Insulin Resistance Response Research Articles

Effects of exercise and lifestyle modification on fitness, insulin resistance, skeletal muscle oxidative phosphorylation and intramyocellular lipid content in obese children and adolescents

Obesity is associated with poor fitness and adverse metabolic consequences in children. To investigate how exercise and lifestyle modification may improve fitness and insulin sensitivity in this population. Randomized controlled trial, 21 obese (body mass index ≥ 95% percentile) subjects, ages 10 to 17 years. Subjects were given standardized healthful lifestyle advice for 8 weeks. In addition, they were randomized to an in-home supervised exercise intervention (n = 10) or control group (n = 11). Fasting laboratory studies (insulin, glucose, lipid profile) and assessments of fitness, body composition, skeletal muscle oxidative phosphorylation and intramyocellular lipid content (IMCL), were performed at baseline and study completion. Subjects were 13.0 ± 1.9 (standard deviation) years old, 72% female and 44% non-white. Exercise improved fitness (P = 0.03) and power (P = 0.01), and increased IMCL (P = 0.02). HOMA-IR decreased among all subjects in response to lifestyle modification advice (P = 0.01), regardless of exercise training assignment. In univariate analysis in all subjects, change in cardiovascular fitness was associated with change in HOMA-IR. In exploratory analyses, increased IMCL was associated with greater resting energy expenditure (r = 0.78, P = 0.005) and a decrease in fasting respiratory quotient (r = -0.70, P = 0.02) (n = 11). Change in fitness was found to be related to change in insulin resistance in response to lifestyle modification and exercise in obese children. IMCL increased with exercise in these obese children, which may reflect greater muscle lipid oxidative capacity.

Circulation: Clinical Summaries

<i>Circulation:</i> Clinical Summaries

Genetic Determinant for Amino Acid Metabolites and Changes in Body Weight and Insulin Resistance in Response to Weight-Loss Diets

Background— Circulating branched-chain amino acids and aromatic amino acids were recently related to insulin resistance and diabetes mellitus in prospective cohorts. We tested the effects of a genetic determinant of branched-chain amino acid/aromatic amino acid ratio on changes in body weight and insulin resistance in a 2-year diet intervention trial. Methods and Results— We genotyped the branched-chain amino acid/aromatic amino acid ratio—associated variant rs1440581 near the PPM1K gene in 734 overweight or obese adults who were assigned to 1 of 4 diets varying in macronutrient content. At 6 months, dietary fat significantly modified genetic effects on changes in weight, fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) after adjustment for the confounders (all P for interaction ≤0.006). Further adjustment for weight change did not appreciably change the interactions for fasting insulin and HOMA-IR. In the high-fat diet group, the C allele was related to less weight loss and smaller decreases in serum insulin and HOMA-IR (all P ≤ 0.02 in an additive pattern), whereas an opposite genotype effect on changes in insulin and HOMA-IR was observed in the low-fat diet group ( P =0.02 and P =0.04, respectively). At 2 years, the gene-diet interactions remained significant for weight loss ( P =0.008) but became null for changes in serum insulin and HOMA-IR resulting from weight regain. Conclusions— Individuals carrying the C allele of the branched-chain amino acid/aromatic amino acid ratio—associated variant rs1440581 may benefit less in weight loss and improvement of insulin sensitivity than those without this allele when undertaking an energy-restricted high-fat diet. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00072995.

Insulin Resistance by Adiponectin Deficiency: Is the Action in Skeletal Muscle?

Adiponectin is rapidly approaching its 20th anniversary, but it is still unclear how this apparently potent adipokine exerts its actions. The link to obesity and insulin resistance is obvious; the negative associations between plasma adiponectin concentrations and increasing fat mass or insulin sensitivity are reproducible and strong. The high abundance of adiponectin in plasma also implies a biological purpose. Adiponectin deficiency in mice gives rise to a reasonably mild insulin resistance upon high-fat feeding in most (1–3) but not all (4) models. Obviously, this fits well with the relative absence of adiponectin seen in insulin-resistant obese humans, but human monogenic causes of adiponectin deficiency are yet to be described. To further explore potential mechanisms of insulin resistance in response to adiponectin deficiency, Sweeney and colleagues (5) have used the most classic of endocrine approaches, i.e., to supplement a missing hormone or signal and observe the metabolic effect. The focus is on skeletal muscle and in particular the metabolomic patterns emerging in skeletal muscle after high-fat feeding and controlled adiponectin replenishment. Mice deficient for adiponectin were given a chow or high-fat diet …

Metformin: a cheap and well‐tolerated drug that provides benefits for viral infections

Insulin resistance in viral infections is common. We have explored the effectiveness of metformin for alleviating insulin resistance in HIV-infected patients and assessed the relevance of the ataxia-telangiectasia mutated (ATM) rs11212617 variant in the clinical response with the rationale that metformin modulates cellular bioenergetics in an ATM-dependent process. HIV-infected patients (n = 385) were compared with controls recruited from the general population (n = 300) with respect to the genotype distribution of the ATM rs11212617 variant and its influence on selected metabolic and inflammatory variables. We also followed up a subset of male patients with HIV and hepatitis C virus (HCV) coinfection (n = 47) who were not receiving antiviral treatment and for whom metformin was prescribed for insulin resistance, which tends to have a higher incidence and severity in coinfected patients. Among the HIV-infected patients, human cytomegalovirus (91.9%) and HCV (62.3%) coinfections were frequent. Selected metabolic and/or inflammatory variables were significantly altered in infected patients. Treatment with metformin in HIV and HCV coinfected patients was well tolerated and significantly increased the sensitivity of peripheral tissues to insulin. The minor allele (C) of the rs11212617 variant was associated with treatment success and may affect the course of insulin resistance in response to metformin (odds ratio 1.21; 95% confidence interval 1.07-1.39; P = 0.005). There were no differences between treated and untreated patients in viral loads or variables measuring immune defence, indicating that toxicity is unlikely. We provide novel data suggesting that identification of the ATM rs11212617 variant may be important in assessing the glycaemic response to metformin treatment for insulin resistance in HIV-infected patients.

Addition of Metformin to Sildenafil Treatment for Erectile Dysfunction in Eugonadal Nondiabetic Men With Insulin Resistance. A Prospective, Randomized, Double‐Blind Pilot Study

Erection depends largely on the release of nitric oxide (NO) by vascular endothelial cells. Insulin resistance (IR) is a metabolic abnormality that produces endothelial dysfunction characterized by decreased synthesis and release of NO. The aim of this paper is to evaluate the effect of treatment with metformin on the response to sildenafil in patients with erectile dysfunction (ED) and IR enrolled in a prospective, randomized, controlled, double-blind placebo study. We included 30 male patients with ED, IR, and poor response to sildenafil. Exclusion criteria included pharmacologic, anatomic, or endocrine ED; diabetes; prostatic surgery; or chronic illnesses. Erectile function was rated according to the International Index of Erectile Function 5 (IIEF-5); IR was measured by homeostasis model assessment (HOMA; IR = HOMA ≥ 3). Patients were randomized to receive metformin (n = 17) or placebo (n = 13). After treatment with metformin, patients with ED showed a significant increase in IIEF-5 score and a significant decrease in HOMA, both occurring at month 2 (IIEF-5: 17.0 ± 6.0 vs 14.3 ± 3.9, P = .01; HOMA: 3.9 ± 1.6 vs 5.5 ± 2.4, P = .01) to 4 of treatment (IIEF-5: 19.8 ± 3.8 vs 14.3 ± 3.9, P = .005; HOMA: 4.5 ± 1.9 vs 5.5 ± 2.4, P = .04), with no changes in these parameters in patients with ED receiving placebo. Patients treated with metformin had more adverse events than those who received placebo: 61.5% compared with 7.7%, P = .03, respectively. Adverse events were mild, mainly gastrointestinal, and did not cause discontinuation of treatment. Treatment with metformin in patients with ED and poor response to sildenafil reduced the IR and improved erectile function.

Incretin Hormones and the Up-Regulation of Insulin Secretion in Insulin Resistance

The incretin effect is the augmented insulin secretion that is elicited by oral compared with iv administration of glucose, when glucose levels during the two challenges are matched. The incretin effect has been documented in humans (1) and in experimental animals (2). The underlying reason for the incretin effect is attributed to the release of incretin hormones from the gut during oral glucose administration [mainly glucose-dependent insulinotropic polypeptide (GIP) and glucagonlike peptide-1 (GLP-1)]; these incretin hormones potentiate the glucose-stimulated insulin secretion. It has been estimated that the incretin effect is responsible for at least 60–70% of insulin secretion after oral glucose in normal humans (3). Recently, it was demonstrated that an incretin effect also exists after oral fat administration, i.e. it is not specific for glucose (4). It is now well documented that the incretin effect is reduced in type 2 diabetes (3). This impairment could be due to impaired incretin hormone secretion (i.e. incretin hormone deficiency) and/or to a defective insulinotropic action of the incretin hormones (i.e. incretin hormone resistance). Although some controversy still exists in the literature, most data support that the impaired incretin effect in type 2 diabetes is due to defective insulin secretory effects of GIP and GLP-1, rather than to defective secretion of the two incretin hormones (3, 5). Still, GLP-1 retains a high efficacy in type 2 diabetes, which is a rationale behind the incretin-based therapy (6). The defective incretin effect in type 2 diabetes has raised two fundamental questions of importance for the understanding of diabetes pathophysiology. One question is whether a defective incretin effect is involved in the pathophysiology of the disease, i.e. whether defective incretin effect participates in the development of the disease itself or is merely a consequence of the disease (7). A second question is whether the defective insulinotropic actions of GIP and GLP-1 in type 2 diabetics, compared with healthy individuals, are due to specific defects in the -cell effects of the hormones or reflect a more generalized -cell dysfunction (8). In regard to the potential pathophysiological contribution of defective incretin effect, only a few studies have explored this important question, and the results have been controversial. For example, on the one hand, it has been shown that the insulin stimulatory effect of GIP is impaired in first-degree relatives of type 2 diabetic patients (9), which would suggest a pathophysiological involvement. On the other hand, it has also been shown that the insulinotropic effect of GIP is normal in women with a history of gestational diabetes (10), which instead suggests that the defect is secondary to developed diabetes. In regard to the question of a specific defect in incretin hormone effect in type 2 diabetes vs. a generalized -cell defect, no studies have directly focused on this issue. In the present issue of the JCEM, a novel study by Hansen et al. (11) has addressed these two fundamental questions by a novel and interesting approach. The authors examined the insulin secretory responses to iv GIP and GLP-1 (given in physiological concentrations) during a hyperglycemic clamp (10 mmol/liter) in healthy subjects before and after experimental induction of insulin resistance. In insulin resistance, insulin secretion is up-regulated, and in healthy subjects, the disposition index (i.e. insulin sensitivity insulin secretion) remains normal (12). The investigators compared the up-regulated insulin secretion after glucose vs. incretin hormones. If there is a defective up-regulation of insulin secretion to insulin resistance in response to the incretin hormones, but not to

Effects of training on body composition, blood lipids, and glucose homeostasis assessed by the homeostasis model assessment

Summary Objective To determine effect of aerobic exercise training on glucose homeostasis, body composition and lipid profile in presence of obesity. Methods A total 34 middle-aged (43 ± 3 years) obese men (BMI = 32.1 ± 2.9 kg/m 2 ) were divided into exercise (3 months aerobic exercise, three times weekly) or control (detraining) group. Fasting glucose, triglyceride (TG), high-density lipoprotein ( HDL ) , beta-cell function and anthropometrical indexes measured before and after aerobic exercise intervention or detraining in exercise and control group respectively. Statistical analysis was performed with the SPSS software version 15.0 using an independent paired t -test. The P -value Results There are no differences in anthropometrical or biochemical variables in baseline in two groups ( P ≥ 0.05). Exercise intervention led to significant decrease in fasting glucose, TG, TG/HDL ratio, systolic blood pressure and all anthropometrical indexes in exercise group ( P P P P ≥ 0.05). Conclusion Despite no significant change on insulin resistance in response to aerobic exercise training in middle-aged obese males, but was associated with an improvement in body composition and lipid profile and particularly fasting glucose in these subjects. It seems that reduction in blood glucose has occurred in response to increased insulin secretion of pancreas beta-cells.

Curcumin Prevents High Fat Diet Induced Insulin Resistance and Obesity via Attenuating Lipogenesis in Liver and Inflammatory Pathway in Adipocytes

BackgroundMechanisms underlying the attenuation of body weight gain and insulin resistance in response to high fat diet (HFD) by the curry compound curcumin need to be further explored. Although the attenuation of the inflammatory pathway is an accepted mechanism, a recent study suggested that curcumin stimulates Wnt signaling pathway and hence suppresses adipogenic differentiation. This is in contrast with the known repressive effect of curcumin on Wnt signaling in other cell lineages.Methodology and Principal FindingsWe conducted the examination on low fat diet, or HFD fed C57BL/6J mice with or without curcumin intervention for 28 weeks. Curcumin significantly attenuated the effect of HFD on glucose disposal, body weight/fat gain, as well as the development of insulin resistance. No stimulatory effect on Wnt activation was observed in the mature fat tissue. In addition, curcumin did not stimulate Wnt signaling in vitro in primary rat adipocytes. Furthermore, curcumin inhibited lipogenic gene expression in the liver and blocked the effects of HFD on macrophage infiltration and the inflammatory pathway in the adipose tissue.Conclusions and SignificanceWe conclude that the beneficial effect of curcumin during HFD consumption is mediated by attenuating lipogenic gene expression in the liver and the inflammatory response in the adipose tissue, in the absence of stimulation of Wnt signaling in mature adipocytes.

Steatosis and insulin resistance in response to treatment of chronic hepatitis C

This review will focus on the impact of steatosis and insulin resistance on the response to antiviral therapy for chronic hepatitis C. Hepatitis C virus (HCV) infection is known to have direct and/or indirect effects on lipid and glucose metabolism, leading to, among other disturbances, steatosis and insulin resistance, respectively. Some of these disturbances have a marked HCV genotype distribution. For example, on average, patients with HCV genotype 3 have the highest prevalence and severity of viral fatty liver. On the other hand, the current global spread of the metabolic syndrome represents a formidable cofactor of morbidity in HCV-related chronic liver disease. Thus, the pathogenesis of steatosis and insulin resistance in patients with chronic hepatitis C may often be dual, i.e. viral and metabolic. This distinction is relevant because the effect (if any) of steatosis or insulin resistance on the response to antiviral agents seems to depend on their pathogenesis. Accumulating data suggest that viral fatty liver may not impact on response to therapy, while metabolic steatosis does. Similarly, viral insulin resistance may not reduce the rate of response to therapy to the same extent that metabolic insulin resistance does. Some implications for patient management are discussed.

Retinol Binding Protein

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. 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. 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). 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.

Association of vitamin D receptor gene polymorphisms with insulin resistance and response to vitamin D

The objectives of the study were to determine associations between single nucleotide polymorphisms (SNPs) of the vitamin D receptor (VDR) gene and insulin resistance and the effects of these SNPs on changes in insulin sensitivity in response to vitamin D supplementation. The research described here was an extension of the Surya study. Genotyping of the Cdx-2, FokI, BsmI, ApaI, and TaqI SNPs was carried out on 239 South Asian women in New Zealand using polymerase chain reaction–based techniques. Associations of these genotypes and 3′ end haplotypes with insulin resistance were determined using multiple regression analysis. Associations between SNP genotypes and responses in insulin sensitivity to vitamin D supplementation (4000 IU vitamin D3 per day) were also determined for a subset (81) of these women. BsmI BB, ApaI AA, and TaqI tt genotypes were significantly associated with lower insulin resistance compared with BsmI bb, ApaI aa, and TaqI TT, respectively, in the cohort of 239 women. Furthermore, homozygosity of the haplotypes baT and BAt was associated with higher and lower insulin resistance, respectively, compared with no copies of their respective alleles. Of the 81 subjects who were supplemented with vitamin D, women with the FokI Ff genotype showed a significantly greater improvement in insulin sensitivity (increase of 29.4 [2.9, 38.1]) compared with women with the FokI FF genotype (increase of 2.3 [−11.5, 10.1]). This study has highlighted the association of vitamin D responsiveness and insulin resistance with VDR gene polymorphisms. This is the first study to determine associations between all three. Genotyping of the VDR gene may provide a predictive measure for insulin resistance in response to vitamin D intervention.

Blocking O-Linked GlcNAc Cycling in Drosophila Insulin-producing Cells Perturbs Glucose-Insulin Homeostasis

A dynamic cycle of O-linked GlcNAc (O-GlcNAc) addition and removal is catalyzed by O-GlcNAc transferase and O-GlcNAcase, respectively, in a process that serves as the final step in a nutrient-driven "hexosamine-signaling pathway." Evidence points to a role for O-GlcNAc cycling in diabetes and insulin resistance. We have used Drosophila melanogaster to determine whether O-GlcNAc metabolism plays a role in modulating Drosophila insulin-like peptide (dilp) production and insulin signaling. We employed transgenesis to either overexpress or knock down Drosophila Ogt(sxc) and Oga in insulin-producing cells (IPCs) or fat bodies using the GAL4-UAS system. Knockdown of Ogt decreased Dilp2, Dilp3, and Dilp5 production, with reduced body size and decreased phosphorylation of Akt in vivo. In contrast, knockdown of Oga increased Dilp2, Dilp3, and Dilp5 production, increased body size, and enhanced phosphorylation of Akt in vivo. However, knockdown of either Ogt(sxc) or Oga in the IPCs increased the hemolymph carbohydrate concentration. Furthermore, phosphorylation of Akt stimulated by extraneous insulin in an ex vivo cultured fat body of third instar larvae was diminished in strains subjected to IPC knockdown of Ogt or Oga. Knockdown of O-GlcNAc cycling enzymes in the fat body dramatically reduced neutral lipid stores. These results demonstrate that altered O-GlcNAc cycling in Drosophila IPCs modulates insulin production and influences the insulin responsiveness of peripheral tissues. The observed phenotypes in O-GlcNAc cycling mimic pancreatic β-cell dysfunction and glucose toxicity related to sustained hyperglycemia in mammals.

Fitness Abrogates the Ability of Free Fatty Acids (FFA) to Inhibit Insulin's Microvascular Action

Insulin acutely (within 20 min) increases microvascular blood volume (MBV) within human forearm muscle as measured by contrast enhanced ultrasound (CEU). This serves to increase insulin delivery to muscle and facilitates insulin's metabolic action. This vascular effect of insulin is impaired by the insulin resistance that accompanies either chronic obesity or acute (within 2-4hr) increases in the circulating levels of FFA. Interestingly, and as yet unexplained, raising plasma FFA via infusion of Intralipid has less effect on insulin sensitivity in individuals who are highly trained. It is not known whether training affects the ability of FFA to inhibit insulin-induced microvascular recruitment. PURPOSE: The current study was undertaken to address whether the level of fitness (VO2 max) or adiposity (% body fat) predicted MBV and/or glucose infusion rate (GIR) during a euglycemic insulin clamp. METHODS: A group (n =11) of young (18-35), lean (BMI≤25), healthy subjects received Intralipid 20% + heparin for 5 hrs (3hr prior to and throughout a 2hr, 1mU/kg/min insulin clamp). MBV as measured by CEU was obtained continuously during the first 30 min of the clamp. Fitness level was assessed by conducting an exercise test (Bruce protocol) to obtain VO2 max in a subset (n=8) on a separate day. RESULTS: We found that VO2 max was a strong predictor of MBV (r = 0.74 p <0.05) the GIR likewise strongly correlated with MBV(r = 0.75, p= 0.01) supporting the hypothesis that insulin's vascular action is a significant contributor to its metabolic effects. We also observed the expected inverse relationship between VO2 max and % body fat (r = -0.79, p= 0.02). CONCLUSION: Fitness limits the ability of elevated FFA to block both insulin's vasodilatory and metabolic effects. The increased microvascular surface area in response to insulin seen in those with higher VO2 max can facilitate exchange of insulin and glucose with muscle interstitium thereby contributing to the higher GIR. In addition the lower body fat %, therefore greater % lean body mass, may also contribute to the higher GIR. Taken together these findings suggest that a more fit person is less likely to develop either vascular or metabolic insulin resistance in response to elevated circulation FFA. The mechanism for the protective effect of fitness is unclear. Supported by NIH Grant RO1 DK073759

Early Overnutrition Results in Early-Onset Arcuate Leptin Resistance and Increased Sensitivity to High-Fat Diet

Childhood obesity increases the risk of adult obesity and diabetes, suggesting that early overnutrition permanently programs altered energy and glucose homeostasis. In the present studies, we used a mouse model to investigate whether early overnutrition increases susceptibility to obesity and insulin resistance in response to a high-fat diet (HFD). Litters from Swiss Webster dams were culled to three [chronic postnatal overnutrition (CPO)] or 10 (control) pups and then weaned onto standard chow at postnatal day (P) 23. At 6 wk of age, a subset of mice was placed on HFD, and glucose and insulin tolerance were examined at 16-17 wk of age. Leptin sensitivity was determined by hypothalamic phosphorylated signal transducer and activator of transcription-3 immunoreactivity at P16 and adulthood after ip leptin. CPO mice exhibited accelerated body weight gain and hyperleptinemia during the preweaning period but only a slightly heavier body weight and normal glucose tolerance in adulthood on standard chow diet. Importantly, CPO mice exhibited significant leptin resistance in the arcuate nucleus, demonstrated by reduced activation of phospho-signal transducer and activator of transcription-3, as early as P16 and throughout life, despite normalized leptin levels. In response to HFD, CPO but not control mice displayed insulin resistance in response to an insulin tolerance test. In conclusion, CPO mice exhibited early and persistent leptin resistance in the arcuate nucleus and, in response to HFD, rapid development of obesity and insulin resistance. These studies suggest that early overnutrition can permanently alter energy homeostasis and significantly increase susceptibility to obesity and insulin resistance.

Influence of macronutrient intake and anthropometric characteristics on plasma insulin after eccentric exercise

To increase understanding of the interaction between macronutrients and insulin resistance (IR), this study sought to determine the influence of macronutrient intake and anthropometric differences on IR and inflammation responses to eccentric resistance exercise. Men and women (n = 12, 19-36 years old) participated in a crossover study and completed 6 sets of 10 unilateral maximal eccentric contractions of the elbow flexors and extensors followed by controlled diet conditions for the first 8 hours postexercise of carbohydrate/fat/protein proportions of either 75%/15%/10% (CHO) or 6%/70%/24% (FAT/PRO). Fasting glucose, insulin, homeostatic model assessment (HOMA) variables, and interleukin (IL)-1 β were measured preexercise and 23 hours postexercise (additional measures of glucose and insulin 1 hour after meals consumed 0.5, 3, and 7 hours postexercise). Insulin increased more ( P < .01) in the CHO compared with the FAT/PRO condition at 1.5, 4, and 8 hours postexercise. Insulin, HOMA-IR, and HOMA- β-cell function increased 23 hours postexercise in both conditions, whereas IL-1 β increased 23 hours postexercise only in the CHO condition. Magnitude of change (Δ) for these variables associated positively with body mass index (BMI) and waist to hip ratio (WHR) in the CHO and inversely in the FAT/PRO condition; that is, r = 0.53 ( P = .10) and r = −0.82 ( P < .01) for BMI vs Δ insulin in CHO and FAT/PRO conditions, respectively. The Δ IL-1 β associated with BMI ( r = 0.62, P < .05) and WHR ( r = 0.84, P < .01) in the CHO condition. The CHO enhanced IR and inflammation as BMI and WHR increased, whereas fat and protein enhanced IR as BMI and WHR decreased. Thus, BMI and WHR may need to be taken into account in the development of nutritional strategies to prevent IR.

Role of Muscle c-Jun NH2-Terminal Kinase 1 in Obesity-Induced Insulin Resistance

Obesity caused by feeding of a high-fat diet (HFD) is associated with an increased activation of c-Jun NH(2)-terminal kinase 1 (JNK1). Activated JNK1 is implicated in the mechanism of obesity-induced insulin resistance and the development of metabolic syndrome and type 2 diabetes. Significantly, Jnk1(-)(/)(-) mice are protected against HFD-induced obesity and insulin resistance. Here we show that an ablation of the Jnk1 gene in skeletal muscle does not influence HFD-induced obesity. However, muscle-specific JNK1-deficient (M(KO)) mice exhibit improved insulin sensitivity compared with control wild-type (M(WT)) mice. Thus, insulin-stimulated AKT activation is suppressed in muscle, liver, and adipose tissue of HFD-fed M(WT) mice but is suppressed only in the liver and adipose tissue of M(KO) mice. These data demonstrate that JNK1 in muscle contributes to peripheral insulin resistance in response to diet-induced obesity.

Effect of metformin therapy on 2-h post-glucose insulin levels in patients of polycystic ovarian syndrome

AIMS:To evaluate if 2-h post glucose insulin level is an effective tool to monitor insulin resistance in response to metformin therapy, in infertile women with polycystic ovarian syndrome (PCOS).SETTINGS AND DESIGN:This prospective observational study was carried out in a tertiary care infertility clinic.MATERIALS AND METHODS:40 women with PCOS were categorized as having insulin resistance if fasting or 2-h post glucose insulin levels were >25 or >41μU/ml respectively. Post glucose insulin was compared before and after six months of metformin therapy along with other clinical, hormonal and metabolic parameters by using McNemar and the Student’s t-test.RESULTS:Fasting insulin was elevated in 4 (10%) and post-load insulin in 34 (85%) patients; after metformin therapy respective values were 2 (5%) and 16 (40%). Metformin therapy reduced post glucose insulin levels (P<0.001), improved the regularity of periods (P<0.001) and resulted in reduction of LH levels (P<0.001), total testosterone (P<0.001) and mean Body mass index (BMI) (P=0.047). Metformin therapy did not alter waist-hip ratio and fasting insulin levels.CONCLUSION:2-h post glucose insulin level is an effective tool to monitor insulin resistance in PCOS patients and improves significantly after metformin therapy, similar to improvements observed in clinical, hormonal and metabolic parameters.

Increased rate of whole body lipolysis before and after 9 days of bed rest in healthy young men born with low birth weight

Individuals born with low birth weight (LBW) are at risk of developing type 2 diabetes mellitus (T2D), which may be precipitated by physical inactivity. Twenty-two LBW subjects and twenty-three controls were studied before and after bed rest by the hyperinsulinemic euglycemic clamp combined with indirect calorimetry and infusion of stable isotope tracers and preceded by an intravenous glucose tolerance test. LBW subjects had a similar body mass index but elevated abdominal obesity compared with controls. The basal rate of whole body lipolysis (WBL) was elevated in LBW subjects with and without correction for abdominal obesity before and after bed rest (all P = 0.01). Skeletal muscle hormone-sensitive lipase (HSL) protein expression and phosphorylation at Ser565 were similar in the two groups. Bed rest resulted in a decrease in WBL and an increased skeletal muscle HSL Ser565 phosphorylation indicating a decreased HSL activity in both groups. All subjects developed peripheral insulin resistance in response to bed rest (all P < 0.0001) with no differences between groups. LBW subjects developed hepatic insulin resistance in response to bed rest. In conclusion, increased WBL may contribute to the development of hepatic insulin resistance when exposed to bed rest in LBW subjects. Nine days of bed rest causes severe peripheral insulin resistance and reduced WBL and skeletal muscle HSL activity, as well as a compensatory increased insulin secretion, with no differences in LBW subjects and controls.

Lipid-induced mTOR activation in rat skeletal muscle reversed by exercise and 5′-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside

The serine/threonine protein kinase, mammalian target of rapamycin (mTOR) is regulated by insulin and nutrient availability and has been proposed to play a central role as a nutrient sensor in skeletal muscle. mTOR associates with its binding partners, raptor and rictor, to form two structurally and functionally distinct complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) respectively. We have investigated the assembly of mTORC1/2 and the activation of their downstream substrates (i.e. Akt, S6K1) in response to known effectors of mTOR, excess lipid availability and AMP-activated protein kinase (AMPK) activation/exercise training in rat skeletal muscle. The in vivo formation of mTORC1 and 2 and the activation of their respective downstream substrates were increased in response to chronic (8 weeks) consumption of a high-fat diet. Diet-induced mTORC activation and skeletal muscle insulin resistance were reversed by 4 weeks of exercise training, which was associated with enhanced muscle AMPK activation. In order to determine whether AMPK activation reverses lipid-induced mTOR activation, L6 myotubes were exposed to 0.4 mM palmitate to activate mTORC1/2 in the absence or presence of 5'-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR). Palmitate exposure (4 h) increased insulin-stimulated S6K1 Thr389 phosphorylation by 60%, indicating activation of mTORC1. AMPK activation with 1 mM AICAR abolished lipid-induced mTOR activation in vitro. Our data implicates reductions in mTOR complex activation with the reversal of lipid-induced skeletal muscle insulin resistance in response to exercise training or AICAR and identifies mTOR as a potential target for the treatment of insulin resistance.