Relation of Abdominal Fat Depots to Systemic Markers of Inflammation in Type 2 Diabetes

OBJECTIVE: Both visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) have been linked to systemic inflammation in nondiabetic cohorts. We examined the relationships between VAT and SAT and systemic inflammatory markers in a large well-characterized cohort of subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: Three hundred eighty-two subjects with type 2 diabetes in the CHICAGO (Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone) study cohort underwent abdominal computed tomography to determine SAT and VAT distribution. Fasting blood was obtained for measurement of inflammatory markers. The relationships between inflammatory markers and BMI, SAT, and VAT were examined using regression models adjusted for age, sex, diabetes treatment, duration of diabetes, smoking, statin use, and A1C. RESULTS: VAT was positively related to CRP, monocyte chemoattractant protein (MCP), intracellular adhesion molecule (ICAM)-1, and plasminogen activator inhibitor type 1 (PAI-1) antigen before adjustment for BMI. After adjustment for BMI, the relationship to CRP was lost but positive associations with MCP (P < 0.01), PAI-1 (P < 0.0001), ICAM-1 (P < 0.01), and vascular cell adhesion molecule (P = 0.01) were evident. BMI was positively related to CRP (P < 0.0001) and IL-6 (P < 0.01) even after adjustment for VAT and SAT. SAT was not related to any inflammatory marker after adjustment for BMI. CONCLUSIONS: In this large group of subjects with type 2 diabetes, BMI was most strongly associated with CRP and IL-6 levels. SAT was not associated with markers of systemic inflammation. The size of the VAT depot provided information additional to that provided by BMI regarding inflammatory markers that are strongly related to vascular wall remodeling and coagulation. Our findings suggest that adipose tissue distribution remains an important determinant of systemic inflammation in type 2 diabetes.National Institutes of Health (DK-71711); University of Illinois at Chicag

Oral Treatment with γ-Aminobutyric Acid Improves Glucose Tolerance and Insulin Sensitivity by Inhibiting Inflammation in High Fat Diet-Fed Mice

Adipocyte and β-cell dysfunction and macrophage-related chronic inflammation are critical for the development of obesity-related insulin resistance and type 2 diabetes mellitus (T2DM), which can be negatively regulated by Tregs. Our previous studies and those of others have shown that activation of γ-aminobutyric acid (GABA) receptors inhibits inflammation in mice. However, whether GABA could modulate high fat diet (HFD)-induced obesity, glucose intolerance and insulin resistance has not been explored. Here, we show that although oral treatment with GABA does not affect water and food consumption it inhibits the HFD-induced gain in body weights in C57BL/6 mice. Furthermore, oral treatment with GABA significantly reduced the concentrations of fasting blood glucose, and improved glucose tolerance and insulin sensitivity in the HFD-fed mice. More importantly, after the onset of obesity and T2DM, oral treatment with GABA inhibited the continual HFD-induced gain in body weights, reduced the concentrations of fasting blood glucose and improved glucose tolerance and insulin sensitivity in mice. In addition, oral treatment with GABA reduced the epididymal fat mass, adipocyte size, and the frequency of macrophage infiltrates in the adipose tissues of HFD-fed mice. Notably, oral treatment with GABA significantly increased the frequency of CD4+Foxp3+ Tregs in mice. Collectively, our data indicated that activation of peripheral GABA receptors inhibited the HFD-induced glucose intolerance, insulin resistance, and obesity by inhibiting obesity-related inflammation and up-regulating Treg responses in vivo. Given that GABA is safe for human consumption, activators of GABA receptors may be valuable for the prevention of obesity and intervention of T2DM in the clinic

Obesity-Related Upregulation of Monocyte Chemotactic Factors in Adipocytes : Involvement of Nuclear Factor-κB and c-Jun NH2-Terminal Kinase Pathways

OBJECTIVE—We sought to evaluate the entire picture of all monocyte chemotactic factors that potentially contribute to adipose tissue macrophage accumulation in obesity

Functional characterization of obesity-associated variants involving the α and β isoforms of human SH2B1.

We have previously reported rare variants in sarcoma (Src) homology 2 (SH2) B adaptor protein 1 (SH2B1) in individuals with obesity, insulin resistance, and maladaptive behavior. Here, we identify 4 additional SH2B1 variants by sequencing 500 individuals with severe early-onset obesity. SH2B1 has 4 alternatively spliced isoforms. One variant (T546A) lies within the N-terminal region common to all isoforms. As shown for past variants in this region, T546A impairs SH2B1β enhancement of nerve growth factor-induced neurite outgrowth, and the individual with the T546A variant exhibits mild developmental delay. The other 3 variants (A663V, V695M, and A723V) lie in the C-terminal tail of SH2B1α. SH2B1α variant carriers were hyperinsulinemic but did not exhibit the behavioral phenotype observed in individuals with SH2B1 variants that disrupt all isoforms. In in vitro assays, SH2B1α, like SH2B1β, enhances insulin- and leptin-induced insulin receptor substrate 2 (IRS2) phosphorylation and GH-induced cell motility. None of the variants affect SH2B1α enhancement of insulin- and leptin-induced IRS2 phosphorylation. However, T546A, A663V, and A723V all impair the ability of SH2B1α to enhance GH-induced cell motility. In contrast to SH2B1β, SH2B1α does not enhance nerve growth factor-induced neurite outgrowth. These studies suggest that genetic variants that disrupt isoforms other than SH2B1β may be functionally significant. Further studies are needed to understand the mechanism by which the individual isoforms regulate energy homeostasis and behavior.This work was supported by the Wellcome Trust (098497/Z/ 12/Z; 077016/Z/05/Z; 096106/Z/11/Z) (to I.S. Farooqi and L.R. Pearce), by the Medical Research Council Metabolic Diseases Unit and NIHR Cambridge Biomedical Research Centre (to I.S. Farooqi, I. Barroso, and S. O’Rahilly) and the Bernard Wolfe Health Neuroscience Fund (I.S. Farooqi); and by NIH grants RO1-DK54222 (to C. Carter-Su), RO1-DK065122 and RO1- DK073601 (to L. Rui), a predoctoral fellowship from the Systems and Integrative Biology Training Grant NIH–T32-GM008322 (to M.E. Doche) and a Rackham Merit Fellowship from the University of Michigan (to R. Joe). Confocal microscopy was performed using the Morphology and Image Analysis Core of the Michigan Diabetes Research Center (NIH grant P60-DK20572).This is the final published version distributed under a Creative Commons Attribution License, which can also be found on the publisher's website at: http://press.endocrine.org/doi/abs/10.1210/en.2014-1264?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubme

Adipokines and Incident Type 2 Diabetes in a Canadian Aborigine Population: The Sandy Lake Health and Diabetes Project

OBJECTIVE—The aim of this study was to investigate associations of adiponectin, leptin, C-reactive protein (CRP), interleukin (IL)-6, and serum amyloid A (SAA), individually or in combinations, with risk of incident type 2 diabetes in a Canadian Aborigine population

c-Jun NH2-Terminal Kinase Activity in Subcutaneous Adipose Tissue but Not Nuclear Factor-κB Activity in Peripheral Blood Mononuclear Cells Is an Independent Determinant of Insulin Resistance in Healthy Individuals

OBJECTIVE Chronic low-grade activation of the immune system (CLAIS) predicts type 2 diabetes via a decrease in insulin sensitivity. Our study investigated potential relationships between nuclear factor-κB (NF-κB) and c-Jun NH2-terminal kinase (JNK) pathways—two pathways proposed as the link between CLAIS and insulin resistance. RESEARCH DESIGN AND METHODS Adiposity (dual-energy X-ray absorptiometry), waist-to-hip ratio (WHR), and insulin sensitivity (M, hyperinsulinemic-euglycemic clamp) were measured in 22 healthy nondiabetic volunteers (aged 29 ± 11 years, body fat 28 ± 11%). NF-κB activity (DNA-binding assay) and JNK1/2 activity (phosphorylated JNK) were assessed in biopsies of the vastus lateralis muscle and subcutaneous adipose tissue and in peripheral blood mononuclear cell (PBMC) lysates. RESULTS NF-κB activities in PBMCs and muscle were positively associated with WHR after adjustment for age, sex, and percent body fat (both P 0.1), although it was inversely related to M (r = −0.54, P < 0.05) and explained 29% of its variance. When both NF-κB and JNK1/2 were examined statistically, only JNK1/2 activity in adipose tissue was a significant determinant of insulin resistance (P = 0.02). CONCLUSIONS JNK1/2 activity in adipose tissue but not NF-κB activity in PBMCs is an independent determinant of insulin resistance in healthy individual

Type 2 Diabetes Is Associated with Altered NF-κB DNA Binding Activity, JNK Phosphorylation, and AMPK Phosphorylation in Skeletal Muscle after LPS

Systemic inflammation is often associated with impaired glucose metabolism. We therefore studied the activation of inflammatory pathway intermediates that interfere with glucose uptake during systemic inflammation by applying a standardised inflammatory stimulus in vivo. After ethical approval, informed consent and a thorough physical examination, 10 patients with type 2 diabetes and 10 participants with normal glucose tolerance (NGT) were given an intravenous bolus of E. coli lipopolysaccharide (LPS) of 0.3 ng/kg. Skeletal muscle biopsies and plasma were obtained at baseline and two, four and six hours after LPS. Nuclear factor (NF)-κB p65 DNA binding activity measured by ELISA, tumor necrosis factor-α and interleukin-6 mRNA expression analysed by real time reverse transcription polymerase chain reaction, and abundance of inhibitor of NF-κB (IκB)α, phosphorylated c-Jun-N-terminal kinase (JNK), AMP-activated protein kinase (AMPK), and acetyl-CoA carboxylase measured by Western blotting were detected in muscle biopsy samples. Relative to subjects with NGT, patients with type 2 diabetes exhibited a more pronounced increase in NF-κB binding activity and JNK phosphorylation after LPS, whereas skeletal muscle cytokine mRNA expression did not differ significantly between groups. AMPK phosphorylation increased in volunteers with NGT, but not in those with diabetes. The present findings indicate that pathways regulating glucose uptake in skeletal muscle may be involved in the development of inflammation-associated hyperglycemia. Patients with type 2 diabetes exhibit changes in these pathways, which may ultimately render such patients more prone to develop dysregulated glucose disposal in the context of systemic inflammation

Effect of the Glycemic Index of Carbohydrates on Acne vulgaris

Acne vulgaris may be improved by dietary factors that increase insulin sensitivity. We hypothesized that a low-glycemic index diet would improve facial acne severity and insulin sensitivity. Fifty-eight adolescent males (mean age ± standard deviation 16.5 ± 1.0 y and body mass index 23.1 ± 3.5 kg/m2) were alternately allocated to high or low glycemic index diets. Severity of inflammatory lesions on the face, insulin sensitivity (homeostasis modeling assessment of insulin resistance), androgens and insulin-like growth factor-1 and its binding proteins were assessed at baseline and at eight weeks, a period corresponding to the school term. Forty-three subjects (n = 23 low glycemic index and n = 20 high glycemic index) completed the study. Diets differed significantly in glycemic index (mean ± standard error of the mean, low glycemic index 51 ± 1 vs. high glycemic index 61 ± 2, p = 0.0002), but not in macronutrient distribution or fiber content. Facial acne improved on both diets (low glycemic index −26 ± 6%, p = 0.0004 and high glycemic index −16 ± 7%, p = 0.01), but differences between diets did not reach significance. Change in insulin sensitivity was not different between diets (low glycemic index 0.2 ± 0.1 and high glycemic index 0.1 ± 0.1, p = 0.60) and did not correlate with change in acne severity (Pearson correlation r = −0.196, p = 0.244). Longer time frames, greater reductions in glycemic load or/and weight loss may be necessary to detect improvements in acne among adolescent boys