HIV-associated adipose redistribution syndrome (HARS): etiology and pathophysiological mechanisms

Human immunodeficiency virus (HIV)-associated adipose redistribution syndrome (HARS) is a fat accumulation disorder characterized by increases in visceral adipose tissue. Patients with HARS may also present with excess truncal fat and accumulation of dorsocervical fat ("buffalo hump"). The pathophysiology of HARS appears multifactorial and is not fully understood at present. Key pathophysiological influences include adipocyte dysfunction and an excessive free fatty acid release by adipocyte lipolysis. The contributory roles of free fatty acids, cytokines, hormones including cortisol, insulin and the growth hormone-adipocyte axis are significant. Other potential humoral, paracrine, endocrine, and neural influences are also discussed

Elevated unmethylated and methylated insulin DNA are unique markers of A + β + ketosis prone diabetes

A + β + ketosis prone diabetes (KPD) is associated with slowly progressive autoimmune beta cell destruction. Plasma unmethylated and methylated insulin DNA (biomarkers of ongoing beta cell damage and systemic inflammation, respectively) were elevated in A + β + KPD compared to all other KPD subgroups

Infectious SIV resides in adipose tissue and induces metabolic defects in chronically infected rhesus macaques

Additional file 1. General method for isolation of stromal-vascular-fraction (AT-SVF) cells from adipose tissue of rhesus macaques, and subsequent analyses. (A) 30-60 mins collagenase digestion of solid adipose tissue samples from rhesus macaques is followed by washing and centrifugation, allowing for separation of mature adipocytes (floater fraction) from the stromal-vascular-fraction (AT-SVF) cells. AT-SVF cells were then analyzed by flow cytometry, nested PCR, and viral outgrowth assays, and floater fraction adipocytes analyzed for mRNA expression. (B) Sample flow cytometry gating schemes for examination of AT-SVF T cells, NKT cells, macrophages, and B cells

Relationship of ethnicity and CD4 Count with glucose metabolism among HIV patients on Highly-Active Antiretroviral Therapy (HAART)

Background HIV patients on HAART are prone to metabolic abnormalities, including insulin resistance, lipodystrophy and diabetes. This study purports to investigate the relationship of ethnicity and CD4+ T cell count attained after stable highly-active antiretroviral treatment (HAART) with glucose metabolism in hyperrtriglyceridemic HIV patients without a history of diabetes. Methods Demographic, anthropometric, clinical, endocrinologic, energy expenditure and metabolic measures were obtained in 199 multiethnic, healthy but hypertriglyceridemic HIV-infected patients [46% Hispanic, 17% African-American, 37% Non-Hispanic White (NHW)] on stable HAART without a history of diabetes. The relationship of glucose and insulin responses to ethnicity, CD4 strata (low (\u3c300/cc) or moderate-to-high (≥ 300/cc)), and their interaction was determined. Results African-Americans had significantly greater impairment of glucose tolerance (P \u3c 0.05) and HbA1c levels (P \u3c .001) than either Hispanics or NHWs. In multivariate models, after adjusting for confounders (age, sex, HIV/HAART duration, smoking, obesity, glucose, insulin and lipids), African-Americans and Hispanics had significantly higher HbA1c and 2-hour glucose levels than NHW’s. Demonstrating a significant interaction between ethnicity and CD4 count (P = 0.023), African Americans with CD4 \u3c300/cc and Hispanics with CD4 ≥300/cc had the most impaired glucose response following oral glucose challenge. Conclusions Among hypertriglyceridemic HIV patients on HAART, African-Americans and Hispanics are at increased risk of developing diabetes. Ethnicity also interacts with CD4+ T cell count attained on stable HAART to affect post-challenge glycemic response

Glucose level decline precedes dementia in elderly African Americans with diabetes

INTRODUCTION: High blood glucose levels may be responsible for the increased risk for dementia in diabetic patients. METHODS: A secondary data analysis merging electronic medical records (EMRs) with data collected from the Indianapolis-Ibadan Dementia project (IIDP). Of the enrolled 4105 African Americans, 3778 were identified in the EMR. Study endpoints were dementia, mild cognitive impairment (MCI), or normal cognition. Repeated serum glucose measurements were used as the outcome variables. RESULTS: Diabetic participants who developed incident dementia had a significant decrease in serum glucose levels in the years preceding the diagnosis compared to the participants with normal cognition (P = .0002). They also had significantly higher glucose levels up to 9 years before the dementia diagnosis (P = .0367). DISCUSSION: High glucose levels followed by a decline occurring years before diagnosis in African American participants with diabetes may represent a powerful presymptomatic metabolic indicator of dementia

Changes of glucose levels precede dementia in African Americans with diabetes but not in Caucasians

INTRODUCTION Changes in glucose levels may represent a powerful metabolic indicator for dementia in African Americans with diabetes. It is unclear whether these changes also occur in Caucasians. METHODS A secondary data analysis using electronic medical records from 5228 African Americans and Caucasians 65 years and older. Mixed effects models with repeated serum glucose measurements were used to compare changes in glucose levels between African Americans and Caucasian patients with and without incident dementia. RESULTS African Americans and Caucasians with diabetes had significantly different changes in glucose levels by dementia status (p<0.0001). African Americans experienced a significant decline in glucose levels before the dementia diagnosis (estimated glucose decline 1.3421 mg/dL per year, p<0.0001) than those who did not develop dementia. Caucasians with and without dementia showed stable glucose levels over time (p=0.3071). DISCUSSION Significant changes in glucose levels precede dementia in African American patients with diabetes but not in Caucasians

Human adipose tissue as a reservoir for memory CD4\u3csup\u3e+\u3c/sup\u3e T cells and HIV

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Objective: The objective of this study is to determine whether adipose tissue functions as a reservoir for HIV-1. Design: We examined memory CD4+ T cells and HIV DNA in adipose tissue-stromal vascular fraction (AT-SVF) of five patients [four antiretroviral therapy (ART)-treated and one untreated]. To determine whether adipocytes stimulate CD4+ T cells and regulate HIV production, primary human adipose cells were cocultured with HIV-infected CD4+ T cells. Methods: AT-SVF T cells were studied by flow cytometry, and AT-SVF HIV DNA (Gag and Env) was examined by nested PCR and sequence analyses. CD4+ T-cell activation and HIV production were measured by flow cytometry and ELISA. Results: AT-SVF CD3+ T cells were activated (\u3e60% CD69+) memory CD4+ and CD8+ T cells in uninfected andHIV-infected persons, but the AT-SVF CD4+/CD8+ ratiowas lower in HIV patients. HIVDNA(Gag and Env)was detected in AT-SVF of all five patients examined by nested PCR, comparably to other tissues [peripheral blood mononuclear cell (PBMC), lymph node or thymus]. In coculture experiments, adipocytes increased CD4+ T-cell activation and HIV production approximately two to three-fold in synergy with gammachain cytokines interleukin (IL)-2, IL7 or IL15. These effects were mitigated by neutralizing antibodies against IL6 and integrin-a1b1. Adipocytes also enhanced T-cell viability. Conclusion: Adipose tissues of ART-treated patients harbour activated memory CD4+ T cells and HIV DNA. Adipocytes promote CD4+ T-cell activation and HIV production in concert with intrinsic adipose factors. Adipose tissue may be an important reservoir for HIV

ANGPTL4 variants E40K and T266M are associated with lower fasting triglyceride levels in Non-Hispanic White Americans from the Look AHEAD Clinical Trial

<p>Abstract</p> <p>Background</p> <p>Elevated triglyceride levels are a risk factor for cardiovascular disease. Angiopoietin-like protein 4 (Angptl4) is a metabolic factor that raises plasma triglyceride levels by inhibiting lipoprotein lipase (LPL). In non-diabetic individuals, the <it>ANGPTL4 </it>coding variant E40K has been associated with lower plasma triglyceride levels while the T266M variant has been associated with more modest effects on triglyceride metabolism. The objective of this study was to determine whether ANGPTL4 E40K and T266M are associated with triglyceride levels in the setting of obesity and T2D, and whether modification of triglyceride levels by these genetic variants is altered by a lifestyle intervention designed to treat T2D.</p> <p>Methods</p> <p>The association of <it>ANGPTL4 </it>E40K and T266M with fasting triglyceride levels was investigated in 2,601 participants from the Look AHEAD Clinical Trial, all of whom had T2D and were at least overweight. Further, we tested for an interaction between genotype and treatment effects on triglyceride levels.</p> <p>Results</p> <p>Among non-Hispanic White Look AHEAD participants, <it>ANGPTL4 </it>K40 carriers had mean triglyceride levels of 1.61 ± 0.62 mmol/L, 0.33 mmol/L lower than E40 homozygotes (p = 0.001). Individuals homozygous for the minor M266 allele (MAF 30%) had triglyceride levels of 1.75 ± 0.58 mmol/L, 0.24 mmol/L lower than T266 homozygotes (p = 0.002). The association of the M266 with triglycerides remained significant even after removing K40 carriers from the analysis (p = 0.002). There was no interaction between the weight loss intervention and genotype on triglyceride levels.</p> <p>Conclusions</p> <p>This is the first study to demonstrate that the <it>ANGPTL4 </it>E40K and T266M variants are associated with lower triglyceride levels in the setting of T2D. In addition, our findings demonstrate that <it>ANGPTL4 </it>genotype status does not alter triglyceride response to a lifestyle intervention in the Look AHEAD study.</p

Large-Scale Gene-Centric Meta-Analysis across 39 Studies Identifies Type 2 Diabetes Loci

To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with similar to 2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 x 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p <2.4 x 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 x 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 x 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 x 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups