Role In Insulin Sensitivity Research Articles

The renin–angiotensin–aldosterone system: a pivotal role in insulin sensitivity and glycemic control

Diabetes mellitus is an exploding epidemic costing billions of dollars yearly. Type 2 diabetes mellitus is characterized by insulin resistance and is closely associated with arterial hypertension. Emerging literature has demonstrated that modulation of the renin-angiotensin-aldosterone system by use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers leads to improved insulin sensitivity, glycemic control and possibly prevention of type 2 diabetes mellitus. Several major studies investigating angiotensin II receptor blocker or angiotensin-converting enzyme inhibitor use in either hypertensive or heart failure patients have found lower incidence of type 2 diabetes mellitus when compared with placebo, beta-blocker, calcium-channel blocker or diuretic. None of these trials, however, studied prevention of diabetes as a primary endpoint. The Dream Trial and upcoming NAVIGATOR, ONTARGET/TRANSCEND trials specifically look at the prevention of diabetes as a primary endpoint. Several studies have evaluated possible mechanisms of how the renin-angiotensin-aldosterone system can alter insulin sensitivity and glycemic control. This review will focus on the recent literature that demonstrates renin-angiotensin-aldosterone system modulation and its effects on diabetes prevention, glycemic control and insulin sensitivity, as well as possible mechanisms for achieving this goal.

P-125 The association between increased alanine aminotransferase activity and metabolic factors in Japanese college students

Recent studies have reported nonalcoholic fatty liver disease (NAFLD) may play important roles in insulin sensitivity and maintenance of energy homeostasis to protect against metabolic perturbation by excessive energy storage. We evaluated the prevalence and association of metabolic and hepatic abnormalities and insulin resistance determined by homeostasis modeling (HOMA-IR) in a large sample of young Japanese. This study was performed in 2006 on 1821 college students aged 18-22 yrs (males 987, females 834). We adapted the International Diabetes Federation (IDF) definition of metabolic syndrome (MS), but used the cut-off waist circumference (WC) of more than 85 cm for men and 80 cm for women. None of the participants were antihepatitis-B-antigen-positive. In addition, most of them did not consume alcohol daily, did not have any disease, nor were on any medication. The prevalence of individual components of MS was 15.7% for WC, 3.3% for impaired fasting glucose, 9.3% for dyslipidemia, and 7.9% for high blood pressure in male students, and respectively 12.2%, 1.2%, 2.5% in female students. MS was detected in 1.7% of men and 0.36% of women according to the IDF definition. The risk factors, fasting glucose, dyslipidemia and hypertension, increased from 0 to 3 and HOMA-IR increased dramatically (1.17, 1.73, 17.1 and 15.9, respectively). The prevalence of increased alanine aminotransferase (ALT) level (27 IU/l<) was 70.3% in young men with WC greater than 85cm, whereas it was 17.2% in those with normal WC. The prevalence of two or more risk factors was 9.1% in young men with increased ALT level and was 0.41% in those with low ALT level. In addition, WC showed stronger correlation with ALT (r=0.501) than HOMA-IR (r=0.213). The prevalence of MS was low in young college students. The present study demonstrated that ALT is significantly associated with features of the MS, and that it is related to WC stronger than to HOMA-IR. It is worse that this homogeneous sample of college students was suitable for studying the first effect of excessive abdominal fat. The results obtained are consistent with the proposal that NAFLD plays an important role in excessive energy storage before insulin resistance increases. As the MS results in a marked elevation of insulin resistance in the young population, ALT may be useful for early detection of the disorder.

Dimethylarginine Dimethylaminohydrolase Overexpression Enhances Insulin Sensitivity

Previous studies suggest that nitric oxide (NO) may modulate insulin-induced uptake of glucose in insulin-sensitive tissues. Asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase (NOS). We hypothesized that a reduction in endogenous ADMA would increase NO synthesis and thereby enhance insulin sensitivity. To test this hypothesis we used a transgenic mouse in which we overexpressed human dimethylarginine dimethylaminohydrolase (DDAH-I). The DDAH-I mice had lower plasma ADMA at all ages (22 to 70 wk) by comparison to wild-type (WT) littermates. With a glucose challenge, WT mice showed a prompt increase in ADMA, whereas DDAH-I mice had a blunted response. Furthermore, DDAH-I mice had a blunted increase in plasma insulin and glucose levels after glucose challenge, with a 50% reduction in the insulin resistance index, consistent with enhanced sensitivity to insulin. In liver, we observed an increased Akt phosphorylation in the DDAH-I mice after i.p. glucose challenge. Incubation of skeletal muscle from WT mice ex vivo with ADMA (2 mumol/L) markedly suppressed insulin-induced glycogen synthesis in fast-twitch but not slow-twitch muscle. These findings suggest that the endogenous NOS inhibitor ADMA reduces insulin sensitivity, consistent with previous observations that NO plays a role in insulin sensitivity.

Peroxisome Proliferator–Activated Receptor α/γ Dual Agonist Tesaglitazar Attenuates Diabetic Nephropathy in db/db Mice

Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors and play a central role in insulin sensitivity, lipid metabolism, and inflammation. Both PPARalpha and -gamma are expressed in the kidney, and their agonists exhibit renoprotective effects in type 2 diabetes. In the present studies, we investigated the effect of the PPARalpha/gamma dual agonist tesaglitazar on diabetic nephropathy in type 2 diabetic db/db mice. Treatment of db/db mice with tesaglitazar for 3 months significantly lowered fasting plasma glucose and homeostasis model assessment of insulin resistance levels but had little effect on body weight, adiposity, or cardiac function. Treatment with tesaglitazar was associated with reduced plasma insulin and total triglyceride levels and increased plasma adiponectin levels. Notably, tesaglitazar markedly attenuated albuminuria and significantly lowered glomerulofibrosis, collagen deposition, and transforming growth factor-beta1 expression in renal tissues of db/db mice. In cultured mesangial cells and proximal tubule cells, where both PPARalpha and -gamma were expressed, tesaglitazar treatment abolished high glucose-induced total collagen protein production and type I and IV collagen gene expression. Collectively, tesaglitazar treatment not only improved insulin resistance, glycemic control, and lipid profile but also markedly attenuated albuminuria and renal glomerular fibrosis in db/db mice. These findings support the utility of dual PPARalpha/gamma agonists in treating type 2 diabetes and diabetic nephropathy.

Free fatty acids and insulin resistance

Dysregulation of free fatty acid metabolism is a key event responsible for insulin resistance and type 2 diabetes. According to the glucose-fatty acid cycle of Randle, preferential oxidation of free fatty acids over glucose plays a major role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. However, other mechanisms are now described to explain the molecular basis of insulin resistance. Recent studies have suggested that local accumulation of fat metabolites such as ceramides, diacylglycerol or acyl-CoA, inside skeletal muscle and liver, may activate a serine kinase cascade leading to defects in insulin signalling and glucose transport. Inflammation and oxidative stress are also potent mechanisms which could lead to a state of insulin resistance. Finally, modulation of transcription by free fatty acids through their binding to peroxisome proliferator-activated receptors could also contribute to impaired glucose metabolism. The increase in free fatty acid flux resulting from increased lipolysis secondary to adipose-tissue insulin resistance induces or aggravates insulin resistance in liver and muscle through direct or indirect (from triglyceride deposits) generation of metabolites, altering the insulin signalling pathway. Alleviating the excess of free fatty acids is a target for the treatment of insulin resistance.

Interleukin-6 does/does not have a beneficial role in insulin sensitivity and glucose homeostasis

Interleukin-6 does/does not have a beneficial role in insulin sensitivity and glucose homeostasis

Last Word on Point:Counterpoint “Interleukin-6 does/does not have a beneficial role in insulin sensitivity and glucose homoestasis”

To the Editor : We thank all of the researchers who contributed to the debate regarding the metabolic effects of the highly pleiotropic cytokine IL-6. In particular we want to thank Dr. Mooney ([1][1]) for his valuable contribution. While we are aware that IL-6 is an important marker of diseases,

Polymorphisms in adiponectin receptor genes ADIPOR1 and ADIPOR2 and insulin resistance

Adiponectin plays an important role in insulin sensitivity via adiponectin receptor 1 and 2 signalling. To date, six genetic association studies have examined the role of polymorphisms in the adiponectin receptor 1 and 2 genes (ADIPOR1 and ADIPOR2) in insulin resistance and type 2 diabetes. These studies are summarized in this review along with unpublished data from the authors. In addition, these polymorphism studies are used to illustrate some of the potential pitfalls and reasons for poor reproducibility of findings in genetic association studies.

Interleukin-6 does/does not have a beneficial role in insulin sensitivity and glucose homeostasis

Growing evidence links Type 2 diabetes to a state of low-grade chronic inflammation, and it has been suggested that interleukin (IL)-6 promotes insulin resistance due to the observation that plasma IL-6 is often elevated in patients with metabolic disease. However, it is now well known that IL-6 is

Orphan nuclear receptors: therapeutic opportunities in skeletal muscle

Nuclear hormone receptors (NRs) are ligand-dependent transcription factors that bind DNA and translate physiological signals into gene regulation. The therapeutic utility of NRs is underscored by the diversity of drugs created to manage dysfunctional hormone signaling in the context of reproductive biology, inflammation, dermatology, cancer, and metabolic disease. For example, drugs that target nuclear receptors generate over $10 billion in annual sales. Almost two decades ago, gene products were identified that belonged to the NR superfamily on the basis of DNA and protein sequence identity. However, the endogenous and synthetic small molecules that modulate their action were not known, and they were denoted orphan NRs. Many of the remaining orphan NRs are highly enriched in energy-demanding major mass tissues, including skeletal muscle, brown and white adipose, brain, liver, and kidney. This review focuses on recently adopted and orphan NR function in skeletal muscle, a tissue that accounts for approximately 35% of the total body mass and energy expenditure, and is a major site of fatty acid and glucose utilization. Moreover, this lean tissue is involved in cholesterol efflux and secretes that control energy expenditure and adiposity. Consequently, muscle has a significant role in insulin sensitivity, the blood lipid profile, and energy balance. Accordingly, skeletal muscle plays a considerable role in the progression of dyslipidemia, diabetes, and obesity. These are risk factors for cardiovascular disease, which is the the foremost cause of global mortality (>16.7 million deaths in 2003). Therefore, it is not surprising that orphan NRs and skeletal muscle are emerging as therapeutic candidates in the battle against dyslipidemia, diabetes, obesity, and cardiovascular disease.

Long-term treatment with interleukin-1β induces insulin resistance in murine and human adipocytes

Adipose tissue inflammation has recently been implicated in the pathogenesis of insulin resistance and is probably linked to high local levels of cytokines. IL1B, a proinflammatory cytokine, may participate in this alteration. We evaluated the chronic effect (1-10 days) of IL1B (0.1-20 ng/ml) on insulin signalling in differentiating 3T3-F442A and differentiated 3T3-L1 murine adipocytes and in human adipocytes. We also assessed expression of the gene encoding IL1B in adipose tissue of wild-type and insulin-resistant mice (diet-induced and genetically obese ob/ob mice). IL1B inhibited insulin-induced phosphorylation of the insulin receptor beta subunit, insulin receptor substrate 1, Akt/protein kinase B and extracellular regulated kinase 1/2 in murine and human adipocytes. Accordingly, IL1B suppressed insulin-induced glucose transport and lipogenesis. Long-term treatment of adipose cells with IL1B decreased cellular lipid content. This could result from enhanced lipolysis and/or decreased expression of genes involved in lipid metabolism (acetyl-CoA carboxylase, fatty acid synthase). Down-regulation of peroxisome proliferating-activated receptor gamma and CCAAT/enhancer-binding protein alpha in response to IL1B may have contributed to the altered phenotype of IL1B-treated adipocytes. Moreover, IL1B altered adipocyte differentiation status in long-term cultures. IL1B also decreased the production of adiponectin, an adipocyte-specific protein that plays a positive role in insulin sensitivity. Expression of the gene encoding IL1B was increased in epididymal adipose tissue of obese insulin-resistant mice. IL1B is upregulated in adipose tissue of obese and insulin-resistant mouse models and may play an important role in the development of insulin resistance in murine and human adipose cells.

Restoration of normal glucose tolerance in severely obese patients after bilio-pancreatic diversion: role of insulin sensitivity and beta cell function

The aim of this study was to analyse the mechanisms underlying the improvement in glucose tolerance seen in morbidly obese patients undergoing bilio-pancreatic diversion (BPD). We evaluated glucose tolerance (by OGTT), insulin sensitivity (euglycaemic-hyperinsulinaemic clamp and the OGTT index OGIS) and beta cell function (OGTT modelling analysis) in 32 morbidly obese (BMI=52+/-7 kg/m(2), mean+/-SD) patients (12 with NGT, 9 with IGT and 11 with type 2 diabetes), before and after BPD, and in 22 lean control subjects. Patients were studied before and from 7 days to 60 months after surgery. BPD improved glucose tolerance in all subjects, who after surgery all had normal glucose tolerance. Insulin sensitivity was restored to normal levels in all subjects (pre-BPD 341+/-79 ml min(-1) m(-2), post-BPD 511+/-57 ml min(-1) m(-2), lean 478+/-49 ml min(-1) m(-2)). The insulin sensitivity change was detectable within 10 days of BPD. At baseline, beta cell sensitivity to glucose was impaired in diabetic subjects (25 [18] pmol min(-1) m(-2) l mmol(-1), median [interquartile range]) compared with lean subjects (82 [98]; p</=0.05). After BPD, beta cell glucose sensitivity showed a tendency towards improvement but remained impaired in diabetic subjects (30 [62]; p<0.01 vs lean). Total insulin output decreased in parallel with the insulin sensitivity increase in all groups. In the whole patient group, mean OGTT glucose levels were inversely related to both insulin sensitivity and beta cell glucose sensitivity (r (2)=0.67, partial r=-0.76 and -0.41, respectively). NEFAs, leptin and adiponectin were related to insulin sensitivity but could not explain the early improvement. Following BPD, glucose tolerance was restored mainly as a result of a rapid and large improvement in insulin sensitivity.

Lipotoxicité et insulinorésistance

Dysregulation of free fatty acids (FFA) metabolism is a key event responsible for etiology of insulin resistance and type 2 diabetes. According to the glucose-fatty acid cycle described by Randle and coll in the early sixties, preferential oxidation of FFA compared to glucose plays a major role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. However, beside the glucose-fatty acid cycle, other mechanisms are now described to explain molecular basis of insulin resistance. Recent studies have suggested that local accumulation of fat metabolites such as ceramides, diacylglycerol or acyl-CoA, inside skeletal muscle and liver may activate a serine kinase cascade -involving c-Jun N-terminal kinase, nuclear factor-kappaB, protein kinase C- leading to defects in insulin signaling and glucose transport. Inflammation and oxidative stress are also potent mechanisms wich could lead to insulin-resistance state. Finally, modulation of transcription by FFA through their binding to peroxisome proliferators activated receptors could also participate to impaired glucose metabolism.

Peroxisome Proliferator-activated Receptor γ-mediated Regulation of Neural Stem Cell Proliferation and Differentiation

Peroxisome proliferator-activated receptor gamma (PPARgamma) plays an important role in insulin sensitivity, tissue homeostasis, and regulating cellular functions. We found high-level expression of PPARgamma in embryo mouse brain and neural stem cells (NSCs), in contrast to extremely low levels in adult mouse brain. Here, we show that PPARgamma mediates the proliferation and differentiation of murine NSCs via up-regulation of the epidermal growth factor receptor and activation of the ERK pathway. Cell growth rates of NSCs prepared from heterozygous PPARgamma-deficient mouse brains, PPARgamma-RNA-silenced NSCs, and PPARgamma dominant-negative NSCs were significantly decreased compared with those of wild-type NSCs. Physiological concentrations of PPARgamma agonists, rosiglitazone and pioglitazone, stimulated NSC growth, whereas antagonists caused cell death in a concentration-dependent manner via activation of the caspase cascade. The stimulation of cell growth by PPARgamma was associated with a rapid activation of the ERK pathway by phosphorylation and up-regulation of epidermal growth factor receptor and cyclin B protein levels. In contrast, activation of PPARgamma by agonists inhibited the differentiation of NSCs into neurons. The inhibition of differentiation was associated with an activation of STAT3. These data indicate that PPARgamma regulates the development of the central nervous system during early embryogenesis via control of NSC proliferation.

Insulin secretion and sensitivity as determinants of HbA1c in type 2 diabetes

Defects in insulin secretion and sensitivity, two major determinants of glycaemic control, can occur and progress or not in parallel. The present study was designed to compare the respective roles of both determinants on HbA1c, in type 2 diabetic patients, according to whether or not residual beta-cell function was stimulated with insulin secretagogues. Insulin secretion and insulin sensitivity were both estimated using the homeostasis model assessment (HOMA). HbA1c, insulin sensitivity (HOMA2%S) and insulin secretion (HOMA2%B) were determined in 289 noninsulin-using type 2 diabetic patients who were further divided into two groups according to treatment: metformin alone (group I, n = 57) or metformin and glyburide (group II, n = 232). The patients of both groups were further divided into three subsets in order to test the dependence of HbA1c on HOMA2%B and HOMA2%S. In group I mean HbA1c were greater (8.4%) in patients with HOMA2%B < 50% than in the two subsets with HOMA2%B > or = 50%: 7.2 and 6.8% (P = 0.0013). In group II mean values of stimulated-insulin secretion (HOMA2%B) were lesser (40.7 and 30.1%) in the two subsets of patients with HbA1c > or = 8% than in patients with HbA1c < 8%: 55.1% (P < 0.0001). By contrast, we found no differences in both groups with HOMA2%S. A stepwise multiple regression showed that HOMA2%B contributed to HbA1c more than HOMA2%S both in groups I (33.5% vs. 23.4%) and II (22.7% vs. 8%). Although the role of insulin sensitivity is not negligible, insulin secretion appears to be the major determinant of diabetic control in overt type 2 diabetic patients who are treated with metformin alone or with a two-drug therapy combining metformin and glyburide.

Physical Activity, Insulin Sensitivity, and Hypertension among US Adults: Findings from the Insulin Resistance Atherosclerosis Study

Although regular physical activity is associated with less hypertension and improved insulin sensitivity, there is debate regarding the role of insulin sensitivity in hypertension. Thus, in this cross-sectional study, the authors investigated whether physical activity and insulin sensitivity were associated with hypertension. The sample consisted of 1,599 persons aged 40-69 years who participated in the Insulin Resistance Atherosclerosis Study. The outcome measure was hypertension as measured by a standard protocol. Energy expended in vigorous physical activity was calculated from a recall interview on past-year physical activity. Descriptive statistics revealed that 590 (37%) participants had prevalent hypertension. In adjusted logistic regression analysis, participants expending >or=150 kcal/day in vigorous physical activity had an odds ratio for hypertension of 0.73 (95% confidence interval (CI): 0.55, 0.98) in comparison with participants who were sedentary. Further adjustment for insulin sensitivity resulted in attenuation of the effect of vigorous physical activity on hypertension (odds ratio = 0.97, 95% CI: 0.71, 1.33), while the effect of insulin sensitivity was significant (odds ratio = 0.33, 95% CI: 0.26, 0.41). These results suggest that longitudinal studies are warranted to determine whether insulin sensitivity is a mediator of the relation between physical activity and hypertension.

Possible Role of Adiponectin and Insulin Sensitivity in Mediating the Favorable Effects of Lower Body Fat Mass on Blood Lipids

The objective of this study was to investigate the role of insulin sensitivity and serum adiponectin concentration as determinants, in middle-aged men, of the relationship between lower body fat and blood lipids after truncal fat has been accounted for. Men (443) aged 39-65 yr, body mass index 18-43 kg/m(2), participated in the study. The following variables were measured: regional body fat distribution as assessed by dual-energy x-ray absorptiometry, maximal oxygen uptake, physical activity, fasting levels of serum adiponectin, triglycerides, and high-density lipoprotein- and total cholesterol. Plasma glucose and serum insulin were measured in the fasting state and after an oral glucose load. Lower body fat mass was inversely associated with serum triglycerides and total cholesterol and positively with serum high-density lipoprotein-cholesterol after adjustment for age, lean tissue mass, truncal fat mass, weight history, maximal oxygen uptake, and the level of physical activity (P < 0.0005). Serum adiponectin level and Matsudas insulin sensitivity index were positively intercorrelated, and both were positively correlated to lower body fat mass. When including adiponectin and insulin sensitivity in the analyses, the relationships between lower body fat mass and serum lipids were partly explained. For a given level of truncal fat mass, a large lower body fat mass is associated with an advantageous blood lipid profile, which may be partially mediated by the relationships to both insulin sensitivity and serum adiponectin level.

Nitric oxide-induced downregulation of leptin production by 3T3-L1 adipocytes

Leptin secreted mainly by adipocytes plays an important role in insulin sensitivity in metabolic syndrome. Inducible nitric oxide synthase (iNOS) in 3T3-L1 adipocytes is induced by lipopolysaccharide (LPS) and several proinflammatory cytokines such as tumor necrosis factor-alpha and interferon-gamma (IFN-gamma). Because the role of iNOS-derived nitric oxide (NO) in adipocyte function has not been fully clarified, the question that we addressed in the present study was whether iNOS-derived NO is involved in regulation of leptin secretion by adipocytes. Incubation of 3T3-L1 adipocytes for 12h with a mixture of IFN-gamma and LPS caused not only a 55% reduction in leptin secretion and a 52% reduction in leptin mRNA, but also significant induction of iNOS at both protein and mRNA levels. Inhibition of leptin secretion that had been induced by the IFN-gamma-LPS mixture was completely nullified by NOS inhibitors such as Nomega-monomethyl-L-arginine and aminoguanidine. Treatment of adipocytes with NO donors such as an NONOate and S-nitrosoglutathione produced an effect on leptin secretion similar to that of the IFN-gamma-LPS mixture. It is likely therefore that NO mediates downregulation of leptin caused by the IFN-gamma-LPS mixture in 3T3-L1 adipocytes, which suggests an important role for NO in adipocyte functions.

Human adiponectin binds to bacterial lipopolysaccharide

Adiponectin has anti-inflammatory and anti-atherogenic properties in addition to its acknowledged roles in insulin sensitivity and energy homeostasis. These properties include the suppression of lipopolysaccharide [LPS]-mediated inflammatory events. We demonstrated that both recombinant and native adiponectin directly bind LPS derived from three different bacteria. The interaction occurred at pH 5.0–6.0 and was inhibited by the presence of Ca 2+ and Mg 2+, but enhanced by the sequestration of these cations. Maximal binding occurred at pH 6.0 in the presence of ethylenediaminetetraacetic acid. Lipid A and C1q were not inhibitory, although LPS, heparin, zymosan, and individual sugars all inhibited the reaction. Periodate-mediated deglycosylation of adiponectin, and reduction and alkylation also inhibited binding. Since adiponectin infiltrates into [relatively] acidic sites of inflammation, it may act as a scavenging anti-inflammatory agent in atherosclerosis and vascular damage where LPS [and other pro-inflammatory molecules] are present.

Inositol phosphoglycan putative insulin mediator in human amniotic fluid

Background. Many hormones such as insulin, insulin-like growth factors, and the glucocorticoids are involved in regulating fetal growth. Inositol phosphoglycans (IPGs), a family of putative second messengers of insulin, are reported to exert several of insulin's metabolic effects.Methods. A prospective cross-sectional study was carried out to investigate IPG P-type (P-IPG) in human amniotic fluid and in adult urine under physiological conditions. An amniotic fluid sample was taken from 78 women undergoing early amniocentesis and a mid-stream urine specimen was collected from 109 healthy pregnant and 66 non-pregnant women. All samples were assessed using a polyclonal antibody-based ELISA.Results. The P-IPG content was a thousand times higher in the amniotic fluid than in the urine (p < 0.0001). Urinary specimens showed a four-fold higher P-IPG content during pregnancy than in healthy non-pregnant women (p < 0.001).Conclusions. Under physiological conditions, human amniotic fluid was found to be enriched in P-IPG compared with maternal urine, suggesting a possible fetal origin. Therefore, IPGs may play a role in insulin sensitivity and fetal growth and, perhaps, be involved in some of its abnormalities such as macrosomia and intrauterine growth restriction.