal rate was decreased in all obese subjects compared with controls (101 +/- 16 vs. 186 +/- 16 mg/M2/min) during the 40 mU/M2/min insulin infusion. The mean dose-response curve for the obese subjects was displaced to the right, i.e., the half-maximally effective insulin concentration was 270 +/- 27 microU/ml for the obese compared with 130 +/- 10 microU/ml for controls. In nine of the obese subjects, the dose-response curves were shifted to the right, and maximal glucose disposal rates (at a maximally effective insulin concentration) were markedly decreased, indicating both a receptor and a postreceptor defect. On the other hand, four obese patients had right-shifted dose-response curves but reached normal maximal glucose disposal rates, consistent with decreased insulin receptors as the only abnormality. When the individual data were analyzed, it was found that the lease hyperinsulinemic, least insulin-resistant patients displayed only the receptor defect, whereas those with the greatest hyperinsulinemia exhibited the largest post-receptor defect, suggesting a continuous spectrum of defects as one advances from mild to severe insulin resistance. When insulin's ability to suppress hepatic glucose output was assessed, hyperinsulinemia produced total suppresssion in all subjects. The dose-response curve for the obese subjects was shifted to the right, indicating a defect in insulin receptors. Insulin binding to isolated adipocytes obtained from the obese subjects was decreased, and a highly significant inverse linear relationship was demonstrated between insulin

  16. Role of Resistant Starch in Improving Gut Health, Adiposity, and Insulin Resistance1234

    PubMed Central

    Keenan, Michael J; Zhou, June; Hegsted, Maren; Pelkman, Christine; Durham, Holiday A; Coulon, Diana B; Martin, Roy J

    2015-01-01

    The realization that low–glycemic index diets were formulated using resistant starch led to more than a decade of research on the health effects of resistant starch. Determination of the metabolizable energy of the resistant starch product allowed for the performance of isocaloric studies. Fermentation of resistant starch in rodent studies results in what appears to be a healthier gut, demonstrated by increased amounts of short-chain fatty acids, an apparent positive change in the microbiota, and increased gene expression for gene products involved in normal healthy proliferation and apoptosis of potential cancer cells. Additionally, consumption of resistant starch was associated with reduced abdominal fat and improved insulin sensitivity. Increased serum glucagon-like peptide 1 (GLP-1) likely plays a role in promoting these health benefits. One rodent study that did not use isocaloric diets demonstrated that the use of resistant starch at 8% of the weight of the diet reduced body fat. This appears to be approximately equivalent to the human fiber requirement. In human subjects, insulin sensitivity is increased with the feeding of resistant starch. However, only 1 of several studies reports an increase in serum GLP-1 associated with resistant starch added to the diet. This means that other mechanisms, such as increased intestinal gluconeogenesis or increased adiponectin, may be involved in the promotion of improved insulin sensitivity. Future research may confirm that there will be improved health if human individuals consume the requirement for dietary fiber and a large amount of the fiber is fermentable. PMID:25770258

  17. Role of resistant starch in improving gut health, adiposity, and insulin resistance.

    PubMed

    Keenan, Michael J; Zhou, June; Hegsted, Maren; Pelkman, Christine; Durham, Holiday A; Coulon, Diana B; Martin, Roy J

    2015-03-01

    The realization that low-glycemic index diets were formulated using resistant starch led to more than a decade of research on the health effects of resistant starch. Determination of the metabolizable energy of the resistant starch product allowed for the performance of isocaloric studies. Fermentation of resistant starch in rodent studies results in what appears to be a healthier gut, demonstrated by increased amounts of short-chain fatty acids, an apparent positive change in the microbiota, and increased gene expression for gene products involved in normal healthy proliferation and apoptosis of potential cancer cells. Additionally, consumption of resistant starch was associated with reduced abdominal fat and improved insulin sensitivity. Increased serum glucagon-like peptide 1 (GLP-1) likely plays a role in promoting these health benefits. One rodent study that did not use isocaloric diets demonstrated that the use of resistant starch at 8% of the weight of the diet reduced body fat. This appears to be approximately equivalent to the human fiber requirement. In human subjects, insulin sensitivity is increased with the feeding of resistant starch. However, only 1 of several studies reports an increase in serum GLP-1 associated with resistant starch added to the diet. This means that other mechanisms, such as increased intestinal gluconeogenesis or increased adiponectin, may be involved in the promotion of improved insulin sensitivity. Future research may confirm that there will be improved health if human individuals consume the requirement for dietary fiber and a large amount of the fiber is fermentable.

  18. Direct Evidence that Myocardial Insulin Resistance following Myocardial Ischemia Contributes to Post-Ischemic Heart Failure.

    PubMed

    Fu, Feng; Zhao, Kun; Li, Jia; Xu, Jie; Zhang, Yuan; Liu, Chengfeng; Yang, Weidong; Gao, Chao; Li, Jun; Zhang, Haifeng; Li, Yan; Cui, Qin; Wang, Haichang; Tao, Ling; Wang, Jing; Quon, Michael J; Gao, Feng

    2015-12-14

    A close link between heart failure (HF) and systemic insulin resistance has been well documented, whereas myocardial insulin resistance and its association with HF are inadequately investigated. This study aims to determine the role of myocardial insulin resistance in ischemic HF and its underlying mechanisms. Male Sprague-Dawley rats subjected to myocardial infarction (MI) developed progressive left ventricular dilation with dysfunction and HF at 4 wk post-MI. Of note, myocardial insulin sensitivity was decreased as early as 1 wk after MI, which was accompanied by increased production of myocardial TNF-α. Overexpression of TNF-α in heart mimicked impaired insulin signaling and cardiac dysfunction leading to HF observed after MI. Treatment of rats with a specific TNF-α inhibitor improved myocardial insulin signaling post-MI. Insulin treatment given immediately following MI suppressed myocardial TNF-α production and improved cardiac insulin sensitivity and opposed cardiac dysfunction/remodeling. Moreover, tamoxifen-induced cardiomyocyte-specific insulin receptor knockout mice exhibited aggravated post-ischemic ventricular remodeling and dysfunction compared with controls. In conclusion, MI induces myocardial insulin resistance (without systemic insulin resistance) mediated partly by ischemia-induced myocardial TNF-α overproduction and promotes the development of HF. Our findings underscore the direct and essential role of myocardial insulin signaling in protection against post-ischemic HF.

  19. 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.

  20. Local insulin therapy affects fracture healing in a rat model.

    PubMed

    Park, Andrew G; Paglia, David N; Al-Zube, Loay; Hreha, Jeremy; Vaidya, Swaroopa; Breitbart, Eric; Benevenia, Joseph; O'Connor, J Patrick; Lin, Sheldon S

    2013-05-01

    A significant number of lower extremity fractures result in mal-union necessitating effective treatments to restore ambulation. Prior research in diabetic animal fracture models demonstrated improved healing following local insulin application to the fracture site and indicated that local insulin therapy can aid bone regeneration, at least within an insulin-dependent diabetic animal model. This study tested whether local insulin therapy could accelerate femur fracture repair in normal, non-diabetic rats. High (20 units) and low (10 units) doses of insulin were delivered in a calcium sulfate carrier which provided sustained release of the exogenous insulin for 7 days after fracture. Histomorphometry, radiographic scoring, and torsional mechanical testing were used to measure fracture healing. The fracture calluses from rats treated with high-dose insulin had significantly more cartilage than untreated rats after 7 and 14 days of healing. After 4 weeks of healing, femurs from rats treated with low-dose insulin had significantly higher radiographic scores and mechanical strength (p < 0.05), compared to the no treatment control groups. The results of this study suggest that locally delivered insulin is a potential therapeutic agent for treating bone fractures. Further studies are necessary, such as large animal proof of concepts, prior to the clinical use of insulin for bone fracture treatment.

  1. Insulin resistance in Alzheimer disease: Is heme oxygenase-1 an Achille's heel?

    PubMed

    Barone, Eugenio; Butterfield, D Allan

    2015-12-01

    Insulin resistance, clinically defined as the inability of insulin to increase glucose uptake and utilization, has been found to be associated with the progression of Alzheimer disease (AD). Indeed, postmortem AD brain shows all the signs of insulin resistance including: (i) reduced brain insulin receptor (IR) sensitivity, (ii) hypophosphorylation of the insulin receptor and downstream second messengers such as IRS-1, and (iii) attenuated insulin and insulin growth factor (IGF)-1 receptor expression. However, the exact mechanisms driving insulin resistance have not been completely elucidated. Quite recently, the levels of the peripheral inducible isoform of heme oxygenase (HO-1), a well-known protein up-regulated during cell stress response, were proposed to be among the strongest positive predictors of metabolic disease, including insulin resistance. Because our group previously reported on levels, activation state and oxidative stress-induced post-translational modifications of HO-1 in AD brain and our ongoing studies to better elucidate the role of HO-1 in insulin resistance-associated AD pathology, the aim of this review is to provide reader with a critical analysis on new aspects of the interplay between HO-1 and insulin resistance and on how the available lines of evidence could be useful for further comprehension of processes in AD brain.

  2. Alanine-aminotransferase: an early marker for insulin resistance?

    PubMed

    Salazar, Martin R; Carbajal, Horacio A; Curciarello, Jose O; Aizpurua, Marcelo; Adrover, Raul E; Riondet, Beatriz

    2007-01-01

    In a population-based sample, after excluding alcohol consumption, hepatotoxic drugs and hepatitis B and C infected, we investigated if alanine-aminotransferase (ALT) was associated with metabolic syndrome and insulin resistance, and if this association was caused by non-alcoholic fatty liver disease (NAFLD). The sample (432 female and 119 male) was divided into two ALT thresholds corresponding to the 50th and 75th percentiles (P) (female > or = 15 and > or = 19 U/L; male > or = 17 and > or = 23 U/I, respectively). Blood pressure, body mass index, waist circumference, cholesterol, HDL cholesterol (HDLc), triglyceride (TG), TG/HDLc ratio, glycemia and homeostasis model assessment of insulin resistance (HOMA-IR) were compared between those above and below each ALT threshold. Female placed above the 50th P of ALT had higher levels of TG/HDLc ratio (p=0.029), glycemia (p=0.028), and homeostasis model assessment of insulin resistance, (p=0.045), and above the 75th P had higher SBP (p=0.036), DBP (p=0.018), TG (p=0.024), TG/HDLc ratio (p=0.028), glycemia (p=0.004) and HOMA-IR (p=0.0014). Male placed above the 50th P of ALT had higher BMI (p=0.017) and TG/HDLc ratio (p=0.048), and above the 75th P had lower values of HDLc (p=0.042). Only 16.5% of women and 14.5% of men, above the 75th P of ALT, showed an increase in liver brightness in the echography. This work shows in woman an early association of ALT with TG/HDLc ratio and HOMA-IR. Since the last two are independent predictors of cardiovascular risk, attention should be drawn to ALT values near the upper limit of the normal range even in the absence of NAFLD and obesity. PMID:17593595

  3. Insulin sensitizers prevent fine particulate matter-induced vascular insulin resistance and changes in endothelial progenitor cell homeostasis.

    PubMed

    Haberzettl, Petra; McCracken, James P; Bhatnagar, Aruni; Conklin, Daniel J

    2016-06-01

    Exposure to fine particular matter (PM2.5) increases the risk of developing cardiovascular disease and Type 2 diabetes. Because blood vessels are sensitive targets of air pollutant exposure, we examined the effects of concentrated ambient PM2.5 (CAP) on vascular insulin sensitivity and circulating levels of endothelial progenitor cells (EPCs), which reflect cardiovascular health. We found that CAP exposure for 9 days decreased insulin-stimulated Akt phosphorylation in the aorta of mice maintained on control diet. This change was accompanied by the induction of IL-1β and increases in the abundance of cleaved IL-18 and p10 subunit of Casp-1, consistent with the activation of the inflammasome pathway. CAP exposure also suppressed circulating levels of EPCs (Flk-1(+)/Sca-1(+) cells), while enhancing the bone marrow abundance of these cells. Although similar changes in vascular insulin signaling and EPC levels were observed in mice fed high-fat diet, CAP exposure did not exacerbate diet-induced changes in vascular insulin resistance or EPC homeostasis. Treatment with an insulin sensitizer, metformin or rosiglitazone, prevented CAP-induced vascular insulin resistance and NF-κB and inflammasome activation and restored peripheral blood and bone marrow EPC levels. These findings suggest that PM2.5 exposure induces diet-independent vascular insulin resistance and inflammation and prevents EPC mobilization, and that this EPC mobilization defect could be mediated by vascular insulin resistance. Impaired vascular insulin sensitivity may be an important mechanism underlying PM2.5-induced vascular injury, and pharmacological sensitization to insulin action could potentially prevent deficits in vascular repair and mitigate vascular inflammation due to exposure to elevated levels of ambient air pollution.

  4. Insulin sensitizers prevent fine particulate matter-induced vascular insulin resistance and changes in endothelial progenitor cell homeostasis.

    PubMed

    Haberzettl, Petra; McCracken, James P; Bhatnagar, Aruni; Conklin, Daniel J

    2016-06-01

    Exposure to fine particular matter (PM2.5) increases the risk of developing cardiovascular disease and Type 2 diabetes. Because blood vessels are sensitive targets of air pollutant exposure, we examined the effects of concentrated ambient PM2.5 (CAP) on vascular insulin sensitivity and circulating levels of endothelial progenitor cells (EPCs), which reflect cardiovascular health. We found that CAP exposure for 9 days decreased insulin-stimulated Akt phosphorylation in the aorta of mice maintained on control diet. This change was accompanied by the induction of IL-1β and increases in the abundance of cleaved IL-18 and p10 subunit of Casp-1, consistent with the activation of the inflammasome pathway. CAP exposure also suppressed circulating levels of EPCs (Flk-1(+)/Sca-1(+) cells), while enhancing the bone marrow abundance of these cells. Although similar changes in vascular insulin signaling and EPC levels were observed in mice fed high-fat diet, CAP exposure did not exacerbate diet-induced changes in vascular insulin resistance or EPC homeostasis. Treatment with an insulin sensitizer, metformin or rosiglitazone, prevented CAP-induced vascular insulin resistance and NF-κB and inflammasome activation and restored peripheral blood and bone marrow EPC levels. These findings suggest that PM2.5 exposure induces diet-independent vascular insulin resistance and inflammation and prevents EPC mobilization, and that this EPC mobilization defect could be mediated by vascular insulin resistance. Impaired vascular insulin sensitivity may be an important mechanism underlying PM2.5-induced vascular injury, and pharmacological sensitization to insulin action could potentially prevent deficits in vascular repair and mitigate vascular inflammation due to exposure to elevated levels of ambient air pollution. PMID:27016579

  5. Is this patient insulin resistant? How much does it matter?

    PubMed

    Sheeder, Jeanelle; Travers, Sharon H; Stevens-Simon, Catherine

    2003-01-01

    Alex was an obese 10-year-old girl with a family history of type 2 diabetes, hypertension, and perhaps polycystic ovarian syndrome. Her physical examination was significant for a central accumulation of body fat and acanthosis nigricans. Although the laboratory studies indicated that Alex was not diabetic and probably not glucose intolerant, she could be insulin resistant (IR). Should any further evaluation be done? If Alex is IR, what kind of treatment should be offered? The following discussion addresses these questions by reviewing the pathophysiology, diagnosis, and consequences of isolated IR. PMID:14686557

  6. Abdominal obesity, muscle composition, and insulin resistance in premenopausal women.

    PubMed

    Ross, Robert; Freeman, Jennifer; Hudson, Robert; Janssen, Ian

    2002-11-01

    The independent relationships between visceral and abdominal sc adipose tissue (AT) depots, muscle composition, and insulin sensitivity were examined in 40 abdominally obese, premenopausal women. Measurements included glucose disposal by euglycemic clamp, muscle composition by computed tomography, abdominal and nonabdominal (e.g. leg) AT by magnetic resonance imaging and cardiovascular fitness. Glucose disposal rates were negatively related to visceral AT mass (r = -0.42, P < 0.01). These observations remained significant (P < 0.01) after control for nonabdominal and abdominal sc AT, muscle attenuation, and peak oxygen uptake. Total, abdominal, or leg sc AT or muscle attenuation was not significantly (P > 0.10) related to glucose disposal. Subdivision of abdominal sc AT into anterior and posterior depots did not alter the observed relationships. Further analysis matched two groups of women for abdominal sc AT but with low and high visceral AT. Women with high visceral AT had lower glucose disposal rates compared with those with low visceral AT (P < 0.05). A similar analysis performed on two groups of women matched for visceral AT but high and low abdominal sc AT revealed no statistically different values for insulin sensitivity (P > 0.10). In conclusion, visceral AT alone is a strong correlate of insulin resistance independent of nonabdominal, abdominal sc AT, muscle composition, and cardiovascular fitness. Subdivision of abdominal sc AT did not provide additional insight into the relationship between abdominal obesity and metabolic risk.

  7. Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC

    PubMed Central

    Rubio-Cabezas, Oscar; Puri, Vishwajeet; Murano, Incoronata; Saudek, Vladimir; Semple, Robert K; Dash, Satya; Hyden, Caroline S S; Bottomley, William; Vigouroux, Corinne; Magré, Jocelyne; Raymond-Barker, Philippa; Murgatroyd, Peter R; Chawla, Anil; Skepper, Jeremy N; Chatterjee, V Krishna; Suliman, Sara; Patch, Ann-Marie; Agarwal, Anil K; Garg, Abhimanyu; Barroso, Inês; Cinti, Saverio; Czech, Michael P; Argente, Jesús; O'Rahilly, Stephen; Savage, David B

    2009-01-01

    Lipodystrophic syndromes are characterized by adipose tissue deficiency. Although rare, they are of considerable interest as they, like obesity, typically lead to ectopic lipid accumulation, dyslipidaemia and insulin resistant diabetes. In this paper we describe a female patient with partial lipodystrophy (affecting limb, femorogluteal and subcutaneous abdominal fat), white adipocytes with multiloculated lipid droplets and insulin-resistant diabetes, who was found to be homozygous for a premature truncation mutation in the lipid droplet protein cell death-inducing Dffa-like effector C (CIDEC) (E186X). The truncation disrupts the highly conserved CIDE-C domain and the mutant protein is mistargeted and fails to increase the lipid droplet size in transfected cells. In mice, Cidec deficiency also reduces fat mass and induces the formation of white adipocytes with multilocular lipid droplets, but in contrast to our patient, Cidec null mice are protected against diet-induced obesity and insulin resistance. In addition to describing a novel autosomal recessive form of familial partial lipodystrophy, these observations also suggest that CIDEC is required for unilocular lipid droplet formation and optimal energy storage in human fat. PMID:20049731

  8. Developmental Programming by Maternal Insulin Resistance: Hyperinsulinemia, Glucose Intolerance, and Dysregulated Lipid Metabolism in Male Offspring of Insulin-Resistant Mice

    PubMed Central

    Isganaitis, Elvira; Woo, Melissa; Ma, Huijuan; Chen, Michael; Kong, Wen; Lytras, Aristides; Sales, Vicencia; DeCoste-Lopez, Jennifer; Lee, Kyung-Ju; Leatherwood, Cianna; Lee, Deborah; Fitzpatrick, Connor; Gall, Walter; Watkins, Steven; Patti, Mary-Elizabeth

    2014-01-01

    Maternal obesity and gestational diabetes mellitus (GDM) are associated with obesity and diabetes risk in offspring. We tested whether maternal insulin resistance, which frequently coexists with GDM and obesity, could independently contribute to dysregulation of offspring metabolism. Female mice haploinsufficient for insulin receptor substrate-1 (IRS1-het) are hyperinsulinemic and insulin resistant during pregnancy, despite normal plasma glucose and body weight, and thus serve as a model of isolated maternal insulin resistance. Wild-type (WT) offspring of IRS1-het dams insulin resistance-exposed [IR-exposed] were compared with WT offspring of WT dams. Despite no differences in adiposity, male IR-exposed pups were glucose intolerant (P = 0.04) and hyperinsulinemic (1.3-fold increase, P = 0.02) by 1 month of age and developed progressive fasting hyperglycemia. Moreover, male IR-exposed pups challenged with high-fat diet exhibited insulin resistance. Liver lipidomic analysis of 3-week-old IR-exposed males revealed increases in the 16:1n7 fraction of several lipid classes, suggesting increased Scd1 activity. By 6 months of age, IR-exposed males had increased lipid accumulation in liver as well as increased plasma refed fatty acids, consistent with disrupted lipid metabolism. Our results indicate that isolated maternal insulin resistance, even in the absence of hyperglycemia or obesity, can promote metabolic perturbations in male offspring. PMID:24186867

  9. Disruption of insulin receptor function inhibits proliferation in endocrine resistant breast cancer cells

    PubMed Central

    Chan, Jie Ying; LaPara, Kelly; Yee, Douglas

    2015-01-01

    The insulin-like growth factor (IGF) system is a well-studied growth regulatory pathway implicated in breast cancer biology. Clinical trials testing monoclonal antibodies directed against the type I IGF receptor (IGF1R) in combination with estrogen receptor-α (ER) targeting have been completed, but failed to show benefits in patients with endocrine resistant tumors compared to ER targeting alone. We have previously shown that the closely related insulin receptor (InsR) is expressed in tamoxifen resistant breast cancer cells. Here we examined if inhibition of InsR affected tamoxifen-resistant (TamR) breast cancer cells. InsR function was inhibited by three different mechanisms: InsR shRNA, a small InsR blocking peptide, S961 and an InsR monoclonal antibody (mAb). Suppression of InsR function by these methods in TamR cells successfully blocked insulin-mediated signaling, monolayer proliferation, cell cycle progression and anchorage-independent growth. This strategy was not effective in parental cells likely due to the presence of IGFR/InsR hybrid receptors. Down-regulation of IGF1R in conjunction with InsR inhibition was more effective in blocking IGF- and insulin-mediated signaling and growth in parental cells compared to single receptor targeting alone. Our findings show TamR cells were stimulated by InsR and were not sensitive to IGF1R inhibition, whereas in tamoxifen-sensitive parental cancer cells, the presence of both receptors, especially hybrid receptors, allowed cross-reactivity of ligand-mediated activation and growth. To suppress the IGF system, targeting of both IGF1R and InsR is optimal in endocrine sensitive and resistant breast cancer. PMID:26876199

  10. Hypolactasia is associated with insulin resistance in nonalcoholic steatohepatitis

    PubMed Central

    de Campos Mazo, Daniel Ferraz; Mattar, Rejane; Stefano, José Tadeu; da Silva-Etto, Joyce Matie Kinoshita; Diniz, Márcio Augusto; Duarte, Sebastião Mauro Bezerra; Rabelo, Fabíola; Lima, Rodrigo Vieira Costa; de Campos, Priscila Brizolla; Carrilho, Flair José; Oliveira, Claudia P

    2016-01-01

    AIM To assess lactase gene (LCT)-13910C>T polymorphisms in Brazilian non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) patients in comparison with healthy controls. METHODS This was a transverse observational clinical study with NAFLD patients who were followed at the Hepatology Outpatient Unit of the Hospital das Clínicas, São Paulo, Brazil. The polymorphism of lactase non-persistence/lactase persistence (LCT-13910C>T) was examined by PCR-restriction fragment length polymorphism technique in 102 liver biopsy-proven NAFLD patients (steatosis in 9 and NASH in 93) and compared to those of 501 unrelated healthy volunteers. Anthropometric, clinical, biochemical and liver histology data were analyzed. Continuous variables were compared using the t or Mann-Whitney tests, and categorical data were compared with the Fisher’s exact test. Univariate logistic regression and multivariate logistic regression adjusted for gender and age were performed. RESULTS No differences in the LCT-13910 genotype frequencies were noted between the NAFLD patients (66.67% of the patients with steatosis were CC, 33.33% were CT, and none were TT; 55.91% of the patients with NASH were CC, 39.78% were CT, and 4.3% were TT; P = 0.941) and the healthy controls (59.12% were CC, 35.67% were CT, and 5.21% were TT) or between the steatosis and NASH patients. That is, the distribution of the lactase non-persistence/lactase persistence polymorphism (LCT-13910C>T) in the patients with NAFLD was equal to that in the general population. In the NASH patients, the univariate analysis revealed that the lactase non-persistence (low lactase activity or hypolactasia) phenotype was associated with higher insulin levels (23.47 ± 15.94 μU/mL vs 15.8 ± 8.33 μU/mL, P = 0.027) and a higher frequency of insulin resistance (91.84% vs 72.22%, P = 0.02) compared with the lactase persistence phenotype. There were no associations between the LCT genotypes and diabetes (P = 0

  11. Hypolactasia is associated with insulin resistance in nonalcoholic steatohepatitis

    PubMed Central

    de Campos Mazo, Daniel Ferraz; Mattar, Rejane; Stefano, José Tadeu; da Silva-Etto, Joyce Matie Kinoshita; Diniz, Márcio Augusto; Duarte, Sebastião Mauro Bezerra; Rabelo, Fabíola; Lima, Rodrigo Vieira Costa; de Campos, Priscila Brizolla; Carrilho, Flair José; Oliveira, Claudia P

    2016-01-01

    AIM To assess lactase gene (LCT)-13910C>T polymorphisms in Brazilian non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) patients in comparison with healthy controls. METHODS This was a transverse observational clinical study with NAFLD patients who were followed at the Hepatology Outpatient Unit of the Hospital das Clínicas, São Paulo, Brazil. The polymorphism of lactase non-persistence/lactase persistence (LCT-13910C>T) was examined by PCR-restriction fragment length polymorphism technique in 102 liver biopsy-proven NAFLD patients (steatosis in 9 and NASH in 93) and compared to those of 501 unrelated healthy volunteers. Anthropometric, clinical, biochemical and liver histology data were analyzed. Continuous variables were compared using the t or Mann-Whitney tests, and categorical data were compared with the Fisher’s exact test. Univariate logistic regression and multivariate logistic regression adjusted for gender and age were performed. RESULTS No differences in the LCT-13910 genotype frequencies were noted between the NAFLD patients (66.67% of the patients with steatosis were CC, 33.33% were CT, and none were TT; 55.91% of the patients with NASH were CC, 39.78% were CT, and 4.3% were TT; P = 0.941) and the healthy controls (59.12% were CC, 35.67% were CT, and 5.21% were TT) or between the steatosis and NASH patients. That is, the distribution of the lactase non-persistence/lactase persistence polymorphism (LCT-13910C>T) in the patients with NAFLD was equal to that in the general population. In the NASH patients, the univariate analysis revealed that the lactase non-persistence (low lactase activity or hypolactasia) phenotype was associated with higher insulin levels (23.47 ± 15.94 μU/mL vs 15.8 ± 8.33 μU/mL, P = 0.027) and a higher frequency of insulin resistance (91.84% vs 72.22%, P = 0.02) compared with the lactase persistence phenotype. There were no associations between the LCT genotypes and diabetes (P = 0

  12. Comparison of plasminogen activator inhibitor-1 concentration in insulin-resistant versus insulin-sensitive healthy women.

    PubMed

    Abbasi, F; McLaughlin, T; Lamendola, C; Lipinska, I; Tofler, G; Reaven, G M

    1999-11-01

    The primary goal of this investigation was to see whether plasminogen activator inhibitor-1 (PAI-1) concentrations varied as a function of differences in insulin-mediated glucose disposal in 2 groups of healthy women matched for every other variable that might play a role in regulation of PAI-1. For this purpose, we recruited 32 healthy women, divided on the basis of their steady-state plasma glucose (SSPG) concentrations during the insulin suppression test into an insulin-resistant (SSPG=216+/-12 mg/dL, n=16) and an insulin-sensitive (94+/-6 mg/dL, n=16) group. PAI-1 antigen concentrations were significantly higher (26+/-4 versus 14+/-3 ng/mL, P<0.02) in the insulin-resistant group. In addition, fasting plasma insulin (18+/-3 versus 11+/-2 microU/mL, P<0.02) and triglyceride (160+/-19 versus 93+/-10 mg/dL, P<0.001) concentrations were higher in the insulin-resistant individuals, whereas HDL concentrations were lower (44+/-3 versus 58+/-3 mg/dL, P<0.005). However, the 2 groups were essentially identical in terms of age, menopausal status, hormone replacement therapy, body mass index (BMI), ratio of waist-to-hip girth, and blood pressure. When the experimental population was considered as 1 group, there were statistically significant correlations between PAI-1 antigen and the following variables: adjusting for differences in age and BMI, SSPG (r=0.56, P<0.001); triglyceride (r=0.39, P<0.05); and HDL cholesterol (r=-0. 65, P<0.001) concentrations. Finally, multiple regression analysis revealed the major determinants of PAI-1 to be insulin resistance, or insulin concentration, and HDL cholesterol. These results: 1) demonstrate that PAI-1 concentrations are higher in healthy, insulin-resistant women as compared with insulin-sensitive individuals, independent of differences in BMI or ratio of waist-to-hip girth; and 2) provide another mechanism by which insulin-resistant individuals are at increased thrombotic cardiovascular risk.

  13. Important genetic checkpoints for insulin resistance in salt-sensitive (S) Dahl rats

    PubMed Central

    Shehata, Marlene F

    2008-01-01

    Despite the marked advances in research on insulin resistance (IR) in humans and animal models of insulin resistance, the mechanisms underlying high salt-induced insulin resistance remain unclear. Insulin resistance is a multifactorial disease with both genetic and environmental factors (such as high salt) involved in its pathogenesis. High salt triggers insulin resistance in genetically susceptible patients and animal models of insulin resistance. One of the mechanisms by which high salt might precipitate insulin resistance is through its ability to enhance an oxidative stress-induced inflammatory response that disrupts the insulin signaling pathway. The aim of this hypothesis is to discuss two complementary approaches to find out how high salt might interact with genetic defects along the insulin signaling and inflammatory pathways to predispose to insulin resistance in a genetically susceptible model of insulin resistance. The first approach will consist of examining variations in genes involved in the insulin signaling pathway in the Dahl S rat (an animal model of insulin resistance and salt-sensitivity) and the Dahl R rat (an animal model of insulin sensitivity and salt-resistance), and the putative cellular mechanisms responsible for the development of insulin resistance. The second approach will consist of studying the over-expressed genes along the inflammatory pathway whose respective activation might be predictive of high salt-induced insulin resistance in Dahl S rats. Variations in genes encoding the insulin receptor substrates -1 and/or -2 (IRS-1, -2) and/or genes encoding the glucose transporter (GLUTs) proteins have been found in patients with insulin resistance. To better understand the combined contribution of excessive salt and genetic defects to the etiology of the disease, it is essential to investigate the following question: Question 1: Do variations in genes encoding the IRS -1 and -2 and/or genes encoding the GLUTs proteins predict high salt

  14. [Insulin resistance as a mechanism of adaptation during human evolution].

    PubMed

    Ricart, W; Fernández-Real, J M

    2010-10-01

    The recent application of concepts of evolution to human disease is proving useful to understand certain pathophysiological mechanisms of different entities that span genomic alterations of immunity, respiratory and hormone function, and the circulatory and neural systems. However, effort has concentrated on explaining the keys to adaptation that define human metabolism and, since the early 1960s, several theories have been developed. This article reviews some of the hypotheses postulated in recent years on the potential benefit of insulin resistance and discusses the most recent knowledge. The concept of the thrifty gene seems to have been definitively refuted by current knowledge. The current paradigm describes an interaction between the metabolic and the immune systems resulting from their coevolution, promoted by evolutionary pressures triggered by fasting, infection and intake of different foods. The activation and regulation of these ancient mechanisms in integrated and interdependent areas defines insulin resistance as a survival strategy that is critical during fasting and in the fight against infection. The relationship with some components of the diet and, particularly, with the symbiotic intestinal microflora points to new paradigms in understanding the pathophysiology of obesity, metabolic syndrome and type 2 diabetes mellitus.

  15. [Insulin resistance as a mechanism of adaptation during human evolution].

    PubMed

    Ricart, W; Fernández-Real, J M

    2010-10-01

    The recent application of concepts of evolution to human disease is proving useful to understand certain pathophysiological mechanisms of different entities that span genomic alterations of immunity, respiratory and hormone function, and the circulatory and neural systems. However, effort has concentrated on explaining the keys to adaptation that define human metabolism and, since the early 1960s, several theories have been developed. This article reviews some of the hypotheses postulated in recent years on the potential benefit of insulin resistance and discusses the most recent knowledge. The concept of the thrifty gene seems to have been definitively refuted by current knowledge. The current paradigm describes an interaction between the metabolic and the immune systems resulting from their coevolution, promoted by evolutionary pressures triggered by fasting, infection and intake of different foods. The activation and regulation of these ancient mechanisms in integrated and interdependent areas defines insulin resistance as a survival strategy that is critical during fasting and in the fight against infection. The relationship with some components of the diet and, particularly, with the symbiotic intestinal microflora points to new paradigms in understanding the pathophysiology of obesity, metabolic syndrome and type 2 diabetes mellitus. PMID:20675202

  16. Insulin sensitivity indices: a proposal of cut-off points for simple identification of insulin-resistant subjects.

    PubMed

    Radikova, Z; Koska, J; Huckova, M; Ksinantova, L; Imrich, R; Vigas, M; Trnovec, T; Langer, P; Sebokova, E; Klimes, I

    2006-05-01

    Demanding measurement of insulin sensitivity using clamp methods does not simplify the identification of insulin resistant subjects in the general population. Other approaches such as fasting- or oral glucose tolerance test-derived insulin sensitivity indices were proposed and validated with the euglycemic clamp. Nevertheless, a lack of reference values for these indices prevents their wider use in epidemiological studies and clinical practice. The aim of our study was therefore to define the cut-off points of insulin resistance indices as well as the ranges of the most frequently obtained values for selected indices. A standard 75 g oral glucose tolerance test was carried out in 1156 subjects from a Caucasian rural population with no previous evidence of diabetes or other dysglycemias. Insulin resistance/sensitivity indices (HOMA-IR, HOMA-IR2, ISI Cederholm, and ISI Matsuda) were calculated. The 75th percentile value as the cut-off point to define IR corresponded with a HOMA-IR of 2.29, a HOMA-IR2 of 1.21, a 25th percentile for ISI Cederholm, and ISI Matsuda of 57 and 5.0, respectively. For the first time, the cut-off points for selected indices and their most frequently obtained values were established for groups of subjects as defined by glucose homeostasis and BMI. Thus, insulin-resistant subjects can be identified using this simple approach. PMID:16804799

  17. Anesthesia with propofol induces insulin resistance systemically in skeletal and cardiac muscles and liver of rats

    SciTech Connect

    Yasuda, Yoshikazu; Fukushima, Yuji; Kaneki, Masao; Martyn, J.A. Jeevendra

    2013-02-01

    Highlights: ► Propofol, as a model anesthetic drug, induced whole body insulin resistance. ► Propofol anesthesia decreased glucose infusion rate to maintain euglycemia. ► Propofol decreased insulin-mediated glucose uptake in skeletal and cardiac muscles. ► Propofol increased hepatic glucose output confirming hepatic insulin resistance. -- Abstract: Hyperglycemia together with hepatic and muscle insulin resistance are common features in critically ill patients, and these changes are associated with enhanced inflammatory response, increased susceptibility to infection, muscle wasting, and worsened prognosis. Tight blood glucose control by intensive insulin treatment may reduce the morbidity and mortality in intensive care units. Although some anesthetics have been shown to cause insulin resistance, it remains unknown how and in which tissues insulin resistance is induced by anesthetics. Moreover, the effects of propofol, a clinically relevant intravenous anesthetic, also used in the intensive care unit for sedation, on insulin sensitivity have not yet been investigated. Euglycemic hyperinsulinemic clamp study was performed in rats anesthetized with propofol and conscious unrestrained rats. To evaluate glucose uptake in tissues and hepatic glucose output [{sup 3}H]glucose and 2-deoxy[{sup 14}C]glucose were infused during the clamp study. Anesthesia with propofol induced a marked whole-body insulin resistance compared with conscious rats, as reflected by significantly decreased glucose infusion rate to maintain euglycemia. Insulin-stimulated tissue glucose uptake was decreased in skeletal muscle and heart, and hepatic glucose output was increased in propofol anesthetized rats. Anesthesia with propofol induces systemic insulin resistance along with decreases in insulin-stimulated glucose uptake in skeletal and heart muscle and attenuation of the insulin-mediated suppression of hepatic glucose output in rats.

  18. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome

    PubMed Central

    Kadowaki, Takashi; Yamauchi, Toshimasa; Kubota, Naoto; Hara, Kazuo; Ueki, Kohjiro; Tobe, Kazuyuki

    2006-01-01

    Adiponectin is an adipokine that is specifically and abundantly expressed in adipose tissue and directly sensitizes the body to insulin. Hypoadiponectinemia, caused by interactions of genetic factors such as SNPs in the Adiponectin gene and environmental factors causing obesity, appears to play an important causal role in insulin resistance, type 2 diabetes, and the metabolic syndrome, which are linked to obesity. The adiponectin receptors, AdipoR1 and AdipoR2, which mediate the antidiabetic metabolic actions of adiponectin, have been cloned and are downregulated in obesity-linked insulin resistance. Upregulation of adiponectin is a partial cause of the insulin-sensitizing and antidiabetic actions of thiazolidinediones. Therefore, adiponectin and adiponectin receptors represent potential versatile therapeutic targets to combat obesity-linked diseases characterized by insulin resistance. This Review describes the pathophysiology of adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. PMID:16823476

  19. TM-25659-Induced Activation of FGF21 Level Decreases Insulin Resistance and Inflammation in Skeletal Muscle via GCN2 Pathways

    PubMed Central

    Jung, Jong Gab; Yi, Sang-A; Choi, Sung-E; Kang, Yup; Kim, Tae Ho; Jeon, Ja Young; Bae, Myung Ae; Ahn, Jin Hee; Jeong, Hana; Hwang, Eun Sook; Lee, Kwan-Woo

    2015-01-01

    The TAZ activator 2-butyl-5-methyl-6-(pyridine-3-yl)-3-[2′-(1H-tetrazole-5-yl)-biphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine] (TM-25659) inhibits adipocyte differentiation by interacting with peroxisome proliferator-activated receptor gamma. TM-25659 was previously shown to decrease weight gain in a high fat (HF) diet-induced obesity (DIO) mouse model. However, the fundamental mechanisms underlying the effects of TM-25659 remain unknown. Therefore, we investigated the effects of TM-25659 on skeletal muscle functions in C2 myotubes and C57BL/6J mice. We studied the molecular mechanisms underlying the contribution of TM-25659 to palmitate (PA)-induced insulin resistance in C2 myotubes. TM-25659 improved PA-induced insulin resistance and inflammation in C2 myotubes. In addition, TM-25659 increased FGF21 mRNA expression, protein levels, and FGF21 secretion in C2 myotubes via activation of GCN2 pathways (GCN2-phosphoeIF2α-ATF4 and FGF21). This beneficial effect of TM-25659 was diminished by FGF21 siRNA. C57BL/6J mice were fed a HF diet for 30 weeks. The HF-diet group was randomly divided into two groups for the next 14 days: the HF-diet and HF-diet + TM-25659 groups. The HF diet + TM-25659-treated mice showed improvements in their fasting blood glucose levels, insulin sensitivity, insulin-stimulated Akt phosphorylation, and inflammation, but neither body weight nor food intake was affected. The HF diet + TM-25659-treated mice also exhibited increased expression of both FGF21 mRNA and protein. These data indicate that TM-25659 may be beneficial for treating insulin resistance by inducing FGF21 in models of PA-induced insulin resistance and HF diet-induced insulin resistance. PMID:26537193

  20. Myotubes derived from human-induced pluripotent stem cells mirror in vivo insulin resistance.

    PubMed

    Iovino, Salvatore; Burkart, Alison M; Warren, Laura; Patti, Mary Elizabeth; Kahn, C Ronald

    2016-02-16

    Induced pluripotent stem cells (iPS cells) represent a unique tool for the study of the pathophysiology of human disease, because these cells can be differentiated into multiple cell types in vitro and used to generate patient- and tissue-specific disease models. Given the critical role for skeletal muscle insulin resistance in whole-body glucose metabolism and type 2 diabetes, we have created a novel cellular model of human muscle insulin resistance by differentiating iPS cells from individuals with mutations in the insulin receptor (IR-Mut) into functional myotubes and characterizing their response to insulin in comparison with controls. Morphologically, IR-Mut cells differentiated normally, but had delayed expression of some muscle differentiation-related genes. Most importantly, whereas control iPS-derived myotubes exhibited in vitro responses similar to primary differentiated human myoblasts, IR-Mut myotubes demonstrated severe impairment in insulin signaling and insulin-stimulated 2-deoxyglucose uptake and glycogen synthesis. Transcriptional regulation was also perturbed in IR-Mut myotubes with reduced insulin-stimulated expression of metabolic and early growth response genes. Thus, iPS-derived myotubes from individuals with genetically determined insulin resistance demonstrate many of the defects observed in vivo in insulin-resistant skeletal muscle and provide a new model to analyze the molecular impact of muscle insulin resistance. PMID:26831110

  1. Myotubes derived from human-induced pluripotent stem cells mirror in vivo insulin resistance.

    PubMed

    Iovino, Salvatore; Burkart, Alison M; Warren, Laura; Patti, Mary Elizabeth; Kahn, C Ronald

    2016-02-16

    Induced pluripotent stem cells (iPS cells) represent a unique tool for the study of the pathophysiology of human disease, because these cells can be differentiated into multiple cell types in vitro and used to generate patient- and tissue-specific disease models. Given the critical role for skeletal muscle insulin resistance in whole-body glucose metabolism and type 2 diabetes, we have created a novel cellular model of human muscle insulin resistance by differentiating iPS cells from individuals with mutations in the insulin receptor (IR-Mut) into functional myotubes and characterizing their response to insulin in comparison with controls. Morphologically, IR-Mut cells differentiated normally, but had delayed expression of some muscle differentiation-related genes. Most importantly, whereas control iPS-derived myotubes exhibited in vitro responses similar to primary differentiated human myoblasts, IR-Mut myotubes demonstrated severe impairment in insulin signaling and insulin-stimulated 2-deoxyglucose uptake and glycogen synthesis. Transcriptional regulation was also perturbed in IR-Mut myotubes with reduced insulin-stimulated expression of metabolic and early growth response genes. Thus, iPS-derived myotubes from individuals with genetically determined insulin resistance demonstrate many of the defects observed in vivo in insulin-resistant skeletal muscle and provide a new model to analyze the molecular impact of muscle insulin resistance.

  2. Beneficial insulin-sensitizing and vascular effects of S15261 in the insulin-resistant JCR:LA-cp rat.

    PubMed

    Russell, J C; Ravel, D; Pégorier, J P; Delrat, P; Jochemsen, R; O'Brien, S F; Kelly, S E; Davidge, S T; Brindley, D N

    2000-11-01

    S15261, a compound developed for the oral treatment of type II diabetes, is cleaved by esterases to the fragments Y415 and S15511. The aim was to define the insulin-sensitizing effects of S15261, the cleavage products, and troglitazone and metformin in the JCR:LA-cp rat, an animal model of the obesity/insulin resistance syndrome that exhibits an associated vasculopathy and cardiovascular disease. Treatment of the animals from 8 to 12 weeks of age with S15261 or S15511 resulted in reductions in food intake and body weights, whereas Y415 had no effect. Troglitazone caused a small increase in food intake (P <.05). Treatment with S15261 or S15511 decreased plasma insulin levels in fed rats and prevented the postprandial peak in insulin levels in a meal tolerance test. Y415 had no effect on insulin levels. Troglitazone halved the insulin response to the test meal, but metformin gave no improvement. S15261 decreased the expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase and stimulated the expression of acetyl-CoA carboxylase and acyl-CoA synthase. S15261 also reduced the expression of carnitine palmitoyltransferase I and hydroxymethyl-glutaryl-CoA synthase. S15261, but not troglitazone, reduced the exaggerated contractile response of mesenteric resistance vessels to norepinephrine, and increased the maximal nitric oxide-mediated relaxation. S15261, through S15511, increased insulin sensitivity, decreased insulin levels, and reduced the vasculopathy of the JCR:LA-cp rat. S15261 may thus offer effective treatment for the insulin resistance syndrome and its associated vascular complications.

  3. Features of Hepatic and Skeletal Muscle Insulin Resistance Unique to Type 1 Diabetes

    PubMed Central

    Howard, David; Schauer, Irene E.; Maahs, David M.; Snell-Bergeon, Janet K.; Eckel, Robert H.; Perreault, Leigh; Rewers, Marian

    2012-01-01

    Context: Type 1 diabetes is known to be a state of insulin resistance; however, the tissues involved in whole-body insulin resistance are less well known. It is unclear whether insulin resistance is due to glucose toxicity in the post-Diabetes Control and Complications Trial era of tighter glucose control. Objective: We performed this study to determine muscle and liver insulin sensitivity individuals with type 1 diabetes after overnight insulin infusion to lower fasting glucose concentration. Design, Patients, and Methods: Fifty subjects [25 controls without and 25 individuals with type 1 diabetes (diabetes duration 22.9 ± 1.7 yr, without known end organ damage] were frequency matched on age and body mass index by group and studied. After 3 d of dietary control and overnight insulin infusion to normalize glucose, we performed a three-stage hyperinsulinemic/euglycemic clamp infusing insulin at 4, 8, and 40 mU/m2 · min. Glucose metabolism was quantified using an infusion of [6,6-2H2]glucose. Hepatic insulin sensitivity was measured using the insulin IC50 for glucose rate of appearance (Ra), whereas muscle insulin sensitivity was measured using the glucose rate of disappearance during the highest insulin dose. Results: Throughout the study, glucose Ra was significantly greater in individuals compared with those without type 1 diabetes. The concentration of insulin required for 50% suppression of glucose Ra was 2-fold higher in subjects with type 1 diabetes. Glucose rate of disappearance was significantly lower in individuals with type 1 diabetes during the 8- and 40-mU/m2 · min stages. Conclusion: Insulin resistance in liver and skeletal muscle was a significant feature in type 1 diabetes. Nevertheless, the etiology of insulin resistance was not explained by body mass index, percentage fat, plasma lipids, visceral fat, and physical activity and was also not fully explained by hyperglycemia. PMID:22362823

  4. Genetic insulin resistance is a potent regulator of gene expression and proliferation in human iPS cells.

    PubMed

    Iovino, Salvatore; Burkart, Alison M; Kriauciunas, Kristina; Warren, Laura; Hughes, Katelyn J; Molla, Michael; Lee, Youn-Kyoung; Patti, Mary-Elizabeth; Kahn, C Ronald

    2014-12-01

    Insulin resistance is central to diabetes and metabolic syndrome. To define the consequences of genetic insulin resistance distinct from those secondary to cellular differentiation or in vivo regulation, we generated induced pluripotent stem cells (iPSCs) from individuals with insulin receptor mutations and age-appropriate control subjects and studied insulin signaling and gene expression compared with the fibroblasts from which they were derived. iPSCs from patients with genetic insulin resistance exhibited altered insulin signaling, paralleling that seen in the original fibroblasts. Insulin-stimulated expression of immediate early genes and proliferation were also potently reduced in insulin resistant iPSCs. Global gene expression analysis revealed marked differences in both insulin-resistant iPSCs and corresponding fibroblasts compared with control iPSCs and fibroblasts. Patterns of gene expression in patients with genetic insulin resistance were particularly distinct in the two cell types, indicating dependence on not only receptor activity but also the cellular context of the mutant insulin receptor. Thus, iPSCs provide a novel approach to define effects of genetically determined insulin resistance. This study demonstrates that effects of insulin resistance on gene expression are modified by cellular context and differentiation state. Moreover, altered insulin receptor signaling and insulin resistance can modify proliferation and function of pluripotent stem cell populations. PMID:25059784

  5. Large Size Cells in the Visceral Adipose Depot Predict Insulin Resistance in the Canine Model

    PubMed Central

    Kabir, Morvarid; Stefanovski, Darko; Hsu, Isabel R.; Iyer, Malini; Woolcott, Orison O.; Zheng, Dan; Catalano, Karyn J.; Chiu, Jenny D.; Kim, Stella P.; Harrison, Lisa N.; Ionut, Viorica; Lottati, Maya; Bergman, Richard N.; Richey, Joyce M.

    2015-01-01

    Adipocyte size plays a key role in the development of insulin resistance. We examined longitudinal changes in adipocyte size and distribution in visceral (VIS) and subcutaneous (SQ) fat during obesity-induced insulin resistance and after treatment with CB-1 receptor antagonist, rimonabant (RIM) in canines. We also examined whether adipocyte size and/or distribution is predictive of insulin resistance. Adipocyte morphology was assessed by direct microscopy and analysis of digital images in previously studied animals 6 weeks after high-fat diet (HFD) and 16 weeks of HFD + placebo (PL; n = 8) or HFD + RIM (1.25 mg/kg/day; n = 11). At 6 weeks, mean adipocyte diameter increased in both depots with a bimodal pattern only in VIS. Sixteen weeks of HFD+PL resulted in four normally distributed cell populations in VIS and a bimodal pattern in SQ. Multilevel mixed-effects linear regression with random-effects model of repeated measures showed that size combined with share of adipocytes >75 µm in VIS only was related to hepatic insulin resistance. VIS adipocytes >75 µm were predictive of whole body and hepatic insulin resistance. In contrast, there was no predictive power of SQ adipocytes >75 µm regarding insulin resistance. RIM prevented the formation of large cells, normalizing to pre-fat status in both depots. The appearance of hypertrophic adipocytes in VIS is a critical predictor of insulin resistance, supporting the deleterious effects of increased VIS adiposity in the pathogenesis of insulin resistance. PMID:21836643

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  7. Childhood wrist circumference is not a predictor of insulin resistance in adulthood.

    PubMed

    Watkins, Ashley N; Kelly, Aaron S; Prineas, Ronald J; Marlatt, Kara L; Dengel, Donald R; Sinaiko, Alan R; Moran, Antoinette; Steinberger, Julia

    2015-04-01

    We sought to determine whether childhood wrist circumference predicts insulin resistance in adulthood. Measures were taken in prepubertal children and then approximately 30 years later in the same subjects as adults. Our findings suggest that wrist circumference in childhood is not a predictor of insulin resistance in adulthood. PMID:25596104

  8. Evaluation of body weight, insulin resistance, leptin and adiponectin levels in premenopausal women with hyperprolactinemia.

    PubMed

    Atmaca, Aysegul; Bilgici, Birsen; Ecemis, Gulcin Cengiz; Tuncel, Ozgur Korhan

    2013-12-01

    The effects of hyperprolactinemia on metabolic parameters are not clear and a few data evaluating adiponectin levels in prolactinoma and idiopathic hyperprolactinemia exist. The aim of this study was to evaluate the effects of hyperprolactinemia on body weight, insulin resistance, beta cell function, and leptin and adiponectin levels in premenopausal women with hyperprolactinemia. Forty premenopausal women with prolactinoma or idiopathic hyperprolactinemia were compared to 41 age-matched healthy premenopausal women with regard to body weight, body mass index, waist and hip circumferences, waist to hip ratio, fasting plasma glucose, insulin levels, insulin resistance measured by homeostasis model assessment (HOMA)-insulin resistance index, beta cell function measured by HOMA-β index, leptin and adiponectin levels. Plasma insulin levels and HOMA indexes (both insulin resistance and beta indexes) were significantly higher in hyperprolactinemic women. The other parameters were similar between both groups. There was a positive correlation between prolactin levels and fasting plasma glucose in hyperprolactinemic women. The results of this study showed that high prolactin levels may be associated with hyperinsulinemia and insulin resistance in premenopausal women. This effect seems to be independent of body weight, leptin and adiponectin levels. High prolactin levels may directly stimulate insulin secretion from pancreas and directly cause hepatic and whole-body insulin resistance.

  9. Insulin resistance and response to antiviral therapy in chronic hepatitis C: mechanisms and management.

    PubMed

    del Campo, José A; López, Reyes Aparcero; Romero-Gómez, Manuel

    2010-01-01

    Insulin resistance has been found to be an independent factor predicting sustained response to peginterferon plus ribavirin in patients with chronic hepatitis C. Insulin resistance seems to be involved in decreased sensitivity to interferon and could block interferon intracellular signaling. Insulin resistance promotes steatosis and fibrosis progression, induces pro-inflammatory cytokine secretion and increases adipose tissue, decreasing interferon availability. Moreover, suppressor of cytokines 3 and protein tyrosine-phosphatase seems to be able to block interferon and insulin signaling, building a feed-forward loop. Insulin resistance can be treated with exercise, diet or through the use of drugs that improve insulin sensitivity, like biguanides or glitazones. A recent controlled, randomized, double-blind clinical trial (TRIC-1) examined the effect of adding metformin to standard therapy in the treatment of hepatitis C. This study demonstrated that women infected with hepatitis C virus genotype 1 and HOMA >2 treated with metformin showed a greater drop in viral load during the first 12 weeks and a doubled sustained viral response in comparison with females receiving placebo. Pioglitazone has been used in previous nonresponders and naïve patients with disappointing results in two pilot trials. The mechanisms by which the virus promotes insulin resistance seems to be genotype-dependent and could explain, at least in part, the discrepancies between insulin sensitizers. Insulin resistance is a new target in the challenging management of chronic hepatitis C. PMID:20460925

  10. Role of Protein Farnesylation in Burn-Induced Metabolic Derangements and Insulin Resistance in Mouse Skeletal Muscle

    PubMed Central

    Tanaka, Tomokazu; Kramer, Joshua; Yu, Yong-Ming; Fischman, Alan J.; Martyn, J. A. Jeevendra; Tompkins, Ronald G.; Kaneki, Masao

    2015-01-01

    Objective Metabolic derangements, including insulin resistance and hyperlactatemia, are a major complication of major trauma (e.g., burn injury) and affect the prognosis of burn patients. Protein farnesylation, a posttranslational lipid modification of cysteine residues, has been emerging as a potential component of inflammatory response in sepsis. However, farnesylation has not yet been studied in major trauma. To study a role of farnesylation in burn-induced metabolic aberration, we examined the effects of farnesyltransferase (FTase) inhibitor, FTI-277, on burn-induced insulin resistance and metabolic alterations in mouse skeletal muscle. Methods A full thickness burn (30% total body surface area) was produced under anesthesia in male C57BL/6 mice at 8 weeks of age. After the mice were treated with FTI-277 (5 mg/kg/day, IP) or vehicle for 3 days, muscle insulin signaling, metabolic alterations and inflammatory gene expression were evaluated. Results Burn increased FTase expression and farnesylated proteins in mouse muscle compared with sham-burn at 3 days after burn. Simultaneously, insulin-stimulated phosphorylation of insulin receptor (IR), insulin receptor substrate (IRS)-1, Akt and GSK-3β was decreased. Protein expression of PTP-1B (a negative regulator of IR-IRS-1 signaling), PTEN (a negative regulator of Akt-mediated signaling), protein degradation and lactate release by muscle, and plasma lactate levels were increased by burn. Burn-induced impaired insulin signaling and metabolic dysfunction were associated with increased inflammatory gene expression. These burn-induced alterations were reversed or ameliorated by FTI-277. Conclusions Our data demonstrate that burn increased FTase expression and protein farnesylation along with insulin resistance, metabolic alterations and inflammatory response in mouse skeletal muscle, all of which were prevented by FTI-277 treatment. These results indicate that increased protein farnesylation plays a pivotal role in burn

  11. Identification of nuclear hormone receptor pathways causing insulin resistance by transcriptional and epigenomic analysis.

    PubMed

    Kang, Sona; Tsai, Linus T; Zhou, Yiming; Evertts, Adam; Xu, Su; Griffin, Michael J; Issner, Robbyn; Whitton, Holly J; Garcia, Benjamin A; Epstein, Charles B; Mikkelsen, Tarjei S; Rosen, Evan D

    2015-01-01

    Insulin resistance is a cardinal feature of Type 2 diabetes (T2D) and a frequent complication of multiple clinical conditions, including obesity, ageing and steroid use, among others. How such a panoply of insults can result in a common phenotype is incompletely understood. Furthermore, very little is known about the transcriptional and epigenetic basis of this disorder, despite evidence that such pathways are likely to play a fundamental role. Here, we compare cell autonomous models of insulin resistance induced by the cytokine tumour necrosis factor-α or by the steroid dexamethasone to construct detailed transcriptional and epigenomic maps associated with cellular insulin resistance. These data predict that the glucocorticoid receptor and vitamin D receptor are common mediators of insulin resistance, which we validate using gain- and loss-of-function studies. These studies define a common transcriptional and epigenomic signature in cellular insulin resistance enabling the identification of pathogenic mechanisms. PMID:25503565

  12. An Immunomodulatory Device Improves Insulin Resistance in Obese Porcine Model of Metabolic Syndrome

    PubMed Central

    Westover, Angela J.

    2016-01-01

    Obesity is associated with tissue inflammation which is a crucial etiology of insulin resistance. This inflammation centers around circulating monocytes which form proinflammatory adipose tissue macrophages (ATM). Specific approaches targeting monocytes/ATM may improve insulin resistance without the adverse side effects of generalized immunosuppression. In this regard, a biomimetic membrane leukocyte processing device, called the selective cytopheretic device (SCD), was evaluated in an Ossabaw miniature swine model of insulin resistance with metabolic syndrome. Treatment with the SCD in this porcine model demonstrated a decline in circulating neutrophil activation parameters and monocyte counts. These changes were associated with improvements in insulin resistance as determined with intravenous glucose tolerance testing. These improvements were also reflected in lowering of homeostatic model assessment- (HOMA-) insulin resistant (IR) scores for up to 2 weeks after SCD therapy. These results allow for the planning of first-in-man studies in obese type 2 diabetic patients.

  13. Brain Insulin Resistance at the Crossroads of Metabolic and Cognitive Disorders in Humans.

    PubMed

    Kullmann, Stephanie; Heni, Martin; Hallschmid, Manfred; Fritsche, Andreas; Preissl, Hubert; Häring, Hans-Ulrich

    2016-10-01

    Ever since the brain was identified as an insulin-sensitive organ, evidence has rapidly accumulated that insulin action in the brain produces multiple behavioral and metabolic effects, influencing eating behavior, peripheral metabolism, and cognition. Disturbances in brain insulin action can be observed in obesity and type 2 diabetes (T2D), as well as in aging and dementia. Decreases in insulin sensitivity of central nervous pathways, i.e., brain insulin resistance, may therefore constitute a joint pathological feature of metabolic and cognitive dysfunctions. Modern neuroimaging methods have provided new means of probing brain insulin action, revealing the influence of insulin on both global and regional brain function. In this review, we highlight recent findings on brain insulin action in humans and its impact on metabolism and cognition. Furthermore, we elaborate on the most prominent factors associated with brain insulin resistance, i.e., obesity, T2D, genes, maternal metabolism, normal aging, inflammation, and dementia, and on their roles regarding causes and consequences of brain insulin resistance. We also describe the beneficial effects of enhanced brain insulin signaling on human eating behavior and cognition and discuss potential applications in the treatment of metabolic and cognitive disorders.

  14. Chronic cadmium exposure in rats produces pancreatic impairment and insulin resistance in multiple peripheral tissues.

    PubMed

    Treviño, Samuel; Waalkes, Michael P; Flores Hernández, José Angel; León-Chavez, Bertha Alicia; Aguilar-Alonso, Patricia; Brambila, Eduardo

    2015-10-01

    Previous studies have linked cadmium exposure to disturbances in carbohydrate and lipid metabolism. In this study we investigate the effects in Wistar rats of an oral cadmium exposure in drinking water on carbohydrates, lipids and insulin release. Also, using mathematical models we studied the effect of cadmium on insulin resistance and sensitivity in liver, muscle, adipose and cardiovascular tissue. Cadmium exposure induced hyperglycemia, increased insulin release after a glucose load, and caused increases in serum triglycerides, cholesterol, LDL-C and VLDL-C, and a decrease of HDL-C. In addition, there was an accumulation of cadmium in pancreas and an increase of insulin. After exposure, HOMA-IR was increased, while the HOMA-S%, QUICKI and Matsuda-DeFronzo indexes showed decreases. A decrease of insulin sensitivity was shown in muscle and liver. Additionally, cadmium increases insulin resistance in the liver, adipose tissue and cardiovascular system. Finally, β-cell functioning was evaluated by HOMA-B% index and insulin disposition index, which were decreased, while insulin generation index increased. In conclusion, cadmium increases insulin release, induces hyperglycemia and alters lipid metabolism. These changes likely occur as a consequence of reduced sensitivity and increased insulin resistance in multiple insulin-dependent and non-dependent tissues, producing a biochemical phenotype similar to metabolic syndrome and diabetes.

  15. High-fat diet induces hepatic insulin resistance and impairment of synaptic plasticity.

    PubMed

    Liu, Zhigang; Patil, Ishan Y; Jiang, Tianyi; Sancheti, Harsh; Walsh, John P; Stiles, Bangyan L; Yin, Fei; Cadenas, Enrique

    2015-01-01

    High-fat diet (HFD)-induced obesity is associated with insulin resistance, which may affect brain synaptic plasticity through impairment of insulin-sensitive processes underlying neuronal survival, learning, and memory. The experimental model consisted of 3 month-old C57BL/6J mice fed either a normal chow diet (control group) or a HFD (60% of calorie from fat; HFD group) for 12 weeks. This model was characterized as a function of time in terms of body weight, fasting blood glucose and insulin levels, HOMA-IR values, and plasma triglycerides. IRS-1/Akt pathway was assessed in primary hepatocytes and brain homogenates. The effect of HFD in brain was assessed by electrophysiology, input/output responses and long-term potentiation. HFD-fed mice exhibited a significant increase in body weight, higher fasting glucose- and insulin levels in plasma, lower glucose tolerance, and higher HOMA-IR values. In liver, HFD elicited (a) a significant decrease of insulin receptor substrate (IRS-1) phosphorylation on Tyr608 and increase of Ser307 phosphorylation, indicative of IRS-1 inactivation; (b) these changes were accompanied by inflammatory responses in terms of increases in the expression of NFκB and iNOS and activation of the MAP kinases p38 and JNK; (c) primary hepatocytes from mice fed a HFD showed decreased cellular oxygen consumption rates (indicative of mitochondrial functional impairment); this can be ascribed partly to a decreased expression of PGC1α and mitochondrial biogenesis. In brain, HFD feeding elicited (a) an inactivation of the IRS-1 and, consequentially, (b) a decreased expression and plasma membrane localization of the insulin-sensitive neuronal glucose transporters GLUT3/GLUT4; (c) a suppression of the ERK/CREB pathway, and (d) a substantial decrease in long-term potentiation in the CA1 region of hippocampus (indicative of impaired synaptic plasticity). It may be surmised that 12 weeks fed with HFD induce a systemic insulin resistance that impacts

  16. Retinol Binding Protein: Marker for Insulin Resistance and Inflammation Postburn?

    PubMed Central

    Kraft, Robert; Herndon, David N.; Kulp, Gabriela A.; Mecott, Gabriel A.; Trentzsch, Heiko; Jeschke, Marc G.

    2013-01-01

    Introduction Burn injury leads to vast changes in both metabolic and inflammatory responses and is associated with increased morbidity and mortality. Insulin resistance (IR) and hyperglycemia are major components of the hypermetabolic response found in burn-injured patients and subsequently contribute to adverse outcomes. Studies have shown that increased systemic retinol binding protein (RBP) levels are associated with IR and hyperinflammation in diabetic and obese patients. The aim of this study was to determine RBP profiles and to test the hypothesis that elevated RBP levels are associated with both IR and the inflammatory response in burned patients. Methods RBP was measured in 372 patients during the acute stay postburn. Patients’ demographics, glucose levels, and insulin administration were recorded. Cytokines, hormones, plasma proteins, and organ markers were measured. The average of all measurements of RBP (2.1 mg/dL) was used to divide patients into high and low groups. Statistical analysis was performed by Student t test. Statistical significance was accepted at P < .05. Results Fifty-one patients (high group) had elevated RBP levels during acute hospitalization and demonstrated a significant higher incidence of multiorgan failure, sepsis, and mortality (P < .05). Moreover, in the high group, a significant increase of IR, inflammatory cytokines, and catabolic and organ-specific markers were detected (P < .05). Conclusions Increased RBP levels postburn correlate with increased IR, inflammatory and catabolic responses, incidence of multiorgan failure, and mortality. RBP may be a novel biomarker to monitor these detrimental responses postburn. PMID:22042048

  17. Intergenerational transmission of insulin resistance and type 2 diabetes.

    PubMed

    Poston, Lucilla

    2011-07-01

    Studies in women with type 1 or type 2 diabetes mellitus (DM) and their children suggest that the in utero 'diabetic' environment in which the fetus develops can increase the risk of diabetes in the child, in a non-genetic but heritable fashion. Studies in rodents provide strong evidence for maternal transmission of diabetes, but are based primarily on a model type 1 DM and there is no standard animal model of type 2 DM in pregnancy or of gestational diabetes mellitus (GDM), although those reported uniformly show glucose intolerance in the offspring. Rodent models of diet-induced obesity have relevance to current upward trends in maternal obesity and GDM, although maternal glucose homeostasis is not always assessed and elements of the diet may have an independent influence. The mechanisms by which maternal type 2DM evokes a higher risk of the disorder in the offspring are likely to result from epigenetic modification in early life of pathways of pancreatic β cells and of liver and muscle insulin signalling pathways. Also, epigenetic processes associated with hormonal imbalance may lead to irreversible 'reordering' of hypothalamic neural networks in fetal/neonatal life, permanently alter energy balance and lead to obesity with associated insulin resistance.

  18. Depletion of Fat Tregs Prevents Age-Associated Insulin Resistance

    PubMed Central

    Bapat, Sagar P.; Suh, Jae Myoung; Fang, Sungsoon; Liu, Sihao; Zhang, Yang; Cheng, Albert; Zhou, Carmen; Liang, Yuqiong; LeBlanc, Mathias; Liddle, Christopher; Atkins, Annette R.; Yu, Ruth T.; Downes, Michael; Evans, Ronald M.; Zheng, Ye

    2015-01-01

    Age-associated insulin resistance (IR) and obesity-associated IR are two physiologically distinct forms of adult onset diabetes. While macrophage-driven inflammation is a core driver of obesity-associated IR1–6, the underlying mechanisms of the obesity-independent yet highly prevalent age-associated IR7 are largely unexplored. Comparative adipo-immune profiling (AIP) reveals that fat-resident regulatory T cells, termed fTregs, accumulate in adipose tissue as a function of age, but not obesity. Supporting the existence of two distinct mechanisms underlying IR, mice deficient in fTregs are protected against age-associated IR, yet remain susceptible to obesity-associated IR and metabolic disease. In contrast, selective depletion of fTregs via anti-ST2 antibody treatment increases adipose tissue insulin sensitivity. These findings establish that distinct immune cell populations within adipose tissue underlie aging- and obesity-associated IR and implicate fTregs as adipo-immune drivers and potential therapeutic targets in the treatment of age-associated IR. PMID:26580014

  19. Independent effects of obesity and insulin resistance on postprandial thermogenesis in men.

    PubMed Central

    Segal, K R; Albu, J; Chun, A; Edano, A; Legaspi, B; Pi-Sunyer, F X

    1992-01-01

    The putative blunted thermogenesis in obesity may be related to insulin resistance, but insulin sensitivity and obesity are potentially confounding factors. To determine the independent effects of obesity and insulin resistance on the thermic effect of food, at rest and after exercise, lean and obese men were matched at two levels of insulin sensitivity determined by insulin-stimulated glucose disposal (milligrams per kilogram fat-free mass [FFM] per minute) during the euglycemic, hyperinsulinemic (40 mU/m2.min) clamp: 5.4 mg/kg FFM for the lean and obese groups with low insulin sensitivity, and 8.1 mg/kg FFM for the groups with high insulin sensitivity. The two lean groups were matched for percent fat (approximately 15 +/- 1% fat), as were the two obese groups (approximately 33 +/- 2% fat). Energy expenditure was measured for 3 h in the fasting state and for 3 h after a 720-kcal mixed meal, each at rest and immediately after 1 h of cycling at 100 W. The thermic effect of food (TEF) was calculated as the postprandial minus fasting energy expenditure (kcal/3 h) during rest and after exercise. During rest, TEF was blunted by both obesity (24 +/- 5 and 34 +/- 6 kcal/3 h for obese groups with low and high insulin sensitivity vs. 56 +/- 6 and 74 +/- 6 kcal/3 h for the lean groups with low and high insulin sensitivity; P less than 0.01 lean vs. obese) and insulin resistance (insulin-resistant less than insulin-sensitive, at both levels of obesity; P less than 0.01). After exercise, TEF was also impaired in the obese (47 +/- 6 and 44 +/- 5 kcal/3 h for the insulin-resistant and -sensitive groups) and in the lean insulin-resistant (55 +/- 5 kcal/3 h), compared with the lean insulin-sensitive men (71 +/- 3 kcal/3 h), P less than 0.01. Compared with rest, TEF after exercise was improved, but not normalized, in both obese groups (P less than 0.05), but unchanged in the lean groups. These results suggest that both insulin resistance and obesity are independently associated

  20. Non-invasive cell type selective in vivo monitoring of insulin resistance dynamics

    PubMed Central

    Paschen, Meike; Moede, Tilo; Leibiger, Barbara; Jacob, Stefan; Bryzgalova, Galyna; Leibiger, Ingo B.; Berggren, Per-Olof

    2016-01-01

    Insulin resistance contributes to the development of cardio-vascular disease and diabetes. An important but unresolved task is to study the dynamics of insulin resistance in selective cell types of insulin target tissues in vivo. Here we present a novel technique to monitor insulin resistance dynamics non-invasively and longitudinally in vivo in a cell type-specific manner, exemplified by the pancreatic β-cell situated within the micro-organ the islet of Langerhans. We utilize the anterior chamber of the eye (ACE) as a transplantation site and the cornea as a natural body-window to study the development and reversibility of insulin resistance. Engrafted islets in the ACE that express a FoxO1-GFP-based biosensor in their β-cells, report on insulin resistance measured by fluorescence microscopy at single-cell resolution in the living mouse. This technique allows monitoring of cell type specific insulin sensitivity/resistance in real-time in the context of whole body insulin resistance during progression and intervention of disease. PMID:26899548

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

    PubMed Central

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

    2015-01-01

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

  2. 4-Hydroxyisoleucine improves insulin resistance in HepG2 cells by decreasing TNF-α and regulating the expression of insulin signal transduction proteins.

    PubMed

    Gao, Feng; Jian, Liumeng; Zafar, Mohammad Ishraq; Du, Wen; Cai, Qin; Shafqat, Raja Adeel; Lu, Furong

    2015-11-01

    Previous studies have indicated that 4‑hydroxyisoleucine (4‑HIL) improves insulin resistance, however, the underlying mechanisms remain to be elucidated. In the present study, the molecular mechanisms underlying how 4‑HIL improves insulin resistance in hepatocytes were examined. HepG2 cells were co‑cultured with insulin and a high glucose concentration to obtain insulin‑resistant (IR) HepG2 cells. Insulin sensitivity was determined by measuring the glucose uptake rate. The IR HepG2 cells were treated with different concentrations of 4‑HIL to determine its effect on IR Hep2 cells. The levels of tumor necrosis factor‑α (TNF‑α) were measured by an enzyme‑linked immunosorbent assay and protein levels of TNF‑α converting enzyme (TACE)/tissue inhibitor of metalloproteinase 3 (TIMP3), insulin receptor substrate (IRS)‑1, IRS‑2, phosphorylated (p)‑IRS‑1 (Ser307) and glucose transporter type 4 (GLUT4) were measured by western blot analysis. The results of the present study demonstrated that insulin‑induced glucose uptake was reduced in IR HepG2 cells; however, this reduction was reversed by 4‑HIL in a dose‑dependent manner. 4‑HIL achieved this effect by downregulating the expression of TNF‑α and TACE, and upregulating the expression of TIMP3 in IR HepG2 cells. In addition, 4‑HIL increased the expression of the insulin transduction regulators IRS‑1 and GLUT4, and decreased the expression of p‑IRS‑1 (Ser307), without affecting the expression of IRS‑2. The present study suggests that 4‑HIL improved insulin resistance in HepG2 cells by the following mechanisms: 4‑HIL reduced TNF‑α levels by affecting the protein expression of the TACE/TIMP3 system and 4‑HIL stimulated the expression of IRS‑1 and GLUT4, but inhibited the expression of p‑IRS‑1 (Ser307). PMID:26352439

  3. Possible role of cytosolic free calcium concentrations in mediating insulin resistance of obesity and hyperinsulinemia.

    PubMed Central

    Draznin, B; Sussman, K E; Eckel, R H; Kao, M; Yost, T; Sherman, N A

    1988-01-01

    Insulin- and glyburide-stimulated changes in cytosolic free calcium concentrations [( Ca2+]i) were studied in gluteal adipocytes obtained from six obese women (139 +/- 3% ideal body wt) and six healthy, normal weight age- and sex-matched controls. Biopsies were performed after an overnight fast and twice (at 3 and 6 h) during an insulin infusion (40 mU/m2 per min) (euglycemic clamp). In adipocytes obtained from normal subjects before insulin infusion, insulin (10 ng/ml) increased [Ca2+]i from 146 +/- 26 nM to 391 +/- 66 nM. Similar increases were evoked by 2 microM glyburide (329 +/- 41 nM). After 3 h of insulin infusion, basal [Ca2+]i rose to 234 +/- 21 nM, but the responses to insulin and glyburide were completely abolished. In vitro insulin-stimulated 2-deoxyglucose uptake was reduced by insulin and glucose infusion (25% stimulation before infusion, 5.4% at 3 h, and 0.85% at 6 h of infusion). In obese patients, basal adipocyte [Ca2+]i was increased (203 +/- 14 nM, P less than 0.05 vs. normals). The [Ca2+]i response demonstrated resistance to insulin (230 +/- 23 nM) and glyburide (249 +/- 19 nM) stimulation. Continuous insulin infusion increased basal [Ca2+]i (244 +/- 24 nM) and there was no response to either insulin or glyburide at 3 and 6 h of study. Rat adipocytes were preincubated with 1-10 mM glucose and 10 ng/ml insulin for 24 h. Measurements of 2-deoxyglucose uptake demonstrated insulin resistance in these cells. Under these experimental conditions, increased levels of [Ca2+]i that were no longer responsive to insulin were demonstrated. Verapamil in the preincubation medium prevented the development of insulin resistance. PMID:3143744

  4. NOD2 activation induces muscle cell-autonomous innate immune responses and insulin resistance.

    PubMed

    Tamrakar, Akhilesh K; Schertzer, Jonathan D; Chiu, Tim T; Foley, Kevin P; Bilan, Philip J; Philpott, Dana J; Klip, Amira

    2010-12-01

    Insulin resistance is associated with chronic low-grade inflammation in vivo, largely mediated by activated innate immune cells. Cytokines and pathogen-derived ligands of surface toll-like receptors can directly cause insulin resistance in muscle cells. However, it is not known if intracellular pathogen sensors can, on their own, provoke insulin resistance. Here, we show that the cytosolic pattern recognition receptors nucleotide-binding oligomerization domain-containing protein (NOD)1 and NOD2 are expressed in immune and metabolic tissues and hypothesize that their activation in muscle cells would result in cell-autonomous responses leading to insulin resistance. Bacterial peptidoglycan motifs that selectively activate NOD2 were directly administered to L6- GLUT4myc myotubes in culture. Within 3 h, insulin resistance arose, characterized by reductions in each insulin-stimulated glucose uptake, GLUT4 translocation, Akt Ser(473) phosphorylation, and insulin receptor substrate 1 tyrosine phosphorylation. Muscle cell-autonomous responses to NOD2 ligand included activation of the stress/inflammation markers c-Jun N-terminal kinase, ERK1/2, p38 MAPK, degradation of inhibitor of κBα, and production of proinflammatory cytokines. These results show that NOD2 alone is capable of acutely inducing insulin resistance within muscle cells, possibly by activating endogenous inflammatory signals and/or through cytokine production, curbing upstream insulin signals. NOD2 is hence a new inflammation target connected to insulin resistance, and this link occurs without the need of additional contributing cell types. This study provides supporting evidence for the integration of innate immune and metabolic responses through the involvement of NOD proteins and suggests the possible participation of cell autonomous immune responses in the development of insulin resistance in skeletal muscle, the major depot for postprandial glucose utilization.

  5. Does Inflammation Mediate the Association Between Obesity and Insulin Resistance?

    PubMed

    Adabimohazab, Razieh; Garfinkel, Amanda; Milam, Emily C; Frosch, Olivia; Mangone, Alexander; Convit, Antonio

    2016-06-01

    In adult obesity, low-grade systemic inflammation is considered an important step in the pathogenesis of insulin resistance (IR). The association between obesity and inflammation is less well established in adolescents. Here, we ascertain the importance of inflammation in IR among obese adolescents by utilizing either random forest (RF) classification or mediation analysis approaches. The inflammation balance score, composed of eight pro- and anti-inflammatory makers, as well as most of the individual inflammatory markers differed significantly between lean and overweight/obese. In contrast, adiponectin was the only individual marker selected as a predictor of IR by RF, and the balance score only revealed a medium-to-low importance score. Neither adiponectin nor the inflammation balance score was found to mediate the relationship between obesity and IR. These findings do not support the premise that low-grade systemic inflammation is a key for the expression of IR in the human. Prospective longitudinal studies should confirm these findings.

  6. Normoglycemic Diabetic Nephropathy: The Role of Insulin Resistance

    PubMed Central

    Filippone, Edward J.; Gupta, Astha; Farber, John L.

    2014-01-01

    The pathophysiology of diabetic nephropathy (DN) is complex and incompletely understood. Whereas hyperglycemia is clearly important, the role of insulin resistance (IR) is increasingly recognized. We present the case of a normotensive non-smoking obese woman with nephrotic syndrome who was found to have DN by biopsy. All measures of glucose metabolism, including fasting glucose, glycosylated hemoglobin, and oral glucose tolerance testing, were repeatedly normal with little exception. IR was documented, however, based on the presence of the metabolic syndrome and an elevated homeostasis model assessment of IR. We posit that this IR is central to the pathogenesis of our patient's lesion, and this may explain other cases of DN with normoglycemia. The literature supporting this concept is discussed. PMID:25076962

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

    PubMed

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

    2006-02-01

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

  8. Predictability of childhood adiposity and insulin for developing insulin resistance syndrome (syndrome X) in young adulthood: the Bogalusa Heart Study.

    PubMed

    Srinivasan, Sathanur R; Myers, Leann; Berenson, Gerald S

    2002-01-01

    The occurrence of insulin resistance syndrome (syndrome X) is common in the general population. However, information is scant on the childhood predictors of syndrome X. This study examined the relative contribution of childhood adiposity and insulin to the adulthood risk of developing syndrome X in a biracial (black-white) community-based longitudinal cohort (n = 745; baseline age, 8-17 years; mean +/- SD follow-up period, 11.6 +/- 3.4 years). The four criterion risk variables considered were the highest quartile (specific for age, race, sex, and study year) of 1) BMI, 2) fasting insulin, 3) systolic or mean arterial blood pressure, and 4) total cholesterol to HDL cholesterol ratio or triglycerides to HDL cholesterol ratio. Clustering was defined as the combination of all four risk variables. In addition to the criterion risk variables, clustered adults had adverse levels of total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, diastolic blood pressure, and glucose compared with those who did not cluster (P < 0.001). Childhood variables, except glucose, showed adverse trends with increasing number of criterion risk variables present in adulthood (P for trend, 0.01-0.0001). The proportion of individuals who developed clustering as adults increased across childhood BMI (P for trend <0.0001) and insulin (P for trend <0.01) quartiles. The relationship to childhood BMI remained significant even after adjusting for childhood insulin. In contrast, corresponding association with childhood insulin disappeared after adjusting for childhood BMI. In a logistic regression model, childhood BMI and insulin were significant predictors of adulthood clustering, with BMI being the strongest and showing a curvilinear relationship. Using an insulin resistance index instead of insulin did not change the above findings. These results indicate that childhood obesity is a powerful predictor of development of syndrome X and underscore the importance of weight control early in

  9. IL-1 family members in the pathogenesis and treatment of metabolic disease: Focus on adipose tissue inflammation and insulin resistance

    PubMed Central

    Ballak, Dov B; Stienstra, Rinke; Tack, Cees J; Dinarello, Charles A; van Diepen, Janna A

    2015-01-01

    Obesity is characterized by a chronic, low-grade inflammation that contributes to the development of insulin resistance and type 2 diabetes. Cytokines and chemokines produced by immunocompetent cells influence local as well as systemic inflammation and are therefore critical contributors to the pathogenesis of type 2 diabetes. Hence, cytokines that modulate inflammatory responses are emerging as potential targets for intervention and treatment of the metabolic consequences of obesity. The interleukin-1 (IL-1) family of cytokines and receptors are key mediators of innate inflammatory responses and exhibit both pro- and anti-inflammatory functions. During the last decades, mechanistic insights into how the IL-1 family affects the initiation and progression of obesity-induced insulin resistance have increased significantly. Here, we review the current knowledge and understanding, with emphasis on the therapeutic potential of individual members of the IL-1 family of cytokines for improving insulin sensitivity in patients with diabetes. PMID:26194067

  10. Endothelin-1 exacerbates development of hypertension and atherosclerosis in modest insulin resistant syndrome

    SciTech Connect

    Lin, Yan-Jie; Juan, Chi-Chang; Kwok, Ching-Fai; Hsu, Yung-Pei; Shih, Kuang-Chung; Chen, Chin-Chang; Ho, Low-Tone

    2015-05-08

    Endothelin-1 (ET-1) is known as potent vasoconstrictor, by virtue of its mitogenic effects, and may deteriorate the process of hypertension and atherosclerosis by aggravating hyperplasia and migration in VSMCs. Our previous study demonstrated that insulin infusion caused sequential induction of hyperinsulinemia, hyperendothelinemia, insulin resistance, and then hypertension in rats. However, the underlying mechanism of ET-1 interfere insulin signaling in VSMCs remains unclear. To characterize insulin signaling during modest insulin resistant syndrome, we established and monitored rats by feeding high fructose-diet (HFD) until high blood pressure and modest insulin resistance occurred. To explore the role of ET-1/ET{sub A}R during insulin resistance, ET{sub A}R expression, ET-1 binding, and insulin signaling were investigated in the HFD-fed rats and cultured A-10 VSMCs. Results showed that high blood pressure, tunica medial wall thickening, plasma ET-1 and insulin, and accompanied with modest insulin resistance without overweight and hyperglycemia occurred in early-stage HFD-fed rats. In the endothelium-denuded aorta from HFD-fed rats, ET{sub A}R expression, but not ET{sub B}R, and ET-1 binding in aorta were increased. Moreover, decreasing of insulin-induced Akt phosphorylation and increasing of insulin-induced ERK phosphorylation were observed in aorta during modest insulin resistance. Interestingly, in ET-1 pretreated VSMCs, the increment of insulin-induced Akt phosphorylation was decreased whereas the increment of insulin-induced ERK phosphorylation was increased. In addition, insulin potentiated ET-1-induced VSMCs migration and proliferation due to increasing ET-1 binding. ETAR antagonist reversed effects of ET-1 on insulin-induced signaling and VSMCs migration and proliferation. In summary, modest insulin resistance syndrome accompanied with hyperinsulinemia leading to the potentiation on ET-1-induced actions in aortic VSMCs. ET-1 via ET{sub A}R pathway

  11. Effect of BI-1 on insulin resistance through regulation of CYP2E1.

    PubMed

    Lee, Geum-Hwa; Oh, Kyoung-Jin; Kim, Hyung-Ryong; Han, Hye-Sook; Lee, Hwa-Young; Park, Keun-Gyu; Nam, Ki-Hoan; Koo, Seung-Hoi; Chae, Han-Jung

    2016-01-01

    Diet-induced obesity is a major contributing factor to the progression of hepatic insulin resistance. Increased free fatty acids in liver enhances endoplasmic reticulum (ER) stress and production of reactive oxygen species (ROS), both are directly responsible for dysregulation of hepatic insulin signaling. BI-1, a recently studied ER stress regulator, was examined to investigate its association with ER stress and ROS in insulin resistance models. To induce obesity and insulin resistance, BI-1 wild type and BI-1 knock-out mice were fed a high-fat diet for 8 weeks. The BI-1 knock-out mice had hyperglycemia, was associated with impaired glucose and insulin tolerance under high-fat diet conditions. Increased activity of NADPH-dependent CYP reductase-associated cytochrome p450 2E1 (CYP2E1) and exacerbation of ER stress in the livers of BI-1 knock-out mice was also observed. Conversely, stable expression of BI-1 in HepG2 hepatocytes was shown to reduce palmitate-induced ER stress and CYP2E1-dependent ROS production, resulting in the preservation of intact insulin signaling. Stable expression of CYP2E1 led to increased ROS production and dysregulation of insulin signaling in hepatic cells, mimicking palmitate-mediated hepatic insulin resistance. We propose that BI-1 protects against obesity-induced hepatic insulin resistance by regulating CYP2E1 activity and ROS production. PMID:27576594

  12. Edible Bird's Nest Prevents High Fat Diet-Induced Insulin Resistance in Rats

    PubMed Central

    Yida, Zhang; Imam, Mustapha Umar; Ismail, Maznah; Ooi, Der-Jiun; Sarega, Nadarajan; Azmi, Nur Hanisah; Ismail, Norsharina; Chan, Kim Wei; Hou, Zhiping; Yusuf, Norhayati Binti

    2015-01-01

    Edible bird's nest (EBN) is used traditionally in many parts of Asia to improve wellbeing, but there are limited studies on its efficacy. We explored the potential use of EBN for prevention of high fat diet- (HFD-) induced insulin resistance in rats. HFD was given to rats with or without simvastatin or EBN for 12 weeks. During the intervention period, weight measurements were recorded weekly. Blood samples were collected at the end of the intervention and oral glucose tolerance test conducted, after which the rats were sacrificed and their liver and adipose tissues collected for further studies. Serum adiponectin, leptin, F2-isoprostane, insulin, and lipid profile were estimated, and homeostatic model assessment of insulin resistance computed. Effects of the different interventions on transcriptional regulation of insulin signaling genes were also evaluated. The results showed that HFD worsened metabolic indices and induced insulin resistance partly through transcriptional regulation of the insulin signaling genes. Additionally, simvastatin was able to prevent hypercholesterolemia but promoted insulin resistance similar to HFD. EBN, on the other hand, prevented the worsening of metabolic indices and transcriptional changes in insulin signaling genes due to HFD. The results suggest that EBN may be used as functional food to prevent insulin resistance. PMID:26273674

  13. Effect of BI-1 on insulin resistance through regulation of CYP2E1

    PubMed Central

    Lee, Geum-Hwa; Oh, Kyoung-Jin; Kim, Hyung-Ryong; Han, Hye-Sook; Lee, Hwa-Young; Park, Keun-Gyu; Nam, Ki-Hoan; Koo, Seung-Hoi; Chae, Han-Jung

    2016-01-01

    Diet-induced obesity is a major contributing factor to the progression of hepatic insulin resistance. Increased free fatty acids in liver enhances endoplasmic reticulum (ER) stress and production of reactive oxygen species (ROS), both are directly responsible for dysregulation of hepatic insulin signaling. BI-1, a recently studied ER stress regulator, was examined to investigate its association with ER stress and ROS in insulin resistance models. To induce obesity and insulin resistance, BI-1 wild type and BI-1 knock-out mice were fed a high-fat diet for 8 weeks. The BI-1 knock-out mice had hyperglycemia, was associated with impaired glucose and insulin tolerance under high-fat diet conditions. Increased activity of NADPH-dependent CYP reductase-associated cytochrome p450 2E1 (CYP2E1) and exacerbation of ER stress in the livers of BI-1 knock-out mice was also observed. Conversely, stable expression of BI-1 in HepG2 hepatocytes was shown to reduce palmitate-induced ER stress and CYP2E1-dependent ROS production, resulting in the preservation of intact insulin signaling. Stable expression of CYP2E1 led to increased ROS production and dysregulation of insulin signaling in hepatic cells, mimicking palmitate-mediated hepatic insulin resistance. We propose that BI-1 protects against obesity-induced hepatic insulin resistance by regulating CYP2E1 activity and ROS production. PMID:27576594

  14. Edible Bird's Nest Prevents High Fat Diet-Induced Insulin Resistance in Rats.

    PubMed

    Yida, Zhang; Imam, Mustapha Umar; Ismail, Maznah; Ooi, Der-Jiun; Sarega, Nadarajan; Azmi, Nur Hanisah; Ismail, Norsharina; Chan, Kim Wei; Hou, Zhiping; Yusuf, Norhayati Binti

    2015-01-01

    Edible bird's nest (EBN) is used traditionally in many parts of Asia to improve wellbeing, but there are limited studies on its efficacy. We explored the potential use of EBN for prevention of high fat diet- (HFD-) induced insulin resistance in rats. HFD was given to rats with or without simvastatin or EBN for 12 weeks. During the intervention period, weight measurements were recorded weekly. Blood samples were collected at the end of the intervention and oral glucose tolerance test conducted, after which the rats were sacrificed and their liver and adipose tissues collected for further studies. Serum adiponectin, leptin, F2-isoprostane, insulin, and lipid profile were estimated, and homeostatic model assessment of insulin resistance computed. Effects of the different interventions on transcriptional regulation of insulin signaling genes were also evaluated. The results showed that HFD worsened metabolic indices and induced insulin resistance partly through transcriptional regulation of the insulin signaling genes. Additionally, simvastatin was able to prevent hypercholesterolemia but promoted insulin resistance similar to HFD. EBN, on the other hand, prevented the worsening of metabolic indices and transcriptional changes in insulin signaling genes due to HFD. The results suggest that EBN may be used as functional food to prevent insulin resistance. PMID:26273674

  15. Analysis of in vitro insulin-resistance models and their physiological relevance to in vivo diet-induced adipose insulin resistance.

    PubMed

    Lo, Kinyui Alice; Labadorf, Adam; Kennedy, Norman J; Han, Myoung Sook; Yap, Yoon Sing; Matthews, Bryan; Xin, Xiaofeng; Sun, Lei; Davis, Roger J; Lodish, Harvey F; Fraenkel, Ernest

    2013-10-17

    Diet-induced obesity (DIO) predisposes individuals to insulin resistance, and adipose tissue has a major role in the disease. Insulin resistance can be induced in cultured adipocytes by a variety of treatments, but what aspects of the in vivo responses are captured by these models remains unknown. We use global RNA sequencing to investigate changes induced by TNF-α, hypoxia, dexamethasone, high insulin, and a combination of TNF-α and hypoxia, comparing the results to the changes in white adipose tissue from DIO mice. We found that different in vitro models capture distinct features of DIO adipose insulin resistance, and a combined treatment of TNF-α and hypoxia is most able to mimic the in vivo changes. Using genome-wide DNase I hypersensitivity followed by sequencing, we further examined the transcriptional regulation of TNF-α-induced insulin resistance, and we found that C/EPBβ is a potential key regulator of adipose insulin resistance.

  16. Abnormal glucose tolerance and insulin resistance in polycystic ovary syndrome amongst the Taiwanese population- not correlated with insulin receptor substrate-1 Gly972Arg/Ala513Pro polymorphism

    PubMed Central

    Lin, Ta-Chin; Yen, Jui-Mei; Gong, Kum-Bing; Kuo, Tsung-Cheng; Ku, Dong-Chi; Liang, Shu-Fen; Wu, Ming-Jiuan

    2006-01-01

    Background Insulin resistance and glucose dysmetabolism in polycystic ovary syndrome (PCOS) are related with the polymorphisms in the genes encoding the insulin receptor substrate (IRS) proteins, especially Gly972Arg/Ala513Pro polymorphism being reported to be associated with type-2 diabetes and PCOS. We intended to assess the prevalence of abnormal glucose tolerance (AGT) and insulin resistance in Taiwanese PCOS women. We also tried to assess whether the particular identity of Gly972Arg/Ala513Pro polymorphic alleles of the IRS-1 gene mutation can be used as an appropriate diagnostic indicator for PCOS. Methods We designed a prospective clinical study. Forty-seven Taiwanese Hoklo and Hakka women, diagnosed with PCOS were enrolled in this study as were forty-five healthy Hoklo and Hakka women as the control group. Insulin resistance was evaluated with fasting insulin, fasting glucose/insulin ratio, and homeostasis model assessment index for insulin resistance (HOMAIR). The genomic DNA of the subjects was amplified by PCR and digested by restriction fragmented length polymorphism (RFLP) with Bst N1 used for codon 972 and Dra III for codon 513. Results AGT was found in 46.8% of these PCOS patients and was significantly related to high insulin resistance rather than the low insulin resistance. Those patients with either insulin resistance or AGT comprised the majority of PCOS affected patients (AGT + fasting insulin ≥17: 83%, AGT + glucose/insulin ratio ≥6.5: 85.1%, AGT + HOMAIR ≥ 2: 87.2%, and AGT + HOMAIR ≥ 3.8: 72.3%). None of the tested samples revealed any polymorphism due to the absence of any Dra III recognition site or any Bst N1 recognition site in the amplified PCR fragment digested by restriction fragmented length polymorphism. Conclusion There is significantly high prevalence of AGT and insulin resistance in PCOS women, but Gly972Arg and Ala513Pro polymorphic alleles of IRS-1 are rare and are not associated with the elevated risk of PCOS amongst

  17. Fatty Liver, Insulin Resistance, and Features of Metabolic Syndrome

    PubMed Central

    Sung, Ki-Chul; Wild, Sarah H.; Kwag, Hyon Joo; Byrne, Christopher D.

    2012-01-01

    OBJECTIVE Nonalcoholic fatty liver disease (NAFLD) coexists with insulin resistance (IR), but it is uncertain whether NAFLD and IR contribute independently to atherosclerosis. We tested whether fatty liver, IR, and metabolic syndrome (MetS) features (waist, glucose, triglyceride, HDL cholesterol [HDL-C], and blood pressure) were associated with a marker of atherosclerosis (coronary artery calcium [CAC] score >0), independently of cardiovascular risk factors and cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS Data were analyzed from a South Korean occupational cohort of 10,153 people who all received ultrasound measurements of fatty liver and a cardiac computed tomography CAC score. IR was defined by homeostasis model assessment of IR (HOMA-IR) ≥75th percentile. Odds ratios (ORs) (95% CIs) for the presence of a CAC score >0 were estimated using logistic regression. RESULTS There were 915 people with a CAC score >0. MetS features were increased (glucose, blood pressure, triglyceride, and waist) or decreased (HDL-C) among people with a CAC score >0 (all comparisons against CAC score ≤0; P < 0.0001). Of subjects with a CAC score >0, 55% had fatty liver and 33.7% were insulin resistant. Fatty liver (OR 1.21 [95% CI 1.01–1.45]; P = 0.04) and HOMA-IR (1.10 [1.02–1.18]; P = 0.02) were associated with CAC score >0, independently of all MetS features, conventional cardiovascular risk factors, and prior evidence of CVD. The presence of IR and fatty liver combined was associated with CAC score >0 (1.53 [1.20–1.95]; P = 0.001). CONCLUSIONS Fatty liver and HOMA-IR are both associated with a CAC score >0 (independently of each other), features of MetS, conventional cardiovascular risk factors, and existing CVD. PMID:22829522

  18. A Novel Insulin Resistance Index to Monitor Changes in Insulin Sensitivity and Glucose Tolerance: the ACT NOW Study

    PubMed Central

    Tripathy, Devjit; Cobb, Jeff E.; Gall, Walter; Adam, Klaus-Peter; George, Tabitha; Schwenke, Dawn C.; Banerji, MaryAnn; Bray, George A.; Buchanan, Thomas A.; Clement, Stephen C.; Henry, Robert R.; Kitabchi, Abbas E.; Mudaliar, Sunder; Ratner, Robert E.; Stentz, Frankie B.; Reaven, Peter D.; Musi, Nicolas; Ferrannini, Ele

    2015-01-01

    insulin-resistant patients. PMID:25603459

  19. TOR-centric view on insulin resistance and diabetic complications: perspective for endocrinologists and gerontologists

    PubMed Central

    Blagosklonny, M V

    2013-01-01

    This article is addressed to endocrinologists treating patients with diabetic complications as well as to basic scientists studying an elusive link between diseases and aging. It answers some challenging questions. What is the link between insulin resistance (IR), cellular aging and diseases? Why complications such as retinopathy may paradoxically precede the onset of type II diabetes. Why intensive insulin therapy may initially worsen retinopathy. How nutrient- and insulin-sensing mammalian target of rapamycin (mTOR) pathway can drive insulin resistance and diabetic complications. And how rapamycin, at rational doses and schedules, may prevent IR, retinopathy, nephropathy and beta-cell failure, without causing side effects. PMID:24336084

  20. Effect of beta-blockers on insulin resistance in patients with dilated cardiomyopathy.

    PubMed

    Hara, Yuji; Hamada, Mareomi; Shigematsu, Yuji; Ohtsuka, Tomoaki; Ogimoto, Akiyoshi; Higaki, Jitsuo

    2003-08-01

    The aim of this study was to evaluate the effect of beta-blockers on insulin resistance in patients with dilated cardiomyopathy (DCM). A secondary aim was to determine the effect of this treatment on plasma concentrations of tumor necrosis factor-alpha (TNF-alpha) and to investigate the relationships between this adipocytokine and insulin resistance. Insulin resistance determined using the Homeostatic Model Assessment (HOMA), echocardiographic measurements and analysis of plasma TNF-alpha concentration were carried out in 47 patients with DCM without diabetes mellitus before and after 6 months of beta-blocker therapy. A reduction in left ventricular dimensions and an associated increase in ejection fraction occurred with beta-blocker. The treatment resulted in a significant decrease in insulin resistance (HOMA index: Baseline, 2.73+/-3.36 vs, Month 6, 1.58+/-1.33, p=0.0347). Beta-blockade was also associated with a decrease in plasma TNF-alpha concentration although no significant relationship between this change and the improvement in insulin resistance was observed. Beta-blocker therapy in patients with DCM improved not only cardiac function, but also insulin resistance. The mechanism of the change in insulin function remains unclear, but may be related to improvements in left ventricular function or an attenuation of the inhibitory effect of reduction in TNF-alpha on insulin signaling.

  1. Nox2 mediates skeletal muscle insulin resistance induced by a high fat diet.

    PubMed

    Souto Padron de Figueiredo, Alvaro; Salmon, Adam B; Bruno, Francesca; Jimenez, Fabio; Martinez, Herman G; Halade, Ganesh V; Ahuja, Seema S; Clark, Robert A; DeFronzo, Ralph A; Abboud, Hanna E; El Jamali, Amina

    2015-05-22

    Inflammation and oxidative stress through the production of reactive oxygen species (ROS) are consistently associated with metabolic syndrome/type 2 diabetes. Although the role of Nox2, a major ROS-generating enzyme, is well described in host defense and inflammation, little is known about its potential role in insulin resistance in skeletal muscle. Insulin resistance induced by a high fat diet was mitigated in Nox2-null mice compared with wild-type mice after 3 or 9 months on the diet. High fat feeding increased Nox2 expression, superoxide production, and impaired insulin signaling in skeletal muscle tissue of wild-type mice but not in Nox2-null mice. Exposure of C2C12 cultured myotubes to either high glucose concentration, palmitate, or H2O2 decreases insulin-induced Akt phosphorylation and glucose uptake. Pretreatment with catalase abrogated these effects, indicating a key role for H2O2 in mediating insulin resistance. Down-regulation of Nox2 in C2C12 cells by shRNA prevented insulin resistance induced by high glucose or palmitate but not H2O2. These data indicate that increased production of ROS in insulin resistance induced by high glucose in skeletal muscle cells is a consequence of Nox2 activation. This is the first report to show that Nox2 is a key mediator of insulin resistance in skeletal muscle.

  2. Selection of the appropriate method for the assessment of insulin resistance.

    PubMed

    Borai, Anwar; Livingstone, Callum; Kaddam, Ibrahim; Ferns, Gordon

    2011-01-01

    Insulin resistance is one of the major aggravating factors for metabolic syndrome. There are many methods available for estimation of insulin resistance which range from complex techniques down to simple indices. For all methods of assessing insulin resistance it is essential that their validity and reliability is established before using them as investigations. The reference techniques of hyperinsulinaemic euglycaemic clamp and its alternative the frequently sampled intravenous glucose tolerance test are the most reliable methods available for estimating insulin resistance. However, many simple methods, from which indices can be derived, have been assessed and validated e.g. homeostasis model assessment (HOMA), quantitative insulin sensitivity check index (QUICKI). Given the increasing number of simple indices of IR it may be difficult for clinicians and researchers to select the most appropriate index for their studies. This review therefore provides guidelines and advices which must be considered before proceeding with a study.

  3. Genetic factors determine the blood pressure response to insulin resistance and hyperinsulinemia: A call to refocus the insulin hypothesis of hypertension

    SciTech Connect

    Mark, A.L.; Anderson, E.A.

    1995-04-01

    The hypothesis that insulin resistance and compensatory hyperinsulinemia contribute to the pathogenesis of essential hypertension and hypertension in obesity has gained enormous interest. We have concluded that future progress in evaluating the insulin hypothesis will require inclusion of the concept that there is {open_quotes}sensitivity or resistance{close_quotes} to the blood pressure effects of insulin resistance and that genetic factors may play a decisive influence in this effect. 58 refs., 3 figs.

  4. Progranulin induces adipose insulin resistance and autophagic imbalance via TNFR1 in mice.

    PubMed

    Zhou, Bo; Li, Huixia; Liu, Jiali; Xu, Lin; Guo, Qinyue; Sun, Hongzhi; Wu, Shufang

    2015-12-01

    Progranulin (PGRN) has recently emerged as an important regulator for insulin resistance. However, the direct effect of PGRN in vivo and the underlying role of progranulin in adipose insulin resistance involving the autophagy mechanism is not fully understood. In this study, mice treated with PGRN for 21 days exhibited the impaired glucose tolerance and insulin sensitivity, remarkable adipose autophagy as well as attenuated insulin signaling via inhibition of mammalian target of rapamycin (mTOR) pathway. Furthermore, blockade of tumor necrosis factor receptor 1 (TNFR1) by TNFR1BP-Fc injection resulted in the restoration of impaired insulin sensitivity and insulin signaling induced by PGRN. Consistent with these findings in vivo, PGRN treatment induced defective insulin signaling, abnormal autophagic and mitochondrial activity in cultured adipocytes, while such effects were nullified by the blockade of TNFR1. In addition, PGRN-deficient adipocytes were more refractory to tunicamycin- or dexamethasone-induced insulin resistance, indicating the causative role of the TNFR1 pathway in the action of PGRN. Collectively, our findings support the notion that PGRN is a key regulator of insulin resistance and that PGRN may mediate its effects, at least in part, by inducing autophagy via the TNFR1-dependent mechanism.

  5. Low fish oil intake improves insulin sensitivity, lipid profile and muscle metabolism on insulin resistant MSG-obese rats

    PubMed Central

    2011-01-01

    Background Obesity is commonly associated with diabetes, cardiovascular diseases and cancer. The purpose of this study was to determinate the effect of a lower dose of fish oil supplementation on insulin sensitivity, lipid profile, and muscle metabolism in obese rats. Methods Monosodium glutamate (MSG) (4 mg/g body weight) was injected in neonatal Wistar male rats. Three-month-old rats were divided in normal-weight control group (C), coconut fat-treated normal weight group (CO), fish oil-treated normal weight group (FO), obese control group (Ob), coconut fat-treated obese group (ObCO) and fish oil-treated obese group (ObFO). Obese insulin-resistant rats were supplemented with fish oil or coconut fat (1 g/kg/day) for 4 weeks. Insulin sensitivity, fasting blood biochemicals parameters, and skeletal muscle glucose metabolism were analyzed. Results Obese animals (Ob) presented higher Index Lee and 2.5 fold epididymal and retroperitoneal adipose tissue than C. Insulin sensitivity test (Kitt) showed that fish oil supplementation was able to maintain insulin sensitivity of obese rats (ObFO) similar to C. There were no changes in glucose and HDL-cholesterol levels amongst groups. Yet, ObFO revealed lower levels of total cholesterol (TC; 30%) and triacylglycerol (TG; 33%) compared to Ob. Finally, since exposed to insulin, ObFO skeletal muscle revealed an increase of 10% in lactate production, 38% in glycogen synthesis and 39% in oxidation of glucose compared to Ob. Conclusions Low dose of fish oil supplementation (1 g/kg/day) was able to reduce TC and TG levels, in addition to improved systemic and muscle insulin sensitivity. These results lend credence to the benefits of n-3 fatty acids upon the deleterious effects of insulin resistance mechanisms. PMID:21526994

  6. Hypertension and insulin resistance are not directly related in obese dogs.

    PubMed

    Rocchini, Albert P; Yang, John Q; Gokee, Amy

    2004-05-01

    In dogs fed a high-fat diet, we determined whether there was a direct relation between obesity-induced insulin resistance and obesity-induced hypertension. Thirty-six adult mongrel dogs were chronically instrumented and assigned to receive either a high-fat diet alone (n=7) or a high-fat diet combined with a low-sodium diet plus furosemide (n=6), prazosin plus atenolol (n=7), clonidine (n=10), or aspirin (n=6). Blood pressure, heart rate, and body weight were measured daily. Insulin resistance was assessed with a single-dose euglycemic hyperinsulinemic clamp (2 mU x kg(-1) x min(-1)) before and after 1, 3, and 6 weeks of the high-fat diet. The low-salt diet plus furosemide, prazosin plus atenolol, and clonidine treatments prevented the hypertension associated with feeding the dogs a high-fat diet. Only clonidine treatment totally prevented the development of insulin resistance, and high-dose aspirin, known to prevent insulin resistance by inhibition of the activity of IkappaB kinase-beta, decreased the degree of insulin resistance by almost 70%. However, aspirin had no effect on the development of hypertension. We conclude that obesity-induced hypertension and obesity-induced insulin resistance are not directly related. In addition, there is a suggestion that insulin resistance in this experimental model is mediated through the central and or peripheral alpha2-adrenoceptors, whereas hypertension is mediated through the alpha1- and or beta-adrenoceptors.

  7. The Effect of Spirulina platensis versus Soybean on Insulin Resistance in HIV-Infected Patients: A Randomized Pilot Study

    PubMed Central

    Marcel, Azabji-Kenfack; Ekali, Loni G.; Eugene, Sobngwi; Arnold, Onana E.; Sandrine, Edie D.; von der Weid, Denis; Gbaguidi, Emmanuel; Ngogang, Jeanne; Mbanya, Jean C.

    2011-01-01

    HIV-infected patients develop abnormalities of glucose metabolism due to the virus and antiretroviral drugs. Spirulina and soybean are nutritional supplements that are cheap, accessible in our community and affect glucose metabolism. We carried out a randomized study to assess the effect of Spirulina platensis versus soybean as a food supplement on HIV/HAART-associated insulin resistance (IR) in 33 insulin-resistant HIV-infected patients. The study lasted for two months at the National Obesity Centre of Cameroon. Insulin resistance was measured using the short insulin tolerance test. Physical activity and diet did not change over the study duration. On-treatment analysis was used to analyze data. The Mann-Whitney U test, the Students T test and the Chi square test were used as appropriate. Curve gradients were analyzed using ANCOVA. Seventeen subjects were randomized to spirulina and 16 to soybean. Each received 19 g of supplement daily. The follow up rate was 65% vs. 100% for spirulina and soybean groups, respectively, and both groups were comparable at baseline. After eight weeks, insulin sensitivity (IS) increased by 224.7% vs. 60% in the spirulina and soybean groups respectively (p < 0.001). One hundred per cent vs. 69% of subjects on spirulina versus soybean, respectively, improved their IS (p = 0.049) with a 1.45 (1.05–2.02) chance of improving insulin sensitivity on spirulina. This pilot study suggests that insulin sensitivity in HIV patients improves more when spirulina rather than soybean is used as a nutritional supplement. Trial registration: ClinicalTrials.gov identifier NCT01141777. PMID:22254118

  8. Risk of postprandial insulin resistance: the liver/vagus rapport.

    PubMed

    Macedo, Maria Paula; Lima, Inês S; Gaspar, Joana M; Afonso, Ricardo A; Patarrão, Rita S; Kim, Young-Bum; Ribeiro, Rogério T

    2014-03-01

    Ingestion of a meal is the greatest challenge faced by glucose homeostasis. The surge of nutrients has to be disposed quickly, as high concentrations in the bloodstream may have pathophysiological effects, and also properly, as misplaced reserves may induce problems in affected tissues. Thus, loss of the ability to adequately dispose of ingested nutrients can be expected to lead to glucose intolerance, and favor the development of pathologies. Achieving interplay of several organs is of upmost importance to maintain effectively postprandial glucose clearance, with the liver being responsible of orchestrating global glycemic control. This dogmatic role of the liver in postprandial insulin sensitivity is tightly associated with the vagus nerve. Herein, we uncover the behaviour of metabolic pathways determined by hepatic parasympathetic function status, in physiology and in pathophysiology. Likewise, the inquiry expands to address the impact of a modern lifestyle, especially one's feeding habits, on the hepatic parasympathetic nerve control of glucose metabolism.

  9. Downregulation of diacylglycerol kinase delta contributes to hyperglycemia-induced insulin resistance.

    PubMed

    Chibalin, Alexander V; Leng, Ying; Vieira, Elaine; Krook, Anna; Björnholm, Marie; Long, Yun Chau; Kotova, Olga; Zhong, Zhihui; Sakane, Fumio; Steiler, Tatiana; Nylén, Carolina; Wang, Jianjun; Laakso, Markku; Topham, Matthew K; Gilbert, Marc; Wallberg-Henriksson, Harriet; Zierath, Juleen R

    2008-02-01

    Type 2 (non-insulin-dependent) diabetes mellitus is a progressive metabolic disorder arising from genetic and environmental factors that impair beta cell function and insulin action in peripheral tissues. We identified reduced diacylglycerol kinase delta (DGKdelta) expression and DGK activity in skeletal muscle from type 2 diabetic patients. In diabetic animals, reduced DGKdelta protein and DGK kinase activity were restored upon correction of glycemia. DGKdelta haploinsufficiency increased diacylglycerol content, reduced peripheral insulin sensitivity, insulin signaling, and glucose transport, and led to age-dependent obesity. Metabolic flexibility, evident by the transition between lipid and carbohydrate utilization during fasted and fed conditions, was impaired in DGKdelta haploinsufficient mice. We reveal a previously unrecognized role for DGKdelta in contributing to hyperglycemia-induced peripheral insulin resistance and thereby exacerbating the severity of type 2 diabetes. DGKdelta deficiency causes peripheral insulin resistance and metabolic inflexibility. These defects in glucose and energy homeostasis contribute to mild obesity later in life. PMID:18267070

  10. Investigation of the Relationship Between Chronic Stress and Insulin Resistance in a Chinese Population

    PubMed Central

    Yan, Yu-Xiang; Xiao, Huan-Bo; Wang, Si-Si; Zhao, Jing; He, Yan; Wang, Wei; Dong, Jing

    2016-01-01

    Background Chronic stress may facilitate the development of metabolic diseases. Insulin resistance is present long before the clinical manifestations of individual metabolic abnormalities. To explore whether chronic stress is an independent risk factor of insulin resistance, we investigated the relationship between the stress system, selected parameters of energy homeostasis, and insulin resistance in a Chinese population. Methods We recruited 766 workers employed at four companies in Beijing. The degree of insulin resistance was determined using the homeostasis model assessment of insulin resistance (HOMA-IR). The highest quartile of HOMA-IR among all study subjects was further defined as insulin resistance in our study. The short standard version of the Copenhagen Psychosocial Questionnaire (COPSOQ) was used to assess job-related psychosocial stress. Pearson’s correlation coefficients were calculated between cortisol level and HOMA-IR and components of metabolic syndrome, with stratification by gender. The relationship between cortisol and HOMA-IR independent of obesity was analyzed using a linear mixed model with company as a cluster unit. Results The values of the two scales of COPSOQ, including “demands at work” and “insecurity at work”, were significantly associated with insulin resistance and cortisol concentration (P < 0.05). Cortisol was significantly positively correlated with glucose, HOMA-IR, and waist circumference in males and females (P < 0.05). After adjusting for potential confounders, cortisol was an independent positive predictor for HOMA-IR (P < 0.05). Conclusions These findings showed that chronic stress was associated with insulin resistance and may contribute to the development of insulin resistance. PMID:26830350

  11. Abdominal adiposity and insulin resistance in obese men.

    PubMed

    Ross, Robert; Aru, James; Freeman, Jennifer; Hudson, Robert; Janssen, Ian

    2002-03-01

    We examined the independent relationships among various visceral and abdominal subcutaneous adipose tissue (AT) depots, glucose tolerance, and insulin sensitivity in 89 obese men. Measurements included an oral glucose tolerance test (OGTT), glucose disposal by euglycemic clamp, and abdominal and nonabdominal (e.g., peripheral) AT by magnetic resonance imaging (MRI). OGTT glucose and glucose disposal rates were related (P < 0.05) to visceral AT (r = 0.50 and -0.41, respectively). These observations remained significant (P < 0.05) after control for nonabdominal and abdominal subcutaneous AT, and maximal O(2) consumption (VO(2 max)). Abdominal subcutaneous AT was not a significant correlate (P > 0.05) of any metabolic variable after control for nonabdominal and visceral AT and VO(2 max). Division of abdominal subcutaneous AT into deep and superficial depots and visceral AT into intra- and extraperitoneal AT depots did not alter the observed relationships. Further analysis matched two groups of men for abdominal subcutaneous AT but also for low and high visceral AT. Men with high visceral AT had higher OGTT glucose values and lower glucose disposal rates compared with those with low visceral AT values (P < 0.05). A similar analysis performed on two groups of men matched for visceral AT but also for high and low abdominal subcutaneous AT revealed no statistically different values for any metabolic variable (P > 0.10). In conclusion, visceral AT alone is a strong correlate of insulin resistance independent of nonabdominal and abdominal subcutaneous AT and cardiovascular fitness. Subdivision of visceral and abdominal subcutaneous AT by MRI did not provide additional insight into the relationship between abdominal obesity and metabolic risk in obese men.

  12. Dietary zinc affects concentrations of insulin, insulin-like growth factor-I and growth hormone in lambs

    SciTech Connect

    Droke, E.A.; Spears, J.W.; Armstrong, J.D. )

    1991-03-15

    Glucose tolerance and concentrations of insulin, growth hormone (GH) and insulin-like growth factor-I (IGF-I) were evaluated in lambs deficient, marginal or adequate in zinc (Zn). Lambs were fed a semipurified diet that contained either 3.7, 8.7, or 43.7 mg Zn/kg. Zinc deficiency resulted in lower serum insulin levels 1 h after feeding while levels in marginal lambs were not different from that of adequate lambs. Dietary Zn did not affect plasma glucose post feeding. One h after IV glucose administration plasma glucose concentrations were lower in deficient lambs compared to adequate lambs; marginal lambs had intermediate glucose levels. Concentration of GH before and after feeding or glucose challenge were not affected by Zn status; however, serum IGF-I was lower in deficient than in marginal or adequate lambs. A GH releasing factor (GRF) analog was given to evaluate the release of GH. Serum GH in response to GRF challenge was higher in deficient lambs and tended to be higher in marginal lambs when compared to adequate lambs. Impaired growth observed with Zn deficiency may be mediated in part by its effect on insulin, GH and IGF-I concentrations.

  13. Adipose Cell Size and Regional Fat Deposition as Predictors of Metabolic Response to Overfeeding in Insulin-Resistant and Insulin-Sensitive Humans.

    PubMed

    McLaughlin, Tracey; Craig, Colleen; Liu, Li-Fen; Perelman, Dalia; Allister, Candice; Spielman, Daniel; Cushman, Samuel W

    2016-05-01

    Obesity is associated with insulin resistance, but significant variability exists between similarly obese individuals, pointing to qualitative characteristics of body fat as potential mediators. To test the hypothesis that obese, insulin-sensitive (IS) individuals possess adaptive adipose cell/tissue responses, we measured subcutaneous adipose cell size, insulin suppression of lipolysis, and regional fat responses to short-term overfeeding in BMI-matched overweight/obese individuals classified as IS or insulin resistant (IR). At baseline, IR subjects exhibited significantly greater visceral adipose tissue (VAT), intrahepatic lipid (IHL), plasma free fatty acids, adipose cell diameter, and percentage of small adipose cells. With weight gain (3.1 ± 1.4 kg), IR subjects demonstrated no significant change in adipose cell size, VAT, or insulin suppression of lipolysis and only 8% worsening of insulin-mediated glucose uptake (IMGU). Alternatively, IS subjects demonstrated significant adipose cell enlargement; decrease in the percentage of small adipose cells; increase in VAT, IHL, and lipolysis; 45% worsening of IMGU; and decreased expression of lipid metabolism genes. Smaller baseline adipose cell size and greater enlargement with weight gain predicted decline in IMGU, as did increase in IHL and VAT and decrease in insulin suppression of lipolysis. Weight gain in IS humans causes maladaptive changes in adipose cells, regional fat distribution, and insulin resistance. The correlation between development of insulin resistance and changes in adipose cell size, VAT, IHL, and insulin suppression of lipolysis highlight these factors as potential mediators between obesity and insulin resistance. PMID:26884438

  14. Adipose Cell Size and Regional Fat Deposition as Predictors of Metabolic Response to Overfeeding in Insulin-Resistant and Insulin-Sensitive Humans.

    PubMed

    McLaughlin, Tracey; Craig, Colleen; Liu, Li-Fen; Perelman, Dalia; Allister, Candice; Spielman, Daniel; Cushman, Samuel W

    2016-05-01

    Obesity is associated with insulin resistance, but significant variability exists between similarly obese individuals, pointing to qualitative characteristics of body fat as potential mediators. To test the hypothesis that obese, insulin-sensitive (IS) individuals possess adaptive adipose cell/tissue responses, we measured subcutaneous adipose cell size, insulin suppression of lipolysis, and regional fat responses to short-term overfeeding in BMI-matched overweight/obese individuals classified as IS or insulin resistant (IR). At baseline, IR subjects exhibited significantly greater visceral adipose tissue (VAT), intrahepatic lipid (IHL), plasma free fatty acids, adipose cell diameter, and percentage of small adipose cells. With weight gain (3.1 ± 1.4 kg), IR subjects demonstrated no significant change in adipose cell size, VAT, or insulin suppression of lipolysis and only 8% worsening of insulin-mediated glucose uptake (IMGU). Alternatively, IS subjects demonstrated significant adipose cell enlargement; decrease in the percentage of small adipose cells; increase in VAT, IHL, and lipolysis; 45% worsening of IMGU; and decreased expression of lipid metabolism genes. Smaller baseline adipose cell size and greater enlargement with weight gain predicted decline in IMGU, as did increase in IHL and VAT and decrease in insulin suppression of lipolysis. Weight gain in IS humans causes maladaptive changes in adipose cells, regional fat distribution, and insulin resistance. The correlation between development of insulin resistance and changes in adipose cell size, VAT, IHL, and insulin suppression of lipolysis highlight these factors as potential mediators between obesity and insulin resistance.

  15. [Effect of chronic blockade of the opiodergic receptor on insulin resistance in a hyperandrogenic woman].

    PubMed

    Sir, T; López, G; Alba, F; Cipriano, A; Candía, M; Castillo, T; Devoto, L

    1994-04-01

    We report a woman with insulin resistance associated with hyperandrogenism and acanthosis nigricans (HAIR-AN syndrome) treated during 30 days with the prolonged action opioid antagonist Naltrexone. During its administration, decreases in basal blood glucose and serum insulin, insulin and glucose response to a glucose load and plasma testosterone were observed. These findings suggest that opioid activity could play a critical role in the physiopathology of hyperinsulinemia in hyperandrogenic women. PMID:7809540

  16. Insulin resistance in penile arteries from a rat model of metabolic syndrome

    PubMed Central

    Contreras, Cristina; Sánchez, Ana; Martínez, Pilar; Raposo, Rafaela; Climent, Belén; García-Sacristán, Albino; Benedito, Sara; Prieto, Dolores

    2010-01-01

    BACKGROUND AND PURPOSE Metabolic and cardiovascular abnormalities accompanying metabolic syndrome, such as obesity, insulin resistance and hypertension, are all associated with endothelial dysfunction and are independent risk factors for erectile dysfunction. The purpose of the present study was to investigate the vascular effects of insulin in penile arteries and whether these effects are impaired in a rat model of insulin resistance and metabolic syndrome. EXPERIMENTAL APPROACH Penile arteries from obese Zucker rats (OZR) and their counterpart, lean Zucker rats (LZR), were mounted on microvascular myographs and the effects of insulin were assessed in the absence and presence of endothelium and of specific inhibitors of nitric oxide (NO) synthesis, phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK). Insulin-induced changes in intracellular Ca2+ concentration [Ca2+]i were also examined. KEY RESULTS OZR exhibited mild hyperglycaemia, hypercholesterolemia, hypertryglyceridemia and hyperinsulinemia. Insulin induced endothelium- and NO-dependent relaxations in LZR that were impaired in OZR. Inhibition of PI3K reduced relaxation induced by insulin and by the β-adrenoceptor agonist isoprenaline, mainly in arteries from LZR. Antagonism of endothelin 1 (ET-1) receptors did not alter insulin-induced relaxation in either LZR or OZR, but MAPK blockade increased the responses in OZR. Insulin decreased [Ca2+]i, a response impaired in OZR. CONCLUSIONS AND IMPLICATIONS Insulin-induced relaxation was impaired in penile arteries of OZR due to altered NO release through the PI3K pathway and unmasking of a MAPK-mediated vasoconstriction. This vascular insulin resistance is likely to contribute to the endothelial dysfunction and erectile dysfunction associated with insulin resistant states. PMID:20735420

  17. Impact of obesity and insulin-resistance on cirrhosis and portal hypertension.

    PubMed

    Berzigotti, Annalisa; Abraldes, Juan G

    2013-10-01

    Obesity is sharply rising worldwide and is increasingly recognized in patients with cirrhosis. This review summarizes the available data documenting a detrimental role of obesity and insulin-resistance on the risk of appearance of clinical events in patients with cirrhosis. Molecular pathways explaining the harmful effect of obesity and insulin resistance in the natural history of cirrhosis are largely unknown. Increasing knowledge of mechanisms leading to white adipose tissue dysfunction on one side, and to portal hypertension on the other side, allow hypothesizing that a link between the pathophysiology of obesity, insulin resistance and portal hypertension in cirrhosis exists. Mechanisms likely involved in this interplay are discussed in this article.

  18. Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations

    PubMed Central

    Huang-Doran, Isabel; Tomlinson, Patsy; Payne, Felicity; Gast, Alexandra; Sleigh, Alison; Bottomley, William; Harris, Julie; Daly, Allan; Rocha, Nuno; Rudge, Simon; Clark, Jonathan; Kwok, Albert; Romeo, Stefano; McCann, Emma; Müksch, Barbara; Dattani, Mehul; Zucchini, Stefano; Wakelam, Michael; Foukas, Lazaros C.; Savage, David B.; Murphy, Rinki; O’Rahilly, Stephen; Semple, Robert K.

    2016-01-01

    Obesity-related insulin resistance is associated with fatty liver, dyslipidemia, and low plasma adiponectin. Insulin resistance due to insulin receptor (INSR) dysfunction is associated with none of these, but when due to dysfunction of the downstream kinase AKT2 phenocopies obesity-related insulin resistance. We report 5 patients with SHORT syndrome and C-terminal mutations in PIK3R1, encoding the p85α/p55α/p50α subunits of PI3K, which act between INSR and AKT in insulin signaling. Four of 5 patients had extreme insulin resistance without dyslipidemia or hepatic steatosis. In 3 of these 4, plasma adiponectin was preserved, as in insulin receptor dysfunction. The fourth patient and her healthy mother had low plasma adiponectin associated with a potentially novel mutation, p.Asp231Ala, in adiponectin itself. Cells studied from one patient with the p.Tyr657X PIK3R1 mutation expressed abundant truncated PIK3R1 products and showed severely reduced insulin-stimulated association of mutant but not WT p85α with IRS1, but normal downstream signaling. In 3T3-L1 preadipocytes, mutant p85α overexpression attenuated insulin-induced AKT phosphorylation and adipocyte differentiation. Thus, PIK3R1 C-terminal mutations impair insulin signaling only in some cellular contexts and produce a subphenotype of insulin resistance resembling INSR dysfunction but unlike AKT2 dysfunction, implicating PI3K in the pathogenesis of key components of the metabolic syndrome. PMID:27766312

  19. Insulin Resistance in Human iPS Cells Reduces Mitochondrial Size and Function

    PubMed Central

    Burkart, Alison M.; Tan, Kelly; Warren, Laura; Iovino, Salvatore; Hughes, Katelyn J.; Kahn, C. Ronald; Patti, Mary-Elizabeth

    2016-01-01

    Insulin resistance, a critical component of type 2 diabetes (T2D), precedes and predicts T2D onset. T2D is also associated with mitochondrial dysfunction. To define the cause-effect relationship between insulin resistance and mitochondrial dysfunction, we compared mitochondrial metabolism in induced pluripotent stem cells (iPSC) from 5 healthy individuals and 4 patients with genetic insulin resistance due to insulin receptor mutations. Insulin-resistant iPSC had increased mitochondrial number and decreased mitochondrial size. Mitochondrial oxidative function was impaired, with decreased citrate synthase activity and spare respiratory capacity. Simultaneously, expression of multiple glycolytic enzymes was decreased, while lactate production increased 80%. These perturbations were accompanied by an increase in ADP/ATP ratio and 3-fold increase in AMPK activity, indicating energetic stress. Insulin-resistant iPSC also showed reduced catalase activity and increased susceptibility to oxidative stress. Thus, insulin resistance can lead to mitochondrial dysfunction with reduced mitochondrial size, oxidative activity, and energy production. PMID:26948272

  20. Fas (CD95) expression in myeloid cells promotes obesity-induced muscle insulin resistance

    PubMed Central

    Wueest, Stephan; Mueller, Rouven; Blüher, Matthias; Item, Flurin; Chin, Annie S H; Wiedemann, Michael S F; Takizawa, Hitoshi; Kovtonyuk, Larisa; Chervonsky, Alexander V; Schoenle, Eugen J; Manz, Markus G; Konrad, Daniel

    2014-01-01

    Low-grade inflammation in adipose tissue and liver has been implicated in obesity-associated insulin resistance and type 2 diabetes. Yet, the contribution of inflammatory cells to the pathogenesis of skeletal muscle insulin resistance remains elusive. In a large cohort of obese human individuals, blood monocyte Fas (CD95) expression correlated with systemic and skeletal muscle insulin resistance. To test a causal role for myeloid cell Fas expression in the development of skeletal muscle insulin resistance, we generated myeloid/haematopoietic cell-specific Fas-depleted mice. Myeloid/haematopoietic Fas deficiency prevented the development of glucose intolerance in high fat-fed mice, in ob/ob mice, and in mice acutely challenged by LPS. In vivo, ex vivo and in vitro studies demonstrated preservation of muscle insulin responsiveness with no effect on adipose tissue or liver. Studies using neutralizing antibodies demonstrated a role for TNFα as mediator between myeloid Fas and skeletal muscle insulin resistance, supported by significant correlations between monocyte Fas expression and circulating TNFα in humans. In conclusion, our results demonstrate an unanticipated crosstalk between myeloid cells and skeletal muscle in the development of obesity-associated insulin resistance. PMID:24203314

  1. Effect of folic acid on homocysteine and insulin resistance of overweight and obese children and adolescents

    PubMed Central

    Dehkordi, Elham Hashemi; Sedehi, Morteza; Shahraki, Zohre Gholipour; Najafi, Reza

    2016-01-01

    Background: Considering the increasing trend of childhood obesity and subsequent burden of the disease in Iran and other countries and importance of early life intervention for achieving sustained effect on health of children and adolescents, this study aimed to investigate the effect of two different dose of folic acid on homocysteine (Hcy) level and insulin resistance of obese children. Materials and Methods: In this randomized, double-blind controlled clinical trial study, 60 obese and overweight children aged 5–12 years were enrolled. Selected obese children randomly allocated in two interventional (1 mg/day folic acid and 5 mg/day folic acid, for 8 weeks) and one control groups. Biochemical measurements including folic acid, Hcy, insulin and insulin resistance were measured between and within groups before and after trial. Results: In each group, 20 obese children were studied. The three groups were age and sex matched. After folic acid administration, mean of Hcy, insulin resistance and insulin decreased significantly in two groups which folic acid administrated with two different doses (P < 0.05). The reduction in studied biochemical variables was similar in two interventional groups (1 and 5 mg folic acid daily) (P > 0.05). Mean differences for Hcy, insulin resistance and insulin, in two intervention groups were significantly higher than the control group (P < 0.0001). Mean differences of Hcy, insulin resistance and insulin, in two intervention groups were not different significantly (P > 0.05). Conclusion: The findings of current trial showed that folic acid in two studied doses could be a safe and effective supplement for obese children to reduce Hcy level and insulin resistance, which consequently could prevent obesity-related complications including cardiovascular and metabolic disorders. PMID:27274503

  2. N-Acetylneuraminic Acid Supplementation Prevents High Fat Diet-Induced Insulin Resistance in Rats through Transcriptional and Nontranscriptional Mechanisms

    PubMed Central

    Yida, Zhang; Imam, Mustapha Umar; Ismail, Maznah; Ismail, Norsharina; Azmi, Nur Hanisah; Wong, Waiteng; Altine Adamu, Hadiza; Md Zamri, Nur Diyana; Ideris, Aini; Abdullah, Maizaton Atmadini

    2015-01-01

    N-Acetylneuraminic acid (Neu5Ac) is a biomarker of cardiometabolic diseases. In the present study, we tested the hypothesis that dietary Neu5Ac may improve cardiometabolic indices. A high fat diet (HFD) + Neu5Ac (50 or 400 mg/kg BW/day) was fed to rats and compared with HFD + simvastatin (10 mg/kg BW/day) or HFD alone for 12 weeks. Weights and serum biochemicals (lipid profile, oral glucose tolerance test, leptin, adiponectin, and insulin) were measured, and mRNA levels of insulin signaling genes were determined. The results indicated that low and high doses of sialic acid (SA) improved metabolic indices, although only the oral glucose tolerance test, serum triglycerides, leptin, and adiponectin were significantly better than those in the HFD and HFD + simvastatin groups (P < 0.05). Furthermore, the results showed that only high-dose SA significantly affected the transcription of hepatic and adipose tissue insulin signaling genes. The data suggested that SA prevented HFD-induced insulin resistance in rats after 12 weeks of administration through nontranscriptionally mediated biochemical changes that may have differentially sialylated glycoprotein structures at a low dose. At higher doses, SA induced transcriptional regulation of insulin signaling genes. These effects suggest that low and high doses of SA may produce similar metabolic outcomes in relation to insulin sensitivity through multiple mechanisms. These findings are worth studying further. PMID:26688813

  3. Resveratrol improves insulin signaling in a tissue-specific manner under insulin-resistant conditions only: in vitro and in vivo experiments in rodents.

    PubMed

    Kang, Wonyoung; Hong, Hyun Ju; Guan, Jian; Kim, Dong Geon; Yang, Eun-Jin; Koh, Gwanpyo; Park, Doekbae; Han, Chang Hoon; Lee, Young-Jae; Lee, Dae-Ho

    2012-03-01

    Resveratrol (RSV) has various metabolic effects, especially with relatively high-dose therapy. However, the ability of RSV to modulate insulin signaling has not been completely evaluated. Here, we determined whether RSV alters insulin signaling in insulin-responsive cells and tissues. The effects of RSV on insulin signaling in 3T3-L1 adipocytes under both insulin-sensitive and insulin-resistant states and in insulin-sensitive tissues of high fat-fed diet-induced obese (DIO) mice were investigated. Insulin-stimulated insulin receptor substrate-1 tyrosine phosphorylation (Y612) was suppressed in RSV-treated adipocytes compared with untreated adipocytes, as was the insulin-stimulated Akt phosphorylation (Ser473). However, under an insulin-resistant condition that was made by incubating 3T3-L1 adipocytes in the conditioned medium from lipopolysaccharide-stimulated LAW264.7 cells, RSV reduced inducible nitric oxide synthase expression and IκBα protein degradation and improved insulin-stimulated Akt phosphorylation (Ser473). In DIO mice, relatively low-dose RSV (30 mg/kg daily for 2 weeks) therapy lowered fasting blood glucose level and serum insulin, increased hepatic glycogen content, and ameliorated fatty liver without change in body weight. The insulin-stimulated Akt phosphorylation was decreased in the liver and white adipose tissue of DIO mice, but it was completely normalized by RSV treatment. However, in the skeletal muscle of DIO mice, insulin signaling was not improved by RSV treatment, whereas the phosphorylation of adenosine monophosphate-activated protein kinase α (Thr172) was improved by it. Our results show that RSV enhances insulin action only under insulin-resistant conditions and suggest that the effect of RSV may depend on the type of tissue being targeted and its metabolic status. PMID:21945106

  4. Oleanolic acid supplement attenuates liquid fructose-induced adipose tissue insulin resistance through the insulin receptor substrate-1/phosphatidylinositol 3-kinase/Akt signaling pathway in rats

    SciTech Connect

    Li, Ying; Wang, Jianwei; Gu, Tieguang; Yamahara, Johji; Li, Yuhao

    2014-06-01

    Oleanolic acid, a triterpenoid contained in more than 1620 plants including various fruits and foodstuffs, has numerous metabolic effects, such as hepatoprotection. However, its underlying mechanisms remain poorly understood. Adipose tissue insulin resistance (Adipo-IR) may contribute to the development and progress of metabolic abnormalities through release of excessive free fatty acids from adipose tissue. This study investigated the effect of oleanolic acid on Adipo-IR. The results showed that supplement with oleanolic acid (25 mg/kg, once daily, by oral gavage) over 10 weeks attenuated liquid fructose-induced increase in plasma insulin concentration and the homeostasis model assessment of insulin resistance (HOMA-IR) index in rats. Simultaneously, oleanolic acid reversed the increase in the Adipo-IR index and plasma non-esterified fatty acid concentrations during the oral glucose tolerance test assessment. In white adipose tissue, oleanolic acid enhanced mRNA expression of the genes encoding insulin receptor, insulin receptor substrate (IRS)-1 and phosphatidylinositol 3-kinase. At the protein level, oleanolic acid upregulated total IRS-1 expression, suppressed the increased phosphorylated IRS-1 at serine-307, and restored the increased phosphorylated IRS-1 to total IRS-1 ratio. In contrast, phosphorylated Akt to total Akt ratio was increased. Furthermore, oleanolic acid reversed fructose-induced decrease in phosphorylated-Akt/Akt protein to plasma insulin concentration ratio. However, oleanolic acid did not affect IRS-2 mRNA expression. Therefore, these results suggest that oleanolic acid supplement ameliorates fructose-induced Adipo-IR in rats via the IRS-1/phosphatidylinositol 3-kinase/Akt pathway. Our findings may provide new insights into the mechanisms of metabolic actions of oleanolic acid. - Highlights: • Adipose insulin resistance (Adipo-IR) contributes to metabolic abnormalities. • We investigated the effect of oleanolic acid (OA) on adipo-IR in

  5. Insulin resistance in the NIDDM model Psammomys obesus in the normoglycaemic, normoinsulinaemic state.

    PubMed

    Ziv, E; Kalman, R; Hershkop, K; Barash, V; Shafrir, E; Bar-On, H

    1996-11-01

    The desert gerbil Psammomys obesus ("sand rat"), a model of nutritionally induced insulin resistance and non-insulin-dependent diabetes mellitus, was treated after weaning with exogenous insulin implants in the normoglycaemic, normoinsulinaemic state. Albino rats matched for weight and age served as high energy diet adjusted reference animals. Insulin administration, elevating the serum insulin to 6000 pmol/l resulted in only a mild reduction in blood glucose levels in Psammomys, but caused a severe, often fatal hypoglycaemia in the albino rats. The hepatic response to insulin-induced hypoglycaemia in rats involved a significant loss in glycogen and suppression of phosphoenolpyruvate carboxykinase (PEPCK) activity. In Psammomys under similar hyperinsulinaemia no appreciable changes in liver glycogen and PEPCK activity were evident, indicating that blood glucose was replenished by continuing gluconeogenesis. Euglycaemic, hyperinsulinaemic clamp caused a complete shut-down of hepatic glucose production in albino rats. However, in both diabetes-prone and diabetes-resistant Psammomys lines, mean hepatic glucose production was reduced by only 62 to 53% respectively, despite longer lasting and higher levels of hyperinsulinaemia. These results indicate that Psammomys is characterized by muscle and liver insulin resistance prior to diet-induced hyperglycaemia and hyperinsulinaemia. This is assumed to be a species feature of Psammomys, exemplifying a metabolic adjustment to survival in conditions of food scarcity of both animal and human populations. It may reflect a propensity to insulin resistance and hyperglycaemia in population groups exposed to affluent nutrition.

  6. Insulin resistance for glucose metabolism in disused soleus muscle of mice

    NASA Technical Reports Server (NTRS)

    Seider, M. J.; Nicholson, W. F.; Booth, F. W.

    1981-01-01

    Results of this study on mice provide the first direct evidence of insulin resistance for glucose metabolism in skeletal muscle that has undergone a previous period of reduced muscle usage. This lack of responsiveness to insulin developed in one day and in the presence of hypoinsulinemia. Future studies will utilize the model of hindlimb immobilization to determine the causes of these changes.

  7. Odontella aurita-enriched diet prevents high fat diet-induced liver insulin resistance.

    PubMed

    Amine, Hamza; Benomar, Yacir; Haimeur, Adil; Messaouri, Hafida; Meskini, Nadia; Taouis, Mohammed

    2016-01-01

    The beneficial effect of polyunsaturated omega-3 fatty acid (w-3 FA) consumption regarding cardiovascular diseases, insulin resistance and inflammation has been widely reported. Fish oil is considered as the main source of commercialized w-3 FAs, and other alternative sources have been reported such as linseed or microalgae. However, despite numerous reports, the underlying mechanisms of action of w-3 FAs on insulin resistance are still not clearly established, especially those from microalgae. Here, we report that Odontella aurita, a microalga rich in w-3 FAs eicosapentaenoic acid, prevents high fat diet-induced insulin resistance and inflammation in the liver of Wistar rats. Indeed, a high fat diet (HFD) increased plasma insulin levels associated with the impairment of insulin receptor signaling and the up-regulation of toll-like receptor 4 (TLR4) expressions. Importantly, Odontella aurita-enriched HFD (HFOA) reduces body weight and plasma insulin levels and maintains normal insulin receptor expression and responsiveness. Furthermore, HFOA decreased TLR4 expression, JNK/p38 phosphorylation and pro-inflammatory factors. In conclusion, we demonstrate for the first time, to our knowledge, that diet supplementation with whole Ondontella aurita overcomes HFD-induced insulin resistance through the inhibition of TLR4/JNK/p38 MAP kinase signaling pathways.

  8. Odontella aurita-enriched diet prevents high fat diet-induced liver insulin resistance.

    PubMed

    Amine, Hamza; Benomar, Yacir; Haimeur, Adil; Messaouri, Hafida; Meskini, Nadia; Taouis, Mohammed

    2016-01-01

    The beneficial effect of polyunsaturated omega-3 fatty acid (w-3 FA) consumption regarding cardiovascular diseases, insulin resistance and inflammation has been widely reported. Fish oil is considered as the main source of commercialized w-3 FAs, and other alternative sources have been reported such as linseed or microalgae. However, despite numerous reports, the underlying mechanisms of action of w-3 FAs on insulin resistance are still not clearly established, especially those from microalgae. Here, we report that Odontella aurita, a microalga rich in w-3 FAs eicosapentaenoic acid, prevents high fat diet-induced insulin resistance and inflammation in the liver of Wistar rats. Indeed, a high fat diet (HFD) increased plasma insulin levels associated with the impairment of insulin receptor signaling and the up-regulation of toll-like receptor 4 (TLR4) expressions. Importantly, Odontella aurita-enriched HFD (HFOA) reduces body weight and plasma insulin levels and maintains normal insulin receptor expression and responsiveness. Furthermore, HFOA decreased TLR4 expression, JNK/p38 phosphorylation and pro-inflammatory factors. In conclusion, we demonstrate for the first time, to our knowledge, that diet supplementation with whole Ondontella aurita overcomes HFD-induced insulin resistance through the inhibition of TLR4/JNK/p38 MAP kinase signaling pathways. PMID:26459640

  9. Evidence of Insulin Resistance in Adult Uncomplicated Malaria: Result of a Two-Year Prospective Study

    PubMed Central

    Acquah, Samuel; Boampong, Johnson Nyarko; Eghan Jnr, Benjamin Ackon; Eriksson, Magdalena

    2014-01-01

    The study aimed at investigating the effects of adult uncomplicated malaria on insulin resistance. Fasting levels of blood glucose (FBG), glycosylated hemoglobin (HbA1c), and serum insulin were measured in 100 diabetics and 100 age-matched controls before and during Plasmodium falciparum malaria. Insulin resistance and beta cell function were computed by homeostatic models assessment of insulin resistance (HOMAIR) and beta cell function (HOMAB) formulae, respectively. Body mass index (BMI) was computed. At baseline, diabetics had significantly (P < 0.05) higher levels of BMI, FBG, HbA1c, and HOMAIR but lower level of HOMAB than controls. Baseline insulin levels were comparable (P > 0.05) between the two study groups. During malaria, diabetics maintained significantly (P < 0.05) higher levels of BMI, FBG, and HbA1c but lower levels of insulin and HOMAB than controls. Malaria-induced HOMAIR levels were comparable (P > 0.05) between the two study groups but higher than baseline levels. Apart from BMI and HOMAB, mean levels of all the remaining parameters increased in malaria-infected controls. In malaria-infected diabetics, significant (P < 0.05) increase was only observed for insulin and HOMAIR but not the other measured parameters. Uncomplicated malaria increased insulin resistance in diabetics and controls independent of BMI. This finding may have implications for the evolution of T2DM in malaria-endemic regions. PMID:25587486

  10. Insulin

    MedlinePlus

    ... pump is connected to your body by a flexible tube that has a tip that sticks under your skin. A cartridge of insulin is put in the pump. The insulin flows through the tube into your body. The pump controls how much insulin goes into your body. The ...

  11. Insulin and GLP-1 infusions demonstrate the onset of adipose-specific insulin resistance in a large fasting mammal: potential glucogenic role for GLP-1.

    PubMed

    Viscarra, Jose A; Rodriguez, Ruben; Vazquez-Medina, Jose Pablo; Lee, Andrew; Tift, Michael S; Tavoni, Stephen K; Crocker, Daniel E; Ortiz, Rudy M

    2013-08-01

    Prolonged food deprivation increases lipid oxidation and utilization, which may contribute to the onset of the insulin resistance associated with fasting. Because insulin resistance promotes the preservation of glucose and oxidation of fat, it has been suggested to be an adaptive response to food deprivation. However, fasting mammals exhibit hypoinsulinemia, suggesting that the insulin resistance-like conditions they experience may actually result from reduced pancreatic sensitivity to glucose/capacity to secrete insulin. To determine whether fasting results in insulin resistance or in pancreatic dysfunction, we infused early- and late-fasted seals (naturally adapted to prolonged fasting) with insulin (0.065 U/kg), and a separate group of late-fasted seals with low (10 pM/kg) or high (100 pM/kg) dosages of glucagon-like peptide-1 (GLP-1) immediately following a glucose bolus (0.5g/kg), and measured the systemic and cellular responses. Because GLP-1 facilitates glucose-stimulated insulin secretion, these infusions provide a method to assess pancreatic insulin-secreting capacity. Insulin infusions increased the phosphorylation of insulin receptor and Akt in adipose and muscle of early and late fasted seals; however the timing of the signaling response was blunted in adipose of late fasted seals. Despite the dose-dependent increases in insulin and increased glucose clearance (high dose), both GLP-1 dosages produced increases in plasma cortisol and glucagon, which may have contributed to the glucogenic role of GLP-1. Results suggest that fasting induces adipose-specific insulin resistance in elephant seal pups, while maintaining skeletal muscle insulin sensitivity, and therefore suggests that the onset of insulin resistance in fasting mammals is an evolved response to cope with prolonged food deprivation. PMID:23997935

  12. Insulin Resistance: A Proinflammatory State Mediated by Lipid-Induced Signaling Dysfunction and Involved in Atherosclerotic Plaque Instability

    PubMed Central

    Montecucco, Fabrizio; Steffens, Sabine; Mach, François

    2008-01-01

    The dysregulation of the insulin-glucose axis represents the crucial event in insulin resistance syndrome. Insulin resistance increases atherogenesis and atherosclerotic plaque instability by inducing proinflammatory activities on vascular and immune cells. This condition characterizes several diseases, such as type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), obesity, hypertension, dyslipidemia, and other endocrinopathies, but also cancer. Recent studies suggest that the pathophysiology of insulin resistance is closely related to interferences with insulin-mediated intracellular signaling on skeletal muscle cells, hepatocytes, and adipocytes. Strong evidence supports the role of free fatty acids (FFAs) in promoting insulin resistance. The FFA-induced activation of protein kinase C (PKC) delta, inhibitor kappaB kinase (IKK), or c-Jun N-terminal kinase (JNK) modulates insulin-triggered intracellular pathway (classically known as PI3-K-dependent). Therefore, reduction of FFA levels represents a selective target for modulating insulin resistance. PMID:18604303

  13. Anti-CD44 antibody treatment lowers hyperglycemia and improves insulin resistance, adipose inflammation, and hepatic steatosis in diet-induced obese mice.

    PubMed

    Kodama, Keiichi; Toda, Kyoko; Morinaga, Shojiroh; Yamada, Satoru; Butte, Atul J

    2015-03-01

    Type 2 diabetes (T2D) is a metabolic disease affecting >370 million people worldwide. It is characterized by obesity-induced insulin resistance, and growing evidence has indicated that this causative link between obesity and insulin resistance is associated with visceral adipose tissue inflammation. However, using anti-inflammatory drugs to treat insulin resistance and T2D is not a common practice. We recently applied a bioinformatics methodology to open public data and found that CD44 plays a critical role in the development of adipose tissue inflammation and insulin resistance. In this report, we examined the role of CD44 in T2D by administering daily injections of anti-CD44 monoclonal antibody (mAb) in a high-fat-diet mouse model. Four weeks of therapy with CD44 mAb suppressed visceral adipose tissue inflammation compared with controls and reduced fasting blood glucose levels, weight gain, liver steatosis, and insulin resistance to levels comparable to or better than therapy with the drugs metformin and pioglitazone. These findings suggest that CD44 mAb may be useful as a prototype drug for therapy of T2D by breaking the links between obesity and insulin resistance.

  14. S961, an insulin receptor antagonist causes hyperinsulinemia, insulin-resistance and depletion of energy stores in rats

    SciTech Connect

    Vikram, Ajit; Jena, Gopabandhu

    2010-07-23

    Research highlights: {yields}Insulin receptor antagonist S961 causes hyperglycemia, hyperinsulinemia and insulin resistance in rats. {yields}Peroxysome-proliferator-activated-receptor-gamma agonist pioglitazone improves S961 induced hyperglycemia and glucose intolerance. {yields}Long term treatment with insulin receptor antagonist S961 results in the decreased adiposity and hepatic glycogen content. {yields}Improvement in the hyperglycemia and glucose intolerance by pioglitazone clearly demonstrates that S961 treated rats can be successfully used to screen the novel therapeutic interventions having potential to improve glucose disposal through receptor independent mechanisms. -- Abstract: Impairment in the insulin receptor signaling and insulin mediated effects are the key features of type 2 diabetes. Here we report that S961, a peptide insulin receptor antagonist induces hyperglycemia, hyperinsulinemia ({approx}18-fold), glucose intolerance and impairment in the insulin mediated glucose disposal in the Sprague-Dawley rats. Further, long-term S961 treatment (15 day, 10 nM/kg/day) depletes energy storage as evident from decrease in the adiposity and hepatic glycogen content. However, peroxysome-proliferator-activated-receptor-gamma (PPAR{gamma}) agonist pioglitazone significantly (P < 0.001) restored S961 induced hyperglycemia (196.73 {+-} 16.32 vs. 126.37 {+-} 27.07 mg/dl) and glucose intolerance ({approx}78%). Improvement in the hyperglycemia and glucose intolerance by pioglitazone clearly demonstrates that S961 treated rats can be successfully used to screen the novel therapeutic interventions having potential to improve glucose disposal through receptor independent mechanisms. Further, results of the present study reconfirms and provide direct evidence to the crucial role of insulin receptor signaling in the glucose homeostasis and fuel metabolism.

  15. 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. PMID:25230322

  16. An extract of Urtica dioica L. mitigates obesity induced insulin resistance in mice skeletal muscle via protein phosphatase 2A (PP2A).

    PubMed

    Obanda, Diana N; Ribnicky, David; Yu, Yongmei; Stephens, Jacqueline; Cefalu, William T

    2016-01-01

    The leaf extract of Urtica dioica L. (UT) has been reported to improve glucose homeostasis in vivo, but definitive studies on efficacy and mechanism of action are lacking. We investigated the effects of UT on obesity- induced insulin resistance in skeletal muscle. Male C57BL/6J mice were divided into three groups: low-fat diet (LFD), high-fat diet (HFD) and HFD supplemented with UT. Body weight, body composition, plasma glucose and plasma insulin were monitored. Skeletal muscle (gastrocnemius) was analyzed for insulin sensitivity, ceramide accumulation and the post translational modification and activity of protein phosphatase 2A (PP2A). PP2A is activated by ceramides and dephosphorylates Akt. C2C12 myotubes exposed to excess free fatty acids with or without UT were also evaluated for insulin signaling and modulation of PP2A. The HFD induced insulin resistance, increased fasting plasma glucose, enhanced ceramide accumulation and PP2A activity in skeletal muscle. Supplementation with UT improved plasma glucose homeostasis and enhanced skeletal muscle insulin sensitivity without affecting body weight and body composition. In myotubes, UT attenuated the ability of FFAs to induce insulin resistance and PP2A hyperactivity without affecting ceramide accumulation and PP2A expression. UT decreased PP2A activity through posttranslational modification that was accompanied by a reduction in Akt dephosphorylation. PMID:26916435

  17. An extract of Urtica dioica L. mitigates obesity induced insulin resistance in mice skeletal muscle via protein phosphatase 2A (PP2A)

    PubMed Central

    Obanda, Diana N.; Ribnicky, David; Yu, Yongmei; Stephens, Jacqueline; Cefalu, William T.

    2016-01-01

    The leaf extract of Urtica dioica L. (UT) has been reported to improve glucose homeostasis in vivo, but definitive studies on efficacy and mechanism of action are lacking. We investigated the effects of UT on obesity- induced insulin resistance in skeletal muscle. Male C57BL/6J mice were divided into three groups: low-fat diet (LFD), high-fat diet (HFD) and HFD supplemented with UT. Body weight, body composition, plasma glucose and plasma insulin were monitored. Skeletal muscle (gastrocnemius) was analyzed for insulin sensitivity, ceramide accumulation and the post translational modification and activity of protein phosphatase 2A (PP2A). PP2A is activated by ceramides and dephosphorylates Akt. C2C12 myotubes exposed to excess free fatty acids with or without UT were also evaluated for insulin signaling and modulation of PP2A. The HFD induced insulin resistance, increased fasting plasma glucose, enhanced ceramide accumulation and PP2A activity in skeletal muscle. Supplementation with UT improved plasma glucose homeostasis and enhanced skeletal muscle insulin sensitivity without affecting body weight and body composition. In myotubes, UT attenuated the ability of FFAs to induce insulin resistance and PP2A hyperactivity without affecting ceramide accumulation and PP2A expression. UT decreased PP2A activity through posttranslational modification that was accompanied by a reduction in Akt dephosphorylation. PMID:26916435

  18. Effects of Noise Exposure on Systemic and Tissue-Level Markers of Glucose Homeostasis and Insulin Resistance in Male Mice

    PubMed Central

    Liu, Lijie; Wang, Fanfan; Lu, Haiying; Cao, Shuangfeng; Du, Ziwei; Wang, Yongfang; Feng, Xian; Gao, Ye; Zha, Mingming; Guo, Min; Sun, Zilin; Wang, Jian

    2016-01-01

    Background: Epidemiological studies have indicated that noise exposure is associated with an increased risk of type 2 diabetes mellitus (T2DM). However, the nature of the connection between noise exposure and T2DM remains to be explored. Objectives: We explored whether and how noise exposure affects glucose homeostasis in mice as the initial step toward T2DM development. Methods: Male ICR mice were randomly assigned to one of four groups: the control group and three noise groups (N20D, N10D, and N1D), in which the animals were exposed to white noise at 95 decibel sound pressure level (dB SPL) for 4 hr per day for 20 successive days, 10 successive days, or 1 day, respectively. Glucose tolerance and insulin sensitivity were evaluated 1 day, 1 week, and 1 month after the final noise exposure (1DPN, 1WPN, and 1MPN). Standard immunoblots, immunohistochemical methods, and enzyme-linked immunosorbent assays (ELISA) were performed to assess insulin signaling in skeletal muscle, the morphology of β cells, and plasma corticosterone levels. Results: Noise exposure for 1 day caused transient glucose intolerance and insulin resistance, whereas noise exposure for 10 and 20 days had no effect on glucose tolerance but did cause prolonged insulin resistance and an increased insulin response to glucose challenge. Akt phosphorylation and GLUT4 translocation in response to exogenous insulin were decreased in the skeletal muscle of noise-exposed animals. Conclusions: Noise exposure at 95 dB SPL caused insulin resistance in male ICR mice, which was prolonged with longer noise exposure and was likely related to the observed blunted insulin signaling in skeletal muscle. Citation: Liu L, Wang F, Lu H, Cao S, Du Z, Wang Y, Feng X, Gao Y, Zha M, Guo M, Sun Z, Wang J. 2016. Effects of noise exposure on systemic and tissue-level markers of glucose homeostasis and insulin resistance in male mice. Environ Health Perspect 124:1390–1398; http://dx.doi.org/10.1289/EHP162 PMID:27128844

  19. 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

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

    PubMed

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

    2016-01-01

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

  1. (-)-Epicatechin mitigates high fructose-associated insulin resistance by modulating redox signaling and endoplasmic reticulum stress

    PubMed Central

    Bettaieb, Ahmed; Vazquez Prieto, Marcela A.; Rodriguez Lanzi, Cecilia; Miatello, Roberto M.; Haj, Fawaz G.; Fraga, César G.; Oteiza, Patricia I.

    2014-01-01

    We investigated the capacity of dietary (-)-epicatechin (EC) to mitigate insulin resistance through the modulation of redox-regulated mechanisms in a rat model of metabolic syndrome (MetS). Adolescent rats were fed a regular chow diet without or with high fructose (HFr) (10% (w/v)) in drinking water for 8 weeks, and a group of HFr-fed rats was supplemented with EC in the diet. HFr-fed rats developed insulin resistance which was mitigated by EC supplementation. Accordingly, the activation of components of the insulin signaling cascade (insulin receptor (IR), IRS-1, Akt and ERK1/2) was impaired, while negative regulators (PKC, IKK, JNK and PTP1B) were upregulated in the liver and adipose tissue of HFr rats. These alterations were partially or totally prevented by EC supplementation. In addition, EC inhibited events which contribute to insulin resistance: HFr-associated increased expression and activity of NADPH oxidase, activation of redox-sensitive signals, expression of NF-κB-regulated pro-inflammatory cytokines and chemokines, and some sub-arms of endoplasmic reticulum stress signaling. Collectively, these findings indicate that EC supplementation can mitigate HFr-induced insulin resistance and are relevant to define interventions that can prevent/mitigate MetS-associated insulin resistance. PMID:24746618

  2. Diabetes, Insulin Resistance, and Metabolic Syndrome in Horses

    PubMed Central

    Johnson, Philip J.; Wiedmeyer, Charles E.; LaCarrubba, Alison; Ganjam, V. K. (Seshu); Messer, Nat T.

    2012-01-01

    Analogous to the situation in human medicine, contemporary practices in horse management, which incorporate lengthy periods of physical inactivity coupled with provision of nutritional rations characterized by inappropriately high sugar and starch, have led to obesity being more commonly recognized by practitioners of equine veterinary practice. In many of these cases, obesity is associated with insulin resistance (IR) and glucose intolerance. An equine metabolic syndrome (MS) has been described that is similar to the human MS in that both IR and aspects of obesity represent cornerstones of its definition. Unlike its human counterpart, identification of the equine metabolic syndrome (EMS) portends greater risk for development of laminitis, a chronic, crippling affliction of the equine hoof. When severe, laminitis sometimes necessitates euthanasia. Unlike the human condition, the risk of developing type 2 diabetes mellitus and many other chronic conditions, for which the risk is recognized as increased in the face of MS, is less likely in horses. The equine veterinary literature has been replete with reports of scientific investigations regarding the epidemiology, pathophysiology, and treatment of EMS. PMID:22768883

  3. Interacting epidemics? Sleep curtailment, insulin resistance, and obesity

    PubMed Central

    Lucassen, Eliane A; Rother, Kristina I; Cizza, Giovanni

    2012-01-01

    In the last 50 years, the average self-reported sleep duration in the United States has decreased by 1.5–2 hours in parallel with an increasing prevalence of obesity and diabetes. Epidemiological studies and meta-analyses report a strong relationship between short or disturbed sleep, obesity, and abnormalities in glucose metabolism. This relationship is likely to be bidirectional and causal in nature, but many aspects remain to be elucidated. Sleep and the internal circadian clock influence a host of endocrine parameters. Sleep curtailment in humans alters multiple metabolic pathways, leading to more insulin resistance, possibly decreased energy expenditure, increased appetite, and immunological changes. On the other hand, psychological, endocrine, and anatomical abnormalities in individuals with obesity and/or diabetes can interfere with sleep duration and quality, thus creating a vicious cycle. In this review, we address mechanisms linking sleep with metabolism, highlight the need for studies conducted in real-life settings, and explore therapeutic interventions to improve sleep, with a potential beneficial effect on obesity and its comorbidities. PMID:22827862

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

    PubMed Central

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

    2015-01-01

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

  5. Link between insulin resistance and hypertension: What is the evidence from evolutionary biology?

    PubMed Central

    2014-01-01

    Insulin resistance and hypertension are considered as prototypical “diseases of civilization” that are manifested in the modern environment as plentiful food and sedentary life. The human propensity for insulin resistance and hypertension is a product, at least in part, of our evolutionary history. Adaptation to ancient lifestyle characterized by a low sodium, low-calorie food supply and physical stress to injury response has driven our evolution to shape and preserve a thrifty genotype, which is favorite with energy-saving and sodium conservation. As our civilization evolved, a sedentary lifestyle and sodium- and energy-rich diet, the thrifty genotype is no longer advantageous, and may be maladaptive to disease phenotype, such as hypertension, obesity and insulin resistance syndrome. This article reviews human evolution and the impact of the modern environment on hypertension and insulin resistance. PMID:24485020

  6. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance.

    PubMed

    Holland, William L; Brozinick, Joseph T; Wang, Li-Ping; Hawkins, Eric D; Sargent, Katherine M; Liu, Yanqi; Narra, Krishna; Hoehn, Kyle L; Knotts, Trina A; Siesky, Angela; Nelson, Don H; Karathanasis, Sotirios K; Fontenot, Greg K; Birnbaum, Morris J; Summers, Scott A

    2007-03-01

    Insulin resistance occurs in 20%-25% of the human population, and the condition is a chief component of type 2 diabetes mellitus and a risk factor for cardiovascular disease and certain forms of cancer. Herein, we demonstrate that the sphingolipid ceramide is a common molecular intermediate linking several different pathological metabolic stresses (i.e., glucocorticoids and saturated fats, but not unsaturated fats) to the induction of insulin resistance. Moreover, inhibition of ceramide synthesis markedly improves glucose tolerance and prevents the onset of frank diabetes in obese rodents. Collectively, these data have two important implications. First, they indicate that different fatty acids induce insulin resistance by distinct mechanisms discerned by their reliance on sphingolipid synthesis. Second, they identify enzymes required for ceramide synthesis as therapeutic targets for combating insulin resistance caused by nutrient excess or glucocorticoid therapy.

  7. A Stress Signaling Pathway in Adipose Tissue Regulates Hepatic Insulin Resistance

    PubMed Central

    Sabio, Guadalupe; Das, Madhumita; Mora, Alfonso; Zhang, Zhiyou; Jun, John Y.; Ko, Hwi Jin; Barrett, Tamera; Kim, Jason K.; Davis, Roger J.

    2008-01-01

    A high-fat diet causes activation of the regulatory protein cJun NH2-terminal kinase 1 (JNK1) and triggers the development of insulin resistance. JNK1 is therefore a potential target for therapeutic treatment of metabolic syndrome. We explored the mechanism of JNK1 signaling by engineering mice in which the Jnk1 gene was ablated selectively in adipose tissue. JNK1-deficiency in adipose tissue suppressed high fat diet-induced insulin resistance in the liver. JNK1-dependent secretion of the inflammatory cytokine IL6 by adipose tissue caused increased expression of liver SOCS3, a protein that induces hepatic insulin resistance. Thus, JNK1 activation in adipose tissue can cause insulin resistance in the liver. PMID:19056984

  8. Insulin Resistance and Endothelial Dysfunction Constitute a Common Therapeutic Target in Cardiometabolic Disorders

    PubMed Central

    Mazur, G.

    2016-01-01

    Insulin resistance and other risk factors for atherosclerosis, such as hypertension and hypercholesterolemia, promote endothelial dysfunction and lead to development of metabolic syndrome which constitutes an introduction to cardiovascular disease. The insulin resistance and endothelial dysfunction cross talk between each other by numerous metabolic pathways. Hence, targeting one of these pathologies with pleiotropic treatment exerts beneficial effect on another one. Combined and expletive treatment of hypertension, lipid disorders, and insulin resistance with nonpharmacological interventions and conventional pharmacotherapy may inhibit the transformation of metabolic disturbances to fully developed cardiovascular disease. This paper summarises the common therapeutic targets for insulin resistance, endothelial dysfunction, and vascular inflammatory reaction at molecular level and analyses the potential pleiotropic effects of drugs used currently in management of cardiovascular disease, metabolic syndrome, and diabetes. PMID:27413253

  9. Red blood cell sodium-proton exchange in hypertensive blacks with insulin-resistant glucose disposal.

    PubMed

    Canessa, M; Falkner, B; Hulman, S

    1993-08-01

    To define the potential pathogenic role of hyperinsulinemia as a mediator of alterations in sodium transport, we have examined red blood cell Na(+)-H+ and Na(+)-Li+ exchanges in a young adult black population characterized for blood pressure and insulin-mediated glucose disposal. Normotensive and mildly hypertensive blacks (blood pressure, 120 +/- 2/76 +/- 2 and 139 +/- 3/94 +/- 2 mm Hg, respectively) with a mean age of 26.1 years were studied for insulin sensitivity with the euglycemic hyperinsulinemic clamp (molar index of insulin sensitivity, M/I = moles glucose metabolized/insulin in milliliters of plasma). Na(+)-H+ exchange (U = mmol/L cell.h) was measured before and after the insulin clamp as a function of cell pH to determine the maximum transport rate. In the normotensive subjects, 18 were insulin sensitive (M/I = 9.37 +/- 0.6 x 10(4)) and 4 were insulin resistant (M/I = 3.64 +/- 0.6 x 10(4)). In the hypertensive subjects, 4 were insulin sensitive (M/I = 9.15 +/- 1.1 x 10(4)) and 16 were insulin resistant (M/I = 3.02 +/- 0.3 x 10(4)). The maximum rate of Na(+)-H+ exchange was significantly higher in all hypertensive vs normotensive individuals (35 +/- 3 vs 23 +/- 3 U, P < .005). Na(+)-H+ exchange activity was higher in insulin-resistant vs insulin-sensitive hypertensive subjects (40 +/- 3 vs 20 +/- 2 U, P < .001) but not in insulin-resistant normotensive subjects. Na(+)-Li+ exchange was not different in hypertensive and normotensive individuals but was higher in all insulin-resistant compared with all insulin-sensitive subjects (0.26 +/- 0.03 vs 0.16 +/- 0.02 U, P < .01). Na(+)-Li+ exchange also was higher in insulin-resistant vs insulin-sensitive normotensive subjects (0.35 +/- 0.03 vs 0.15 +/- 0.02 U, P < .001) and in insulin-resistant hypertensive subjects vs insulin-sensitive normotensive subjects (0.24 +/- 0.03 vs 0.15 +/- 0.02 U, P < .001). A stepwise multiple regression analysis for all variables revealed that with Na(+)-H+ exchange as a dependent

  10. A single night of sleep curtailment increases plasma acylcarnitines: Novel insights in the relationship between sleep and insulin resistance.

    PubMed

    van den Berg, Rosa; Mook-Kanamori, Dennis O; Donga, Esther; van Dijk, Marieke; van Dijk, J Gert; Lammers, Gert-Jan; van Kralingen, Klaas W; Prehn, Cornelia; Adamski, Jerzy; Romijn, Johannes A; van Dijk, Ko Willems; Corssmit, Eleonora P M; Rensen, Patrick C N; Biermasz, Nienke R

    2016-01-01

    We have previously shown that acute sleep curtailment induces insulin resistance, both in healthy individuals as well as in patients with type 1 diabetes, suggesting a causal role for sleep disturbances in pathogenesis of insulin resistance, independent of endogenous insulin production. However, the underlying mechanisms remain unclear. This study aimed to explore the metabolic pathways affected by sleep loss using targeted metabolomics in human fasting plasma samples. Healthy individuals (n = 9) and patients with type 1 diabetes (n = 7) were studied after a single night of short sleep (4 h) versus normal sleep (8 h) in a cross-over design. Strikingly, one night of short sleep specifically increased the plasma levels of acylcarnitines, essential intermediates in mitochondrial fatty acid oxidation (FAO). Specifically, short sleep increased plasma levels of tetradecenoyl-l-carnitine (C14:1) (+32%, p = 2.67*10(-4)), octadecanoyl-l-carnitine (C18:1) (+22%, p = 1.92*10(-4)) and octadecadienyl-l-carnitine (C18:2) (+27%, p = 1.32*10(-4)). Since increased plasma acylcarnitine levels could be a sign of disturbed FAO, it is possible that sleep curtailment acutely induces inefficient mitochondrial function. Our observations provide a basis for further research into the role of acylcarnitines as a potential mechanistic pathway by which sleep deprivation - even short term - causes adverse metabolic effects, such as insulin resistance.

  11. Insulin resistance and delayed clearance of peptide hormones in cirrhotic rat liver.

    PubMed

    Shankar, T P; Drake, S; Solomon, S S

    1987-06-01

    Clearance of porcine insulin, glucagon, and human growth hormone was measured in intact perfused cirrhotic and normal rat livers. Binding and degradation of 125I-insulin by hepatocytes isolated from cirrhotic and normal livers were also studied. The half-lives (t1/2) of immunoreactive insulin and glucagon were 14.0 +/- 3.1 and 9.6 +/- 2.1 min in normal livers and 26.0 +/- 6.1 and 25.0 +/- 7.1 min in cirrhotic livers (P less than 0.001). Insulin binding and degradation by hepatocytes from control and cirrhotic livers showed no significant differences. Intraportal insulin infusion in perfusion studies suppressed glucagon-stimulated increases in glucose output from control livers but failed to suppress glucose production by cirrhotic livers, suggesting the presence of hepatic insulin resistance in cirrhosis. Impaired clearance of insulin and glucagon by the intact cirrhotic liver and normal binding and degradation of insulin by isolated hepatocytes suggest that factors such as intrahepatic fibrosis and shunting and postbinding defects may be responsible for the impaired hormone clearance and hepatic insulin resistance. PMID:3296781

  12. Insulin resistance and delayed clearance of peptide hormones in cirrhotic rat liver

    SciTech Connect

    Shankar, T.P.; Drake, S.; Solomon, S.S.

    1987-06-01

    Clearance of porcine insulin, glucagon, and human growth hormone was measured in intact perfused cirrhotic and normal rat livers. Binding and degradation of /sup 125/I-insulin by hepatocytes isolated from cirrhotic and normal livers were also studied. The half-lives (t/sub 1/2/) of immunoreactive insulin and glucagon were 14.0 +/- 3.1 and 9.6 +/- 2.1 min in normal livers and 26.0 +/- 6.1 and 25.0 +/- 7.1 min in cirrhotic livers. Insulin binding and degradation by hepatocytes from control and cirrhotic livers showed no significant differences. Intraportal insulin infusion in perfusion studies suppressed glucagon-stimulated increases in glucose output from control livers but failed to suppress glucose production by cirrhotic livers, suggesting the presence of hepatic insulin resistance in cirrhosis. Impaired clearance of insulin and glucagon by the intact cirrhotic liver and normal binding and degradation of insulin by isolated hepatocytes suggest that factors such as intrahepatic fibrosis and shunting and postbinding defects may be responsible for the impaired hormone clearance and hepatic insulin resistance.

  13. The Insulin/IGF System in Colorectal Cancer Development and Resistance to Therapy.

    PubMed

    Vigneri, Paolo Giovanni; Tirrò, Elena; Pennisi, Maria Stella; Massimino, Michele; Stella, Stefania; Romano, Chiara; Manzella, Livia

    2015-01-01

    The insulin/insulin-like growth factor (IGF) system is a major determinant in the pathogenesis and progression of colorectal cancer (CRC). Indeed, several components of this signaling network, including insulin, IGF-1, IGF-2, the IGF-binding proteins, the insulin receptor (IR), the IGF-1 receptor (IGF-1R), and IR substrate proteins 1 and 2 contribute to the transformation of normal colon epithelial cells. Moreover, the insulin/IGF system is also implicated in the development of resistance to both chemotherapeutic drugs and epidermal growth factor receptor targeted agents. The identification of hybrid receptors comprising both the IR and IGF-1R adds further complexity to this signaling network. Thus, a comprehensive understanding of the biological functions performed by each component of the insulin/IGF system is required to design successful drugs for the treatment of CRC patients. PMID:26528439

  14. The Insulin/IGF System in Colorectal Cancer Development and Resistance to Therapy

    PubMed Central

    Vigneri, Paolo Giovanni; Tirrò, Elena; Pennisi, Maria Stella; Massimino, Michele; Stella, Stefania; Romano, Chiara; Manzella, Livia

    2015-01-01

    The insulin/insulin-like growth factor (IGF) system is a major determinant in the pathogenesis and progression of colorectal cancer (CRC). Indeed, several components of this signaling network, including insulin, IGF-1, IGF-2, the IGF-binding proteins, the insulin receptor (IR), the IGF-1 receptor (IGF-1R), and IR substrate proteins 1 and 2 contribute to the transformation of normal colon epithelial cells. Moreover, the insulin/IGF system is also implicated in the development of resistance to both chemotherapeutic drugs and epidermal growth factor receptor targeted agents. The identification of hybrid receptors comprising both the IR and IGF-1R adds further complexity to this signaling network. Thus, a comprehensive understanding of the biological functions performed by each component of the insulin/IGF system is required to design successful drugs for the treatment of CRC patients. PMID:26528439

  15. (Pro)renin receptor in skeletal muscle is involved in the development of insulin resistance associated with postinfarct heart failure in mice.

    PubMed

    Fukushima, Arata; Kinugawa, Shintaro; Takada, Shingo; Matsushima, Shouji; Sobirin, Mochamad Ali; Ono, Taisuke; Takahashi, Masashige; Suga, Tadashi; Homma, Tsuneaki; Masaki, Yoshihiro; Furihata, Takaaki; Kadoguchi, Tomoyasu; Yokota, Takashi; Okita, Koichi; Tsutsui, Hiroyuki

    2014-09-15

    We previously reported that insulin resistance was induced by the impairment of insulin signaling in the skeletal muscle from heart failure (HF) via NAD(P)H oxidase-dependent oxidative stress. (Pro)renin receptor [(P)RR] is involved in the activation of local renin-angiotensin system and subsequent oxidative stress. We thus examined whether (P)RR inhibitor, handle region peptide (HRP), could ameliorate insulin resistance in HF after myocardial infarction (MI) by improving oxidative stress and insulin signaling in the skeletal muscle. C57BL6J mice were divided into four groups: sham operated (Sham, n = 10), Sham treated with HRP (Sham+HRP, 0.1 mg·kg(-1)·day(-1), n = 10), MI operated (MI, n = 10), and MI treated with HRP (MI+HRP, 0.1 mg/kg/day, n = 10). After 4 wk, MI mice showed left ventricular dysfunction, which was not affected by HRP. (P)RR was upregulated in the skeletal muscle after MI (149% of sham, P < 0.05). The decrease in plasma glucose after insulin load was smaller in MI than in Sham (21 ± 2 vs. 44 ± 3%, P < 0.05), and was greater in MI+HRP (38 ± 2%, P < 0.05) than in MI. Insulin-stimulated serine phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle from MI by 48 and 49% of Sham, both of which were ameliorated in MI+HRP. Superoxide production and NAD(P)H oxidase activities were increased in MI, which was inhibited in MI+HRP. HRP ameliorated insulin resistance associated with HF by improving insulin signaling via the inhibition of NAD(P)H oxidase-induced superoxide production in the skeletal muscle. The (P)RR pathway is involved in the development of insulin resistance, at least in part, via the impairment of insulin signaling in the skeletal muscle from HF.

  16. Chlorogenic Acid Improves High Fat Diet-Induced Hepatic Steatosis and Insulin Resistance in Mice

    PubMed Central

    Ma, Yongjie; Gao, Mingming

    2015-01-01

    Purpose Chlorogenic acid (CGA), the most abundant component in coffee, has exhibited many biological activities. The objective of this study is to assess preventive and therapeutic effects of CGA on obesity and obesity-related liver steatosis and insulin resistance. Methods Two sets of experiments were conducted. In set 1, 6-week old C57BL/6 mice were fed a regular chow or high-fat diet (HFD) for 15 weeks with twice intra-peritoneal (IP) injection of CGA (100 mg/kg) or DMSO (carrier solution) per week. In set 2, obese mice (average 50 g) were treated by CGA (100 mg/kg, IP, twice weekly) or DMSO for 6 weeks. Body weight, body composition and food intake were monitored. Blood glucose, insulin and lipid levels were measured at end of the study. Hepatic lipid accumulation and glucose homeostasis were evaluated. Additionally, genes involved in lipid metabolism and inflammation were analyzed by real time PCR. Results CGA significantly blocked the development of diet-induced obesity but did not affect body weight in obese mice. CGA treatment curbed HFD-induced hepatic steatosis and insulin resistance. Quantitative PCR analysis shows that CGA treatment suppressed hepatic expression Pparγ, Cd36, Fabp4, and Mgat1 gene. CGA treatment also attenuated inflammation in the liver and white adipose tissue accompanied by a decrease in mRNA levels of macrophage marker genes including F4/80, Cd68, Cd11b, Cd11c, and Tnfa, Mcp-1 and Ccr2 encoding inflammatory proteins. Conclusion Our study provides direct evidence in support of CGA as a potent compound in preventing diet-induced obesity and obesity-related metabolic syndrome. Our results suggest that drinking coffee is beneficial in maintaining metabolic homeostasis when on a high fat diet. PMID:25248334

  17. In Vivo Interrelationship between Insulin Resistance and Interferon Gamma Production: Protective and Therapeutic Effect of Berberine

    PubMed Central

    Sahyoun, Heba Abdelghany; Elshehawy, Ashraf Abdelhamed; Elsayed, Mohammad Mohammad

    2016-01-01

    This research was conducted to investigate if there is a relation between insulin resistance incidence and inhibition of interferon gamma production or not. Firstly, insulin resistance was induced by high fat diet (HFD) intake for 6 weeks. Secondly, berberine was used as protective/curative compound for insulin resistance. Results revealed that feeding rats HFD for 6 weeks developed features of insulin resistance (IR) syndrome. These features presented in increased body weight, hyperglycemia, hyperinsulinemia, hypercholesterolemia (with increased LDL-cholesterol and decreased HDL-cholesterol), and hypertriglyceridemia. Level of antioxidant enzymes in HFD group was higher than in normal one. Also there was an increasing in level of proinflammatory cytokines as interleukin- (IL-) 6 and IL-12 in HFD group. Feeding rats HFD for 6 weeks also decreased level of interferon gamma (IFN-γ). The decreased level of IFN-γ has been shown to predict infection with infectious diseases especially viral infection. Treatment and protection with berberine 50 mg/kg/day for 2 weeks were found to be effective against the features of insulin resistance syndrome, improved levels of insulin resistance parameters, lipid profile, antioxidant enzymes, proinflammatory cytokines, and IFN-γ. PMID:27642351

  18. Does Diacylglycerol Accumulation in Fatty Liver Disease Cause Hepatic Insulin Resistance?

    PubMed Central

    Finck, Brian N.; Hall, Angela M.

    2015-01-01

    Numerous studies conducted on obese humans and various rodent models of obesity have identified a correlation between hepatic lipid content and the development of insulin resistance in liver and other tissues. Despite a large body of the literature on this topic, the cause and effect relationship between hepatic steatosis and insulin resistance remains controversial. If, as many believe, lipid aggregation in liver drives insulin resistance and other metabolic abnormalities, there are significant unanswered questions as to which lipid mediators are causative in this cascade. Several published papers have now correlated levels of diacylglycerol (DAG), the penultimate intermediate in triglyceride synthesis, with development of insulin resistance and have postulated that this occurs via activation of protein kinase C signaling. Although many studies have confirmed this relationship, many others have reported a disconnect between DAG content and insulin resistance. It has been postulated that differences in methods for DAG measurement, DAG compartmentalization within the cell, or fatty acid composition of the DAG may explain these discrepancies. The purpose of this review is to compare and contrast some of the relevant findings in this area and to discuss a number of unanswered questions regarding the relationship between DAG and insulin resistance. PMID:26273583

  19. In Vivo Interrelationship between Insulin Resistance and Interferon Gamma Production: Protective and Therapeutic Effect of Berberine

    PubMed Central

    Sahyoun, Heba Abdelghany; Elshehawy, Ashraf Abdelhamed; Elsayed, Mohammad Mohammad

    2016-01-01

    This research was conducted to investigate if there is a relation between insulin resistance incidence and inhibition of interferon gamma production or not. Firstly, insulin resistance was induced by high fat diet (HFD) intake for 6 weeks. Secondly, berberine was used as protective/curative compound for insulin resistance. Results revealed that feeding rats HFD for 6 weeks developed features of insulin resistance (IR) syndrome. These features presented in increased body weight, hyperglycemia, hyperinsulinemia, hypercholesterolemia (with increased LDL-cholesterol and decreased HDL-cholesterol), and hypertriglyceridemia. Level of antioxidant enzymes in HFD group was higher than in normal one. Also there was an increasing in level of proinflammatory cytokines as interleukin- (IL-) 6 and IL-12 in HFD group. Feeding rats HFD for 6 weeks also decreased level of interferon gamma (IFN-γ). The decreased level of IFN-γ has been shown to predict infection with infectious diseases especially viral infection. Treatment and protection with berberine 50 mg/kg/day for 2 weeks were found to be effective against the features of insulin resistance syndrome, improved levels of insulin resistance parameters, lipid profile, antioxidant enzymes, proinflammatory cytokines, and IFN-γ.

  20. In Vivo Interrelationship between Insulin Resistance and Interferon Gamma Production: Protective and Therapeutic Effect of Berberine.

    PubMed

    Mahmoud, Mohammad Ahmad; Ghareeb, Doaa Ahmad; Sahyoun, Heba Abdelghany; Elshehawy, Ashraf Abdelhamed; Elsayed, Mohammad Mohammad

    2016-01-01

    This research was conducted to investigate if there is a relation between insulin resistance incidence and inhibition of interferon gamma production or not. Firstly, insulin resistance was induced by high fat diet (HFD) intake for 6 weeks. Secondly, berberine was used as protective/curative compound for insulin resistance. Results revealed that feeding rats HFD for 6 weeks developed features of insulin resistance (IR) syndrome. These features presented in increased body weight, hyperglycemia, hyperinsulinemia, hypercholesterolemia (with increased LDL-cholesterol and decreased HDL-cholesterol), and hypertriglyceridemia. Level of antioxidant enzymes in HFD group was higher than in normal one. Also there was an increasing in level of proinflammatory cytokines as interleukin- (IL-) 6 and IL-12 in HFD group. Feeding rats HFD for 6 weeks also decreased level of interferon gamma (IFN-γ). The decreased level of IFN-γ has been shown to predict infection with infectious diseases especially viral infection. Treatment and protection with berberine 50 mg/kg/day for 2 weeks were found to be effective against the features of insulin resistance syndrome, improved levels of insulin resistance parameters, lipid profile, antioxidant enzymes, proinflammatory cytokines, and IFN-γ. PMID:27642351

  1. The role of uric acid in the insulin resistance in children and adolescents with obesity

    PubMed Central

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

    2015-01-01

    Objective: To investigate the association between serum uric acid levels and insulin resistance in children and adolescents with obesity. Methods: Cross-sectional study with 245 children and adolescents (134 obese and 111 controls), aged 8-18 years. The anthropometric variables (weight, height and waist circumference), blood pressure and biochemical parameters were collected. The clinical characteristics of the groups were analyzed by t-test or chi-square test. To evaluate the association between uric acid levels and insulin resistance the Pearson's test and logistic regression were applied. Results: The prevalence of insulin resistance was 26.9%. The anthropometric variables, systolic and diastolic blood pressure and biochemical variables were significantly higher in the obese group (p<0.001), except for the high-density-lipoprotein cholesterol. There was a positive and significant correlation between anthropometric variables and uric acid with HOMA-IR in the obese and in the control groups, which was higher in the obese group and in the total sample. The logistic regression model that included age, gender and obesity, showed an odds ratio of uric acid as a variable associated with insulin resistance of 1.91 (95%CI 1.40-2.62; p<−0.001). Conclusions: The increase in serum uric acid showed a positive statistical correlation with insulin resistance and it is associated with and increased risk of insulin resistance in obese children and adolescents. PMID:26300523

  2. Why can insulin resistance be a natural consequence of thyroid dysfunction?

    PubMed

    Brenta, Gabriela

    2011-01-01

    Evidence for a relationship between T4 and T3 and glucose metabolism appeared over 100 years ago when the influence of thyroid hormone excess in the deterioration of glucose metabolism was first noticed. Since then, it has been known that hyperthyroidism is associated with insulin resistance. More recently, hypothyroidism has also been linked to decreased insulin sensitivity. The explanation to this apparent paradox may lie in the differential effects of thyroid hormones at the liver and peripheral tissues level. The purpose of this paper is to explore the effects of thyroid hormones in glucose metabolism and analyze the mechanisms whereby alterations of thyroid hormones lead to insulin resistance. PMID:21941681

  3. Why can insulin resistance be a natural consequence of thyroid dysfunction?

    PubMed

    Brenta, Gabriela

    2011-01-01

    Evidence for a relationship between T4 and T3 and glucose metabolism appeared over 100 years ago when the influence of thyroid hormone excess in the deterioration of glucose metabolism was first noticed. Since then, it has been known that hyperthyroidism is associated with insulin resistance. More recently, hypothyroidism has also been linked to decreased insulin sensitivity. The explanation to this apparent paradox may lie in the differential effects of thyroid hormones at the liver and peripheral tissues level. The purpose of this paper is to explore the effects of thyroid hormones in glucose metabolism and analyze the mechanisms whereby alterations of thyroid hormones lead to insulin resistance.

  4. Why Can Insulin Resistance Be a Natural Consequence of Thyroid Dysfunction?

    PubMed Central

    Brenta, Gabriela

    2011-01-01

    Evidence for a relationship between T4 and T3 and glucose metabolism appeared over 100 years ago when the influence of thyroid hormone excess in the deterioration of glucose metabolism was first noticed. Since then, it has been known that hyperthyroidism is associated with insulin resistance. More recently, hypothyroidism has also been linked to decreased insulin sensitivity. The explanation to this apparent paradox may lie in the differential effects of thyroid hormones at the liver and peripheral tissues level. The purpose of this paper is to explore the effects of thyroid hormones in glucose metabolism and analyze the mechanisms whereby alterations of thyroid hormones lead to insulin resistance. PMID:21941681

  5. Hypochlorous acid via peroxynitrite activates protein kinase Cθ and insulin resistance in adipocytes

    PubMed Central

    Zhou, Jun; Wang, Qilong; Ding, Ye; Zou, Ming-Hui

    2015-01-01

    We recently reported that genetic deletion of myeloperoxidase (MPO) alleviates obesity-related insulin resistance in mice in vivo. How MPO impairs insulin sensitivity in adipocytes is poorly characterized. As hypochlorous acid (HOCl) is a principal oxidant product generated by MPO, we evaluated the effects of HOCl on insulin signaling in adipocytes differentiated from 3T3-L1 cells. Exposure of 3T3-L1 adipocytes to exogenous HOCl (200 μmol/l) attenuated insulin-stimulated 2-deoxyglucose uptake, GLUT4 translocation, and insulin signals, including tyrosine phosphorylation of insulin receptor substrate 1 (IRS1) and phosphorylation of Akt. Furthermore, treatment with HOCl induced phosphorylation of IRS1 at serine 307, inhibitor κB kinase (IKK), c-Jun NH2-terminal kinase (JNK), and phosphorylation of PKCθ (PKCθ). In addition, genetic and pharmacological inhibition of IKK and JNK abolished serine phosphorylation of IRS1 and impairment of insulin signaling by HOCl. Furthermore, knockdown of PKCθ using siRNA transfection suppressed phosphorylation of IKK and JNK and consequently attenuated the HOCl-impaired insulin signaling pathway. Moreover, activation of PKCθ by peroxynitrite was accompanied by increased phosphorylation of IKK, JNK, and IRS1-serine 307. In contrast, ONOO− inhibitors abolished HOCl-induced phosphorylation of PKCθ, IKK, JNK, and IRS1-serine 307, as well as insulin resistance. Finally, high-fat diet (HFD)-induced insulin resistance was associated with enhanced phosphorylation of PKCθ, IKK, JNK, and IRS1 at serine 307 in white adipose tissues from WT mice, all of which were not found in Mpo knockout mice fed HFDs. We conclude that HOCl impairs insulin signaling pathway by increasing ONOO− mediated phosphorylation of PKCθ, resulting in phosphorylation of IKK/JNK and consequent serine phosphorylation of IRS1 in adipocytes. PMID:25381390

  6. Exercise Intensity Modulates Glucose-Stimulated Insulin Secretion when Adjusted for Adipose, Liver and Skeletal Muscle Insulin Resistance

    PubMed Central

    Malin, Steven K.; Rynders, Corey A.; Weltman, Judy Y.; Barrett, Eugene J.; Weltman, Arthur

    2016-01-01

    Little is known about the effects of exercise intensity on compensatory changes in glucose-stimulated insulin secretion (GSIS) when adjusted for adipose, liver and skeletal muscle insulin resistance (IR). Fifteen participants (8F, Age: 49.9±3.6yr; BMI: 31.0±1.5kg/m2; VO2peak: 23.2±1.2mg/kg/min) with prediabetes (ADA criteria, 75g OGTT and/or HbA1c) underwent a time-course matched Control, and isocaloric (200kcal) exercise at moderate (MIE; at lactate threshold (LT)), and high-intensity (HIE; 75% of difference between LT and VO2peak). A 75g OGTT was conducted 1 hour post-exercise/Control, and plasma glucose, insulin, C-peptide and free fatty acids were determined for calculations of skeletal muscle (1/Oral Minimal Model; SMIR), hepatic (HOMAIR), and adipose (ADIPOSEIR) IR. Insulin secretion rates were determined by deconvolution modeling for GSIS, and disposition index (DI; GSIS/IR; DISMIR, DIHOMAIR, DIADIPOSEIR) calculations. Compared to Control, exercise lowered SMIR independent of intensity (P<0.05), with HIE raising HOMAIR and ADIPOSEIR compared with Control (P<0.05). GSIS was not reduced following exercise, but DIHOMAIR and DIADIPOSEIR were lowered more following HIE compared with Control (P<0.05). However, DISMIR increased in an intensity based manner relative to Control (P<0.05), which corresponded with lower post-prandial blood glucose levels. Taken together, pancreatic insulin secretion adjusts in an exercise intensity dependent manner to match the level of insulin resistance in skeletal muscle, liver and adipose tissue. Further work is warranted to understand the mechanism by which exercise influences the cross-talk between tissues that regulate blood glucose in people with prediabetes. PMID:27111219

  7. Reduced Systemic Levels of IL-10 Are Associated with the Severity of Obstructive Sleep Apnea and Insulin Resistance in Morbidly Obese Humans

    PubMed Central

    Leon-Cabrera, Sonia; Arana-Lechuga, Yoaly; Esqueda-León, Enrique; Terán-Pérez, Guadalupe; Gonzalez-Chavez, Antonio; Velázquez Moctezuma, Javier

    2015-01-01

    Obstructive sleep apnea (OSA) has been related to elevation of inflammatory cytokines and development of insulin resistance in morbidly obese (MO) subjects. However, it is still unclear whether the systemic concentration of anti-inflammatory mediators is also affected in MO subjects directly related to the severity of OSA and level of insulin resistance. Normal weight and MO subjects were subjected to overnight polysomnography in order to establish the severity of OSA, according to the apnea-hypopnea index (AHI). Blood samples were obtained for estimation of total cholesterol and triglycerides, insulin, glucose, insulin resistance, tumor necrosis factor alpha (TNF-α), interleukin 12 (IL12), and interleukin 10 (IL-10). Serum levels of IL-10 were significantly lower in MO subjects with OSA than in MO and control individuals without OSA. Besides being inversely associated with serum TNF-α and IL-12, decreased IL-10 levels were significantly related to increased AHI, hyperinsulinemia, and insulin resistance. Serum IL-10 is significantly reduced in morbidly obese subjects with severe OSA while also showing a clear relationship with a state of hyperinsulinemia and insulin resistance probably regardless of obesity in the present sample. It may be of potential clinical interest to identify the stimulatory mechanisms of IL-10 in obese individuals with OSA. PMID:25944984

  8. 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

  9. FOXO1 Mediates Vitamin D Deficiency-induced Insulin Resistance in Skeletal Muscle

    PubMed Central

    Chen, Songcang; Villalta, Armando; Agrawal, Devendra K.

    2015-01-01

    Prospective epidemiological studies have consistently shown a relationship between vitamin D deficiency, insulin resistance, and type 2 diabetes mellitus (DM2). This is supported by recent trials showing that vitamin D supplementation in prediabetic or insulin-resistant patients with inadequate vitamin D levels improves insulin sensitivity. However, the molecular mechanisms underlying vitamin D deficiency-induced insulin resistance and DM2 remain unknown. Skeletal muscle insulin resistance is a primary defect in the majority of patients with DM2. While sustained activation of forkhead box O1 (FOXO1) in skeletal muscle causes insulin resistance, a relationship between vitamin D deficiency and FOXO1 activation in muscle is unknown. We generated skeletal muscle-specific vitamin D receptor (VDR)-null mice and discovered that these mice developed insulin resistance and glucose intolerance accompanied by increased expression and activity of FOXO1. We also found sustained FOXO1 activation in the skeletal muscle of global VDR-null mice. Treatment of C2C12 muscle cells with 1,25-dihydroxyvitamin D (VD3) reduced FOXO1 expression, nuclear translocation, and activity. The VD3-dependent suppression of FOXO1 activation disappeared by knockdown of VDR, indicating that it is VDR-dependent. Taken together, these results suggest that FOXO1 is a critical target mediating VDR-null signaling in skeletal muscle. The novel findings provide the conceptual support that persistent FOXO1 activation may be responsible for insulin resistance and impaired glucose metabolism in vitamin D signaling-deficient mice, as well as evidence for the utility of vitamin D supplementation for intervention in DM2. PMID:26462119

  10. Relationship of hepatic and peripheral insulin resistance with plasminogen activator inhibitor-1 in Pima Indians.

    PubMed

    Nagi, D K; Tracy, R; Pratley, R

    1996-10-01

    Plasminogen activator inhibitor-1 (PAI-1) is related to insulin resistance and several components of the insulin resistance syndrome, and PAI-1 levels are elevated in subjects with non-insulin-dependent diabetes mellitus. Many Pima Indians are obese, insulin-resistant, and hyperinsulinemic, and they have high rates of diabetes but a low risk of ischemic heart disease. In contrast to whites and Asians, PAI-1 activity is similar between nondiabetic and diabetic Pima Indians. We therefore examined the association of PAI-1 with hepatic and peripheral insulin action measured using the hyperinsulinemic-euglycemic clamp. To investigate if insulin per se has any effect on PAI-1 in vivo, we also assessed the effects of endogenous (during a 75-g oral glucose load) and exogenous (during hyperinsulinemic clamp) insulin on PAI-1 antigen. Twenty-one (14 men and seven women; mean age, 26.3 +/- 4.8 years) Pima Indians underwent a 75-g oral glucose tolerance test (OGTT) and a sequential hyperinsulinemic-euglycemic clamp. Peripheral insulin action was measured as absolute glucose uptake (M value) and normalized to estimated metabolic body size (EMBS). Hepatic insulin action was measured as percent suppression of basal hepatic glucose output during hyperinsulinemia. PAI-1 antigen was determined using a two-site enzyme-linked immunosorbent assay that detects only free PAI-1. PAI-1 antigen concentrations were significantly related to body mass index ([BMI] rs = .54, P = .012), waist (rs=.52, P=.016) and thigh (rs=.63, P=.002) circumference, and fasting plasma insulin concentration (rs=.59, P=.004). PAI-1 antigen concentrations were not significantly associated with peripheral glucose uptake (M value) during either low-dose (rs= -.01, P=NS) or high-dose (rs= -.11, P=NS) insulin infusion. PAI-1 antigen was negatively correlated with basal hepatic glucose output (rs= -.57, P=.013) and percent suppression of hepatic glucose output during hyperinsulinemia (rs= -.69, P=.005). However, this

  11. In vivo JNK activation in pancreatic β-cells leads to glucose intolerance caused by insulin resistance in pancreas.

    PubMed

    Lanuza-Masdeu, Jordi; Arévalo, M Isabel; Vila, Cristina; Barberà, Albert; Gomis, Ramon; Caelles, Carme

    2013-07-01

    Insulin resistance is a key condition in the development of type 2 diabetes. It is well established that exacerbated Jun NH2-terminal kinase (JNK) activity is involved in promoting insulin resistance in peripheral insulin-target tissues; however, this involvement is less documented in pancreatic β-cells. Using a transgenic mouse model, here we show that JNK activation in β-cells led to glucose intolerance as a result of impaired capacity to increase insulinemia in response to hyperglycemia. Pancreatic islets from these mice showed no obvious morphostructural abnormalities or decreased insulin content. In contrast, these islets failed to secrete insulin in response to glucose or insulin but were competent in succinate-, ketoisocaproate-, 3-isobutyl-1-methylxanthine (IBMX-), KCl-, and tolbutamide-induced insulin secretion. At the molecular level, JNK activation in β-cells inhibited insulin-induced Akt phosphorylation, pancreatic and duodenal homeobox 1 nucleocytoplasmic shuttling, and transcription of insulin-target genes. Remarkably, rosiglitazone restored insulin secretion in response to hyperglycemia in mice and insulin-induced insulin secretion and signaling in isolated islets. In conclusion, the mere activation of JNK suffices to induce insulin resistance in pancreatic β-cells by inhibition of insulin signaling in these cells, but it is not sufficient to elicit β-cell death. In addition, we provide the first evidence that thiazolidinediones exert insulin-sensitizing action directly on pancreatic β-cells.

  12. Shifts in metabolic parameters surrounding glucose homoeostasis resulting from tricyclic antidepressant therapy: implications of insulin resistance?

    PubMed

    Chadwick, W; Wilson, G; van de Venter, M; Oelofsen, W; Roux, S

    2007-01-01

    This study displayed the physiological effects the tricyclic antidepressants amitriptyline or trimipramine have on glucose homoeostasis in male Wistar rats. An insulin secreting cell line (INS-1) was also used to determine effects tricyclic antidepressants have on insulin secretion and insulin displacement. Thirty rats each received a 1 mg kg-1 dose of amitriptyline or trimipramine for a period of 14 weeks; another 14 rats served as the control group. Blood glucose, serum insulin and muscle and liver glycogen levels were determined. Kidney, liver and muscle insulin degradation was measured and compared with insulin degrading enzyme concentrations in the latter two tissues. INS-1 cells were used to determine the effect 1 microM amitriptyline has on insulin secretion. Displacement studies for [3H]glibenclamide by amitriptyline or trimipramine were undertaken on INS-1 cells. A significant increase in blood glucose (P<0.01) was found for both test groups after 6 and 14 weeks of receiving the medication, which may be related to a significant decrease in liver and muscle glycogen levels (P<0.001). Serum insulin levels remained unchanged, although a significant increase in insulin degradation was observed in the muscle, liver and kidney, which may be related to a significant increase in insulin degrading enzyme (P<0.001) that was found. A significant increase in insulin secretion was observed for the INS-1 cells treated with amitriptyline, although no significant displacement for the [3H]glibenclamide was evident for amitriptyline or trimipramine. The significant alterations in glucose homoeostasis observed, as well as the significant changes associated with insulin secretion and degradation associated with amitriptyline or trimipramine treatment, imply that prolonged use of these medicines may lead to insulin resistance and full blown diabetes. PMID:17227626

  13. Disruption of insulin signalling affects the neuroendocrine stress reaction in Drosophila females.

    PubMed

    Rauschenbach, Inga Y; Karpova, Evgenia K; Adonyeva, Natalya V; Andreenkova, Olga V; Faddeeva, Natalya V; Burdina, Elena V; Alekseev, Alexander A; Menshanov, Petr N; Gruntenko, Nataly E

    2014-10-15

    Juvenile hormone (JH) and dopamine are involved in the stress response in insects. The insulin/insulin-like growth factor signalling pathway has also recently been found to be involved in the regulation of various processes, including stress tolerance. However, the relationships between the JH, dopamine and insulin signalling pathways remain unclear. Here, we study the role of insulin signalling in the regulation of JH and dopamine metabolism under normal and heat stress conditions in Drosophila melanogaster females. We show that suppression of the insulin-like receptor (InR) in the corpus allatum, a specialised endocrine gland that synthesises JH, causes an increase in dopamine level and JH-hydrolysing activity and alters the activities of enzymes that produce as well as those that degrade dopamine [alkaline phosphatase (ALP), tyrosine hydroxylase (TH) and dopamine-dependent arylalkylamine N-acetyltransferase (DAT)]. We also found that InR suppression in the corpus allatum modulates dopamine, ALP, TH and JH-hydrolysing activity in response to heat stress and that it decreases the fecundity of the flies. JH application restores dopamine metabolism and fecundity in females with decreased InR expression in the corpus allatum. Our data provide evidence that the insulin/insulin-like growth factor signalling pathway regulates dopamine metabolism in females of D. melanogaster via the system of JH metabolism and that it affects the development of the neuroendocrine stress reaction and interacts with JH in the control of reproduction in this species.

  14. Simvastatin may induce insulin resistance through a novel fatty acid mediated cholesterol independent mechanism

    PubMed Central

    Kain, Vasundhara; Kapadia, Bandish; Misra, Parimal; Saxena, Uday

    2015-01-01

    Statins are a class of oral drugs that are widely used for treatment of hypercholesterolemia. Recent clinical data suggest that chronic use of these drugs increases the frequency of new onset diabetes. Studies to define the risks of statin-induced diabetes and its underlying mechanisms are clearly necessary. We explored the possible mechanism of statin induced insulin resistance using a well-established cell based model and simvastatin as a prototype statin. Our data show that simvastatin induces insulin resistance in a cholesterol biosynthesis inhibition independent fashion but does so by a fatty acid mediated effect on insulin signaling pathway. These data may help design strategies for prevention of statin induced insulin resistance and diabetes in patients with hypercholesterolemia. PMID:26345110

  15. Exercise in aging: its important role in mortality, obesity and insulin resistance

    PubMed Central

    Ryan, Alice S

    2011-01-01

    The prevalence of overweight and obesity has increased dramatically over the last several decades. Obesity and physical inactivity increase the risk for cardiovascular disease, Type 2 diabetes mellitus, hypertension, dyslipidemia and certain cancers. Obesity and low levels of physical fitness are also associated with increased risk of all-cause and cardiovascular mortality. Central and total obesity, insulin resistance and inactivity increase with age. Exercise training and increased fitness promote positive changes in body composition and improve insulin sensitivity. This article will describe the effects of exercise training, both aerobic and resistive, on body composition and obesity as well as review studies investigating the effects of exercise training on glucose metabolism and insulin sensitivity in older adults. Adopting a physically active lifestyle should be emphasized in overweight and obese individuals with insulin resistance to reduce the risk for cardiovascular events in the aging population. PMID:21359160

  16. Mitochondrial Respiratory Capacity and Content Are Normal in Young Insulin-Resistant Obese Humans

    PubMed Central

    Fisher-Wellman, Kelsey H.; Weber, Todd M.; Cathey, Brook L.; Brophy, Patricia M.; Gilliam, Laura A.A.; Kane, Constance L.; Maples, Jill M.; Gavin, Timothy P.; Houmard, Joseph A.; Neufer, P. Darrell

    2014-01-01

    Considerable debate exists about whether alterations in mitochondrial respiratory capacity and/or content play a causal role in the development of insulin resistance during obesity. The current study was undertaken to determine whether such alterations are present during the initial stages of insulin resistance in humans. Young (∼23 years) insulin-sensitive lean and insulin-resistant obese men and women were studied. Insulin resistance was confirmed through an intravenous glucose tolerance test. Measures of mitochondrial respiratory capacity and content as well as H2O2 emitting potential and the cellular redox environment were performed in permeabilized myofibers and primary myotubes prepared from vastus lateralis muscle biopsy specimens. No differences in mitochondrial respiratory function or content were observed between lean and obese subjects, despite elevations in H2O2 emission rates and reductions in cellular glutathione. These findings were apparent in permeabilized myofibers as well as in primary myotubes. The results suggest that reductions in mitochondrial respiratory capacity and content are not required for the initial manifestation of peripheral insulin resistance. PMID:23974920

  17. Potential Roles of Stevia rebaudiana Bertoni in Abrogating Insulin Resistance and Diabetes: A Review

    PubMed Central

    Mohd-Radzman, Nabilatul Hani; Ismail, W. I. W.; Adam, Zainah; Jaapar, Siti Safura; Adam, Aishah

    2013-01-01

    Insulin resistance is a key factor in metabolic disorders like hyperglycemia and hyperinsulinemia, which are promoted by obesity and may later lead to Type II diabetes mellitus. In recent years, researchers have identified links between insulin resistance and many noncommunicable illnesses other than diabetes. Hence, studying insulin resistance is of particular importance in unravelling the pathways employed by such diseases. In this review, mechanisms involving free fatty acids, adipocytokines such as TNFα and PPARγ and serine kinases like JNK and IKKβ, asserted to be responsible in the development of insulin resistance, will be discussed. Suggested mechanisms for actions in normal and disrupted states were also visualised in several manually constructed diagrams to capture an overall view of the insulin-signalling pathway and its related components. The underlying constituents of medicinal significance found in the Stevia rebaudiana Bertoni plant (among other plants that potentiate antihyperglycemic activities) were explored in further depth. Understanding these factors and their mechanisms may be essential for comprehending the progression of insulin resistance towards the development of diabetes mellitus. PMID:24324517

  18. Myeloperoxidase deletion prevents high-fat diet-induced obesity and insulin resistance.

    PubMed

    Wang, Qilong; Xie, Zhonglin; Zhang, Wencheng; Zhou, Jun; Wu, Yue; Zhang, Miao; Zhu, Huaiping; Zou, Ming-Hui

    2014-12-01

    Activation of myeloperoxidase (MPO), a heme protein primarily expressed in granules of neutrophils, is associated with the development of obesity. However, whether MPO mediates high-fat diet (HFD)-induced obesity and obesity-associated insulin resistance remains to be determined. Here, we found that consumption of an HFD resulted in neutrophil infiltration and enhanced MPO expression and activity in epididymal white adipose tissue, with an increase in body weight gain and impaired insulin signaling. MPO knockout (MPO(-/-)) mice were protected from HFD-enhanced body weight gain and insulin resistance. The MPO inhibitor 4-aminobenzoic acid hydrazide reduced peroxidase activity of neutrophils and prevented HFD-enhanced insulin resistance. MPO deficiency caused high body temperature via upregulation of uncoupling protein-1 and mitochondrial oxygen consumption in brown adipose tissue. Lack of MPO also attenuated HFD-induced macrophage infiltration and expression of proinflammatory cytokines. We conclude that activation of MPO in adipose tissue contributes to the development of obesity and obesity-associated insulin resistance. Inhibition of MPO may be a potential strategy for prevention and treatment of obesity and insulin resistance.

  19. Mesenteric Fat Lipolysis Mediates Obesity-Associated Hepatic Steatosis and Insulin Resistance.

    PubMed

    Wueest, Stephan; Item, Flurin; Lucchini, Fabrizio C; Challa, Tenagne D; Müller, Werner; Blüher, Matthias; Konrad, Daniel

    2016-01-01

    Hepatic steatosis and insulin resistance are among the most prevalent metabolic disorders and are tightly associated with obesity and type 2 diabetes. However, the underlying mechanisms linking obesity to hepatic lipid accumulation and insulin resistance are incompletely understood. Glycoprotein 130 (gp130) is the common signal transducer of all interleukin 6 (IL-6) cytokines. We provide evidence that gp130-mediated adipose tissue lipolysis promotes hepatic steatosis and insulin resistance. In obese mice, adipocyte-specific gp130 deletion reduced basal lipolysis and enhanced insulin's ability to suppress lipolysis from mesenteric but not epididymal adipocytes. Consistently, free fatty acid levels were reduced in portal but not in systemic circulation of obese knockout mice. Of note, adipocyte-specific gp130 knockout mice were protected from high-fat diet-induced hepatic steatosis as well as from insulin resistance. In humans, omental but not subcutaneous IL-6 mRNA expression correlated positively with liver lipid accumulation (r = 0.31, P < 0.05) and negatively with hyperinsulinemic-euglycemic clamp glucose infusion rate (r = -0.28, P < 0.05). The results show that IL-6 cytokine-induced lipolysis may be restricted to mesenteric white adipose tissue and that it contributes to hepatic insulin resistance and steatosis. Therefore, blocking IL-6 cytokine signaling in (mesenteric) adipocytes may be a novel approach to blunting detrimental fat-liver crosstalk in obesity.

  20. Defective NOD2 peptidoglycan sensing promotes diet-induced inflammation, dysbiosis, and insulin resistance

    PubMed Central

    Denou, Emmanuel; Lolmède, Karine; Garidou, Lucile; Pomie, Celine; Chabo, Chantal; Lau, Trevor C; Fullerton, Morgan D; Nigro, Giulia; Zakaroff-Girard, Alexia; Luche, Elodie; Garret, Céline; Serino, Matteo; Amar, Jacques; Courtney, Michael; Cavallari, Joseph F; Henriksbo, Brandyn D; Barra, Nicole G; Foley, Kevin P; McPhee, Joseph B; Duggan, Brittany M; O'Neill, Hayley M; Lee, Amanda J; Sansonetti, Philippe; Ashkar, Ali A; Khan, Waliul I; Surette, Michael G; Bouloumié, Anne; Steinberg, Gregory R; Burcelin, Rémy; Schertzer, Jonathan D

    2015-01-01

    Pattern recognition receptors link metabolite and bacteria-derived inflammation to insulin resistance during obesity. We demonstrate that NOD2 detection of bacterial cell wall peptidoglycan (PGN) regulates metabolic inflammation and insulin sensitivity. An obesity-promoting high-fat diet (HFD) increased NOD2 in hepatocytes and adipocytes, and NOD2−/− mice have increased adipose tissue and liver inflammation and exacerbated insulin resistance during a HFD. This effect is independent of altered adiposity or NOD2 in hematopoietic-derived immune cells. Instead, increased metabolic inflammation and insulin resistance in NOD2−/− mice is associated with increased commensal bacterial translocation from the gut into adipose tissue and liver. An intact PGN-NOD2 sensing system regulated gut mucosal bacterial colonization and a metabolic tissue dysbiosis that is a potential trigger for increased metabolic inflammation and insulin resistance. Gut dysbiosis in HFD-fed NOD2−/− mice is an independent and transmissible factor that contributes to metabolic inflammation and insulin resistance when transferred to WT, germ-free mice. These findings warrant scrutiny of bacterial component detection, dysbiosis, and protective immune responses in the links between inflammatory gut and metabolic diseases, including diabetes. PMID:25666722

  1. Insulin Resistance, Diabetes Mellitus, and Brain Structure in Bipolar Disorders

    PubMed Central

    Hajek, Tomas; Calkin, Cynthia; Blagdon, Ryan; Slaney, Claire; Uher, Rudolf; Alda, Martin

    2014-01-01

    Type 2 diabetes mellitus (T2DM) damages the brain, especially the hippocampus, and frequently co-occurs with bipolar disorders (BD). Reduced hippocampal volumes are found only in some studies of BD subjects and may thus be secondary to the presence of certain clinical variables. Studying BD patients with abnormal glucose metabolism could help identify preventable risk factors for hippocampal atrophy in BD. We compared brain structure using optimized voxel-based morphometry of 1.5T MRI scans in 33 BD subjects with impaired glucose metabolism (19 with insulin resistance/glucose intolerance (IR/GI), 14 with T2DM), 15 euglycemic BD participants and 11 euglycemic, nonpsychiatric controls. The group of BD patients with IR, GI or T2DM had significantly smaller hippocampal volumes than the euglycemic BD participants (corrected p=0.02) or euglycemic, nonpsychiatric controls (corrected p=0.004). Already the BD subjects with IR/GI had smaller hippocampal volumes than euglycemic BD participants (t(32)=−3.15, p=0.004). Age was significantly more negatively associated with hippocampal volumes in BD subjects with IR/GI/T2DM than in the euglycemic BD participants (F(2, 44)=9.96, p=0.0003). The gray matter reductions in dysglycemic subjects extended to the cerebral cortex, including the insula. In conclusion, this is the first study demonstrating that T2DM or even prediabetes may be risk factors for smaller hippocampal and cortical volumes in BD. Abnormal glucose metabolism may accelerate the age-related decline in hippocampal volumes in BD. These findings raise the possibility that improving diabetes care among BD subjects and intervening already at the level of prediabetes could slow brain aging in BD. PMID:25074491

  2. Insulin resistance, small LDL particles, and risk for atherosclerotic disease.

    PubMed

    Toth, Peter P

    2014-01-01

    There is a global epidemic of obesity, metabolic syndrome, and diabetes mellitus. Insulin resistance (IR) is etiologic for both metabolic syndrome and diabetes mellitus. IR induces a broad range of toxic systemic effects, including dyslipidemia, hypertension, hyperglycemia, increased production of advanced glycosylation end products, increased inflammatory tone, as well as a prothrombotic and pro-oxidative state. Patients with IR are highly vulnerable to the development of accelerated atherosclerosis as well its clinical sequelae, including coronary artery disease and myocardial infarction, carotid artery disease and ischemic stroke, peripheral arterial disease and claudication/lower extremity amputation, and coronary mortality. Among the most important risk factors patients afflicted with IR develop is the so-called atherogenic lipid triad: large numbers of small, dense low-density lipoprotein (sdLDL) particles, hypertriglyceridemia, and low serum concentrations of high-density lipoprotein cholesterol. Though controversial, much recent evidence suggests that the formation of sdLDL particles in the setting of IR is an important metabolic transition. Some studies suggest that these smaller particles are more atherogenic than their larger, more buoyant counterparts. At least part of the explanation for the apparent augmented atherogenicity of small LDL particles is their reduced systemic clearance by the LDL receptor, increased vulnerability to oxidation rendering them more apt for scavenging by macrophages, and possible increased flux into the subendothelial space of arterial walls. Numerous small studies suggest that sdLDL is highly correlated with cardiovascular events. Cardiovascular medicine is in need of a large prospective, randomized study that would more definitively investigate the impact of small, dense LDL (sdLDL) on risk for cardiovascular disease and whether therapeutic interventions designed to specifically reduce the burden of sdLDL are associated

  3. Activation of Proteinase 3 Contributes to Nonalcoholic Fatty Liver Disease and Insulin Resistance

    PubMed Central

    Toonen, Erik JM; Mirea, Andreea-Manuela; Tack, Cees J; Stienstra, Rinke; Ballak, Dov B; van Diepen, Janna A; Hijmans, Anneke; Chavakis, Triantafyllos; Dokter, Wim H; Pham, Christine TN; Netea, Mihai G; Dinarello, Charles A; Joosten, Leo AB

    2016-01-01

    Activation of inflammatory pathways is known to accompany development of obesity-induced nonalcoholic fatty liver disease (NAFLD), insulin resistance and type 2 diabetes. In addition to caspase-1, the neutrophil serine proteases proteinase 3, neutrophil elastase and cathepsin G are able to process the inactive proinflammatory mediators interleukin (IL)-1β and IL-18 to their bioactive forms, thereby regulating inflammatory responses. In this study, we investigated whether proteinase 3 is involved in obesity-induced development of insulin resistance and NAFLD. We investigated the development of NAFLD and insulin resistance in mice deficient for neutrophil elastase/proteinase 3 and neutrophil elastase/cathepsin G and in wild-type mice treated with the neutrophil serine proteinase inhibitor human α-1 antitrypsin. Expression profiling of metabolically relevant tissues obtained from insulin-resistant mice showed that expression of proteinase 3 was specifically upregulated in the liver, whereas neutrophil elastase, cathepsin G and caspase-1 were not. Neutrophil elastase/proteinase 3-deficient mice showed strongly reduced levels of lipids in the liver after being fed a high-fat diet. Moreover, these mice were resistant to high–fat–diet-induced weight gain, inflammation and insulin resistance. Injection of proteinase 3 exacerbated insulin resistance in caspase-1–/– mice, indicating that proteinase 3 acts independently of caspase-1. Treatment with α-1 antitrypsin during the last 10 d of a 16-wk high-fat diet reduced hepatic lipid content and decreased fasting glucose levels. We conclude that proteinase 3 is involved in NAFLD and insulin resistance and that inhibition of proteinase 3 may have therapeutic potential. PMID:27261776

  4. Biochemical adaptations of mammalian hibernation: exploring squirrels as a perspective model for naturally induced reversible insulin resistance.

    PubMed

    Wu, C-W; Biggar, K K; Storey, K B

    2013-01-01

    An important disease among human metabolic disorders is type 2 diabetes mellitus. This disorder involves multiple physiological defects that result from high blood glucose content and eventually lead to the onset of insulin resistance. The combination of insulin resistance, increased glucose production, and decreased insulin secretion creates a diabetic metabolic environment that leads to a lifetime of management. Appropriate models are critical for the success of research. As such, a unique model providing insight into the mechanisms of reversible insulin resistance is mammalian hibernation. Hibernators, such as ground squirrels and bats, are excellent examples of animals exhibiting reversible insulin resistance, for which a rapid increase in body weight is required prior to entry into dormancy. Hibernator studies have shown differential regulation of specific molecular pathways involved in reversible resistance to insulin. The present review focuses on this growing area of research and the molecular mechanisms that regulate glucose homeostasis, and explores the roles of the Akt signaling pathway during hibernation. Here, we propose a link between hibernation, a well-documented response to periods of environmental stress, and reversible insulin resistance, potentially facilitated by key alterations in the Akt signaling network, PPAR-γ/PGC-1α regulation, and non-coding RNA expression. Coincidentally, many of the same pathways are frequently found to be dysregulated during insulin resistance in human type 2 diabetes. Hence, the molecular networks that may regulate reversible insulin resistance in hibernating mammals represent a novel approach by providing insight into medical treatment of insulin resistance in humans.

  5. Pharmacological TLR4 Inhibition Protects against Acute and Chronic Fat-Induced Insulin Resistance in Rats

    PubMed Central

    Zhang, Ning; Liang, Hanyu; Farese, Robert V.; Li, Ji

    2015-01-01

    Aims To evaluate whether pharmacological TLR4 inhibition protects against acute and chronic fat-induced insulin resistance in rats. Materials and Methods For the acute experiment, rats received a TLR4 inhibitor [TAK-242 or E5564 (2x5 mg/kg i.v. bolus)] or vehicle, and an 8-h Intralipid (20%, 8.5 mg/kg/min) or saline infusion, followed by a two-step hyperinsulinemic-euglycemic clamp. For the chronic experiment, rats were subcutaneously implanted with a slow-release pellet of TAK-242 (1.5 mg/d) or placebo. Rats then received a high fat diet (HFD) or a low fat control diet (LFD) for 10 weeks, followed by a two-step insulin clamp. Results Acute experiment; the lipid-induced reduction (18%) in insulin-stimulated glucose disposal (Rd) was attenuated by TAK-242 and E5564 (the effect of E5564 was more robust), suggesting improved peripheral insulin action. Insulin was able to suppress hepatic glucose production (HGP) in saline- but not lipid-treated rats. TAK-242, but not E5564, partially restored this effect, suggesting improved HGP. Chronic experiment; insulin-stimulated Rd was reduced ~30% by the HFD, but completely restored by TAK-242. Insulin could not suppress HGP in rats fed a HFD and TAK-242 had no effect on HGP. Conclusions Pharmacological TLR4 inhibition provides partial protection against acute and chronic fat-induced insulin resistance in vivo. PMID:26196892

  6. Altered Skeletal Muscle Lipase Expression and Activity Contribute to Insulin Resistance in Humans

    PubMed Central

    Badin, Pierre-Marie; Louche, Katie; Mairal, Aline; Liebisch, Gerhard; Schmitz, Gerd; Rustan, Arild C.; Smith, Steven R.; Langin, Dominique; Moro, Cedric

    2011-01-01

    OBJECTIVE Insulin resistance is associated with elevated content of skeletal muscle lipids, including triacylglycerols (TAGs) and diacylglycerols (DAGs). DAGs are by-products of lipolysis consecutive to TAG hydrolysis by adipose triglyceride lipase (ATGL) and are subsequently hydrolyzed by hormone-sensitive lipase (HSL). We hypothesized that an imbalance of ATGL relative to HSL (expression or activity) may contribute to DAG accumulation and insulin resistance. RESEARCH DESIGN AND METHODS We first measured lipase expression in vastus lateralis biopsies of young lean (n = 9), young obese (n = 9), and obese-matched type 2 diabetic (n = 8) subjects. We next investigated in vitro in human primary myotubes the impact of altered lipase expression/activity on lipid content and insulin signaling. RESULTS Muscle ATGL protein was negatively associated with whole-body insulin sensitivity in our population (r = −0.55, P = 0.005), whereas muscle HSL protein was reduced in obese subjects. We next showed that adenovirus-mediated ATGL overexpression in human primary myotubes induced DAG and ceramide accumulation. ATGL overexpression reduced insulin-stimulated glycogen synthesis (−30%, P < 0.05) and disrupted insulin signaling at Ser1101 of the insulin receptor substrate-1 and downstream Akt activation at Ser473. These defects were fully rescued by nonselective protein kinase C inhibition or concomitant HSL overexpression to restore a proper lipolytic balance. We show that selective HSL inhibition induces DAG accumulation and insulin resistance. CONCLUSIONS Altogether, the data indicate that altered ATGL and HSL expression in skeletal muscle could promote DAG accumulation and disrupt insulin signaling and action. Targeting skeletal muscle lipases may constitute an interesting strategy to improve insulin sensitivity in obesity and type 2 diabetes. PMID:21498783

  7. Dietary (n-3) long chain polyunsaturated fatty acids prevent sucrose-induced insulin resistance in rats.

    PubMed

    Ghafoorunissa; Ibrahim, Ahamed; Rajkumar, Laxmi; Acharya, Vani

    2005-11-01

    This study was designed to determine the effect of substituting (n-3) long-chain PUFAs (LCPUFAs) for linoleic acid and hence decreasing the (n-6):(n-3) fatty acid ratio on sucrose-induced insulin resistance in rats. Weanling male Wistar rats were fed casein-based diets containing 100 g/kg fat for 12 wk. Insulin resistance was induced by replacing starch (ST) with sucrose (SU). The dietary fats were formulated with groundnut oil, palmolein, and fish oil to provide the following ratios of (n-6):(n-3) fatty acids: 210 (ST-210, SU-210), 50 (SU-50), 10 (SU-10), and 5 (SU-5). Compared with starch (ST-210), sucrose feeding (SU-210) significantly increased the plasma insulin and triglyceride concentrations and the plasma insulin area under the curve (AUC) in response to an oral glucose load. Adipocytes isolated from rats fed SU-210 had greater lipolytic rate, lower insulin stimulated glucose transport, and lower insulin-mediated antilipolysis than those from rats fed ST-210. Decreasing the dietary (n-6):(n-3) ratio in sucrose-fed rats (SU-10 and SU-5) normalized the plasma insulin concentration and the AUC of insulin after a glucose load. The sucrose-induced increase in plasma triglyceride concentration was normalized in rats fed SU-50, SU-10 and SU-5. Further, sucrose-induced alterations in adipocyte lipolysis and antilipolysis were partially reversed and glucose transport improved in rats fed diets SU-5 and SU-10. In diaphragm phospholipids, decreasing the (n-6):(n-3) ratio in the diet increased the concentration of (n-3) LCPUFAs with concomitant decreases in the concentration of (n-6) LCPUFAs. These results suggest that (n-3) LCPUFAs at a level of 2.6 g/kg diet [0.56% energy (n-3) LCPUFAs, (n-6):(n-3) ratio = 10] may prevent sucrose-induced insulin resistance by improving peripheral insulin sensitivity.

  8. Secretagogin affects insulin secretion in pancreatic β-cells by regulating actin dynamics and focal adhesion

    PubMed Central

    Yang, Seo-Yun; Lee, Jae-Jin; Lee, Jin-Hee; Lee, Kyungeun; Oh, Seung Hoon; Lim, Yu-Mi; Lee, Myung-Shik; Lee, Kong-Joo

    2016-01-01

    Secretagogin (SCGN), a Ca2+-binding protein having six EF-hands, is selectively expressed in pancreatic β-cells and neuroendocrine cells. Previous studies suggested that SCGN enhances insulin secretion by functioning as a Ca2+-sensor protein, but the underlying mechanism has not been elucidated. The present study explored the mechanism by which SCGN enhances glucose-induced insulin secretion in NIT-1 insulinoma cells. To determine whether SCGN influences the first or second phase of insulin secretion, we examined how SCGN affects the kinetics of insulin secretion in NIT-1 cells. We found that silencing SCGN suppressed the second phase of insulin secretion induced by glucose and H2O2, but not the first phase induced by KCl stimulation. Recruitment of insulin granules in the second phase of insulin secretion was significantly impaired by knocking down SCGN in NIT-1 cells. In addition, we found that SCGN interacts with the actin cytoskeleton in the plasma membrane and regulates actin remodelling in a glucose-dependent manner. Since actin dynamics are known to regulate focal adhesion, a critical step in the second phase of insulin secretion, we examined the effect of silencing SCGN on focal adhesion molecules, including FAK (focal adhesion kinase) and paxillin, and the cell survival molecules ERK1/2 (extracellular-signal-regulated kinase 1/2) and Akt. We found that glucose- and H2O2-induced activation of FAK, paxillin, ERK1/2 and Akt was significantly blocked by silencing SCGN. We conclude that SCGN controls glucose-stimulated insulin secretion and thus may be useful in the therapy of Type 2 diabetes. PMID:27095850

  9. Secretagogin affects insulin secretion in pancreatic β-cells by regulating actin dynamics and focal adhesion.

    PubMed

    Yang, Seo-Yun; Lee, Jae-Jin; Lee, Jin-Hee; Lee, Kyungeun; Oh, Seung Hoon; Lim, Yu-Mi; Lee, Myung-Shik; Lee, Kong-Joo

    2016-06-15

    Secretagogin (SCGN), a Ca(2+)-binding protein having six EF-hands, is selectively expressed in pancreatic β-cells and neuroendocrine cells. Previous studies suggested that SCGN enhances insulin secretion by functioning as a Ca(2+)-sensor protein, but the underlying mechanism has not been elucidated. The present study explored the mechanism by which SCGN enhances glucose-induced insulin secretion in NIT-1 insulinoma cells. To determine whether SCGN influences the first or second phase of insulin secretion, we examined how SCGN affects the kinetics of insulin secretion in NIT-1 cells. We found that silencing SCGN suppressed the second phase of insulin secretion induced by glucose and H2O2, but not the first phase induced by KCl stimulation. Recruitment of insulin granules in the second phase of insulin secretion was significantly impaired by knocking down SCGN in NIT-1 cells. In addition, we found that SCGN interacts with the actin cytoskeleton in the plasma membrane and regulates actin remodelling in a glucose-dependent manner. Since actin dynamics are known to regulate focal adhesion, a critical step in the second phase of insulin secretion, we examined the effect of silencing SCGN on focal adhesion molecules, including FAK (focal adhesion kinase) and paxillin, and the cell survival molecules ERK1/2 (extracellular-signal-regulated kinase 1/2) and Akt. We found that glucose- and H2O2-induced activation of FAK, paxillin, ERK1/2 and Akt was significantly blocked by silencing SCGN. We conclude that SCGN controls glucose-stimulated insulin secretion and thus may be useful in the therapy of Type 2 diabetes. PMID:27095850

  10. mRNA expression of diacylglycerol kinase isoforms in insulin-sensitive tissues: effects of obesity and insulin resistance.

    PubMed

    Mannerås-Holm, Louise; Kirchner, Henriette; Björnholm, Marie; Chibalin, Alexander V; Zierath, Juleen R

    2015-04-01

    Diacylglycerol kinase (DGK) isoforms regulate signal transduction and lipid metabolism. DGKδ deficiency leads to hyperglycemia, peripheral insulin resistance, and metabolic inflexibility. Thus, dysregulation of other DGK isoforms may play a role in metabolic dysfunction. We investigated DGK isoform mRNA expression in extensor digitorum longus (EDL) and soleus muscle, liver as well as subcutaneous and epididymal adipose tissue in C57BL/6J mice and obese and insulin-resistant ob/ob mice. All DGK isoforms, except for DGKκ, were detectable, although with varying mRNA expression. Liver DGK expression was generally lowest, with several isoforms undetectable. In soleus muscle, subcutaneous and epididymal adipose tissue, DGKδ was the most abundant isoform. In EDL muscle, DGKα and DGKζ were the most abundant isoforms. In liver, DGKζ was the most abundant isoform. Comparing obese insulin-resistant ob/ob mice to lean C57BL/6J mice, DGKβ, DGKι, and DGKθ were increased and DGKε expression was decreased in EDL muscle, while DGKβ, DGKη and DGKθ were decreased and DGKδ and DGKι were increased in soleus muscle. In liver, DGKδ and DGKζ expression was increased in ob/ob mice. DGKη was increased in subcutaneous fat, while DGKζ was increased and DGKβ, DGKδ, DGKη and DGKε were decreased in epididymal fat from ob/ob mice. In both adipose tissue depots, DGKα and DGKγ were decreased and DGKι was increased in ob/ob mice. In conclusion, DGK mRNA expression is altered in an isoform- and tissue-dependent manner in obese insulin-resistant ob/ob mice. DGK isoforms likely have divergent functional roles in distinct tissues, which may contribute to metabolic dysfunction. PMID:25847921

  11. Molecular Events Linking Oxidative Stress and Inflammation to Insulin Resistance and β-Cell Dysfunction

    PubMed Central

    Keane, Kevin Noel; Cruzat, Vinicius Fernandes; Carlessi, Rodrigo; de Bittencourt, Paulo Ivo Homem; Newsholme, Philip

    2015-01-01

    The prevalence of diabetes mellitus (DM) is increasing worldwide, a consequence of the alarming rise in obesity and metabolic syndrome (MetS). Oxidative stress and inflammation are key physiological and pathological events linking obesity, insulin resistance, and the progression of type 2 DM (T2DM). Unresolved inflammation alongside a “glucolipotoxic” environment of the pancreatic islets, in insulin resistant pathologies, enhances the infiltration of immune cells which through secretory activity cause dysfunction of insulin-secreting β-cells and ultimately cell death. Recent molecular investigations have revealed that mechanisms responsible for insulin resistance associated with T2DM are detected in conditions such as obesity and MetS, including impaired insulin receptor (IR) signalling in insulin responsive tissues, oxidative stress, and endoplasmic reticulum (ER) stress. The aim of the present review is to describe the evidence linking oxidative stress and inflammation with impairment of insulin secretion and action, which result in the progression of T2DM and other conditions associated with metabolic dysregulation. PMID:26257839

  12. Adaptation of β-Cell and Endothelial Function to Carbohydrate Loading: Influence of Insulin Resistance

    PubMed Central

    Hurwitz, Barry E.; Schneiderman, Neil; Marks, Jennifer B.; Mendez, Armando J.; Gonzalez, Alex; Llabre, Maria M.; Smith, Steven R.; Bizzotto, Roberto; Santini, Eleonora; Manca, Maria Laura; Skyler, Jay S.; Mari, Andrea

    2015-01-01

    High-carbohydrate diets have been associated with β-cell strain, dyslipidemia, and endothelial dysfunction. We examined how β-cell and endothelial function adapt to carbohydrate overloading and the influence of insulin resistance. On sequential days in randomized order, nondiabetic subjects (classified as insulin-sensitive [IS] [n = 64] or insulin-resistant [IR] [n = 79] by euglycemic clamp) received four mixed meals over 14 h with either standard (300 kcal) or double carbohydrate content. β-Cell function was reconstructed by mathematical modeling; brachial artery flow-mediated dilation (FMD) was measured before and after each meal. Compared with IS, IR subjects showed higher glycemia and insulin hypersecretion due to greater β-cell glucose and rate sensitivity; potentiation of insulin secretion, however, was impaired. Circulating free fatty acids (FFAs) were less suppressed in IR than IS subjects. Baseline FMD was reduced in IR, and postprandial FMD attenuation occurred after each meal, particularly with high carbohydrate, similarly in IR and IS. Throughout the two study days, higher FFA levels were significantly associated with lower (incretin-induced) potentiation and impaired FMD. In nondiabetic individuals, enhanced glucose sensitivity and potentiation upregulate the insulin secretory response to carbohydrate overloading. With insulin resistance, this adaptation is impaired. Defective suppression of endogenous FFA is one common link between impaired potentiation and vascular endothelial dysfunction. PMID:25754957

  13. Angelica acutiloba root attenuates insulin resistance induced by high-fructose diet in rats.

    PubMed

    Liu, I-Min; Tzeng, Thing-Fong; Liou, Shorong-Shii; Chang, Chia Ju

    2011-09-01

    Angelica acutiloba root (Japanese Dong Quai), used for treatment of gynecological disorders, is currently cultivated in Taiwan. The present study evaluated the preventative effect of Angelica acutiloba root (Japanese Dong Quai) on the induction of insulin resistance. Insulin resistance was induced in rats by feeding a high fructose diet for 6 weeks. Thereafter, the rats were maintained on the same diet and treated with oral A. acutiloba root extract or pioglitazone once daily for 8 weeks. At the end of treatment, the degree of basal insulin resistance was measured by homeostasis model assessment (HOMA-IR). Insulin sensitivity was calculated using the composite whole body insulin sensitivity index (ISIcomp). Protein expression was evaluated by immunoblotting. A. acutiloba (300 mg/kg/day) displayed similar characteristics to pioglitazone (20 mg/kg/day) in reducing HOMA-IR and elevating ISIcomp. Elevated glycosylated hemoglobin levels and hyperinsulinemia were ameliorated by A. acutiloba treatment without hepatotoxic or nephrotoxic effects. A. acutiloba treatment improved dyslipidemia, induced lipoprotein lipase activity and enhanced hepatic glycogen accumulation. Further, A. acutiloba treatment enhanced the action of insulin on muscle glucose transporter subtype 4 translocation and attenuated hepatic phosphoenolpyruvate carboxykinase expression. The findings suggest that A. acutiloba may be an effective ethnomedicine for improving insulin sensitivity.

  14. Insulin resistance after a 72-h fast is associated with impaired AS160 phosphorylation and accumulation of lipid and glycogen in human skeletal muscle

    PubMed Central

    Vendelbo, M. H.; Clasen, B. F. F.; Treebak, J. T.; Møller, L.; Krusenstjerna-Hafstrøm, T.; Madsen, M.; Nielsen, T. S.; Stødkilde-Jørgensen, H.; Pedersen, S. B.; Jørgensen, J. O. L.; Goodyear, L. J.; Wojtaszewski, J. F. P.; Møller, N.

    2012-01-01

    During fasting, human skeletal muscle depends on lipid oxidation for its energy substrate metabolism. This is associated with the development of insulin resistance and a subsequent reduction of insulin-stimulated glucose uptake. The underlying mechanisms controlling insulin action on skeletal muscle under these conditions are unresolved. In a randomized design, we investigated eight healthy subjects after a 72-h fast compared with a 10-h overnight fast. Insulin action on skeletal muscle was assessed by a hyperinsulinemic euglycemic clamp and by determining insulin signaling to glucose transport. In addition, substrate oxidation, skeletal muscle lipid content, regulation of glycogen synthesis, and AMPK signaling were assessed. Skeletal muscle insulin sensitivity was reduced profoundly in response to a 72-h fast and substrate oxidation shifted to predominantly lipid oxidation. This was associated with accumulation of both lipid and glycogen in skeletal muscle. Intracellular insulin signaling to glucose transport was impaired by regulation of phosphorylation at specific sites on AS160 but not TBC1D1, both key regulators of glucose uptake. In contrast, fasting did not impact phosphorylation of AMPK or insulin regulation of Akt, both of which are established upstream kinases of AS160. These findings show that insulin resistance in muscles from healthy individuals is associated with suppression of site-specific phosphorylation of AS160, without Akt or AMPK being affected. This impairment of AS160 phosphorylation, in combination with glycogen accumulation and increased intramuscular lipid content, may provide the underlying mechanisms for resistance to insulin in skeletal muscle after a prolonged fast. PMID:22028408

  15. Genipin ameliorates age-related insulin resistance through inhibiting hepatic oxidative stress and mitochondrial dysfunction.

    PubMed

    Guan, Lili; Feng, Haiyan; Gong, Dezheng; Zhao, Xu; Cai, Li; Wu, Qiong; Yuan, Bo; Yang, Mei; Zhao, Jie; Zou, Yuan

    2013-12-01

    Insulin resistance (IR) increases with age and plays a key role in the pathogenesis of type 2 diabetes mellitus. Oxidative stress and mitochondrial dysfunction are supposed to be major factors leading to age-related IR. Genipin, an extract from Gardenia jasminoides Ellis fruit, has been reported to stimulate insulin secretion in pancreatic islet cells by regulating mitochondrial function. In this study, we first investigated the effects of genipin on insulin sensitivity and the potential mitochondrial mechanisms in the liver of aging rats. The rats were randomly assigned to receive intraperitoneal injections of either 25mg/kg genipin or vehicle once daily for 12days. The aging rats showed hyperinsulinemia and hyperlipidemia, and insulin resistance as examined by the decreased glucose decay constant rate during insulin tolerance test (kITT). The hepatic tissues showed steatosis and reduced glycogen content. Hepatic malondialdehyde level and mitochondrial reactive oxygen species (ROS) were higher, and levels of mitochondrial membrane potential (MMP) and ATP were lower as compared with the normal control rats. Administration of genipin ameliorated systemic and hepatic insulin resistance, alleviated hyperinsulinemia, hyperglyceridemia and hepatic steatosis, relieved hepatic oxidative stress and mitochondrial dysfunction in aging rats. Furthermore, genipin not only improved insulin sensitivity by promoting insulin-stimulated glucose consumption and glycogen synthesis, inhibited cellular ROS overproduction and alleviated the reduction of levels of MMP and ATP, but also reversed oxidative stress-associated JNK hyperactivation and reduced Akt phosphorylation in palmitate-treated L02 hepatocytes. In conclusion, genipin ameliorates age-related insulin resistance through inhibiting hepatic oxidative stress and mitochondrial dysfunction. PMID:24041487

  16. Prolonged weightlessness affects promyelocytic multidrug resistance.

    PubMed

    Piepmeier, E H; Kalns, J E; McIntyre, K M; Lewis, M L

    1997-12-15

    An immortalized promyelocytic cell line was studied to detect how doxorubicin uptake is affected by microgravity. The purpose of this experiment was to identify the effect that microgravity may have on multidrug resistance in leukocytes. HL60 cells and HL60 cells resistant to anthracycline (HL60/AR) were grown in RPMI and 10% FBS. Upon reaching orbit in the Space Shuttle Endeavour, the cells were robotically mixed with doxorubicin. Three days after mixing, cells were fixed with paraformaldehyde/glutaraldehyde. Ground control experiments were conducted concurrently using a robot identical to the one used on the Shuttle. Fixed cells were analyzed within 2 weeks of launch. Confocal micrographs identified changes in cell structure (transmittance), drug distribution (fluorescence), and microtubule polymerization (fluorescence). Flight cells showed a lack of cytoskeletal polymerization resulting in an overall amorphic globular shape. Doxorubicin distribution in ground cells included a large numbers of vesicles relative to flight cells. There was a greater amount of doxorubicin present in flight cells (85% +/- 9.7) than in ground control cells (43% +/- 26) as determined by image analysis. Differences in microtubule formation between flight cells and ground cells could be partially responsible for the differences in drug distribution. Cytoskeletal interactions are critical to the function of P-glycoprotein as a drug efflux pump responsible for multidrug resistance.

  17. Effects of high-sucrose feeding on insulin resistance and hemodynamic responses to insulin in spontaneously hypertensive rats.

    PubMed

    Mélançon, Sébastien; Bachelard, Hélène; Badeau, Mylène; Bourgoin, Frédéric; Pitre, Maryse; Larivière, Richard; Nadeau, André

    2006-06-01

    This study was designed to investigate the effects of a sucrose diet on vascular and metabolic actions of insulin in spontaneously hypertensive rats (SHR). Male SHR were randomized to receive a sucrose or regular chow diet for 4 wk. Age-matched, chow-fed Wistar-Kyoto (WKY) rats were used as normotensive control. In a first series of experiments, the three groups of rats had pulsed Doppler flow probes and intravascular catheters implanted to determine blood pressure, heart rate, and blood flows. Insulin sensitivity was assessed during a euglycemic hyperinsulinemic clamp performed in conscious rats. In a second series of experiments, new groups of rats were used to examine glucose transport activity in isolated muscles and to determine endothelial nitric oxide synthase (eNOS) protein expression in muscles and endothelin content in vascular tissues. Sucrose feeding was shown to markedly enhance the pressor response to insulin and its hindquarter vasoconstrictor effect when compared with chow-fed SHR. A reduction in eNOS protein content in muscle, but no change in vascular endothelin-1 protein, was noted in sucrose-fed SHR when compared with WKY rats, but these changes were not different from those noted in chow-fed SHR. Similar reductions in insulin-stimulated glucose transport were observed in soleus muscles from both groups of SHR when compared with WKY rats. In extensor digitorum longus muscles, a significant reduction in insulin-stimulated glucose transport was only seen in sucrose-fed rats when compared with the other two groups. Environmental factors, that is, high intake of simple sugars, could possibly potentiate the genetic predisposition in SHR to endothelial dysfunction and insulin resistance.

  18. Effect of almonds on insulin secretion and insulin resistance in nondiabetic hyperlipidemic subjects: a randomized controlled crossover trial.

    PubMed

    Jenkins, David J A; Kendall, Cyril W C; Marchie, Augustine; Josse, Andrea R; Nguyen, Tri H; Faulkner, Dorothea A; Lapsley, Karen G; Singer, William

    2008-07-01

    Nuts appear to have a marked effect in cohort studies in reducing the risk of coronary heart disease (CHD), but their demonstrated ability to lower cholesterol can only explain a proportion of the reduction in risk. Our aim was to assess whether improvement in carbohydrate metabolism provides a further explanation for the effect of nuts in reducing CHD. The effects of whole almonds, taken as snacks, were compared with the effects of low saturated fat (<5% energy) whole-wheat muffins (control) in the therapeutic diets of hyperlipidemic subjects. In a randomized crossover study, 27 hyperlipidemic men and women consumed 3 isoenergetic (mean, 423 kcal/d) supplements each for 1 month. Supplements provided 22.2% of energy and consisted of full-dose almonds (73 +/- 3 g/d), half-dose almonds plus half-dose muffins, and full-dose muffins. Subjects were assessed at weeks 0, 2, and 4 and fasting blood samples were obtained. Twenty-four-hour urinary output was collected at the end of week 4 on each treatment. Mean body weights differed by less than 300 g between treatments. No differences were seen in baseline or treatment values for fasting glucose, insulin, C-peptide, or insulin resistance as measured by homeostasis model assessment of insulin resistance. However, 24-hour urinary C-peptide output as a marker of 24-hour insulin secretion was significantly reduced on the half-and full-dose almonds by comparison to the control after adjustment for urinary creatinine output (P = .002 and P = .004, respectively). We conclude that reductions in 24-hour insulin secretion appear to be a further metabolic advantage of nuts that in the longer term may help to explain the association of nut consumption with reduced CHD risk.

  19. Serum Autotaxin/ENPP2 Correlates with Insulin Resistance in Older Humans with Obesity

    PubMed Central

    Reeves, Valerie L.; Trybula, Joy S.; Wills, Rachel C.; Goodpaster, Bret H.; Dubé, John J.; Kienesberger, Petra C.; Kershaw, Erin E.

    2015-01-01

    Objective Autotaxin (ATX) is an adipocyte-derived lysophospholipase D that generates the lipid signaling molecule lysophosphatidic acid (LPA). The ATX/LPA pathway in adipose tissue has recently been implicated in obesity and insulin resistance in animal models, but the role of circulating ATX in humans remains unclear. The aim of the present study was to determine the relationship between serum ATX and insulin resistance. Methods In this retrospective study, older (60–75 years), non-diabetic human participants with overweight or obesity (BMI 25–37 kg/m2), were characterized for metabolic phenotype including measures of energy, glucose, and lipid homeostasis. The relationship between serum ATX and metabolic parameters was then determined using correlative and predictive statistics. Results Serum ATX was higher in females than in males. After controlling for sex, serum ATX correlated with multiple measures of adiposity and glucose homeostasis/insulin action. Serum ATX and BMI also independently predicted glucose infusion rate during a hyperinsulinemic euglycemic clamp and homeostatic model assessment of insulin resistance after controlling for sex and medication use. Conclusion Serum ATX correlates with and predicts measures of glucose homeostasis and insulin sensitivity in older humans, suggesting that it may be a potential pathogenic factor and/or diagnostic/therapeutic target for insulin resistance in this population. PMID:26727116

  20. Fucoidan from sea cucumber may improve hepatic inflammatory response and insulin resistance in mice.

    PubMed

    Wang, Jinhui; Hu, Shiwei; Jiang, Wei; Song, Wendong; Cai, Lu; Wang, Jingfeng

    2016-02-01

    Nutrition excess-induced inflammation positively contributed to insulin resistance. Fucoidan from sea cucumber can increase glucose translocation in skeletal muscle. However, its effects on inflammation-associated insulin resistance are not understood. We investigated fucoidan from Isostichopus badionotus (Ib-FUC)-alleviated inflammatory response and signaling as well as -improved insulin resistance in the liver of obesity mice. The results showed that Ib-FUC reduced body weight and glucose levels, increased insulin sensitivity, and inhibited serum lipid concentrations. Meanwhile, Hepatic glycogen synthesis was promoted by Ib-FUC via activation of the PI3K/PKB/GSK-3β signaling and regulation of glucose metabolism-related enzymatic activities. Ib-FUC regulated serum inflammatory cytokines and their mRNA expression in the liver. Ib-FUC-induced inactivation of the JNK and IKKβ/NFκB pathways was involved in the activation of insulin signal cascade and inflammatory factor production. These findings suggested that Ib-FUC supplementary-induced alleviation of inflammatory response could be a mechanism responsible for its beneficial effects against hepatic insulin resistance. PMID:26690975

  1. Fucoidan from sea cucumber may improve hepatic inflammatory response and insulin resistance in mice.

    PubMed

    Wang, Jinhui; Hu, Shiwei; Jiang, Wei; Song, Wendong; Cai, Lu; Wang, Jingfeng

    2016-02-01

    Nutrition excess-induced inflammation positively contributed to insulin resistance. Fucoidan from sea cucumber can increase glucose translocation in skeletal muscle. However, its effects on inflammation-associated insulin resistance are not understood. We investigated fucoidan from Isostichopus badionotus (Ib-FUC)-alleviated inflammatory response and signaling as well as -improved insulin resistance in the liver of obesity mice. The results showed that Ib-FUC reduced body weight and glucose levels, increased insulin sensitivity, and inhibited serum lipid concentrations. Meanwhile, Hepatic glycogen synthesis was promoted by Ib-FUC via activation of the PI3K/PKB/GSK-3β signaling and regulation of glucose metabolism-related enzymatic activities. Ib-FUC regulated serum inflammatory cytokines and their mRNA expression in the liver. Ib-FUC-induced inactivation of the JNK and IKKβ/NFκB pathways was involved in the activation of insulin signal cascade and inflammatory factor production. These findings suggested that Ib-FUC supplementary-induced alleviation of inflammatory response could be a mechanism responsible for its beneficial effects against hepatic insulin resistance.

  2. Impact of Insulin Resistance on Neointimal Tissue Proliferation after 2nd-Generation Drug-Eluting Stent Implantation.

    PubMed

    Komatsu, Takaaki; Yaguchi, Isao; Komatsu, Sachiko; Nakahara, Shiro; Kobayashi, Sayuki; Sakai, Yoshihiko; Taguchi, Isao

    2015-08-01

    Percutaneous coronary intervention is established as an effective treatment for patients with ischemic heart disease; in particular, drug-eluting stent implantation is known to suppress in-stent restenosis. Diabetes mellitus is an independent risk factor for restenosis, so reducing insulin resistance is being studied as a new treatment approach. In this prospective study, we sought to clarify the factors associated with in-stent restenosis after percutaneous coronary intervention, and we evaluated the homeostasis model assessment of insulin resistance (HOMA-IR) index as a predictor of restenosis. We enrolled 136 consecutive patients who underwent elective percutaneous coronary intervention at our hospital from February 2010 through April 2013. All were implanted with a 2nd-generation drug-eluting stent. We distributed the patients in accordance with their HOMA-IR index values into insulin-resistant Group P (HOMA-IR, ≥2.5; n=77) and noninsulin-resistant Group N (HOMA-IR, <2.5; n=59). Before and immediately after stenting, we measured reference diameter, minimal lumen diameter, and percentage of stenosis, and after 8 months we measured the last 2 factors and late lumen loss, all by means of quantitative coronary angiography. After 8 months, the mean minimal lumen diameter was smaller in Group P than that in Group N (1.85 ± 1.02 vs 2.37 ± 0.66 mm; P=0.037), and the mean late lumen loss was larger (0.4 ± 0.48 vs 0.16 ± 0.21 mm; P=0.025). These results suggest that insulin resistance affects neointimal tissue proliferation after 2nd-generation drug-eluting stent implantation. PMID:26413014

  3. Lowering of triglycerides by gemfibrozil affects neither the glucoregulatory nor antilipolytic effect of insulin in type 2 (non-insulin-dependent) diabetic patients.

    PubMed

    Vuorinen-Markkola, H; Yki-Järvinen, H; Taskinen, M R

    1993-02-01

    Hypertriglyceridaemia and insulin resistance are closely associated but it is unknown whether hypertriglyceridaemia per se contributes to insulin resistance. In the present study we examined whether gemfibrozil, by lowering triglyceride levels, improves the glucoregulatory and antilipolytic action of insulin in Type 2 (non-insulin-dependent) diabetes mellitus. Twenty patients were randomly allocated to receive either placebo or gemfibrozil 1200 mg daily for 12 weeks in a double-blind study. Very low density lipoprotein triglyceride levels decreased in the gemfibrozil group by 42 +/- 12% (p < 0.01). Gemfibrozil had no effect on the diurnal concentration of non-esterified fatty acids (NEFA). At the randomization HbA1c levels were comparable (7.6 +/- 0.3 vs 7.8 +/- 0.2%, NS) and increased slightly both in the gemfibrozil (8.2 +/- 0.4%, p < 0.05) and placebo groups (8.0 +/- 0.3%, NS). Pre- and post-treatment diurnal glucose and insulin concentrations remained unchanged. Basal pre- and post-treatment hepatic glucose production rates were comparable in both groups and similarly suppressed by insulin. Rate of whole body glucose disposal during a low-dose insulin infusion (serum insulin -90 pmol/l) (pre- vs post-gemfibrozil 11.9 +/- 1.1 vs 11.1 +/- 0.7, pre- vs post-placebo 9.9 +/- 1.1 vs 10.8 +/- 0.8 mumol.kg-1.min-1, NS for both) and a high-dose insulin infusion (serum insulin approximately 500 pmol/l) (16.2 +/- 1.7 vs 17.7 +/- 2.7, 17.1 +/- 4.2 vs 17.4 +/- 2.9 mumol.kg-1 x min-1, respectively, NS for both) remained unchanged. Basal pre- and post-treatment NEFA turnover rates were comparable in both groups and similarly suppressed by insulin.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8458531

  4. Insulin resistance in the oral glucose tolerance test--a link with hypertension.

    PubMed

    Cederholm, J; Wibell, L

    1991-03-01

    Insulin resistance was evaluated in 807 middle-aged subjects at a health survey, with use of an index measured in 75 g oral glucose tolerance tests. The mean value of insulin resistance was higher in a hypertensive group than among the normotensives, independent of body mass index, physical activity, smoking sex, age, and thiazide treatment. One-third of the hypertensives had a high resistance value. Another third of the hypertensives, and also about one-third of the normotensives, had a slightly increased resistance. The remaining third of the hypertensives had a normal-low resistance. A high resistance was also independently related to obesity, low physical leisure time activity, and a family history of NIDDM, but not to a family history of hypertension. The statistical analysis implied a sequence of events: low physical activity might cause high resistance, which in turn might cause high blood pressure.

  5. The Effects of Insulin Resistance on Individual Tissues: An Application of a Mathematical Model of Metabolism in Humans.

    PubMed

    Pearson, Taliesin; Wattis, Jonathan A D; King, John R; MacDonald, Ian A; Mazzatti, Dawn J

    2016-06-01

    Whilst the human body expends energy constantly, the human diet consists of a mix of carbohydrates and fats delivered in a discontinuous manner. To deal with this sporadic supply of energy, there are transport, storage and utilisation mechanisms, for both carbohydrates and fats, around all tissues of the body. Insulin-resistant states such as type 2 diabetes and obesity are characterised by reduced efficiency of these mechanisms. Exactly how these insulin-resistant states develop, for example whether there is an order in which tissues become insulin resistant, is an active area of research with the hope of gaining a better overall understanding of insulin resistance. In this paper, we use a previously derived system of 12 first-order coupled differential equations that describe the transport between, and storage in, different tissues of the human body. We briefly revisit the derivation of the model before parametrising the model to account for insulin resistance. We then solve the model numerically, separately simulating each individual tissue as insulin resistant, and discuss and compare these results, drawing three main conclusions. The implications of these results are in accordance with biological intuition. First, insulin resistance in a tissue creates a knock-on effect on the other tissues in the body, whereby they attempt to compensate for the reduced efficiency of the insulin-resistant tissue. Second, insulin resistance causes a fatty liver, and the insulin resistance of tissues other than the liver can cause fat to accumulate in the liver. Finally, although insulin resistance in individual tissues can cause slightly reduced skeletal muscle metabolic flexibility, it is when the whole body is insulin resistant that the biggest effect on skeletal muscle flexibility is seen. PMID:27306890

  6. DPP4-inhibitor improves neuronal insulin receptor function, brain mitochondrial function and cognitive function in rats with insulin resistance induced by high-fat diet consumption.

    PubMed

    Pipatpiboon, Noppamas; Pintana, Hiranya; Pratchayasakul, Wasana; Chattipakorn, Nipon; Chattipakorn, Siriporn C

    2013-03-01

    High-fat diet (HFD) consumption has been demonstrated to cause peripheral and neuronal insulin resistance, and brain mitochondrial dysfunction in rats. Although the dipeptidyl peptidase-4 inhibitor, vildagliptin, is known to improve peripheral insulin sensitivity, its effects on neuronal insulin resistance and brain mitochondrial dysfunction caused by a HFD are unknown. We tested the hypothesis that vildagliptin prevents neuronal insulin resistance, brain mitochondrial dysfunction, learning and memory deficit caused by HFD. Male rats were divided into two groups to receive either a HFD or normal diet (ND) for 12 weeks, after which rats in each group were fed with either vildagliptin (3 mg/kg/day) or vehicle for 21 days. The cognitive function was tested by the Morris Water Maze prior to brain removal for studying neuronal insulin receptor (IR) and brain mitochondrial function. In HFD rats, neuronal insulin resistance and brain mitochondrial dysfunction were demonstrated, with impaired learning and memory. Vildagliptin prevented neuronal insulin resistance by restoring insulin-induced long-term depression and neuronal IR phosphorylation, IRS-1 phosphorylation and Akt/PKB-ser phosphorylation. It also improved brain mitochondrial dysfunction and cognitive function. Vildagliptin effectively restored neuronal IR function, increased glucagon-like-peptide 1 levels and prevented brain mitochondrial dysfunction, thus attenuating the impaired cognitive function caused by HFD.

  7. Use of aglepristone for the treatment of P4 induced insulin resistance in dogs

    PubMed Central

    Bresciani, Carla; Callegari, Daniela; Di Ianni, Francesco; Morini, Giorgio; Parmigiani, Enrico; Bianchi, Ezio

    2014-01-01

    Insulin resistance (IR) in dogs is suspected when hyperglycemia is present despite administration of insulin doses greater than 1.0 to 1.5 UI/kg. IR is caused by increases in counter regulatory hormones concentrations (glucagon, glucocorticoids, catecholamines and growth hormone). This study was conducted to investigate the use of aglepristone (RU 46534), a P4 receptor antagonist, for the treatment of IR diabetes mellitus in bitches during the luteal phase. All animals were treated with porcine insulin zinc suspension (Caninsulin) and aglepristone (Alizin) 10 mg/kg subcutaneously at day 1, 2, 9 and 17 from diagnosis. At day 5, no significant variation in glycemia was shown. At day 12 and 20, serum glucose concentrations were significant lower (p < 0.05). From day 12 the insulin dose was reduced to 0.8 IU BID. Insulin was reduced in the following weeks and glycemia was controlled. PMID:24378588

  8. Resistance exercise increase lean body mass and improves basal and hepatic insulin sensitivity in obese adolescents

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Little is known about the metabolic effects of resistance exercise, for instance, weight lifting. We studied whether a resistance exercise program improves insulin sensitivity and glucose metabolism in sedentary obese adolescents. Elevn obese subjects (15.7 +/- 0.4 year; 35.4 +/- 0.8 kg/m2; 41.3 +/-...

  9. Impact of Adiposity on Incident Hypertension Is Modified by Insulin Resistance in Adults: Longitudinal Observation From the Bogalusa Heart Study.

    PubMed

    Zhang, Tao; Zhang, Huijie; Li, Shengxu; Li, Ying; Liu, Yaozhong; Fernandez, Camilo; Harville, Emily; Bazzano, Lydia; He, Jiang; Chen, Wei

    2016-01-01

    Adiposity and insulin resistance are closely associated with hypertension. This study aims to investigate whether the association between adiposity and hypertension is modified by insulin resistance. The cohort consisted of 1624 middle-aged normotensive black and white adults aged 18 to 43 years at baseline who followed for 16 years on average. Overweight/obesity at baseline was defined as body mass index (BMI) ≥25, and insulin resistance was measured using homeostasis model assessment of insulin resistance. Prevalence of incident hypertension was compared between the insulin-sensitive adiposity and insulin-resistant adiposity groups. The prevalence of incident hypertension was higher in the insulin-resistant adiposity than in the insulin-sensitive adiposity group (32.1% versus 22.1%, P<0.001). In multivariable logistic analyses, adjusted for baseline age, race, sex, follow-up years, and smoking, baseline insulin-resistant obesity was associated with incident hypertension (odds ratio, 1.9; P=0.008). Odds ratios did not differ between blacks and whites (P=0.238). Of note, the odds ratios of BMI associated with hypertension significantly increased with increasing quartiles of baseline homeostasis model assessment (odds ratio, 1.3, 1.1, 1.5, and 2.5 in quartiles I, II, III, and IV, respectively; P=0.006 for trend). Slopes of increasing follow-up blood pressure with baseline BMI, measured as regression coefficients (β), were significantly greater in insulin-resistant than in insulin-sensitive individuals (β=0.74 versus β=0.35 for systolic blood pressure, P=0.004 for difference; β=0.51 versus β=0.23 for diastolic blood pressure, P=0.001 for difference). These findings suggest that insulin resistance has a synergistic effect on the obesity-hypertension association in young adults, indicating that the role of adiposity in the development of hypertension is modified by insulin resistance.

  10. Post-Streptococcal Auto-Antibodies Inhibit Protein Disulfide Isomerase and Are Associated with Insulin Resistance

    PubMed Central

    Aran, Adi; Weiner, Karin; Lin, Ling; Finn, Laurel Ann; Greco, Mary Ann; Peppard, Paul; Young, Terry; Ofran, Yanay; Mignot, Emmanuel

    2010-01-01

    Post-streptococcal autoimmunity affects millions worldwide, targeting multiple organs including the heart, brain, and kidneys. To explore the post-streptococcal autoimmunity spectrum, we used western blot analyses, to screen 310 sera from healthy subjects with (33%) and without (67%) markers of recent streptococcal infections [anti-Streptolysin O (ASLO) or anti-DNAse B (ADB)]. A 58 KDa protein, reacting strongly with post-streptococcal sera, was identified as Protein Disulfide Isomerase (PDI), an abundant protein with pleiotropic metabolic, immunologic, and thrombotic effects. Anti-PDI autoantibodies, purified from human sera, targeted similar epitopes in Streptolysin O (SLO, P51-61) and PDI (P328-338). The correlation between post-streptococcal status and anti-human PDI auto-immunity was further confirmed in a total of 2987 samples (13.6% in 530 ASLO positive versus 5.6% in 2457 ASLO negative samples, p<0.0001). Finally, anti-PDI auto-antibodies inhibited PDI-mediated insulin degradation in vitro (n = 90, p<0.001), and correlated with higher serum insulin (14.1 iu/ml vs. 12.2 iu/ml, n = 1215, p = 0.039) and insulin resistance (Homeostatic Model Assessment (HOMA) 4.1 vs. 3.1, n = 1215, p = 0.004), in a population-based cohort. These results identify PDI as a major target of post-streptococcal autoimmunity, and establish a new link between infection, autoimmunity, and metabolic disturbances. PMID:20886095

  11. Insulin resistance in prepubertal obese children correlates with sex-dependent early onset metabolomic alterations

    PubMed Central

    Mastrangelo, A; Martos-Moreno, G Á; García, A; Barrios, V; Rupérez, F J; Chowen, J A; Barbas, C; Argente, J

    2016-01-01

    Background: Insulin resistance (IR) is usually the first metabolic alteration diagnosed in obese children and the key risk factor for development of comorbidities. The factors determining whether or not IR develops as a result of excess body mass index (BMI) are still not completely understood. Objectives: This study aimed to elucidate the mechanisms underpinning the predisposition toward hyperinsulinemia-related complications in obese children by using a metabolomic strategy that allows a profound interpretation of metabolic profiles potentially affected by IR. Methods: Serum from 60 prepubertal obese children (30 girls/30 boys, 50% IR and 50% non-IR in each group, but with similar BMIs) were analyzed by using liquid chromatography–mass spectrometry, gas chromatography–mass spectrometry and capillary electrophoresis–mass spectrometry following an untargeted metabolomics approach. Validation was then performed on a group of 100 additional children with the same characteristics. Results: When obese children with and without IR were compared, 47 metabolites out of 818 compounds (P<0.05) obtained after data pre-processing were found to be significantly different. Bile acids exhibit the greatest changes (that is, approximately a 90% increase in IR). The majority of metabolites differing between groups were lysophospholipids (15) and amino acids (17), indicating inflammation and central carbon metabolism as the most altered processes in impaired insulin signaling. Multivariate analysis (OPLS-DA models) showed subtle differences between groups that were magnified when females were analyzed alone. Conclusions: Inflammation and central carbon metabolism, together with the contribution of the gut microbiota, are the most altered processes in obese children with impaired insulin signaling in a sex-specific fashion despite their prepubertal status. PMID:27163744

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

    PubMed Central

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

    2016-01-01

    Obesity stimulates chronic inflammation in adipose tissue, which is associated with insulin resistance, although the underlying mechanism remains largely unknown. Here we showed that obesity-related adipocyte degeneration causes release of cell-free DNA (cfDNA), which promotes macrophage accumulation in adipose tissue via Toll-like receptor 9 (TLR9), originally known as a sensor of exogenous DNA fragments. Fat-fed obese wild-type mice showed increased release of cfDNA, as determined by the concentrations of single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) in plasma. cfDNA released from degenerated adipocytes promoted monocyte chemoattractant protein-1 (MCP-1) expression in wild-type macrophages, but not in TLR9-deficient (Tlr9−/−) macrophages. Fat-fed Tlr9−/− mice demonstrated reduced macrophage accumulation and inflammation in adipose tissue and better insulin sensitivity compared with wild-type mice, whereas bone marrow reconstitution with wild-type bone marrow restored the attenuation of insulin resistance observed in fat-fed Tlr9−/− mice. Administration of a TLR9 inhibitory oligonucleotide to fat-fed wild-type mice reduced the accumulation of macrophages in adipose tissue and improved insulin resistance. Furthermore, in humans, plasma ssDNA level was significantly higher in patients with computed tomography–determined visceral obesity and was associated with homeostasis model assessment of insulin resistance (HOMA-IR), which is the index of insulin resistance. Our study may provide a novel mechanism for the development of sterile inflammation in adipose tissue and a potential therapeutic target for insulin resistance. PMID:27051864

  13. Baseline correlates of insulin resistance in inner city high-BMI African-American children.

    PubMed

    Raman, Aarthi; Fitch, Mark D; Hudes, Mark L; Lustig, Robert H; Murray, Carolyn B; Ikeda, Joanne P; Fleming, Sharon E

    2008-09-01

    To characterize the influence of diet-, physical activity-, and self-esteem-related factors on insulin resistance in 8- 10-year-old African-American (AA) children with BMI greater than the 85th percentile who were screened to participate in a community-based type 2 diabetes mellitus (T2DM) prevention trial. In 165 subjects, fasting glucose- and insulin-derived values for homeostasis model assessment of insulin resistance (HOMA-IR) assessed insulin resistance. Body fatness was calculated following bioelectrical impedance analysis, and fitness was measured using laps from a 20-m shuttle run. Child questionnaires assessed physical activity, dietary habits, and self-esteem. Pubertal staging was assessed using serum levels of sex hormones. Parent questionnaires assessed family demographics, family health, and family food and physical activity habits. Girls had significantly higher percent body fat but similar anthropometric measures compared with boys, whereas boys spent more time in high-intensity activities than girls. Scores for self-perceived behavior were higher for girls than for boys; and girls desired a more slender body. Girls had significantly higher insulin resistance (HOMA-IR), compared with boys (P < 0.01). Adjusting for age, sex, pubertal stage, socioeconomic index (SE index), and family history of diabetes, multivariate regression analysis showed that children with higher waist circumference (WC) (P < 0.001) and lower Harter's scholastic competence (SC) scale (P = 0.044) had higher insulin resistance. WC and selected self-esteem parameters predicted insulin resistance in high-BMI AA children. The risk of T2DM may be reduced in these children by targeting these factors.

  14. Insulin-resistant brain state: the culprit in sporadic Alzheimer's disease?

    PubMed

    Correia, Sónia C; Santos, Renato X; Perry, George; Zhu, Xiongwei; Moreira, Paula I; Smith, Mark A

    2011-04-01

    Severe abnormalities in brain glucose/energy metabolism and insulin signaling have been documented to take a pivotal role in early sporadic Alzheimer's disease (sAD) pathology. Indeed, the "insulin-resistant brain state" has been hypothesized to form the core of the neurodegenerative events that occur in sAD. In this vein, intracerebroventricular administration of subdiabetogenic doses of streptozotocin (STZ) in rats can induce an insulin-resistant brain state, which is proposed as a suitable experimental model of sAD. This review highlights the involvement of disturbed brain insulin metabolism in sAD etiopathogenesis. Furthermore, current knowledge demonstrates that central STZ administration produces brain pathology and behavioral changes that resemble changes found in sAD patients. The STZ-intracerebroventricularly treated rat represents a promising experimental tool in this field by providing new insights concerning early brain alterations in sAD, which can be translated in novel etiopathogenic and therapeutic approaches in this disease.

  15. [Molecular mechanisms and correlations of insulin resistance, obesity, and type 2 diabetes mellitus].

    PubMed

    Winkler, Gábor; Cseh, Károly

    2009-04-26

    Adipose tissue cells express and secrete numerous proteins influencing the signal transduction pathways of insulin receptor by auto-, para- and endocrine manner. Several cytokines, tumor necrosis factor-alpha and its soluble receptor forms, sTNFR1 and sTNFR2, resistin, retinol-binding protein 4, plasminogen activator inhibitor, lipocain 1 inhibit the signalization of insulin receptor causing insulin resistance in target tissues, mainly in adipose, liver and muscle, brain, endothelial as well as in pancreatic beta-cells. However, many other proteins produced by the fat tissue, such as adiponectin, visfatin, vaspin, apelin, omentin and chemerin enhance the signal transmission of the receptor. Recently discovered common mechanisms leading to insulin and cytokine resistance in obesity and type 2 diabetes mellitus, e.g. protein family of suppressor of cytokine signaling (SOCS) are also discussed. PMID:19362933

  16. PP2A inhibition results in hepatic insulin resistance despite Akt2 activation.

    PubMed

    Galbo, Thomas; Perry, Rachel J; Nishimura, Erica; Samuel, Varman T; Quistorff, Bjørn; Shulman, Gerald I

    2013-10-01

    In the liver, insulin suppresses hepatic gluconeogenesis by activating Akt, which inactivates the key gluconeogenic transcription factor FoxO1 (Forkhead Box O1). Recent studies have implicated hyperactivity of the Akt phosphatase Protein Phosphatase 2A (PP2A) and impaired Akt signaling as a molecular defect underlying insulin resistance. We therefore hypothesized that PP2A inhibition would enhance insulin-stimulated Akt activity and decrease glucose production. PP2A inhibitors increased hepatic Akt phosphorylation and inhibited FoxO1in vitro and in vivo, and suppressed gluconeogenesis in hepatocytes. Paradoxically, PP2A inhibition exacerbated insulin resistance in vivo. This was explained by phosphorylation of both hepatic glycogen synthase (GS) (inactivation) and phosphorylase (activation) resulting in impairment of glycogen storage. Our findings underline the significance of GS and Phosphorylase as hepatic PP2A substrates and importance of glycogen metabolism in acute plasma glucose regulation. PMID:24150286

  17. Liver-derived systemic factors drive β-cell hyperplasia in insulin resistant states

    SciTech Connect

    El Ouaamari, Abdelfattah; Kawamori, Dan; Dirice, Ercument; Liew, Chong Wee; Shadrach, Jennifer L.; Hu, Jiang; Katsuta, Hitoshi; Hollister-Lock, Jennifer; Qian, Weijun; Wagers, Amy J.; Kulkarni, Rohit N.

    2013-02-21

    Integrative organ cross-talk regulates key aspects of energy homeostasis and its dysregulation may underlie metabolic disorders such as obesity and diabetes. To test the hypothesis that cross-talk between the liver and pancreatic islets modulates β-cell growth in response to insulin resistance, we used the Liver-specific Insulin Receptor Knockout (LIRKO) mouse, a unique model that exhibits dramatic islet hyperplasia. Using complementary in vivo parabiosis and transplantation assays, and in vitro islet culture approaches, we demonstrate that humoral, non-neural, non-cell autonomous factor(s) induce β-cell proliferation in LIRKO mice. Furthermore, we report that a hepatocyte-derived factor(s) stimulates mouse and human β-cell proliferation in ex vivo assays, independent of ambient glucose and insulin levels. These data implicate the liver as a critical source of β-cell growth factors in insulin resistant states.

  18. Chromium (D-phenylalanine)3 alleviates high fat-induced insulin resistance and lipid abnormalities.

    PubMed

    Kandadi, Machender Reddy; Unnikrishnan, M K; Warrier, Ajaya Kumar Sankara; Du, Min; Ren, Jun; Sreejayan, Nair

    2011-01-01

    High-fat diet has been implicated as a major cause of insulin resistance and dyslipidemia. The objective of this study was to evaluate the impact of dietary-supplementation of chromium (D-phenylalanine)(3) [Cr(D-Phe)(3)] on glucose and insulin tolerance in high-fat diet fed mice. C57BL/6-mice were randomly assigned to orally receive vehicle or Cr(D-Phe)(3) (45 μg of elemental chromium/kg/day) for 8-weeks. High-fat-fed mice exhibited impaired whole-body-glucose and -insulin tolerance and elevated serum triglyceride levels compared to normal chow-fed mice. Insulin-stimulated glucose up-take in the gastrocnemius muscles, assessed as 2-[(3)H-deoxyglucose] incorporation was markedly diminished in high-fat fed mice compared to control mice. Treatment with chromium reconciled the high-fat diet-induced alterations in carbohydrate and lipid metabolism. Treatment of cultured, differentiated myotubes with palmitic acid evoked insulin resistance as evidenced by lower levels of insulin-stimulated Akt-phosphorylation, elevated JNK-phosphorylation, (assessed by Western blotting), attenuation of phosphoinositol-3-kinase activity (determined in the insulin-receptor substrate-1-immunoprecipitates by measuring the extent of phosphorylation of phosphatidylinositol by γ-(32)P-ATP), and impairment in cellular glucose up-take, all of which were inhibited by Cr(d-Phe)(3). These results suggest a beneficial effect of chromium-supplementation in insulin resistant conditions. It is likely that these effects of chromium may be mediated by augmenting downstream insulin signaling.

  19. Glomerular filtration rate, cardiovascular risk factors and insulin resistance.

    PubMed

    Salazar, Martín R; Carbajal, Horacio A; Marillet, Alberto G; Gallo, Delfina M; Valli, María L; Novello, Miguel; Echeverría, Raúl F

    2009-01-01

    The aim of this paper was to study the estimated glomerular filtration rate (eGFR), its changes with age, and its association with systolic blood pressure (SBP) and diastolic BP (DBP), indicators of obesity, dyslipemia, insulin resistance and inflammation on a random population sample. BP, weight, size and waist circumference (WC) were recorded at home. Fasting morning blood samples were analysed. The eGFR was calculated with MDRD (eGFR-MDRD), Cockroft-Gault (eGFR-CG) adjusted to 1.73 m2 and reciprocal of serum creatinine (100/serum cretinine). A total of 1016 individuals, 722 females (41.97 +/- 0.66 years old) and 294 males (42.06 +/- 0.99 years old), completed the laboratory tests. The mean of 100/Scr was 115.13 +/- 0.60 (dl/mg), the mean eGFR-CG was 98.48 +/- 0.82 ml/min/1.73 m2; the mean eGFR-MDRD was 85.15 +/- 0.58 ml/min/1.73 m2. The eGFR-MDRD decreased with age and with the number of risk factors in both sexes. The eGFR-MDRD < 60 ml/min/1.73 m2 adjusted prevalence was 6.2 per 100 inhabitants (CI 95%, 4.7-7.7), 3.6 (CI 95%, 1.5-5.7) in males and 8.6 (CI 95%, 6.6-10.6) in females. The bivariate analysis showed that the eGFR-MDRD correlates inversely with age, SBP, DBP WC, BMI, serum glucose, serum total cholesterol, LDL cholesterol, serum triglycerides, serum uric acid and, in males, with C-reactive-protein. There was no correlation with either insulinemia or HOMA. The mean eGFR value, its association with cardiovascular risk factors and the prevalence of eGFR < 60 ml/min/1.73 m2 found in a rural population of Argentina are similar to those found in other parts of the world. PMID:19897440

  20. SIRT1 attenuates high glucose-induced insulin resistance via reducing mitochondrial dysfunction in skeletal muscle cells

    PubMed Central

    Zhang, Hao-Hao; Ma, Xiao-Jun; Wu, Li-Na; Zhao, Yan-Yan; Zhang, Peng-Yu; Zhang, Ying-Hui; Shao, Ming-Wei; Liu, Fei; Li, Fei

    2015-01-01

    Insulin resistance is often characterized as the most critical factor contributing to the development of type 2 diabetes mellitus (T2DM). Sustained high glucose is an important extracellular environment that induces insulin resistance. Acquired insulin resistance is associated with reduced insulin-stimulated mitochondrial activity as a result of increased mitochondrial dysfunction. Silent information regulator 1 (SIRT1) is one member of the SIRT2 (Sir2)-like family of proteins involved in glucose homeostasis and insulin secretion in mammals. Although SIRT1 has a therapeutic effect on metabolic deterioration in insulin resistance, it is still not clear how SIRT1 is involved in the development of insulin resistance. Here, we demonstrate that pcDNA3.1 vector-mediated overexpression of SIRT1 attenuates insulin resistance in the high glucose-induced insulin-resistant skeleton muscle cells. These beneficial effects were associated with ameliorated mitochondrial dysfunction. Further studies have demonstrated that SIRT1 restores mitochondrial complex I activity leading to decreased oxidative stress and mitochondrial dysfunction. Furthermore, SIRT1 significantly elevated the level of another SIRT which is named SIRT3, and SIRT3 siRNA-suppressed SIRT1-induced mitochondria complex activity increments. Taken together, these results showed that SIRT1 improves insulin sensitivity via the amelioration of mitochondrial dysfunction, and this is achieved through the SIRT1–SIRT3–mitochondrial complex I pathway. PMID:25710929

  1. Hypoglycemic effect of aqueous shallot and garlic extracts in rats with fructose-induced insulin resistance.

    PubMed

    Jalal, Razieh; Bagheri, Sayyed Majid; Moghimi, Ali; Rasuli, Morteza Behnam

    2007-11-01

    The present study has been carried out to investigate the effect of aqueous extract of shallot (Allium ascalonicum) and garlic (Allium satium) on the fasting insulin resistance index (FIRI) and intraperitoneal glucose tolerance test (IPGTT) of fructose-induced insulin resistance rats. Male albino Wistar rats were fed either normal or high-fructose diet for a period of eight weeks. Fasting blood glucose level, fasting blood triglyceride level, FIRI, and the area under the glucose tolerance curve were significantly elevated in fructose-fed animals. Fructose-induced insulin resistance rats treated by aqueous shallot or garlic extract (500 mg/kg body weight/day, i.p.) for duration of eight weeks. Control animals only received normal saline (0.9%). The results showed that neither shallot nor garlic extracts significantly altered the FIRI and the IPGTT at the fourth week after treatment. The fasting blood glucose in fructose-induced insulin resistance animals has been significantly decreased in 8-week treated animals by both shallot and garlic extracts. Shallot extract administration, but not garlic extract, for a period of eight weeks can significantly improve the intraperitoneal glucose tolerance and diminish the FIRI. These results indicate that shallot and garlic extracts have a hypoglycemic influence on the fructose-induced insulin resistance animals and aqueous shallot extract is a stronger hypoglycemic agent than the garlic extract.

  2. DNA methylation, insulin resistance and second-generation antipsychotics in bipolar disorder

    PubMed Central

    Burghardt, Kyle J; Goodrich, Jacyln M; Dolinoy, Dana C; Ellingrod, Vicki L

    2015-01-01

    Aims This study aimed to assess the effect of second-generation antipsychotic (SGA) use and insulin resistance on a global measure of DNA methylation in patients diagnosed with bipolar disorder. Materials & Methods Subjects stable on medication (either mood stabilizer monotherapy or adjuvant SGAs) were assessed for insulin resistance. Global methylation levels were assessed in leukocyte DNA from whole blood using the Luminometric Methylation Assay. Multivariable linear regression was used to investigate the effect of insulin resistance and SGA use on DNA methylation. Results A total of 115 bipolar I subjects were included in this study. The average age was 43.1 ±12.2 years and 73% were on SGAs. Average% global methylation was 77.0 ± 3.26 and was significantly influenced by insulin resistance, SGA use and smoking. Conclusion This is the first study to show a relationship between SGA use, insulin resistance and global DNA methylation. Further work will be needed to identify tissue- and gene-specific methylation changes. PMID:26077424

  3. Identification of cutoff points for Homeostatic Model Assessment for Insulin Resistance index in adolescents: systematic review

    PubMed Central

    de Andrade, Maria Izabel Siqueira; Oliveira, Juliana Souza; Leal, Vanessa Sá; da Lima, Niedja Maria Silva; Costa, Emília Chagas; de Aquino, Nathalia Barbosa; de Lira, Pedro Israel Cabral

    2016-01-01

    Abstract Objective: To identify cutoff points of the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) index established for adolescents and discuss their applicability for the diagnosis of insulin resistance in Brazilian adolescents. Data source: A systematic review was performed in the PubMed, Lilacs and SciELO databases, using the following descriptors: "adolescents", "insulin resistance" and "Receiver Operating Characteristics Curve". Original articles carried out with adolescents published between 2005 and 2015 in Portuguese, English or Spanish languages, which included the statistical analysis using Receiver Operating Characteristics Curve to determine the index cutoff (HOMA-IR) were included. Data synthesis: A total of 184 articles were identified and after the study phases were applied, seven articles were selected for the review. All selected studies established their cutoffs using a Receiver Operating Characteristics Curve, with the lowest observed cutoff of 1.65 for girls and 1.95 for boys and the highest of 3.82 for girls and 5.22 for boys. Of the studies analyzed, one proposed external validity, recommending the use of the HOMA-IR cutoff>2.5 for both genders. Conclusions: The HOMA-IR index constitutes a reliable method for the detection of insulin resistance in adolescents, as long as it uses cutoffs that are more adequate for the reality of the study population, allowing early diagnosis of insulin resistance and enabling multidisciplinary interventions aiming at health promotion of this population. PMID:26559605

  4. Hypoglycemic effect of aqueous shallot and garlic extracts in rats with fructose-induced insulin resistance.

    PubMed

    Jalal, Razieh; Bagheri, Sayyed Majid; Moghimi, Ali; Rasuli, Morteza Behnam

    2007-11-01

    The present study has been carried out to investigate the effect of aqueous extract of shallot (Allium ascalonicum) and garlic (Allium satium) on the fasting insulin resistance index (FIRI) and intraperitoneal glucose tolerance test (IPGTT) of fructose-induced insulin resistance rats. Male albino Wistar rats were fed either normal or high-fructose diet for a period of eight weeks. Fasting blood glucose level, fasting blood triglyceride level, FIRI, and the area under the glucose tolerance curve were significantly elevated in fructose-fed animals. Fructose-induced insulin resistance rats treated by aqueous shallot or garlic extract (500 mg/kg body weight/day, i.p.) for duration of eight weeks. Control animals only received normal saline (0.9%). The results showed that neither shallot nor garlic extracts significantly altered the FIRI and the IPGTT at the fourth week after treatment. The fasting blood glucose in fructose-induced insulin resistance animals has been significantly decreased in 8-week treated animals by both shallot and garlic extracts. Shallot extract administration, but not garlic extract, for a period of eight weeks can significantly improve the intraperitoneal glucose tolerance and diminish the FIRI. These results indicate that shallot and garlic extracts have a hypoglycemic influence on the fructose-induced insulin resistance animals and aqueous shallot extract is a stronger hypoglycemic agent than the garlic extract. PMID:18299719

  5. Dietary Leucine - An Environmental Modifier of Insulin Resistance Acting on Multiple Levels of Metabolism

    PubMed Central

    Macotela, Yazmin; Emanuelli, Brice; Bång, Anneli M.; Espinoza, Daniel O.; Boucher, Jeremie; Beebe, Kirk; Gall, Walter; Kahn, C. Ronald

    2011-01-01

    Environmental factors, such as the macronutrient composition of the diet, can have a profound impact on risk of diabetes and metabolic syndrome. In the present study we demonstrate how a single, simple dietary factor—leucine—can modify insulin resistance by acting on multiple tissues and at multiple levels of metabolism. Mice were placed on a normal or high fat diet (HFD). Dietary leucine was doubled by addition to the drinking water. mRNA, protein and complete metabolomic profiles were assessed in the major insulin sensitive tissues and serum, and correlated with changes in glucose homeostasis and insulin signaling. After 8 weeks on HFD, mice developed obesity, fatty liver, inflammatory changes in adipose tissue and insulin resistance at the level of IRS-1 phosphorylation, as well as alterations in metabolomic profile of amino acid metabolites, TCA cycle intermediates, glucose and cholesterol metabolites, and fatty acids in liver, muscle, fat and serum. Doubling dietary leucine reversed many of the metabolite abnormalities and caused a marked improvement in glucose tolerance and insulin signaling without altering food intake or weight gain. Increased dietary leucine was also associated with a decrease in hepatic steatosis and a decrease in inflammation in adipose tissue. These changes occurred despite an increase in insulin-stimulated phosphorylation of p70S6 kinase indicating enhanced activation of mTOR, a phenomenon normally associated with insulin resistance. These data indicate that modest changes in a single environmental/nutrient factor can modify multiple metabolic and signaling pathways and modify HFD induced metabolic syndrome by acting at a systemic level on multiple tissues. These data also suggest that increasing dietary leucine may provide an adjunct in the management of obesity-related insulin resistance. PMID:21731668

  6. Diet, insulin resistance, and obesity: zoning in on data for Atkins dieters living in South Beach.

    PubMed

    Lara-Castro, Cristina; Garvey, W Timothy

    2004-09-01

    Insulin resistance is a central pathogenic factor for the metabolic syndrome and is associated with both generalized obesity and the accumulation of fat in the omental and intramyocellular compartments. In the context of the current obesity epidemic, it is imperative to consider diets in terms of their ability to both promote weight loss and ameliorate insulin resistance. Weight loss under any dietary formulation depends on hypocaloric intake, and only moderate weight loss (5-10%) is sufficient to augment insulin sensitivity. However, increments in insulin sensitivity may be more directly related to loss of intramyocellular or omental fat rather than loss of total body weight per se. The widespread acceptance of popular low-carbohydrate high-fat diets (e.g. Atkins Diet, Zone Diet, South Beach diet) further underscores the need to evaluate dietary interventions regarding their safety and metabolic effects. These high-fat diets have been shown to be safe in the short term; however, their long-term safety has not been established. With respect to insulin sensitivity, diets enriched in saturated fats can induce insulin resistance, whereas fat substitution with monounsaturated fats can enhance insulin sensitivity. On the other hand, high-fiber, high-carbohydrate diets comprised of foods with low caloric density can similarly be used for effective weight reduction and to ameliorate insulin resistance. Although some data suggest that low-glycemic index diets are most advantageous in this regard, these effects may have more to do with increments in dietary fiber than differences in available carbohydrates. Popular low-carbohydrate, high-fat diets are being fervently embraced as an alternative to challenging modifications in lifestyle and intentional calorie reduction. Current data do not support such unbridled enthusiasm for these diets, particularly in relationship to high-fiber, high-carbohydrate diets emphasizing intake of fresh vegetables and fruits. Long-term studies

  7. Insulin resistance: an additional risk factor in the pathogenesis of cardiovascular disease in type 2 diabetes.

    PubMed

    Patel, Tushar P; Rawal, Komal; Bagchi, Ashim K; Akolkar, Gauri; Bernardes, Nathalia; Dias, Danielle da Silva; Gupta, Sarita; Singal, Pawan K

    2016-01-01

    Sedentary life style and high calorie dietary habits are prominent leading cause of metabolic syndrome in modern world. Obesity plays a central role in occurrence of various diseases like hyperinsulinemia, hyperglycemia and hyperlipidemia, which lead to insulin resistance and metabolic derangements like cardiovascular diseases (CVDs) mediated by oxidative stress. The mortality rate due to CVDs is on the rise in developing countries. Insulin resistance (IR) leads to micro or macro angiopathy, peripheral arterial dysfunction, hampered blood flow, hypertension, as well as the cardiomyocyte and the endothelial cell dysfunctions, thus increasing risk factors for coronary artery blockage, stroke and heart failure suggesting that there is a strong association between IR and CVDs. The plausible linkages between these two pathophysiological conditions are altered levels of insulin signaling proteins such as IR-β, IRS-1, PI3K, Akt, Glut4 and PGC-1α that hamper insulin-mediated glucose uptake as well as other functions of insulin in the cardiomyocytes and the endothelial cells of the heart. Reduced AMPK, PFK-2 and elevated levels of NADP(H)-dependent oxidases produced by activated M1 macrophages of the adipose tissue and elevated levels of circulating angiotensin are also cause of CVD in diabetes mellitus condition. Insulin sensitizers, angiotensin blockers, superoxide scavengers are used as therapeutics in the amelioration of CVD. It evidently becomes important to unravel the mechanisms of the association between IR and CVDs in order to formulate novel efficient drugs to treat patients suffering from insulin resistance-mediated cardiovascular diseases. The possible associations between insulin resistance and cardiovascular diseases are reviewed here. PMID:26542377

  8. Mild insulin resistance during oral glucose tolerance test (OGTT) in women with acne.

    PubMed

    Aizawa, H; Niimura, M

    1996-08-01

    The purpose of this study was to evaluate serum levels of basal insulin and glucose-stimulated insulin, and to evaluate their correlations with androgen levels in women with acne. Serum levels of total testosterone (T), free testosterone (FT), dihydrotestosterone (DHT), dehydroepiandrosterone sulfate (DHEA-S), sex hormone binding globulin (SHBG), insulin-like growth factor-1 (IFG-1), and immunoreactive insulin (IRI) were measured and compared in thirty women with moderate or severe acne and thirteen healthy controls. Serum FT, DHT and DHEA-S levels in the acne group were significantly higher than those in the control group. In the acne group, there were no significant correlations between insulin or IGF-1 levels and T, FT, DHT and SHBG, despite the positive correlation between insulin and IGF-1. In order to determine the effects of insulin secretion as a dynamic response to an oral glucose tolerance test (OGTT) on serum androgen levels in acne patients, we examined the responses of serum insulin and androgen levels to a 75 g, 2 hour OGTT in the acne group and in the control group. Basal insulin levels were not significantly higher than those in the control group, but the summed insulin levels during the OGTT in the acne group were significantly higher than those in the control group. Serum T and FT levels in the acne group decreased during the OGTT, but these changes were not so significant when compared to normal controls. In conclusion, we tried to demonstrate mild insulin resistance during the OGTT in acne patients. However, postmeal transient hyperinsulinemia does not seem to play an important role in determining hyperandrogenemia in acne patients. PMID:8854583

  9. Novel Grb14-Mediated Cross Talk between Insulin and p62/Nrf2 Pathways Regulates Liver Lipogenesis and Selective Insulin Resistance.

    PubMed

    Popineau, Lucie; Morzyglod, Lucille; Carré, Nadège; Caüzac, Michèle; Bossard, Pascale; Prip-Buus, Carina; Lenoir, Véronique; Ragazzon, Bruno; Fauveau, Véronique; Robert, Lorenne; Guilmeau, Sandra; Postic, Catherine; Komatsu, Masaaki; Canonne-Hergaux, François; Guillou, Hervé; Burnol, Anne-Françoise

    2016-08-15

    A long-standing paradox in the pathophysiology of metabolic diseases is the selective insulin resistance of the liver. It is characterized by a blunted action of insulin to reduce glucose production, contributing to hyperglycemia, while de novo lipogenesis remains insulin sensitive, participating in turn to hepatic steatosis onset. The underlying molecular bases of this conundrum are not yet fully understood. Here, we established a model of selective insulin resistance in mice by silencing an inhibitor of insulin receptor catalytic activity, the growth factor receptor binding protein 14 (Grb14) in liver. Indeed, Grb14 knockdown enhanced hepatic insulin signaling but also dramatically inhibited de novo fatty acid synthesis. In the liver of obese and insulin-resistant mice, downregulation of Grb14 markedly decreased blood glucose and improved liver steatosis. Mechanistic analyses showed that upon Grb14 knockdown, the release of p62/sqstm1, a partner of Grb14, activated the transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2), which in turn repressed the lipogenic nuclear liver X receptor (LXR). Our study reveals that Grb14 acts as a new signaling node that regulates lipogenesis and modulates insulin sensitivity in the liver by acting at a crossroad between the insulin receptor and the p62-Nrf2-LXR signaling pathways. PMID:27215388

  10. Ceylon cinnamon does not affect postprandial plasma glucose or insulin in subjects with impaired glucose tolerance.

    PubMed

    Wickenberg, Jennie; Lindstedt, Sandra; Berntorp, Kerstin; Nilsson, Jan; Hlebowicz, Joanna

    2012-06-01

    Previous studies on healthy subjects have shown that the intake of 6 g Cinnamomum cassia reduces postprandial glucose and that the intake of 3 g C. cassia reduces insulin response, without affecting postprandial glucose concentrations. Coumarin, which may damage the liver, is present in C. cassia, but not in Cinnamomum zeylanicum. The aim of the present study was to study the effect of C. zeylanicum on postprandial concentrations of plasma glucose, insulin, glycaemic index (GI) and insulinaemic index (GII) in subjects with impaired glucose tolerance (IGT). A total of ten subjects with IGT were assessed in a crossover trial. A standard 75 g oral glucose tolerance test (OGTT) was administered together with placebo or C. zeylanicum capsules. Finger-prick capillary blood samples were taken for glucose measurements and venous blood for insulin measurements, before and at 15, 30, 45, 60, 90, 120, 150 and 180 min after the start of the OGTT. The ingestion of 6 g C. zeylanicum had no significant effect on glucose level, insulin response, GI or GII. Ingestion of C. zeylanicum does not affect postprandial plasma glucose or insulin levels in human subjects. The Federal Institute for Risk Assessment in Europe has suggested the replacement of C. cassia by C. zeylanicum or the use of aqueous extracts of C. cassia to lower coumarin exposure. However, the positive effects seen with C. cassia in subjects with poor glycaemic control would then be lost.

  11. Visceral Fat Accumulation, Insulin Resistance, and Elevated Depressive Symptoms in Middle-Aged Japanese Men

    PubMed Central

    Yamamoto, Shuichiro; Matsushita, Yumi; Nakagawa, Toru; Honda, Toru; Hayashi, Takeshi; Noda, Mitsuhiko; Mizoue, Tetsuya

    2016-01-01

    Objective To investigate visceral fat accumulation and markers of insulin resistance in relation to elevated depressive symptoms (EDS). Methods Participants were 4,333 male employees (mean age, 49.3 years) who underwent abdominal computed tomography scanning, measured fasting insulin, and did not self-report diabetes and mental disorders under treatment and history of cancer, myocardial infarction, and stroke. Multivariable logistic regression was used to assess the association of EDS with abdominal fat deposition and markers of insulin resistance. Results Visceral fat area (VFA) and fasting insulin were significantly, positively associated with EDS. Multivariable-adjusted odds ratios (95% confidence interval) of high VFA for the lowest through highest quartile of depression score were 1 (reference), 1.18 (0.97–1.42), 1.25 (1.02–1.54), 1.23 (1.01–1.51), respectively, and corresponding figures for high fasting insulin were 1 (reference), 0.98 (0.80–1.19), 1.12 (0.91–1.38), and 1.29 (1.06–1.57), respectively. Subcutaneous fat area was not associated with EDS. Conclusions Results suggest that EDS is related to visceral, but not subcutaneous, fat accumulation and insulin resistance in middle-aged Japanese men. PMID:26891344

  12. Sodium Salicylate Reduced Insulin Resistance in the Retina of a Type 2 Diabetic Rat Model

    PubMed Central

    Jiang, Youde; Thakran, Shalini; Bheemreddy, Rajini; Coppess, William; Walker, Robert J.; Steinle, Jena J.

    2015-01-01

    Sodium salicylate has been reported to reduce markers of diabetic retinopathy in a type 1 rat model. Because rates of type 2 diabetes are on the rise, we wanted to determine whether salicylate could improve insulin resistance in a type 2 rat model, as well as improve retinal function. We treated lean and obese BBZDR/Wor type 2 diabetic rats with salicylate in their chow for 2 months. Prior to salicylate treatment, rats underwent an electroretinogram to measure retinal function. After 2 months of treatment, rats underwent an additional electroretinogram prior to sacrifice. In addition to the animal model, we also treated retinal endothelial cells (REC) and rat Müller cells with salicylate and performed the same analyses as done for the rat retinal lysates. To investigate the role of salicylate in insulin signaling, we measured TNFα and caspase 3 levels by ELISA, as well as performed Western blotting for insulin receptor substrate 1, insulin receptor, SOCS3, and pro- and anti-apoptotic markers. Data demonstrated that salicylate significantly improved retinal function, as well as reduced TNFα and SOCS3-induced insulin resistance in all samples. Overall, results suggest that salicylate is effective in reducing insulin resistance in the retina of type 2 diabetic rat models. PMID:25874611

  13. The Emerging Role of Branched-Chain Amino Acids in Insulin Resistance and Metabolism

    PubMed Central

    Yoon, Mee-Sup

    2016-01-01

    Insulin is required for maintenance of glucose homeostasis. Despite the importance of insulin sensitivity to metabolic health, the mechanisms that induce insulin resistance remain unclear. Branched-chain amino acids (BCAAs) belong to the essential amino acids, which are both direct and indirect nutrient signals. Even though BCAAs have been reported to improve metabolic health, an increased BCAA plasma level is associated with a high risk of metabolic disorder and future insulin resistance, or type 2 diabetes mellitus (T2DM). The activation of mammalian target of rapamycin complex 1 (mTORC1) by BCAAs has been suggested to cause insulin resistance. In addition, defective BCAA oxidative metabolism might occur in obesity, leading to a further accumulation of BCAAs and toxic intermediates. This review provides the current understanding of the mechanism of BCAA-induced mTORC1 activation, as well as the effect of mTOR activation on metabolic health in terms of insulin sensitivity. Furthermore, the effects of impaired BCAA metabolism will be discussed in detail. PMID:27376324

  14. The Emerging Role of Branched-Chain Amino Acids in Insulin Resistance and Metabolism.

    PubMed

    Yoon, Mee-Sup

    2016-01-01

    Insulin is required for maintenance of glucose homeostasis. Despite the importance of insulin sensitivity to metabolic health, the mechanisms that induce insulin resistance remain unclear. Branched-chain amino acids (BCAAs) belong to the essential amino acids, which are both direct and indirect nutrient signals. Even though BCAAs have been reported to improve metabolic health, an increased BCAA plasma level is associated with a high risk of metabolic disorder and future insulin resistance, or type 2 diabetes mellitus (T2DM). The activation of mammalian target of rapamycin complex 1 (mTORC1) by BCAAs has been suggested to cause insulin resistance. In addition, defective BCAA oxidative metabolism might occur in obesity, leading to a further accumulation of BCAAs and toxic intermediates. This review provides the current understanding of the mechanism of BCAA-induced mTORC1 activation, as well as the effect of mTOR activation on metabolic health in terms of insulin sensitivity. Furthermore, the effects of impaired BCAA metabolism will be discussed in detail. PMID:27376324

  15. Involvement of dietary saturated fats, from all sources or of dairy origin only, in insulin resistance and type 2 diabetes.

    PubMed

    Morio, Béatrice; Fardet, Anthony; Legrand, Philippe; Lecerf, Jean-Michel

    2016-01-01

    Reducing the consumption of saturated fatty acids to a level as low as possible is a European public health recommendation to reduce the risk of cardiovascular disease. The association between dietary intake of saturated fatty acids and development and management of type 2 diabetes mellitus (T2DM), however, is a matter of debate. A literature search was performed to identify prospective studies and clinical trials in humans that explored the association between dietary intake of saturated fatty acids and risk of insulin resistance and T2DM. Furthermore, to assess whether specific foods, and not just the saturated fatty acid content of the food matrix, can have differential effects on human health, the relationship between consumption of full-fat dairy products, a main source of dietary saturated fatty acids, and risk of insulin resistance and T2DM was studied. There is no evidence that dietary saturated fatty acids from varied food sources affect the risk of insulin resistance or T2DM, nor is intake of full-fat dairy products associated with this risk. These findings strongly suggest that future studies on the effects of dietary saturated fatty acids should take into account the complexity of the food matrix. Furthermore, communication on saturated fats and their health effects should be prudent and well informed.

  16. Role of O-GlcNAcylation in nutritional sensing, insulin resistance and in mediating the benefits of exercise.

    PubMed

    Myslicki, Jason P; Belke, Darrell D; Shearer, Jane

    2014-11-01

    The purpose of this review is to highlight the role of O-linked β-N-acetylglucosamine (O-GlcNAc) protein modification in metabolic disease states and to summarize current knowledge of how exercise affects this important post-translational signalling pathway. O-GlcNAc modification is an intracellular tool capable of integrating energy supply with demand. The accumulation of excess energy associated with obesity and insulin resistance is mediated, in part, by the hexosamine biosynthetic pathway (HBP), which results in the O-GlcNAcylation of a myriad of proteins, thereby affecting their respective function, stability, and localization. Insulin resistance is related to the excessive O-GlcNAcylation of key metabolic proteins causing a chronic blunting of insulin signalling pathways and precipitating the accompanying pathologies, such as heart and kidney disease. Lifestyle modifications such as diet and exercise also modify the pathway. Exercise is a front-line and cost-effective therapeutic approach for insulin resistance, and recent work shows that the intervention can alter O-GlcNAc gene expression, signalling, and protein modification. However, there is currently no consensus on the effect of frequency, intensity, type, and duration of exercise on O-GlcNAc modification, the HBP, and its related enzymes. On one end of the spectrum, mild, prolonged swim training reduces O-GlcNAcylation, while on the other end, higher intensity treadmill running increases cardiac protein O-GlcNAc modification. Clearly, a balance between acute and chronic stress of exercise is needed to reap the benefits of the intervention on O-GlcNAc signalling. PMID:25203141

  17. Role of O-GlcNAcylation in nutritional sensing, insulin resistance and in mediating the benefits of exercise.

    PubMed

    Myslicki, Jason P; Belke, Darrell D; Shearer, Jane

    2014-11-01

    The purpose of this review is to highlight the role of O-linked β-N-acetylglucosamine (O-GlcNAc) protein modification in metabolic disease states and to summarize current knowledge of how exercise affects this important post-translational signalling pathway. O-GlcNAc modification is an intracellular tool capable of integrating energy supply with demand. The accumulation of excess energy associated with obesity and insulin resistance is mediated, in part, by the hexosamine biosynthetic pathway (HBP), which results in the O-GlcNAcylation of a myriad of proteins, thereby affecting their respective function, stability, and localization. Insulin resistance is related to the excessive O-GlcNAcylation of key metabolic proteins causing a chronic blunting of insulin signalling pathways and precipitating the accompanying pathologies, such as heart and kidney disease. Lifestyle modifications such as diet and exercise also modify the pathway. Exercise is a front-line and cost-effective therapeutic approach for insulin resistance, and recent work shows that the intervention can alter O-GlcNAc gene expression, signalling, and protein modification. However, there is currently no consensus on the effect of frequency, intensity, type, and duration of exercise on O-GlcNAc modification, the HBP, and its related enzymes. On one end of the spectrum, mild, prolonged swim training reduces O-GlcNAcylation, while on the other end, higher intensity t