Insulin resistance is a determinant of myocardial dysfunction in apparently healthy obese subjects

Background. Obese pts have subclinical myocardial dysfunction that may account for their risk of heart failure. We sought the contribution of insulin resistance (IR) to myocardial dysfunction in obesity. Methods. Asymptomatic obese subjects without known cardiac disease underwent clinical evaluation, homeostasis model assessment (HOMA score) as a measure of insulin sensitivity and echocardiographic assessment. After exclusion of DM, overt myocardial dysfunction or ischemia, subclinical myocardial function was assessed by myocardial systolic (Sm) and diastolic velocity (Em) in 79 pts. Association was sought between myocardial function with clinical and biochemical characteristics. Results HOMA score categorized 36 pts as non-IR (HOMA

Olanzapine treatment is associated with reduced high molecular weight adiponectin in serum: A potential mechanism for Olanzapine-induced insulin resistance in patients with schizophrenia

Treatment of schizophrenia with olanzapine and other atypical antipsychotic agents is associated with insulin resistance and diabetes mellitus. The mechanism for this is not understood. Adiponectin is an insulin-sensitizing cytokine secreted by adipocytes. It is present in serum in multimers of varying size. Trimers and hexamers are referred to as low molecular weight (LMW) adiponectin. Larger multimers (12-, 18-, and 24-mers) have been designated high molecular weight (HMW) adiponectin and seem responsible for the insulin-sensitizing action of this adipokine. The aim of this study was to examine total adiponectin and LMW and HMW multimers in serum from patients with schizophrenia treated with either olanzapine (n = 9) or other typical antipsychotics (n = 9) and compare results with 16 healthy sex-, body mass index-, and age-matched controls. The effects of olanzapine on adiponectin protein expression and secretion in in vitro-differentiated primary human adipocytes were also examined. Patients receiving olanzapine had significantly lower total serum adiponectin as compared with those on conventional treatment and controls (5.23 +/- 1.53 ng/mL vs. 8.20 +/- 3.77 ng/mL and 8.78 +/- 3.8 ng/mL; P < 0.05 and P < 0.01, respectively). The HMW adiponectin was also reduced in patients on olanzapine as compared with the disease and healthy control groups (1.67 +/- 0.96 ng/mL vs. 3.87 +/- 2.69 ng/mL and 4.07 +/- 3.2 ng/mL; P < 0.05 for both). The LMW adiponectin was not different between patient groups (P = 0.15) but lower in patients on olanzapine as compared with controls (3.56 +/- 10.85 ng/mL vs. 4.70 +/- 1.4 ng/mL; P < 0.05). In vitro, short duration (up to 7 days) olanzapine exposure had no effect on total adiponectin expression or multimer composition of secreted protein. In summary, this study demonstrates a correlation between olanzapine treatment and reduced serum adiponectin, particularly HMW multimers. This may not be a direct effect of olanzapine on adipocyte expression or secretion of adiponectin. These observations provide insights into possible mechanisms for the association between olanzapine treatment and insulin resistance.

Palmitate induces insulin resistance in monocytes and increases expression of the integrin CD11b

Obesity and insulin resistance are important risk factors for atherosclerosis, and elevated level of plasma NEFA is a common feature in individuals with obesity and insulin resistance. Palmitate, one of the most abundant non-esterified SFA in plasma, has been reported to induce insulin resistance in adipose tissues and skeletal muscles and to cause an increased inflammatory response in monocytes. The present study investigated whether palmitate can induce insulin resistance in monocytes and its effect on monocyte adhesion molecular expression (CD11b). Insulin resistance was measured by in vitro uptake of insulin-stimulated 3H-labelled 2-deoxy-D-glucose into THP-1 cells, cell surface CD11b expression was measured by flow cytometry. The data showed that palmitate-induced insulin resistance in THP-1 monocytes was concentration and time dependent (Figure 1). The insulin-stimulated glucose uptake was significantly decreased in cells treated with 300 mM-palmitate compared with control cells (P<0.001) and was observed within 6 h, but was not a result of palmitate toxicity. There was no significant increase in caspase 3 activation (P>0.05). Treatment with 300 mM-palmitate for 24 h also caused a significant increase in surface CD11b expression in both U937 and THP-1 monocytic cell lines and human primary monocytes compared with the control (P<0.001). Both these effects were inhibited by co-incubation with Fumonisin B1, an inhibitor of de novo ceramide synthesis. In conclusion, these data show that palmitate, at physiological concentrations, can cause insulin resistance in monocytes and increase monocyte surface integrin CD11b expression, which is in part the result of the synthesis of ceramide.

Oleate protects against palmitate-induced insulin resistance in L6 myotubes

Oleate has been shown to protect against palmitate-induced insulin resistance. The present study investigates mechanisms involved in the interaction between oleate and palmitate on insulin-stimulated glucose uptake by L6 skeletal muscle cells. L6 myotubes were cultured for 6 h with palmitate or oleate alone, and combinations of palmitate with oleate, with and without phosphatidylinositol 3-kinase (PI3-kinase) inhibition. Insulin-stimulated glucose uptake, measured by uptake of 2-deoxy-d-[3H]glucose, was almost completely prevented by 300 microm-palmitate. Cells incubated with oleate up to 750 micromol/l maintained a significant increase in insulin-stimulated glucose uptake. Co-incubation of 50-300 microm-oleate with 300 microm-palmitate partially prevented the decrease in insulin-stimulated glucose uptake associated with palmitate. Adding the PI3-kinase inhibitors wortmannin (10- 7 mol/l) or LY294002 (25 micromol/l) to 50 microm-oleate plus 300 microm-palmitate significantly reduced the beneficial effect of oleate against palmitate-induced insulin resistance, indicating that activation of PI3-kinase is involved in the protective effect of oleate. Thus, the prevention of palmitate-induced insulin resistance by oleate in L6 muscle cells is associated with the ability of oleate to maintain insulin signalling through PI3-kinase.

Avandamet:Combined metformin-rosiglitazone treatment for insulin resistance in type 2 diabetes

Insulin resistance is a major endocrinopathy underlying the development of hyperglycaemia and cardiovascular disease in type 2 diabetes. Metformin (a biguanide) and rosiglitazone (a thiazolidinedione) counter insulin resistance, acting by different cellular mechanisms. The two agents can be used in combination to achieve additive glucose-lowering efficacy in the treatment of type 2 diabetes, without stimulating insulin secretion and without causing hypoglycaemia. Both agents also reduce a range of atherothrombotic factors and markers, indicating a lower cardiovascular risk. Early intervention with metformin is already known to reduce myocardial infarction and increase survival in overweight type 2 patients. Recently, a single-tablet combination of metformin and rosiglitazone, Avandamet, has become available. Avandamet is suitable for type 2-diabetic patients who are inadequately controlled by monotherapy with metformin or rosiglitazone. Patients already receiving separate tablets of metformin and rosiglitazone may switch to the single-tablet combination for convenience. Also, early introduction of the combination before maximal titration of one agent can reduce side effects. Use of Avandamet requires attention to the precautions for both metformin and rosiglitazone, especially renal, cardiac and hepatic competence. In summary, Avandamet is a single-tablet metformin-rosiglitazone combination that doubly targets insulin resistance as therapy for hyperglycaemia and vascular risk in type 2 diabetes. © 2004 Blackwell Publishing Ltd.

Glucosamine-induced insulin resistance in L6 muscle cells

Background: Glucosamine increases flux through the hexosamine pathway, causing insulin resistance and disturbances similar to diabetic glucose toxicity. Aim: This study examines the effect of glucosamine on glucose uptake by cultured L6 muscle cells as a model of insulin resistance. Methods: Glucose uptake by L6 myotubes was measured using the non-metabolized glucose analogue 2-deoxy-D-glucose after incubation with glucosamine for 4 and 24 h, with and without insulin and several other agents (metformin, peroxovanadium and D-pinitol) that improve glucose uptake in diabetic states. Results: After 4 h, high concentrations of glucosamine (5 × 10-3 and 10-2 M) reduced basal and insulin-stimulated glucose uptake by up to 50%. After 24 h, the effect of insulin was completely abolished by 10-2 M glucosamine and reduced over 50% by 5 × 10-3 M glucosamine. Lower concentrations of glucosamine did not significantly alter glucose uptake. The effect of glucosamine could not be attributed to cytotoxicity assessed by the Trypan Blue test. Metformin, peroxovanadium and D-pinitol, each of which increased glucose uptake by L6 cells, did not prevent the decrease in glucose uptake with glucosamine. Conclusion: Glucosamine decreased insulin-stimulated glucose uptake by L6 muscle cells, providing a potential model of insulin resistance with similarities to glucose toxicity. Insulin resistance induced by glucosamine was not reversed by three agents (metformin, peroxovanadium and D-pinitol) known to enhance or partially mimic the effects of insulin. © 2004 Blackwell Publishing Ltd.

Use of Homeostatic Model Assessment Indexes for the Identification of Metabolic Syndrome and Insulin Resistance among Cuban-Americans: A Cross Sectional Study

Aim: to determine cut off points for The Homeostatic Model Assessment Index 1 and 2 (HOMA-1 and HOMA-2) for identifying insulin resistance and metabolic syndrome among a Cuban-American population. Study Design: Cross sectional. Place and Duration of Study: Florida International University, Robert Stempel School of Public Health and Social Work, Department of Dietetics and Nutrition, Miami, FL from July 2010 to December 2011. Methodology: Subjects without diabetes residing in South Florida were enrolled (N=146, aged 37 to 83 years). The HOMA1-IR and HOMA2-IR 90th percentile in the healthy group (n=75) was used as the cut-off point for insulin resistance. A ROC curve was constructed to determine the cut-off point for metabolic syndrome. Results: HOMA1-IR was associated with BMI, central obesity, and triglycerides (P3.95 and >2.20 and for metabolic syndrome were >2.98 (63.4% sensitivity and 73.3% specificity) and >1.55 (60.6% sensitivity and 66.7% specificity), respectively. Conclusion: HOMA cut-off points may be used as a screening tool to identify insulin resistance and metabolic syndrome among Cuban-Americans living in South Florida.

Ethnic Differences in Insulin Resistance, Adiponectin Levels and Abdominal Obesity: Haitian Americans and African Americans, with and without Type 2 Diabetes Mellitus

Background: Metabolic outcomes of obesity and its associated disorders may not be equivalent across ethnicity and diabetes status. Aim: In this paper, we examined the association of abdominal obesity, by ethnicity and diabetes status, for indicators of glucose metabolism in Blacks. Methods: A cross sectional study was conducted in Haitian Americans (n= 186) and African Americans (n= 148) with and without type 2 diabetes mellitus (T2DM). Student’s t-test and Chi-squared test were used to assess differences in mean and proportion values between ethnicities with and without type 2 diabetes mellitus. Relationship between insulin resistance, ethnicity, diabetes status, abdominal obesity, and adiponectin levels were analyzed by analysis of covariance while controlling for confounding variables. Results:Haitian American participants were older (P = .032), had higher fasting plasma glucose (P = .036), and A1C (P = .016), but had lower levels of Hs-CRP (P < .001), insulin and HOMA2-IR and lower abdominal obesity (P = .030), than African Americans. Haitian Americans had significantly lower HOMA2-IR (P = .008) than African Americans when comparing both ethnicities with T2DM, high abdominal obesity, and adiponectin levels lower than the median ( Conclusion: The clinical significance of observed differences in insulin resistance, abdominal obesity, and adiponectin levels between Haitian Americans and African Americans could assist in forming public health policies that are ethnic specific.

Effect of insulin resistance on monounsaturated fatty acid levels : a multi-cohort non-targeted metabolomics and mendelian randomization study

Insulin resistance (IR) and impaired insulin secretion contribute to type 2 diabetes and cardiovascular disease. Both are associated with changes in the circulating metabolome, but causal directions have been difficult to disentangle. We combined untargeted plasma metabolomics by liquid chromatography/mass spectrometry in three non-diabetic cohorts with Mendelian Randomization (MR) analysis to obtain new insights into early metabolic alterations in IR and impaired insulin secretion. In up to 910 elderly men we found associations of 52 metabolites with hyperinsulinemic-euglycemic clamp-measured IR and/or β-cell responsiveness (disposition index) during an oral glucose tolerance test. These implicated bile acid, glycerophospholipid and caffeine metabolism for IR and fatty acid biosynthesis for impaired insulin secretion. In MR analysis in two separate cohorts (n = 2,613) followed by replication in three independent studies profiled on different metabolomics platforms (n = 7,824 / 8,961 / 8,330), we discovered and replicated causal effects of IR on lower levels of palmitoleic acid and oleic acid. A trend for a causal effect of IR on higher levels of tyrosine reached significance only in meta-analysis. In one of the largest studies combining "gold standard" measures for insulin responsiveness with non-targeted metabolomics, we found distinct metabolic profiles related to IR or impaired insulin secretion. We speculate that the causal effects on monounsaturated fatty acid levels could explain parts of the raised cardiovascular disease risk in IR that is independent of diabetes development.

Hyperinsulinism, Insulin Resistance and Impaired Fasting Glucose Revealing an Insulin Autoimmune Syndrome

We report a case of a 55-year-old woman who was evaluated for multiple episodes of late postprandial hypoglycaemia. We diagnosed her condition as insulin autoimmune syndrome (Hirata disease) because of a high insulin autoantibody (IAA) titre in association with high levels of plasmatic insulin and hypoglycaemia in a patient with no history of exogenous insulin administration and the exclusion of other causes of late postprandial hypoglycaemia.

Association of body composition indices with insulin resistance in European adolescents: the HELENA study

Background: The different body components may contribute to the development of insulin resistance and type 2 diabetes mellitus. The aim of the present study was to examine the association of fat mass and fat free mass indices with markers of insulin resistance, independently of each other and giving, at the same time, gender-specific information in a wide cohort of European adolescents. Methods: A cross-sectional study in a school setting was conducted in 925 (430 males) adolescents (14.9 ± 1.2 years). Weight, height, anthropometric, bioimpedance and blood parameters were measured. Indices for fat mass and fat free mass, and homeostatic model assessment (HOMA) were calculated. Multiple regression analyses were performed adjusting for several confounders including fat free mass and fat mass when possible. Results: Indices of fat mass were positively associated with HOMA (all p < 0.01) after adjusting for all the confounders including fat free mass indices, in both sexes. Fat free mass indices were associated with HOMA, in both males and females, after adjusting for center, pubertal status, socioeconomic status and cardiorespiratory fitness, but the associations disappear when including fat mass indices in the adjustment's model. Conclusion: Fat mass indices derived from different methods are positively associated with insulin resistance independently of several confounders including fat free mass indices. In addition, the relationship of fat free mass with insulin resistance is influenced by the amount of fat mass in European adolescents. Nevertheless, future studies should focus not only on the role of fat mass, but also on other body components such as fat free mass because its role could vary depending of the level and distribution of fat mass.