The effects of obesity and polycystic ovary syndrome on serum lipocalin-2 levels: a cross-sectional study

Background  

Lipocalin-2 is a novel adipokine that appears to play a role in the development of insulin resistance. Serum lipocalin-2 levels are elevated in obese patients. Obesity and insulin resistance are cardinal characteristics of the polycystic ovary syndrome (PCOS). However, there are limited data on serum lipocalin-2 levels in patients with PCOS. The aim of the present study was to assess serum lipocalin-2 levels in PCOS.     

Rats with steroid-induced polycystic ovaries develop hypertension and increased sympathetic nervous system activity

Background  

Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder associated with ovulatory dysfunction, abdominal obesity, hyperandrogenism, hypertension, and insulin resistance.     

Bio-informatics analysis of a gene co-expression module in adipose tissue containing the diet-responsive gene <Emphasis Type="Italic">Nnat</Emphasis>

Background  

Obesity causes insulin resistance in target tissues - skeletal muscle, adipose tissue, liver and the brain. Insulin resistance predisposes to type-2 diabetes (T2D) and cardiovascular disease (CVD). Adipose tissue inflammation is an essential characteristic of obesity and insulin resistance. Neuronatin (Nnat) expression has been found to be altered in a number of conditions related to inflammatory or metabolic disturbance, but its physiological roles and regulatory mechanisms in adipose tissue, brain, pancreatic islets and other tissues are not understood.     

Association of TRB3 Q84R polymorphism with polycystic ovary syndrome in Chinese women

Background  

Tribbles 3 (TRB3) affects insulin signalling by inhibiting insulin-stimulated Akt phosphorylation and subsequent activation. A single nucleotide polymorphism located in the second extron of the human TRB3 gene is thought to be associated with insulin resistance. The latter is a core abnormality in PCOS independent of obesity. The present study was designed to clarify the relationships of TRB3 Q84R polymorphism with PCOS in a Chinese women group.     

Gender differences in factors influencing insulin resistance in elderly hyperlipemic non-diabetic subjects

Background  

The increase in the prevalence of insulin resistance-related metabolic syndrome, a disorder that greatly increases the risk of diabetes, heart attack and stroke, is alarming. One of the most frequent and early symptoms of metabolic syndrome is hypertriglyceridemia. We examined the gender differences between various metabolic factors related to insulin resistance in elderly non-diabetic men and postmenopausal women of comparable age suffering from hypertriglyceridemia, and compared them with healthy subjects of equal age.     

Focal Adhesion Kinase contributes to insulin-induced actin reorganization into a mesh harboring Glucose transporter-4 in insulin resistant skeletal muscle cells

Background  

Focal Adhesion Kinase (FAK) is recently reported to regulate insulin resistance by regulating glucose uptake in C2C12 skeletal muscle cells. However, the underlying mechanism for FAK-mediated glucose transporter-4 translocation (Glut-4), responsible for glucose uptake, remains unknown. Recently actin remodeling was reported to be essential for Glut-4 translocation. Therefore, we investigated whether FAK contributes to insulin-induced actin remodeling and harbor Glut-4 for glucose transport and whether downregulation of FAK affects the remodeling and causes insulin resistance.     

The A54T polymorphism at the intestinal fatty acid binding protein 2 is associated with insulin resistance in glucose tolerant Caucasians

Background  

An A54T polymorphism at the fatty acid binding protein 2 (FABP2) locus was found to be associated with insulin resistance in non-diabetic Pima Indians. To see whether this association is present in other populations, we performed a cross sectional study to examine the role of this polymorphism on insulin resistance in 55 healthy and normotensive Caucasian subjects with normal glucose tolerance. Insulin sensitivity (%S) and beta cell function (%B) were assessed using the Homeostasis Model Assessment (HOMA). Their genotypes were determined using a polymerase chain reaction-restriction fragment length polymorphism assay. The relationship between the genotypes and the phenotypes was examined.     

The contrasting roles of PPARδ and PPARγ in regulating the metabolic switch between oxidation and storage of fats in white adipose tissue

Background  

The nuclear receptors peroxisome proliferator-activated receptor γ (PPARγ) and peroxisome proliferator-activated receptor δ (PPARδ) play central roles in regulating metabolism in adipose tissue, as well as being targets for the treatment of insulin resistance. While the role of PPARγ in regulating insulin sensitivity has been well defined, research into PPARδ has been limited until recently due to a scarcity of selective PPARδ agonists.     

Whole-Body and Hepatic Insulin Resistance in Obese Children

Background

Insulin resistance may be assessed as whole body or hepatic.

Objective

To study factors associated with both types of insulin resistance.

Methods

Cross-sectional study of 182 obese children. Somatometric measurements were registered, and the following three adiposity indexes were compared: BMI, waist-to-height ratio and visceral adiposity. Whole-body insulin resistance was evaluated using HOMA-IR, with 2.5 as the cut-off point. Hepatic insulin resistance was considered for IGFBP-1 level quartiles 1 to 3 (<6.67 ng/ml). We determined metabolite and hormone levels and performed a liver ultrasound.

Results

The majority, 73.1%, of obese children had whole-body insulin resistance and hepatic insulin resistance, while 7% did not have either type. HOMA-IR was negatively associated with IGFBP-1 and positively associated with BMI, triglycerides, leptin and mother''s BMI. Girls had increased HOMA-IR. IGFBP-1 was negatively associated with waist-to-height ratio, age, leptin, HOMA-IR and IGF-I. We did not find HOMA-IR or IGFBP-1 associated with fatty liver.

Conclusion

In school-aged children, BMI is the best metric to predict whole-body insulin resistance, and waist-to-height ratio is the best predictor of hepatic insulin resistance, indicating that central obesity is important for hepatic insulin resistance. The reciprocal negative association of IGFBP-1 and HOMA-IR may represent a strong interaction of the physiological processes of both whole-body and hepatic insulin resistance.     

Evolutionary origins of insulin resistance: a behavioral switch hypothesis

Background  

Insulin resistance, which can lead to a number of diseases including type 2 diabetes and coronary heart disease, is believed to have evolved as an adaptation to periodic starvation. The "thrifty gene" and "thrifty phenotype" hypotheses constitute the dominant paradigm for over four decades. With an increasing understanding of the diverse effects of impairment of the insulin signaling pathway, the existing hypotheses are proving inadequate.     

Consistency of the disposition index in the face of diet induced insulin resistance: potential role of FFA

Objective

Insulin resistance induces hyperinsulinemic compensation, which in turn maintains almost a constant disposition index. However, the signal that gives rise to the hyperinsulinemic compensation for insulin resistance remains unknown.

Methods

In a dog model of obesity we examined the possibility that potential early-week changes in plasma FFA, glucose, or both could be part of a cascade of signals that lead to compensatory hyperinsulinemia induced by insulin resistance.

Results

Hypercaloric high fat feeding in dogs resulted in modest weight gain, and an increase in adipose tissue with no change in the non-adipose tissue size. To compensate for the drop in insulin sensitivity, there was a significant rise in plasma insulin, which can be attributed in part to a decrease in the metabolic clearance rate of insulin and increased insulin secretion. In this study we observed complete compensation for high fat diet induced insulin resistance as measured by the disposition index. The compensatory hyperinsulinemia was coupled with significant changes in plasma FFAs and no change in plasma glucose.

Conclusions

We postulate that early in the development of diet induced insulin resistance, a change in plasma FFAs may directly, through signaling at the level of β-cell, or indirectly, by decreasing hepatic insulin clearance, result in the observed hyperinsulinemic compensation.     

Seropositivity is associated with insulin resistance in patients with early inflammatory polyarthritis: results from the Norfolk Arthritis Register (NOAR): an observational study

Introduction  

Cardiovascular disease (CVD) is the leading cause of death in patients with inflammatory polyarthritis (IP), especially in seropositive disease. In established rheumatoid arthritis (RA), insulin resistance (IR) is increased and associated with CVD. We investigated factors associated with IR in an inception cohort of patients with early IP.     

Direct rosiglitazone action on steroidogenesis and proinflammatory factor production in human granulosa-lutein cells

Background  

Ovarian granulosa cells are the predominant source of estradiol and progesterone biosynthesis in vivo. Rosiglitazone, a synthetic agonist of the peroxisome proliferator-activated receptor gamma (PPAR gamma), is applied as the treatment of insulin resistance including women with PCOS. The aim of the study was to investigate the direct effects of rosiglitazone on steroidogenesis and proinflammatory factor production in human granulosa-lutein cells (GLCs).     

The induction of microRNA targeting IRS-1 is involved in the development of insulin resistance under conditions of mitochondrial dysfunction in hepatocytes

Background

Mitochondrial dysfunction induces insulin resistance in myocytes via a reduction of insulin receptor substrate-1 (IRS-1) expression. However, the effect of mitochondrial dysfunction on insulin sensitivity is not understood well in hepatocytes. Although research has implicated the translational repression of target genes by endogenous non-coding microRNAs (miRNA) in the pathogenesis of various diseases, the identity and role of the miRNAs that are involved in the development of insulin resistance also remain largely unknown.

Methodology

To determine whether mitochondrial dysfunction induced by genetic or metabolic inhibition causes insulin resistance in hepatocytes, we analyzed the expression and insulin-stimulated phosphorylation of insulin signaling intermediates in SK-Hep1 hepatocytes. We used qRT-PCR to measure cellular levels of selected miRNAs that are thought to target IRS-1 3′ untranslated regions (3′UTR). Using overexpression of miR-126, we determined whether IRS-1-targeting miRNA causes insulin resistance in hepatocytes.

Principal Findings

Mitochondrial dysfunction resulting from genetic (mitochondrial DNA depletion) or metabolic inhibition (Rotenone or Antimycin A) induced insulin resistance in hepatocytes via a reduction in the expression of IRS-1 protein. In addition, we observed a significant up-regulation of several miRNAs presumed to target IRS-1 3′UTR in hepatocytes with mitochondrial dysfunction. Using reporter gene assay we confirmed that miR-126 directly targeted to IRS-1 3′UTR. Furthermore, the overexpression of miR-126 in hepatocytes caused a substantial reduction in IRS-1 protein expression, and a consequent impairment in insulin signaling.

Conclusions/Significance

We demonstrated that miR-126 was actively involved in the development of insulin resistance induced by mitochondrial dysfunction. These data provide novel insights into the molecular basis of insulin resistance, and implicate miRNA in the development of metabolic disease.     

Silymarin Induces Insulin Resistance through an Increase of Phosphatase and Tensin Homolog in Wistar Rats

Background and aims

Phosphatase and tensin homolog (PTEN) is a phosphoinositide phosphatase that regulates crucial cellular functions, including insulin signaling, lipid and glucose metabolism, as well as survival and apoptosis. Silymarin is the active ingredient in milk thistle and exerts numerous effects through the activation of PTEN. However, the effect of silymarin on the development of insulin resistance remains unknown.

Methods

Wistar rats fed fructose-rich chow or normal chow were administered oral silymarin to identify the development of insulin resistance using the homeostasis model assessment of insulin resistance and hyperinsulinemic- euglycemic clamping. Changes in PTEN expression in skeletal muscle and liver were compared using western blotting analysis. Further investigation was performed in L6 cells to check the expression of PTEN and insulin-related signals. PTEN deletion in L6 cells was achieved by small interfering ribonucleic acid transfection.

Results

Oral administration of silymarin at a dose of 200 mg/kg once daily induced insulin resistance in normal rats and enhanced insulin resistance in fructose-rich chow-fed rats. An increase of PTEN expression was observed in the skeletal muscle and liver of rats with insulin resistance. A decrease in the phosphorylation of Akt in L6 myotube cells, which was maintained in a high-glucose condition, was also observed. Treatment with silymarin aggravated high-glucose-induced insulin resistance. Deletion of PTEN in L6 cells reversed silymarin-induced impaired insulin signaling and glucose uptake.

Conclusions

Silymarin has the ability to disrupt insulin signaling through increased PTEN expression. Therefore, silymarin should be used carefully in type-2 diabetic patients.     

Serum 25-hydroxyvitamin D is not related to cardiac natriuretic peptide in nulliparous and lactating women

Background

Visceral obesity is positively related to insulin resistance. The nature of the relationship between waist circumference and insulin resistance has not been known in Japanese populations. This study examined the relationship between waist circumference and insulin resistance and evaluated the optimal cutoff point for waist circumference in relation to insulin resistance in middle-aged Japanese men.

Methods

Study subjects included 4800 Japanese men aged 39 to 60 years. Insulin resistance was evaluated by the homeostasis model assessment of insulin resistance (HOMA-IR). The relationship of waist circumference with HOMA-IR was assessed by use of adjusted means of HOMA-IR and odds ratios of elevated HOMA-IR defined as the highest quintile (≥2.00). Receiver operating characteristics (ROC) curve analysis using Youden index and the area under curve (AUC) was employed to determine optimal cutoffs of waist circumference in relation to HOMA-IR.

Results

Adjusted geometric means of HOMA-IR and prevalence odds of elevated HOMA-IR were progressively higher with increasing levels of waist circumference. In the ROC curve analysis, the highest value of Youden index was obtained for a cutoff point of 85 cm in waist circumference across different values of HOMA-IR. Multiple logistic regression analysis also indicated that the AUC was consistently the largest for a waist circumference of 85 cm.

Conclusion

Waist circumference is linearly related to insulin resistance, and 85 cm in waist circumference is an optimal cutoff in predicting insulin resistance in middle-aged Japanese men.     

Prevalence of ultrasonography proved polycystic ovaries in North Indian women with type 2 diabetes mellitus

Background  

Polycystic ovaries (PCO) and their clinical expression (the polycystic ovary syndrome [PCOS]) as well as type 2 diabetes mellitus (T2DM) are common medical conditions linked through insulin resistance. We studied the prevalence of PCO and PCOS in women with diet and/or oral hypoglycemic treated T2DM and non-diabetic control women.     

Associations of Trunk Fat Depots with Insulin Resistance, β Cell Function and Glycaemia - A Multiple Technique Study

Objective

Central (truncal) adiposity is associated strongly with insulin resistance and diabetes. There are very few reports comparing methods of trunk fat measurement in their ability to predict glycaemia and insulin resistance. We report a comparative analysis of different trunk fat measurements in predicting glycaemia and insulin resistance in middle aged Indian men.

Materials and Methods

Trunk fat measurements were performed using anthropometry, magnetic resonance imaging (MRI), dual-energy X-ray absorptiometry (DXA) and computed tomography (CT) on 128 men. Additional measurements were taken to characterise insulin resistance (Matsuda index) and beta cell function (Insulinogenic Index), glycaemia (fasting and 120 min glucose concentrations). Using residual approach we compared the ability of different trunk fat measurement techniques to predict insulin resistance, beta cell function and glycaemia.

Results

There was a strong association between trunk fat measures from each technique with glycaemia and insulin resistance indices but not with the Insulinogenic Index. Insulin resistance and glycaemia, were best predicted using anthropometric measurements, notably by waist circumference and subscapular skinfold thickness. Neither MRI measures of trunk or visceral fat nor DXA trunk fat added significantly. CT liver density contributed to some extent to predict insulin resistance and 120 min glucose after anthropometric measurements.

Conclusions

Our results suggest that, in Indian men, anthropometric measurements are good predictors of glycaemia and insulin resistance. Other complex measurements such as MRI, DXA and CT make only a small addition to the prediction. This finding supports the application of anthropometry for determining trunk fat in clinical and epidemiological settings.     

Serum 25-Hydroxyvitamin D and Insulin Resistance in Apparently Healthy Adolescents

Purpose

Vitamin D deficiency is a common condition that is associated with diabetes and insulin resistance. However, the association between vitamin D and insulin resistance has not been fully studied, especially in the general adolescent population. Therefore, we assessed the association between serum 25-hydroxyvitamin D [25(OH)D] level and insulin resistance among apparently healthy Korean adolescents.

Methods

A total of 260 (135 male and 125 female) adolescents in a rural high school were assessed for serum 25(OH)D, fasting plasma glucose, and insulin. All of the participants were aged 15 to 16 years old, and without known hypertension or diabetes. Serum 25(OH)D was analyzed both as a continuous and categorical variable in association with insulin resistance. Insulin resistance was estimated by homeostasis model assessment (HOMA-IR). Increased insulin resistance was operationally defined as a HOMA-IR value higher than the sex-specific 75th percentile.

Results

In male adolescents, every 10 ng/ml decrease in 25(OH)D level was associated with a 0.25 unit increase in HOMA-IR (p = 0.003) after adjusting for age and BMI. Compared to those in the highest quartile, male adolescents in the lowest 25(OH)D quartile were at significantly higher risk for insulin resistance: unadjusted odds ratio 4.06 (95% CI, 1.26 to 13.07); age and BMI adjusted odds ratio 3.59 (95% CI, 1.03 to 12.57). However, 25(OH)D level, either in continuous or categorical measure, was not significantly associated with insulin resistance among female adolescents.

Conclusions

This study suggests that serum 25(OH)D level may be inversely associated with insulin resistance in healthy male adolescents.     

Oral Glucose Tolerance is Associated with Neuroelectric Indices of Attention Among Adults with Overweight and Obesity

Objective

This study aimed to elucidate the relationship between glucose levels and insulin resistance and sensitivity obtained from oral glucose tolerance tests and neurophysiological indices of attention among adults with overweight and obesity.

Methods

Forty adults with overweight or obesity (BMI ≥ 25 kg/m²) underwent dual‐energy x‐ray absorptiometry to assess visceral adipose tissue. Repeated venous blood samples were collected during an oral glucose tolerance test to measure insulin resistance (homeostatic model assessment of insulin resistance) and indices of insulin sensitivity (Matsuda index and Stumvoll metabolic clearance rate). Attention was assessed using event‐related brain potentials recorded during a visual oddball task. Amplitude and latency of the P3 wave form in a central‐parietal region of interest were used to index attentional resource allocation and information processing speed.

Results

Following adjustment for visceral adipose tissue, reduced values of Matsuda index and Stumvoll metabolic clearance rate (indicating poor insulin sensitivity) were correlated with longer peak latency, whereas insulin area under the curve was positively related to peak latency, indicating slower information processing. Individuals with decreased insulin sensitivity (Matsuda index < 4.3) had significantly longer P3 latencies compared with individuals with normal insulin sensitivity.

Conclusions

Higher fasting glucose, but not homeostatic model assessment of insulin resistance, and reduced indices of glucose sensivity are associated with decrements in attention characterized by slower reaction time and slower information processing speed among adults with overweight and obesity.