Improved Glycemic Control and Enhanced Insulin Sensitivity in Type 2 Diabetic Subjects Treated With Pioglitazone

Abstract

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 Ͻ 36 kg/m2 ) who were being treated with a stable dose of sulfonylurea were randomly assigned to receive either placebo (n ϭ 11) or pioglitazone (45 mg/day) (n ϭ 12) for 16 weeks. Before and after 16 weeks of treatment, all subjects received a 75-g oral glucose tolerance test (OGTT); and hepatic and peripheral insulin sensitivity was measured with a two-step euglycemic insulin (40 and 160 mU ⅐ min Ϫ1 ⅐ m -2 ) clamp performed with 3-[ 3 H]glucose and indirect calorimetry. HbA 1c was measured monthly throughout the study period.RESULTS -After 16 weeks of pioglitazone treatment, the fasting plasma glucose (FPG; 184 Ϯ 15 to 135 Ϯ 11 mg/dl, P Ͻ 0.01), mean plasma glucose during OGTT (293 Ϯ 12 to 225 Ϯ 14 mg/dl, P Ͻ 0.01), and HbA 1c (8.9 Ϯ 0.3 to 7.2 Ϯ 0.5%, P Ͻ 0.01) decreased significantly without change in fasting or glucose-stimulated insulin/C-peptide concentrations. Fasting plasma free fatty acid (FFA; 647 Ϯ 39 to 478 Ϯ 49 Eq/l, P Ͻ 0.01) and mean plasma FFA during OGTT (485 Ϯ 30 to 347 Ϯ 33 Eq/l, P Ͻ 0.01) decreased significantly after pioglitazone treatment. Before and after pioglitazone treatment, basal endogenous glucose production (EGP) and FPG were strongly correlated (r ϭ 0.67, P Ͻ 0.01). EGP during the first insulin clamp step was significantly decreased after pioglitazone treatment (P Ͻ 0.05), whereas insulin-stimulated total and nonoxidative glucose disposal during the second insulin clamp was increased (P Ͻ 0.01). The change in FPG was related to the change in basal EGP, EGP during the first insulin clamp step, and total glucose disposal during the second insulin clamp step. The change in mean plasma glucose concentration during the OGTT was strongly related to the change in total body glucose disposal during the second insulin clamp step.CONCLUSIONS -These results suggest that pioglitazone therapy in type 2 diabetic patients decreases fasting and postprandial plasma glucose levels by improving hepatic and peripheral (muscle) tissue sensitivity to insulin. Diabetes Care 24:710 -719, 2001T ype 2 diabetes is characterized by defects in both insulin secretion and insulin sensitivity (1,2). The insulin resistance is established early in the natural history of type 2 diabetes (1-3), but with time there is a progressive failure of ␤-cell function (1,4,5). Based on the pathophysiology of type 2 diabetes, combination therapy with an insulin secretagogue and an insulin sensitizer provides a rational therapeutic approach to reduce blood glucose levels in poorly controlled type 2 diabetic patients (6). Such an approach has been used successfully with sulfonylureas and metformin (7).Recently, a new class of insulinsensitizing agents, the thiazolidinediones, was introduced for the treatment of type 2 diabetic patients (8). Troglitazone, the first thiazolidinedione introduced into the U.S. market, has been...

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Fat redistribution preferentially reflects the anti-inflammatory benefits of pioglitazone treatment

“…Although PPARγ agonists reduce both fasting and postprandial glucose [38,39], these agents may be less effective in postprandial glucose reduction compared with other hypoglycemic agents [40]. In our data, whereas fasting glucose level decreased, postprandial glucose level did not decline significantly.…”

Elevated Plasma Levels of the Atherogenic Mediator Soluble CD40 Ligand in Diabetic Patients

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