Pre-Prediabetes: Insulin Resistance is Associated with Cardiometabolic Risk in Non-obese Patients (STOP DIABETES).

Background/aim: To examine if insulin resistance is associated with markers of glycemic, cardiometabolic and atherosclerotic risk in non-obese, non-prediabetic individuals compared to insulin sensitive subjects matched for BMI, gender, and age.

Methods: Of 1860 patients from STOP DIABETES study, 624 had normal fasting plasma glucose, body mass index < 30, and HbA1c < 5.7%.

Emergence of a New Glucoregulatory Mechanism for Glycemic Control With Dapagliflozin/Exenatide Therapy in Type 2 Diabetes.

Context: This study addresses the development of a new glucoregulatory mechanism in type 2 diabetes (T2D) patients treated with SGLT-2 inhibitors, which is independent of glucose, insulin and glucagon. The data suggest the presence of a potential trigger factor (s) arising in the kidney that stimulates endogenous glucose production (EGP) during sustained glycosuria.

Objective: To investigate effects of SGLT-2 inhibitor therapy together with GLP-1 receptor agonist on EGP and glucose kinetics in patients with T2D.

Type 2 diabetes subgroups and response to glucose-lowering therapy: Results from the EDICT and Qatar studies.

Aim: To examine the efficacy of glucose-lowering medications in subgroups of patients with type 2 diabetes mellitus (T2DM).

Research Design And Methods: Cluster analysis was performed in participants in the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT) study and the Qatar study using age, body mass index (BMI), glycated haemoglobin (HbA1c), and homeostatic model assessment of insulin resistance (HOMA-IR) and beta-cell function (HOMA-β). Participants also underwent an oral glucose tolerance test with measurement of plasma glucose, insulin and C-peptide concentrations to derive independent measures of insulin secretion and insulin sensitivity.

Combination therapy with pioglitazone/exenatide/metformin reduces the prevalence of hepatic fibrosis and steatosis: The efficacy and durability of initial combination therapy for type 2 diabetes (EDICT).

Aim: To compare the efficacy of triple therapy (metformin/exenatide/pioglitazone) versus stepwise conventional therapy (metformin → glipizide → glargine insulin) on liver fat content and hepatic fibrosis in newly diagnosed, drug-naïve patients with type 2 diabetes.

Methods: Sixty-eight patients completed the 6-year follow-up and had an end-of-study (EOS) FibroScan to provide measures of steatosis (controlled attenuation parameter [CAP] in dB/m) and fibrosis (liver stiffness measurement [LSM] in kPa); 59 had magnetic resonance imaging-proton density fat fraction (MRI-PDFF) to measure liver fat.

Results: At EOS, HbA1c was 6.

Insulin Secretion Predicts the Response to Antidiabetic Therapy in Patients With New-onset Diabetes.

Context: The results of the present study demonstrate that beta cell function in newly diagnosed T2DM patients is the key predictor of response to glucose lowering medications and provides a practical tool (C-Pep120 /C-Pep0) to guide the choice of glucose lowering agent.

Objective: This work aims to identify predictors for individualization of antidiabetic therapy in patients with new-onset type 2 diabetes mellitus (T2DM).

Methods: A total of 261 drug-naive participants in the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT) study, with new-onset diabetes, were randomly assigned in a single-center study to receive 1) metformin followed by glipizide and then insulin glargine on failure to achieve glycated hemoglobin A1c (HbA1c) less than 6.

Ultrasound-Targeted Microbubble Destruction Mediates Gene Transfection for Beta-Cell Regeneration and Glucose Regulation.

Ultrasound-targeted microbubble destruction (UTMD) mediates gene transfection with high biosafety and thus has been promising toward treatment of type 1 diabetes. However, the potential application of UTMD in type 2 diabetes (T2D) is still limited, due to the lack of systematic design and dynamic monitoring. Herein, an efficient gene delivery system is constructed by plasmid deoxyribonucleic acid (DNA) encoding glucagon-like peptide 1 (GLP-1) in ultrasound-induced microbubbles, toward treatment of T2D in macaque.

Insulin secretion is a strong predictor for need of insulin therapy in patients with new-onset diabetes and HbA1c of more than 10%: A post hoc analysis of the EDICT study.

Aim: To identify predictors of response to glucose-lowering therapy in patients with new-onset diabetes and very high HbA1c (>10%).

Methods: The study included EDICT participants with an initial HbA1c of more than 10% (N = 104). All subjects received a 75-g oral glucose tolerance test (OGTT) before initiation of therapy, and then were randomized to receive: (a) initial triple therapy with metformin, pioglitazone and exenatide versus (b) stepwise conventional therapy with metformin followed by glipizide and then glargine insulin to reduce HbA1c to less than 6.

Insulin resistance is mechanistically linked to hepatic mitochondrial remodeling in non-alcoholic fatty liver disease.

Objective: Insulin resistance and altered hepatic mitochondrial function are central features of type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD), but the etiological role of these processes in disease progression remains unclear. Here we investigated the molecular links between insulin resistance, mitochondrial remodeling, and hepatic lipid accumulation.

Methods: Hepatic insulin sensitivity, endogenous glucose production, and mitochondrial metabolic fluxes were determined in wild-type, obese (ob/ob) and pioglitazone-treatment obese mice using a combination of radiolabeled tracer and stable isotope NMR approaches.

Durability of Triple Combination Therapy Versus Stepwise Addition Therapy in Patients With New-Onset T2DM: 3-Year Follow-up of EDICT.

Objective: To compare the long-term efficacy of initiating therapy with metformin/pioglitazone/exenatide in patients with new-onset type 2 diabetes mellitus (T2DM) versus sequential addition of metformin followed by glipizide and insulin.

Research Design And Methods: Drug-naive patients ( = 318) with new-onset T2DM were randomly assigned to receive for 3 years either ) combination therapy with metformin, pioglitazone, and exenatide (triple therapy) or ) sequential addition of metformin followed by glipizide and insulin (conventional therapy) to maintain HbA at <6.5% (48 mmol/mol).

Insulin Resistance and Atherosclerosis: Implications for Insulin-Sensitizing Agents.

Patients with type 2 diabetes mellitus (T2DM) are at high risk for macrovascular complications, which represent the major cause of mortality. Despite effective treatment of established cardiovascular (CV) risk factors (dyslipidemia, hypertension, procoagulant state), there remains a significant amount of unexplained CV risk. Insulin resistance is associated with a cluster of cardiometabolic risk factors known collectively as the insulin resistance (metabolic) syndrome (IRS).

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.

Ectopic BAT mUCP-1 overexpression in SKM by delivering a BMP7/PRDM16/PGC-1a gene cocktail or single PRMD16 using non-viral UTMD gene therapy.

Here we present our progress in inducing an ectopic brown adipose tissue (BAT) phenotype in skeletal muscle (SKM) as a potential gene therapy for obesity and its comorbidities. We used ultrasound-targeted microbubble destruction (UTMD), a novel targeted, non-viral approach to gene therapy, to deliver genes in the BAT differentiation pathway into rodent SKM to engineer a thermogenic BAT phenotype with ectopic mUCP-1 overexpression. In parallel, we performed a second protocol using wild-type Ucp-1-null knockout mice to test whether the effects of the gene therapy are UCP-1 dependent.

Endogenous Glucose Production and Hormonal Changes in Response to Canagliflozin and Liraglutide Combination Therapy.

The decrement in plasma glucose concentration with SGLT2 inhibitors (SGLT2i) is blunted by a rise in endogenous glucose production (EGP). We investigated the ability of incretin treatment to offset the EGP increase. Subjects with type 2 diabetes ( = 36) were randomized to ) canagliflozin (CANA), ) liraglutide (LIRA), or ) CANA plus LIRA (CANA/LIRA).

Revitalization of pioglitazone: the optimum agent to be combined with a sodium-glucose co-transporter-2 inhibitor.

The recently completed EMPA-REG study showed that empagliflozin significantly decreased the major adverse cardiac events (MACE) endpoint, which comprised cardiovascular death, non-fatal myocardial infarction (MI) and stroke, in patients with high-risk type 2 diabetes (T2DM), primarily through a reduction in cardiovascular death, without a significant decrease in either MI or stroke. In the PROactive study, pioglitazone decreased the MACE endpoint by a similar degree to that observed in the EMPA-REG study, through a marked reduction in both recurrent MI and stroke and a modest reduction in cardiovascular death. These observations suggest that pioglitazone might be an ideal agent to combine with empagliflozin to further reduce cardiovascular events in patients with high-risk diabetes as empagliflozin also promotes salt/water loss and would be expected to offset any fluid retention associated with pioglitazone therapy.

Empagliflozin and linagliptin combination therapy for treatment of patients with type 2 diabetes mellitus.

Introduction: Many patients with type 2 diabetes mellitus (T2DM) fail to achieve the desired A1c goal because the antidiabetic medications used do not correct the underlying pathophysiologic abnormalities and monotherapy is not sufficiently potent to reduce the A1c to the 6.5 - 7.0% range.

Metabolic effects of muraglitazar in type 2 diabetic subjects.

Aim: To assess the effect of muraglitazar, a dual peroxisome proliferator-activated receptor (PPAR)γ-α agonist, versus placebo on metabolic parameters and body composition in subjects with type 2 diabetes mellitus (T2DM).

Methods: Twenty-seven T2DM subjects received oral glucose tolerance test (OGTT), euglycaemic insulin clamp with deuterated glucose, measurement of total body fat (DEXA), quantitation of muscle/liver (MRS) and abdominal subcutaneous and visceral (MRI) fat, and then were randomized to receive, in addition to diet, muraglitazar (MURA), 5 mg/day, or placebo (PLAC) for 4 months.

Results: HbA1c(c) decreased similarly (2.

Comprehensive assessment of postischemic vascular reactivity in Hispanic children and adults with and without diabetes mellitus.

Background: To examine the whole postischemic hyperemic response period in Hispanic children and adults with and without type 2 diabetes mellitus (T2DM) and offer insight into the potential adaptive mechanisms involved in the arterial response to disturbances in vascular homeostasis.

Methods: Ninety-eight adults and 124 children of Hispanics participated in the study. Endothelial function was assessed in the brachial artery using high-resolution ultrasonography (HRU).

Tumor necrosis factor alpha and insulin resistance in obese type 2 diabetic patients.

The relationship between basal serum tumor necrosis factor alpha (TNFalpha) levels and peripheral tissue (muscle) sensitivity to insulin was examined in 63 subjects with normal glucose tolerance (NGT), 18 subjects with impaired glucose tolerance (IGT), and 123 patients with type 2 diabetes mellitus (T2DM). The BMI was similar in NGT (28.8+/-0.

Abdominal fat distribution and peripheral and hepatic insulin resistance in type 2 diabetes mellitus.

We examined the relationship between peripheral/hepatic insulin sensitivity and abdominal superficial/deep subcutaneous fat (SSF/DSF) and intra-abdominal visceral fat (VF) in patients with type 2 diabetes mellitus (T2DM). Sixty-two T2DM patients (36 males and 26 females, age = 55 +/- 3 yr, body mass index = 30 +/- 1 kg/m2) underwent a two-step euglycemic insulin clamp (40 and 160 mU. m(-2).

Dose-response effect of pioglitazone on insulin sensitivity and insulin secretion in type 2 diabetes.

Objective: To investigate the dose-response effects of pioglitazone on glycemic control, insulin sensitivity, and insulin secretion in patients with type 2 diabetes.

Research Design And Methods: A total of 58 diet-treated patients with type 2 diabetes (aged 54 +/- 1 years; 34 men and 24 women; BMI 31.5 +/- 0.

Improved glycemic control and enhanced insulin sensitivity in type 2 diabetic subjects treated with pioglitazone.

Objective: To elucidate the effects of pioglitazone treatment on glucose and lipid metabolism in patients with type 2 diabetes.

Research Design And Methods: A total of 23 diabetic patients (age 30-70 years BMI < 36 kg/m2) who being treated with a stable dose of sulfonylurea were randomly assigned to receive either placebo (n = 11) or pioglitazone (45 mg/day) (n = 12) for 16 weeks. Before and after 16 weeks of treatment, all subjects received a 75-g oral glucose tolerance test (OGTT) and hepatic peripheral insulin sensitivity was measured with a two-step euglycemic insulin (40 and 160 mU x min(-1) x m(-2) clamp performed with 3-[3H]glucose and indirect calorimetry HbA1c measured monthly throughout the study period.

Bromocriptine: a novel approach to the treatment of type 2 diabetes.

Objective: In vertebrates, body fat stores and insulin action are controlled by the temporal interaction of circadian neuroendocrine oscillations. Bromocriptine modulates neurotransmitter action in the brain and has been shown to improve glucose tolerance and insulin resistance in animal models of obesity and diabetes. We studied the effect of a quick-release bromocriptine formulation on glucose homeostasis and insulin sensitivity in obese type 2 diabetic subjects.