Effects of pioglitazone on intramyocellular fat metabolism in patients with type 2 diabetes mellitus.

Context: Lipotoxicity (increased tissue fat content) has been implicated in the development of muscle insulin resistance and type 2 diabetes mellitus (T2DM).

Objective: The aim was to study the effect of pioglitazone on intramyocellular fat metabolism.

Research Design: Twenty-four T2DM subjects (glycosylated hemoglobin = 8.

Effects of exenatide plus rosiglitazone on beta-cell function and insulin sensitivity in subjects with type 2 diabetes on metformin.

Objective: Study the effects of exenatide (EXE) plus rosiglitazone (ROSI) on beta-cell function and insulin sensitivity using hyperglycemic and euglycemic insulin clamp techniques in participants with type 2 diabetes on metformin.

Research Design And Methods: In this 20-week, randomized, open-label, multicenter study, participants (mean age, 56 +/- 10 years; weight, 93 +/- 16 kg; A1C, 7.8 +/- 0.

Minimal contribution of fasting hyperglycemia to the incidence of type 2 diabetes in subjects with normal 2-h plasma glucose.

OBJECTIVE To assess the relative contribution of increased fasting and postload plasma glucose concentrations to the incidence of type 2 diabetes in subjects with a normal 2-h plasma glucose concentration. RESEARCH DESIGN AND METHODS A total of 3,450 subjects with 2-h plasma glucose concentration <140 mg/dl at baseline were followed up in the San Antonio Heart Study (SAHS) and the Botnia Study for 7-8 years. The incidence of type 2 diabetes at follow-up was related to the fasting, 1-h, and 2-h plasma glucose concentrations.

Effect of short-term free Fatty acids elevation on mitochondrial function in skeletal muscle of healthy individuals.

Context: Mitochondrial dysfunction has been proposed as an underlying mechanism in the pathogenesis of insulin resistance and type 2 diabetes mellitus.

Objective: To determine whether mitochondrial dysfunction plays a role in the free fatty acid (FFA)-induced impairment in insulin action in skeletal muscle of healthy subjects.

Design: Eleven lean normal glucose tolerant individuals received 8 h lipid and saline infusion on separate days with a euglycemic insulin clamp during the last 2 h.

Pancreatic islet amyloidosis, beta-cell apoptosis, and alpha-cell proliferation are determinants of islet remodeling in type-2 diabetic baboons.

beta-Cell dysfunction is an important factor in the development of hyperglycemia of type-2 diabetes mellitus, and pancreatic islet amyloidosis (IA) has been postulated to be one of the main contributors to impaired insulin secretion. The aim of this study was to evaluate the correlation of IA with metabolic parameters and its effect on islets of Langerhans remodeling and relative endocrine-cell volume in baboons. We sequenced the amylin peptide, determined the fibrillogenic propensities, and evaluated pancreatic histology, clinical and biochemical characteristics, and endocrine cell proliferation and apoptosis in 150 baboons with different metabolic status.

Visceral fat dominant distribution in male type 2 diabetic patients is closely related to hepatic insulin resistance, irrespective of body type.

Background: All previous studies that investigated the association between abdominal fat distribution and insulin resistance evaluated subcutaneous and visceral fat area and/or volume, but these values were not related to the body type of each subject. In the present study we have examined the association between abdominal fat distribution and peripheral (muscle)/hepatic sensitivity to insulin using the visceral to abdominal subcutaneous fat area ratio (VF/SF ratio) in male patients with type 2 diabetes mellitus. This ratio defines the predominancy of visceral or subcutaneous abdominal adiposity, independent of the body type of each individual.

Actos Now for the prevention of diabetes (ACT NOW) study.

Background: Impaired glucose tolerance (IGT) is a prediabetic state. If IGT can be prevented from progressing to overt diabetes, hyperglycemia-related complications can be avoided. The purpose of the present study was to examine whether pioglitazone (ACTOS) can prevent progression of IGT to type 2 diabetes mellitus (T2DM) in a prospective randomized, double blind, placebo controlled trial.

Pathophysiology of prediabetes.

The term prediabetes refers to subjects with impaired fasting glucose and/or impaired glucose tolerance who are at increased risk for type 2 diabetes mellitus. Although both types of patients are at increased risk for developing type 2 diabetes mellitus and cardiovascular disease, they manifest distinct metabolic abnormalities. In this article, we summarize the metabolic abnormalities that characterize each state and the contribution of these metabolic abnormalities to the increased risk of diabetes and cardiovascular disease.

Circulating fibroblast growth factor-21 is elevated in impaired glucose tolerance and type 2 diabetes and correlates with muscle and hepatic insulin resistance.

OBJECTIVE Fibroblast growth factor (FGF)-21 is highly expressed in the liver and regulates hepatic glucose production and lipid metabolism in rodents. However, its role in the pathogenesis of type 2 diabetes in humans remains to be defined. The aim of this study was to quantitate circulating plasma FGF-21 levels and examine their relationship with insulin sensitivity in subjects with varying degrees of obesity and glucose tolerance.

The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone.

Objective: This 24-week trial assessed the efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes with inadequate glycemic control with metformin alone.

Research Design And Methods: This was a randomized, double-blind, placebo-controlled study of saxagliptin (2.5, 5, or 10 mg once daily) or placebo plus a stable dose of metformin (1,500-2,500 mg) in 743 patients (A1C > or =7.

Predictive models of insulin resistance derived from simple morphometric and biochemical indices related to obesity and the metabolic syndrome in baboons.

Background: Non-human primates are valuable models for the study of insulin resistance and human obesity. In baboons, insulin sensitivity levels can be evaluated directly with the euglycemic clamp and is highly predicted by adiposity, metabolic markers of obesity and impaired glucose metabolism (i.e.

Whole body overexpression of PGC-1alpha has opposite effects on hepatic and muscle insulin sensitivity.

Type 2 diabetes is characterized by fasting hyperglycemia, secondary to hepatic insulin resistance and increased glucose production. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) is a transcriptional coactivator that is thought to control adaptive responses to physiological stimuli. In liver, PGC-1alpha expression is induced by fasting, and this effect promotes gluconeogenesis.

Retinol-binding protein 4 is associated with impaired glucose tolerance but not with whole body or hepatic insulin resistance in Mexican Americans.

Retinol-binding protein-4 (RBP4), a novel protein secreted mainly by adipose tissue, has been associated with insulin resistance in obese subjects and in individuals with type 2 diabetes mellitus (T2DM). We examined the relationship between plasma RBP4 levels, expression of RBP4 in skeletal muscle and adipose tissue, and insulin sensitivity in Mexican Americans with varying degrees of obesity and glucose tolerance. Seventy-two subjects [16 lean normal-glucose-tolerant (NGT), 17 obese NGT, and 39 subjects with impaired fasting glucose/impaired glucose tolerance/T2DM] received an oral glucose tolerance test (OGTT) and euglycemic-hyperinsulinemic clamp.

Fasting versus postload plasma glucose concentration and the risk for future type 2 diabetes: results from the Botnia Study.

Objective: The purpose of this study was to assess the efficacy of the postload plasma glucose concentration in predicting future risk of type 2 diabetes, compared with prediction models based on measurement of the fasting plasma glucose (FPG) concentration.

Research Design And Methods: A total of 2,442 subjects from the Botnia Study, who were free of type 2 diabetes at baseline, received an oral glucose tolerance test (OGTT) at baseline and after 7-8 years of follow-up. Future risk for type 2 diabetes was assessed with area under the receiver-operating characteristic curve for prediction models based up measurement of the FPG concentration 1) with or without a 1-h plasma glucose concentration during the OGTT and 2) with or without the metabolic syndrome.

Plasma ceramides are elevated in obese subjects with type 2 diabetes and correlate with the severity of insulin resistance.

Objective: To quantitate plasma ceramide subspecies concentrations in obese subjects with type 2 diabetes and relate these plasma levels to the severity of insulin resistance. Ceramides are a putative mediator of insulin resistance and lipotoxicity, and accumulation of ceramides within tissues in obese and diabetic subjects has been well described.

Research Design And Methods: We analyzed fasting plasma ceramide subspecies by quantitative tandem mass spectrometry in 13 obese type 2 diabetic patients and 14 lean healthy control subjects.

Inhibition of renal glucose reabsorption: a novel strategy for achieving glucose control in type 2 diabetes mellitus.

Objective: To review the renal handling of glucose and the role of inhibition of a sodium-glucose transporter (SGLT2) in the treatment of type 2 diabetes mellitus (T2DM).

Methods: We review the published data about (1) the filtration and reabsorption of glucose by the kidneys in normal subjects and patients with diabetes; (2) the deleterious effects of long-term elevation of plasma glucose levels on muscle and hepatic insulin sensitivity and beta cell function (that is, glucotoxicity); (3) the effect of inhibiting the SGLT2 transporter on the induction of glycosuria, glycemic control, insulin resistance, and beta cell dysfunction in animals and humans with diabetes; and (4) the safety of SGLT2 inhibition as a therapeutic modality to treat human T2DM.

Results: Studies in animal models of diabetes document the efficacy of the SGLT2 inhibitors in inducing glycosuria, decreasing both fasting and postprandial glucose levels, augmenting beta cell function, and enhancing hepatic and muscle insulin sensitivity.

Differences in insulin action and secretion, plasma lipids and blood pressure levels between impaired fasting glucose and impaired glucose tolerance in Japanese subjects.

We examined insulin action/secretion and cardiovascular disease risk factors in Japanese subjects with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) who were not taking any medications known to affect glucose tolerance, blood pressure (BP) or plasma lipids (PLs). A total of 1,399 subjects received measurements of anthropometry, BP, PLs, and plasma glucose/insulin concentrations during 75 g-oral glucose tolerance test (OGTT). According to 2003 American Diabetes Association criteria, subjects were classified as having normal fasting glucose (NFG)/normal glucose tolerance (NGT) (n = 1,173), IFG (n = 128), IGT (n = 55), and IFG/IGT (n = 43).

Genome-wide linkage scan for genes influencing plasma triglyceride levels in the Veterans Administration Genetic Epidemiology Study.

Objective: Elevated plasma triglyceride concentration is a component of the insulin resistance syndrome and is commonly associated with type 2 diabetes, obesity, and coronary heart disease. The goal of our study was to perform a genome-wide linkage scan to identify genetic regions that influence variation in plasma triglyceride levels in families that are enriched with individuals with type 2 diabetes.

Research Design And Methods: We used phenotypic and genotypic data from 1,026 individuals distributed across 294 Mexican-American families, who were ascertained for type 2 diabetes, from the Veterans Administration Genetic Epidemiology Study (VAGES).

Elevated concentrations of liver enzymes and ferritin identify a new phenotype of insulin resistance: effect of weight loss after gastric banding.

Background: Several studies have associated elevated liver enzymes (LFTs), obesity, and type 2 diabetes (T2DM), and a link has been established between insulin resistance (IR) and elevated ferritin concentrations. We examined the relationship between LFTs, ferritin, and IR in morbid obese subjects and the effect of weight loss after bariatric surgery.

Methods: We measured liver enzymes, ferritin, insulin resistance, and glucose tolerance (by OGTT) in 159 morbid obese subjects (BMI = 44.

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control: a randomized, double-blind, placebo-controlled study.

Objective: To evaluate the dipeptidyl peptidase-4 (DPP-4) inhibitor alogliptin in drug-naïve patients with inadequately controlled type 2 diabetes.

Research Design And Methods: This double-blind, placebo-controlled, multicenter study included 329 patients with poorly controlled diabetes randomized to once-daily treatment with 12.5 mg alogliptin (n = 133), 25 mg alogliptin (n = 131), or placebo (n = 65) for 26 weeks.