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High Glucose Causes Apoptosis in Cultured Human Pancreatic Islets of Langerhans: A Potential Role for Regulation of Specific Bcl Family Genes Toward an Apoptotic Cell Death Program

Type 2 diabetes is characterized by insulin resistance and inadequate insulin secretion. In the advanced stages of the disease, β-cell dysfunction worsens and insulin therapy may be necessary to achieve satisfactory metabolic control. Studies in autopsies found decreased β-cell mass in pancreas of people with type 2 diabetes. Apoptosis, a constitutive program of cell death...

Insulin Secretory Function Is Impaired in Isolated Human Islets Carrying the Gly972→Arg IRS-1 Polymorphism

Type 2 (non–insulin-dependent) diabetes results from decreased insulin action in peripheral target tissues (insulin resistance) and impaired pancreatic β-cell function. These defects reflect both genetic components and environmental risk factors. Recently, the common Gly972→Arg amino acid polymorphism of insulin receptor substrate 1 (Arg972 IRS-1) has been associated with human...

A Common Polymorphism in the Promoter of UCP2 Contributes to the Variation in Insulin Secretion in Glucose-Tolerant Subjects

It was reported that the common −866G/A polymorphism in the promoter of the human uncoupling protein-2 (UCP2) gene, which enhances its trascriptional activity, is associated with increased mRNA levels in human adipocytes and reduced risk of obesity. Studies in knockout mice and β-cells indicate that UCP2 may play a role in β-cell function. In this study, we addressed the question...

The −866A/A Genotype in the Promoter of the Human Uncoupling Protein 2 Gene Is Associated With Insulin Resistance and Increased Risk of Type 2 Diabetes

Uncoupling protein (UCP)-2 is a member of the mitochondrial inner membrane carriers that uncouple pro-ton entry in the mitochondrial matrix from ATP synthesis. The −866G/A polymorphism in the UCP2 gene, which enhances its transcriptional activity, was associated with enhanced risk for type 2 diabetes in obese subjects. We addressed the question of whether the −866G/A polymorphism...

The Gly972→Arg IRS-1 Variant Is Associated With Type 1 Diabetes in Continental Italy

, Italy. Massimo Federici, MD , Department of Internal Medicine, University of Rome Tor Vergata , via Montpellier 1, 56100, Rome , Italy 4 Istituto Superiore di Sanita`, Immunogenetics Laboratory , Rome

IL12B Polymorphism and Type 1 Diabetes in the Italian Population: A Case-Control Study

A polymorphism in the interleukin 12B gene was recently reported to be strongly associated with type 1 diabetes in 422 Australian and British families. We analyzed the same polymorphism in 470 Italian type 1 diabetic patients and 544 matched control subjects and found no evidence of association with the disease.

The ENPP1 Q121 Variant Predicts Major Cardiovascular Events in High-Risk Individuals: Evidence for Interaction With Obesity in Diabetic Patients

Giovanni Tripepi Rui Xu Davide Mangiacotti Filippo Aucella Renato Lauro Ernest V. Gervino Thomas H. Hauser Massimiliano Copetti Salvatore De Cosmo Fabio Pellegrini Carmine Zoccali Massimo Federici Alessandro

The Arg972 Variant in Insulin Receptor Substrate-1 Is Associated With an Increased Risk of Secondary Failure to Sulfonylurea in Patients With Type 2 Diabetes

OBJECTIVE—The aim of this study was to investigate whether diabetic patients carrying the Arg972 insulin receptor substrate-1 (IRS-1) variant are at increased risk for secondary failure to sulfonylurea. RESEARCH DESIGN AND METHODS—A total of 477 unrelated Caucasian type 2 diabetic patients were recruited according to the following criteria: onset of diabetes after age 35 years...

Plasma Concentration of IGF-I Is Independently Associated With Insulin Sensitivity in Subjects With Different Degrees of Glucose Tolerance

OBJECTIVE—We studied the relationships between plasma IGF-I concentrations and insulin sensitivity in subjects with various degrees of glucose tolerance. RESEARCH DESIGN AND METHODS—A total of 357 nondiabetic subjects, 54 subjects with impaired glucose tolerance and 98 newly diagnosed type 2 diabetic subjects, were consecutively recruited, and anthropometric and biochemical...

Benfotiamine Counteracts Glucose Toxicity Effects on Endothelial Progenitor Cell Differentiation via Akt/FoxO Signaling

Dysfunction of mature endothelial cells is thought to play a major role in both micro- and macrovascular complications of diabetes. However, recent advances in biology of endothelial progenitor cells (EPCs) have highlighted their involvement in diabetes complications. To determine the effect of glucotoxicity on EPCs, human EPCs have been isolated from peripheral blood mononuclear...

Mice Heterozygous for Tumor Necrosis Factor-α Converting Enzyme Are Protected From Obesity-Induced Insulin Resistance and Diabetes

Matteo Serino Rossella Menghini Loredana Fiorentino Roberta Amoruso Alessandro Mauriello Davide Lauro Paolo Sbraccia Marta L. Hribal Renato Lauro Massimo Federici OBJECTIVE-Tumor necrosis factor

Sildenafil Reduces Insulin-Resistance in Human Endothelial Cells

Background The efficacy of Phosphodiesterase 5 (PDE5) inhibitors to re-establish endothelial function is reduced in diabetic patients. Recent evidences suggest that therapy with PDE5 inhibitors, i.e. sildenafil, may increase the expression of nitric oxide synthase (NOS) proteins in the heart and cardiomyocytes. In this study we analyzed the effect of sildenafil on endothelial...

TIMP3 Is Reduced in Atherosclerotic Plaques From Subjects With Type 2 Diabetes and Increased by SirT1

Marina Cardellini Rossella Menghini Eugenio Martelli Viviana Casagrande Arianna Marino Stefano Rizza Ottavia Porzio Alessandro Mauriello Anna Solini Arnaldo Ippoliti Renato Lauro Franco Folli Massimo ... Federici OBJECTIVE-Atherosclerosis is accelerated in subjects with type 2 diabetes by unknown mechanisms. We identified tissue inhibitor of metalloproteinase 3 (TIMP3), the endogenous inhibitor of A

Serum Resistin, Cardiovascular Disease and All-Cause Mortality in Patients with Type 2 Diabetes

Background High serum resistin has been associated with increased risk of cardiovascular disease in the general population, Only sparse and conflicting results, limited to Asian individuals, have been reported, so far, in type 2 diabetes. We studied the role of serum resistin on coronary artery disease, major cardiovascular events and all-cause mortality in type 2 diabetes...

Decreased IRS2 and TIMP3 Expression in Monocytes From Offspring of Type 2 Diabetic Patients Is Correlated With Insulin Resistance and Increased Intima-Media Thickness

Renato Lauro Massimo Federici OBJECTIVE-In humans, it is unclear if insulin resistance at the monocyte level is associated with atherosclerosis in vivo. Here we have studied first-degree relatives of

TIMP3 Overexpression in Macrophages Protects From Insulin Resistance, Adipose Inflammation, and Nonalcoholic Fatty Liver Disease in Mice

Renato Lauro Massimo Federici The tissue inhibitor of metalloproteinase (TIMP)3, a stromal protein that restrains the activity of proteases and receptors, is reduced in inflammatory metabolic disorders

Immunopositivity for Histone MacroH2A1 Isoforms Marks Steatosis-Associated Hepatocellular Carcinoma

Background Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Prevention and risk reduction are important and the identification of specific biomarkers for early diagnosis of HCC represents an active field of research. Increasing evidence indicates that fat accumulation in the liver, defined as hepatosteatosis, is an independent and strong risk factor for...

ITCH Deficiency Protects From Diet-Induced Obesity

Classically activated macrophages (M1) secrete proinflammatory cytokine and are predominant in obese adipose tissue. M2 macrophages, prevalent in lean adipose tissue, are induced by IL-13 and IL-4, mainly secreted by Th2 lymphocytes, and produce the anti-inflammatory cytokine IL-10. ITCH is a ubiquitously expressed E3 ubiquitin ligase involved in T-cell differentiation and in a...

Pioglitazone improves glucose metabolism and modulates skeletal muscle TIMP-3–TACE dyad in type 2 diabetes mellitus: a randomised, double-blind, placebo-controlled, mechanistic study

Aims/hypothesisPioglitazone (PIO) is a peroxisome proliferator-activated receptor (PPAR)γ agonist insulin-sensitiser with anti-inflammatory and anti-atherosclerotic effects. Our objective was to evaluate the effect of low-dose PIO (15 mg/day) on glucose metabolism and inflammatory state in obese individuals with type 2 diabetes.MethodsA randomised, double-blind, placebo...

Toll-Like Receptor 4 Mediates Endothelial Cell Activation Through NF-κB but Is Not Associated with Endothelial Dysfunction in Patients with Rheumatoid Arthritis

Objective To investigate the effects of TLR4 antagonism on human endothelial cells activation and cytokine expression, and whether the Asp299Gly TLR4 polymorphism is associated with better endothelial function in patients with rheumatoid arthritis (RA). Methods Human aortic endothelial cells (HAECs) were treated with lipopolysaccharide (LPS), OxPAPC, and free fatty acids (FFA) at...