Insulin Resistance Risk Factors Research Articles

Adipokines and Hepatic Insulin Resistance

Obesity is a major risk factor for insulin resistance and type 2 diabetes. Adipose tissue is now considered to be an active endocrine organ that secretes various adipokines such as adiponectin, leptin, resistin, tumour necrosis factor-α, and interleukin-6. Recent studies have shown that these factors might provide a molecular link between increased adiposity and impaired insulin sensitivity. Since hepatic insulin resistance plays the key role in the whole body insulin resistance, clarification of the regulatory processes about hepatic insulin resistance by adipokines in rodents and human would seem essential in order to understand the mechanism of type 2 diabetes and for developing novel therapeutic strategies to treat it.

Dietary risk factors for the development of insulin resistance in adolescent girls: a 3-year prospective study.

Identifying risk factors for insulin resistance in adolescence could provide valuable information for early prevention. The study sought to identify risk factors for changes in insulin resistance and fasting blood glucose levels. Prospective cohort of girls participating in the National Heart, Lung, and Blood Institute Growth and Health Study. Adolescent girls (n 774) assessed at the ages of 16-17 and 18-19 years. Over a 3-year period, measurements of fasting blood glucose and insulin and serum cotinine were taken, and dietary intake (3 d food diary), smoking status and physical activity levels were self-reported. Improvements in homeostasis model assessment of insulin resistance (HOMA-IR) were associated with increases in the percentage of energy intake from polyunsaturated fats (β = -3·33, 95% CI -6·28, -0·39, P = 0·03) and grams of soluble fibre (β = -5·20, 95% CI -9·81, -0·59, P = 0·03) between the ages of 16-17 and 18-19 years; with similar findings for insulin. Transitioning into obesity was associated with an increase in insulin (β = 6·34, 95% CI 2·78, 9·91, P < 0·001) and HOMA-IR (β = 28·77, 95% CI 8·13, 49·40, P = 0·006). Serum cotinine concentrations at 16-17 years, indicating exposure to tobacco, were associated with large increases (β = 15·43, 95% CI 6·09, 24·77, P < 0·001) in fasting blood glucose concentrations. Increases in the percentage of energy from polyunsaturated fat and fibre, and avoidance of excess weight gain and tobacco exposure, could substantially reduce the risk of insulin resistance in late adolescence.

Serum Liver Fatty Acid Binding Protein Levels Correlate Positively with Obesity and Insulin Resistance in Chinese Young Adults

BackgroundLiver fatty acid–binding protein (FABP1) plays an inconclusive role in adiposity. We investigated the association of serum FABP1 levels with obesity and insulin resistance in Chinese young people under 30 years old.Methodology and Principal FindingsCross-sectional analysis including 200 obese and 172 normal-weight subjects matched for age and sex, anthropometric measurements were performed and serum FABP1 and biochemical characteristics were measured. Insulin resistance was determined by homeostasis model assessment of insulin resistance (HOMA-IR) and by the insulin sensitivity index (Si) derived from Bergman’s minimal model. FABP1 levels in obese subjects were significantly higher than those in normal-weight subjects (p<0.001) and the significance remained after adjustment for age, gender, alanine and aspartate aminotransferases (p<0.001). Serum FABP1 levels were significantly correlated with many metabolic-related parameters, with BMI and triglycerides as the independent determinants. FABP1 levels remained an independent risk factor of insulin resistance assessed by binary Si (OR = 1.868 per SD unit, 95% CI [1.035–3.373], p = 0.038) after adjustment for age, sex, BMI, waist circumference, systolic blood pressure, serum triacylglycerol, total cholesterol, HDL- and LDL-cholesterol,. FABP1 levels were also elevated with an increasing number of components of the metabolic syndrome (p for trend <0.001). Multiple regression modeling for the MetS and its components demonstrated that hypertriglyceridemia and low HDL-cholesterol were significantly correlated to serum FABP1 levels.Conclusions and SignificanceSerum FABP1 correlates positively with obesity and insulin resistance in Chinese young adults. Our data supports the fact that FABP1 might be an important mediator participating in fatty acid metabolism and energy balance.

Should visceral fat, strictly linked to hepatic steatosis, be depleted to improve survival?

Numerous epidemiologic studies have implicated abdominal obesity as a major risk factor for insulin resistance, type 2 diabetes mellitus, cardiovascular disease, stroke, metabolic syndrome and its further expression, i.e., nonalcoholic fatty liver disease and death. Using novel models of visceral obesity, several studies have demonstrated that the relationship between visceral fat and longevity is causal, while the accrual of subcutaneous fat does not appear to play an important role in the etiology of disease risk. The need of reducing the visceral fat to improve survival, mainly taking into account the strict link between nonalcoholic fatty liver disease and the coronary artery disease is discussed.

Childhhood obesity, insulin resistance and increased cardiovascular risk

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.

Inflammatory Proteins and 5-year Change in Insulin Clearance – the Insulin Resistance Atherosclerosis Study (IRAS)

Insulin clearance may decline as an early compensatory mechanism to deteriorating insulin sensitivity. Low-grade inflammation is an established risk factor for insulin resistance and diabetes. No previous studies have investigated the association between subclinical inflammation and insulin clearance.

Hypoadiponectinemia in Obesity: Association with Insulin Resistance

Obesity is risk factor for insulin resistance, diabetes, and other chronic diseases. Adiponectin, an adipose-specific protein with antiatherogenic and antiinflammatory effects, were found to be associated with obesity, type 2 diabetes, and insulin resistance. Our aim to identify possible relationships between circulating adiponectin and obesity as well as obesity related phenotypes. A total of 642, obese and non-obese individuals were included in this cross-sectional study. Hormone and glucose levels were estimated using standard protocols. The adiponectin levels showed a significant decrease with increasing quartiles of insulin resistance index. Subjects in lowest quartile of adiponectin level had a significantly higher risk than those in the highest quartile, with higher body mass index, waist circumference, blood pressure, percentage body fat, fat mass, fasting insulin, insulin resistance index, total cholesterol (p<0.001), low density lipoprotein-cholesterol (p=0.001), very low density lipoprotein-cholesterol (p=0.002), and Triglyceride (p=0.002). The present study indicates that adiponectin is significantly associated with obesity, insulin resistance and other obesity related phenotypes.

Association of suppressor of cytokine signalling 3 polymorphisms with insulin resistance in patients with chronic hepatitis C

Suppressor of cytokine signalling 3 is thought to be associated with insulin resistance in patients with chronic hepatitis C. We evaluated the role of suppressor of cytokine signalling 3 polymorphisms in determining insulin resistance in patients with chronic hepatitis C. Two hundred and ninety untreated hepatitis C virus-infected patients without diabetes and cirrhosis were genotyped for the SNPs rs4969168, rs4969170 and rs12952093 of suppressor of cytokine signalling 3 using the TaqMan Genotyping Assay. We found that the rs4969170 AA genotype and rs4969170 A allele frequency were significantly more common in the insulin-resistant group than the non-insulin-resistant group (89.5% vs 76.1%, OR = 2.693, 95% CI: 1.221-5.939, P = 0.012 and 94.8% vs 88.0%, OR = 2.463, 95% CI: 1.151-5.271, P = 0.017, respectively). Haplotype G-C was likely associated with non-insulin resistance (adjusted P = 0.011). Multiple logistic regression analysis indicates that the independent risk factors for insulin resistance are the SNP rs4969170 AA genotype (OR = 3.005, 95% CI: 1.194-7.560, P = 0.019), HCV genotype 1 (OR = 2.524, 95% CI: 1.099-5.794, P = 0.029) and BMI (OR = 0.514, 95% CI: 0.265-0.999, P = 0.05).

Selected adipokines and metabolic profiles in normal-weight women with abdominal obesity

Abdominal obesity (AO) is a risk factor of insulin resistance and its metabolic consequences. The aim of the study was to assess the associations between adiponectin and visfatin levels, body fat (BF), abdominal and hip fat depots, blood lipid profile, insulin sensitivity surrogates, and AO. The study included 145 healthy, premenopausal (aged 20-40 years), normal-weight women. Using the cut values of 80 cm waist circumference (WC) and 0.8 waist-to-hip ratio, we identified 38 and 68 women with AO, respectively. We assessed visfatin, adiponectin, blood lipid, glucose, and insulin levels. The body composition was assessed by dual-energy X-ray absorptiometry. Regardless of the criteria used to diagnose AO, we found that women with AO were heavier (P = 0.01), had more deliveries (P = 0.03), and had lower high-density lipoprotein (HDL) cholesterol levels (P = 0.01) than women without AO. Serum visfatin and adiponectin levels, triglycerides, low-density lipoprotein (LDL) cholesterol, glucose, insulin, and indices of insulin sensitivity and resistance were comparable between the groups. AO was associated with higher diastolic blood pressure and higher total, abdominal (android), and hip (gynoid) fat as well as the android/BF ratio (all P <0.01). There was a positive correlation between glucose and WC (r = 0.206; P = 0.02). Adiponectin was positively associated with HDL cholesterol (r = 0.248; P = 0.008) and inversely with the android/BF ratio (r = -0.218; P = 0.009) and android/gynoid ratio (r = -0.201; P = 0.04). Visfatin inversely correlated with total (r = -0.251; P = 0.01) and LDL cholesterol (r = -0.181; P = 0.042). Normal-weight women with AO have normal adiponectin and visfatin levels, higher diastolic blood pressure, and lower HDL cholesterol levels. The android/gynoid ratio and android/BF ratio are inversely correlated with adiponectin levels.

Identification of Pigment Epithelium-Derived Factor as an Adipocyte-Derived Inflammatory Factor

Obesity is a major risk factor for insulin resistance, type 2 diabetes mellitus and cardiovascular disease. The pathophysiology of obesity is associated with chronic low-grade inflammation. Adipose tissue in obesity is significantly infiltrated by macrophages that secrete cytokines. The mechanisms of interaction between macrophages and adipocytes, leading to macrophage activation and increased cytokine release, remain to be elucidated. We reasoned that an adipocyte-derived factor might stimulate activation of macrophages. We have identified pigment epithelium-derived factor (PEDF) as a mediator of inflammation that is secreted by adipocytes and mediates macrophage activation. Recombinant PEDF activates macrophages to release tumor necrosis factor (TNF) and interleukin-1 (IL-1). The PEDF receptor adipose triglyceride lipase (ATGL) is required for PEDF-mediated macrophage activation. Selective inhibition of ATGL on macrophages attenuates PEDF-induced TNF production, and PEDF enhances the phosphorylation of p38 and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases. PEDF administration to rats results in increased serum TNF levels, and insulin resistance. Together, these findings suggest that PEDF secreted by adipocytes contributes to the onset and maintenance of chronic inflammation in obesity, and may be a therapeutic target in ameliorating insulin resistance.

Association of the IL28B genotype with insulin resistance in patients with chronic hepatitis C

Insulin resistance, fibrosis and steatosis are established predictors of response to peg-interferon/ribavirin therapy in chronic hepatitis C (CHC). Several host genetic polymorphisms (IL28B, PNPLA3) modify treatment-outcome, the degree of steatosis or fibrosis. The aim of our study was to evaluate the role of these polymorphisms on insulin resistance (IR) in treatment-naïve patients with chronic hepatitis C. Two hundred and two non-diabetic CHC patients (GT1: 181, GT4: 21; m = 126, f = 76) undergoing liver biopsy in two tertiary academic centers were studied. The SNPs rs12979860 (IL28B) and rs738409 (PNPLA3) were investigated by RT-PCR. HOMA-IR, BMI, stage of fibrosis, extent of steatosis, and genetic data were analyzed. Insulin resistance (HOMA-IR ≥ 3.0) was associated with rs12979860 genotype, presence of advanced fibrosis, and higher BMI. HOMA-IR in CC and in TC/TT was 2.08 ± 1.61 (mean ± SD) and 2.94 ± 2.89 (p=0.041), respectively. HOMA-IR was higher in advanced than in mild fibrosis (F3-4: 3.92 ± 3.15; F0-2: 2.38 ± 2.38; p=0.004). The percentage of steatotic hepatocytes was higher in patients with advanced fibrosis (21.3 ± 21.5 vs. 9.1 ± 14.2; p<0.001), HOMA-IR ≥ 3.0 (17.7 ± 17.8 vs. 8.8 ± 15.4%; p<0.001), and BMI > 25.0 kg/m(2) (14.7 ± 17.0 vs. 9.1 ± 16.1; p<0.001). The rs738409 GG genotype was associated with advanced fibrosis and steatosis, but not with HOMA-IR. Multivariable logistic regression identified advanced fibrosis (OR: 2.820, 95% CI: 1.344-5.917; p = 0.006) and the IL28B genotype non-CC (OR: 3.000, 1.348-6.676; p = 0.007) as independent risk factors for insulin resistance. Insulin resistance is more common in carriers of the T allele of SNP rs12979860 than in CC homozygotes and may partly explain the poor outcome of peginterferon/ribavirin therapy in these patients.

Increased protease activity in obese rats: implications on LDL and insulin receptors

Obesity leads to increased morbidity and mortality from cardiovascular complications. Among other characteristics of the metabolic syndrome, obesity is a major risk factor for Insulin resistance and high levels of LDL, although the mechanisms are not completely understood. We hypothesize that calorie over consumption can lead to increased proteolytic activity which in turn cleave extracellular domains of key receptors e.g. the insulin and LDL receptors, therefore impairing their uptake and contributing to their high levels in the circulation. Wister rats were fed high fat diet (HD) for 16 weeks. A control group was provided with regular chow (ND). Enzymatic activity was measured in vivo on the mesentery microcirculation using intravital fluorescent microscope. Levels of the extracellular domain of the insulin and LDL receptors were measured by immunohistochemistry on isolated leukocytes. Glucose and LDL uptake were measured by fluorescent imaging. HF rats had significantly higher enzymatic activity in the mesentery microcirculation compared to controls. This activity was accompanied with reduced levels of the extracellular domain of both insulin and LDL receptors. Leukocytes of obese rats uptake glucose and LDL in a slower rate compared to controls. Our results suggest that calorie over‐consumption can promote proteolytic activity and cleavage of key receptors thus promoting insulin resistance and high circulating levels of LDL in obesity.

The effects of the interaction between adiponectin genotype and dietary folate, vitamin B6 and vitamin E on serum TNF‐α level in the patients with type 2 diabetes

Adiponectin is known to relate with insulin resistance and CVD risk due to its anti‐inflammatory effect. To evaluate the effect of interaction between the adiponectin genotype and nutrient factors on tumor necrosis factor‐α (TNF‐α), SNP 276G→T at adiponectin gene was evaluated by a PCR‐RFLP analysis and TNF‐α was measured by ELISA kit. Dietary intakes were analyzed by using semi‐quantitative food frequency questionnaire. Sex, age, BMI, smoking, and alcohol drinking were used for adjustment and energy intake was used only in the analysis of dietary factors. 569 patients with T2D (287 males and 282 females) were enrolled, whose prevalence of G/G, G/T and T/T genotype was 45.9%, 45.7% and 8.4%, respectively. TNF‐α was correlated with HbA1c (r=0.237, P&lt;0.0001), KITT, an insulin resistance index (r=−0.160, P&lt;0.0001), atherosclerosis index (r=0.104, P&lt;0.05) and log‐transformed intakes of dietary folate (r=−0.156, P&lt;0.0001), vitamin E (r=−0.145, P&lt;0.01) and vitamin B6 (r=−0.123, P&lt;0.01). However negative relationships between above vitamins and TNF‐α were significant only in the G/G genotype (P‐values for trend were &lt;0.0001, &lt;0.001, and &lt;0.01, respectively). In conclusion, dietary vitamins could reduce serum TNF‐α, a risk factor of insulin resistance and CVD, and it could be more effective in the T2D patients with normal adiponectin genotype. This work was supported by the Brain Korea 21 project.

Short-Term Treatment with Bisphenol-A Leads to Metabolic Abnormalities in Adult Male Mice

Bisphenol-A (BPA) is one of the most widespread endocrine disrupting chemicals (EDC) used as the base compound in the manufacture of polycarbonate plastics. Although evidence points to consider exposure to BPA as a risk factor for insulin resistance, its actions on whole body metabolism and on insulin-sensitive tissues are still unclear. The aim of the present work was to study the effects of low doses of BPA in insulin-sensitive peripheral tissues and whole body metabolism in adult mice. Adult mice were treated with subcutaneous injection of 100 µg/kg BPA or vehicle for 8 days. Whole body energy homeostasis was assessed with in vivo indirect calorimetry. Insulin signaling assays were conducted by western blot analysis. Mice treated with BPA were insulin resistant and had increased glucose-stimulated insulin release. BPA-treated mice had decreased food intake, lower body temperature and locomotor activity compared to control. In skeletal muscle, insulin-stimulated tyrosine phosphorylation of the insulin receptor β subunit was impaired in BPA-treated mice. This impairment was associated with a reduced insulin-stimulated Akt phosphorylation in the Thr308 residue. Both skeletal muscle and liver displayed an upregulation of IRS-1 protein by BPA. The mitogen-activated protein kinase (MAPK) signaling pathway was also impaired in the skeletal muscle from BPA-treated mice. In the liver, BPA effects were of lesser intensity with decreased insulin-stimulated tyrosine phosphorylation of the insulin receptor β subunit.In conclusion, short-term treatment with low doses of BPA slows down whole body energy metabolism and disrupts insulin signaling in peripheral tissues. Thus, our findings support the notion that BPA can be considered a risk factor for the development of type 2 diabetes.

Emerging clinical and experimental evidence for the role of lipocalin‐2 in metabolic syndrome

The inflammatory state, which is associated with the current pandemic of obesity, has been established as an important contributing pathogenic factor to the increased prevalence of the so-called metabolic syndrome. Many studies have focused on the contribution of various adipokines to this phenomenon, and in the present study, we provide an update on the emerging evidence that the pro-inflammatory factor, lipocalin-2, might influence various aspects of metabolic syndrome. Previous reports indicate a positive correlation of serum lipocalin-2 with fasting glucose, the homeostasis model assessment of insulin resistance index, and the inflammatory marker high-sensitivity C-reactive protein, even after adjustment for body mass index, suggesting that it is an independent risk factor for insulin resistance, diabetes, and inflammation. Direct analysis of lipocalin-2 action now also shows effects on peripheral metabolism and on cardiovascular function. A better understanding of how lipocalin-2 is regulated locally and systemically is crucial for adding to our understanding of the pathogenesis of metabolic syndrome, and to uncover potential new avenues for therapeutic approaches.

Spironolactone, but not Eplerenone, Impairs Glucose Tolerance in a Rat Model of Metabolic Syndrome

Although some clinical studies have suggested that spironolactone (SPL), a mineralocorticoid receptor (MR) antagonist, appears to increase the blood glucose levels, experimental studies have not supported this notion. Here, we investigated the effect of SPL on blood glucose levels in SHR/NDmcr-cp(cp/cp) (ND) rats, an animal model of metabolic syndrome, in comparison with that of eplerenone (EPL), another MR antagonist. At the same dose of 100 mg/kg, SPL and EPL increased the urinary sodium-to-potassium ratio to a comparable extent, indicating that both agents have similar renal MR antagonistic efficacy in ND rats. Interestingly, SPL but not EPL significantly increased the level of blood glucose. The oral glucose tolerance test revealed that treatment with SPL led to glucose intolerance. The levels of serum insulin and adiponectin, regulators of the blood glucose level, were virtually unaffected by treatment with SPL. On the other hand, SPL induced a marked increase in the blood level of aldosterone, known to be a risk factor for insulin resistance. These results demonstrate that in comparison with EPL, SPL characteristically impairs glucose tolerance in an animal model of metabolic syndrome, in association with a higher blood level of aldosterone.

Hepatitis C virus induced insulin resistance impairs response to anti viral therapy

Hepatitis C virus (HCV) infection is an important risk factor for insulin resistance (IR). The latter is the pathogenic foundation underlying metabolic syndrome, steatosis and cirrhosis, and possibly hepatocellular carcinoma (HCC). The interplay between genetic and environmental risk factors ultimately leads to the development of IR. Obesity is considered a major risk factor, with dysregulation of levels of secreted adipokines from distended adipose tissue playing a major role in IR. HCV-induced IR may be due to the HCV core protein inducing proteasomal degradation of insulin receptor substrates 1 and 2, blocking intracellular insulin signaling. The latter is mediated by increased levels of both tumour necrosis factor-α (TNF-α) and suppressor of cytokine signaling 3 (SOC-3). IR, through different mechanisms, plays a role in the development of steatosis and its progression to steatohepatitis, cirrhosis and even HCC. In addition, IR has a role in impairing TNF signaling cascade, which in turn blocks STAT-1 translocation and interferon stimulated genes production avoiding the antiviral effect of interferon.

Ursodeoxycholic acid improves insulin sensitivity and hepatic steatosis by inducing the excretion of hepatic lipids in high-fat diet–fed KK-Ay mice

Type 2 diabetes mellitus is frequently accompanied by fatty liver/nonalcoholic fatty liver disease. Hence, accumulation of lipids in the liver is considered to be one of the risk factors for insulin resistance and metabolic syndrome. Ursodeoxycholic acid (UDCA) is widely used for the treatment of liver dysfunction. We investigated the therapeutic effects of UDCA on type 2 diabetes mellitus exacerbating hepatic steatosis and the underlying mechanisms of its action using KK-Ay mice fed a high-fat diet. KK-Ay mice were prefed a high-fat diet; and 50, 150, and 450 mg/kg of UDCA was orally administered for 2 or 3 weeks. Administration of UDCA decreased fasting hyperglycemia and hyperinsulinemia. Hyperinsulinemic-euglycemic clamp analyses showed that UDCA improved hepatic (but not peripheral) insulin resistance. Hepatic triglyceride and cholesterol contents were significantly reduced by treatment with UDCA, although the genes involved in the synthesis of fatty acids and cholesterol, including fatty acid synthase and 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, were upregulated. Fecal levels of bile acids, neutral sterols, fatty acids, and phospholipids were significantly increased by UDCA treatment. The gene expression levels and protein phosphorylation levels of endoplasmic reticulum stress markers were not changed by UDCA treatment. These results indicate that UDCA ameliorates hyperglycemia and hyperinsulinemia by improving hepatic insulin resistance and steatosis in high-fat diet–fed KK-Ay mice. Reduction of hepatic lipids might be due to their excretion in feces, followed by enhanced utilization of glucose for the synthesis of fatty acids and cholesterol. Ursodeoxycholic acid should be effective for the treatment of type 2 diabetes mellitus accompanying hepatic steatosis.

Sleep disturbances and insulin resistance

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

Impact of Sleepiness and Sleep Deficiency on Public Health—Utility of Biomarkers

Sleep disorders and sleep deficiency are important causes of adverse health effects and increased mortality in the United States and worldwide. Sleep deficiency can also result in myriad adverse behavioral consequences, including profound sleepiness, cognitive slowing, automatic behavior, attentional failures and performance degradation, errors, and accidents. It is important to recognize that sleepiness and sleep deficiency are not synonymous.