Empagliflozin Enhances Hepatic Glucose Production and Reduces Total-Body Norepinephrine Turnover Rate: A Randomized Trial.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) cause an increase in hepatic glucose production (HGP). We previously showed that SGLT2i cause a rapid (within 4 h) increase in the total-body norepinephrine (NE) turnover rate, which could explain the increase in HGP. Because the increase in HGP caused by SGLT2i is long-lasting, we examined the long-term effect of SGLT2i on the NE turnover rate.

Glycemic and non-glycemic benefits of initial triple therapy versus sequential add-on therapy in patients with new-onset diabetes: results from the EDICT study.

Introduction: To compare carotid intima-media thickness (cIMT) and liver fat content in subjects who maintained good glycemic control for 6 years on initial triple therapy with metformin/exenatide/pioglitazone versus sequential add-on therapy with metformin followed with glipizide and basal insulin in subjects with new-onset diabetes.

Research Design And Methods: Liver fat content and cIMT were compared among patients with T2DM who received initial triple therapy with metformin/pioglitazone/exenatide (n=29) versus metformin, followed by stepwise addition of glipizide and then insulin glargine (n=26) and who maintained HbA1c<6.5% for 6 years in Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes.

Chronic physiologic hyperglycemia impairs insulin-mediated suppression of plasma glucagon concentration in healthy humans.

Background And Aims: Hyperglucagonemia is a characteristic feature of type 2 diabetes mellitus (T2DM). We examined the effect of chronic (48-72 h) physiologic increase (+50 mg/dl) in plasma glucose concentration on suppression of plasma glucagon concentration by insulin and by hyperglycemia in normal glucose tolerance (NGT) individuals.

Materials And Methods: Study One: 16 NGT subjects received OGTT and 3-step hyperinsulinemic (10, 20, 40 mU/m·min) euglycemic clamp before and after 48 hour glucose infusion to increase plasma glucose by ~50 mg/dl.

Pioglitazone reduces epicardial fat and improves diastolic function in patients with type 2 diabetes.

Aims: To examine the effect of pioglitazone on epicardial (EAT) and paracardial adipose tissue (PAT) and measures of diastolic function and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM).

Methods: Twelve patients with T2DM without clinically manifest cardiovascular disease and 12 subjects with normal glucose tolerance (NGT) underwent cardiac magnetic resonance imaging to quantitate EAT and PAT and diastolic function before and after pioglitazone treatment for 24 weeks. Whole-body insulin sensitivity was measured with a euglycaemic insulin clamp and the Matsuda Index (oral glucose tolerance test).

Effects of Sustained Hyperglycemia on Skeletal Muscle Lipids in Healthy Subjects.

Context: Sustained increases in plasma glucose promote skeletal muscle insulin resistance independent from obesity and dyslipidemia (ie, glucotoxicity). Skeletal muscle lipids are key molecular determinants of insulin action, yet their involvement in the development of glucotoxicity is unclear.

Objective: To explore the impact of mild physiologic hyperglycemia on skeletal muscle lipids.

Effect of Mild Physiologic Hyperglycemia on Insulin Secretion, Insulin Clearance, and Insulin Sensitivity in Healthy Glucose-Tolerant Subjects.

The aim of the current study was to evaluate the effect of sustained physiologic increase of ∼50 mg/dL in plasma glucose concentration on insulin secretion in normal glucose-tolerant (NGT) subjects. Twelve NGT subjects without family history of type 2 diabetes mellitus (T2DM; FH-) and 8 NGT with family history of T2DM (FH+) received an oral glucose tolerance test and two-step hyperglycemic clamp (100 and 300 mg/dL) followed by intravenous arginine bolus before and after 72-h glucose infusion. Fasting plasma glucose increased from 94 ± 2 to 142 ± 4 mg/dL for 72 h.

Mild Physiologic Hyperglycemia Induces Hepatic Insulin Resistance in Healthy Normal Glucose-Tolerant Participants.

Context: Chronic hyperglycemia worsens skeletal muscle insulin resistance and β-cell function. However, the effect of sustained physiologic hyperglycemia on hepatic insulin sensitivity is not clear.

Objective: To examine the effect of sustained physiologic hyperglycemia (similar to that observed in patients with type 2 diabetes) on endogenous (primarily reflecting hepatic) glucose production (EGP) in healthy individuals.

Effect of Chronic Hyperglycemia on Glucose Metabolism in Subjects With Normal Glucose Tolerance.

Chronic hyperglycemia causes insulin resistance, but the inheritability of glucotoxicity and the underlying mechanisms are unclear. We examined the effect of 3 days of hyperglycemia on glucose disposal, enzyme activities, insulin signaling, and protein -GlcNAcylation in skeletal muscle of individuals without (FH) or with (FH) family history of type 2 diabetes. Twenty-five subjects with normal glucose tolerance received a [3-H]glucose euglycemic insulin clamp, indirect calorimetry, and vastus-lateralis biopsies before and after 3 days of saline ( = 5) or glucose ( = 10 FH and 10 FH) infusion to raise plasma glucose by ∼45 mg/dL.

Pioglitazone Improves Left Ventricular Diastolic Function in Subjects With Diabetes.

Objective: To examine the effect of pioglitazone on myocardial insulin sensitivity and left ventricular (LV) function in patients with type 2 diabetes (T2D).

Research Design And Methods: Twelve subjects with T2D and 12 with normal glucose tolerance received a euglycemic insulin clamp. Myocardial glucose uptake (MGU) and myocardial perfusion were measured with [F]fluoro-2-deoxy-d-glucose and [O]HO positron emission tomography before and after 24 weeks of pioglitazone treatment.

Dapagliflozin Enhances Fat Oxidation and Ketone Production in Patients With Type 2 Diabetes.

Objective: Insulin resistance is associated with mitochondrial dysfunction and decreased ATP synthesis. Treatment of individuals with type 2 diabetes mellitus (T2DM) with sodium-glucose transporter 2 inhibitors (SGLT2i) improves insulin sensitivity. However, recent reports have demonstrated development of ketoacidosis in subjects with T2DM treated with SGLT2i.

Effect of Dapagliflozin With and Without Acipimox on Insulin Sensitivity and Insulin Secretion in T2DM Males.

Aim: To investigate the effect of lowering the plasma glucose and free fatty acid (FFA) concentrations with dapagliflozin and acipimox, respectively, on insulin sensitivity and insulin secretion in T2DM individuals.

Methods: Fourteen male T2DM patients received an oral glucose tolerance test and euglycemic hyperinsulinemic clamp at baseline and were treated for 3 weeks with dapagliflozin (10 mg per day). During week 3, acipimox (250 mg four times per day) treatment was added to dapagliflozin.

Dapagliflozin lowers plasma glucose concentration and improves β-cell function.

Background: β-Cell dysfunction is a core defect in T2DM, and chronic, sustained hyperglycemia has been implicated in progressive β-cell failure, ie, glucotoxicity. The aim of the present study was to examine the effect of lowering the plasma glucose concentration with dapagliflozin, a glucosuric agent, on β-cell function in T2DM individuals.

Research Design And Methods: Twenty-four subjects with T2DM received dapagliflozin (n = 16) or placebo (n = 8) for 2 weeks, and a 75-g oral glucose tolerance test (OGTT) and insulin clamp were performed before and after treatment.

Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production.

Chronic hyperglycemia impairs insulin action, resulting in glucotoxicity, which can be ameliorated in animal models by inducing glucosuria with renal glucose transport inhibitors. Here, we examined whether reduction of plasma glucose with a sodium-glucose cotransporter 2 (SGLT2) inhibitor could improve insulin-mediated tissue glucose disposal in patients with type 2 diabetes. Eighteen diabetic men were randomized to receive either dapagliflozin (n = 12) or placebo (n = 6) for 2 weeks.

Chronic reduction of plasma free fatty acid improves mitochondrial function and whole-body insulin sensitivity in obese and type 2 diabetic individuals.

Insulin resistance and dysregulation of free fatty acid (FFA) metabolism are core defects in type 2 diabetic (T2DM) and obese normal glucose tolerant (NGT) individuals. Impaired muscle mitochondrial function (reduced ATP synthesis) also has been described in insulin-resistant T2DM and obese subjects. We examined whether reduction in plasma FFA concentration with acipimox improved ATP synthesis rate and altered reactive oxygen species (ROS) production.