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 were 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 and peripheral insulin sensitivity was measured with a two-step euglycemic insulin (40 and 160 mU · min^-1 · m^-2) clamp performed with 3-[³H]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 ± 15 to 135 ± 11 mg/dl, P < 0.01), mean plasma glucose during OGTT (293 ± 12 to 225 ± 14 mg/dl, P < 0.01), and HbA_1c (8.9 ± 0.3 to 7.2 ± 0.5%, P < 0.01) decreased significantly without change in fasting or glucose-stimulated insulin/C-peptide concentrations. Fasting plasma free fatty acid (FFA; 647 ± 39 to 478 ± 49 μEq/l, P < 0.01) and mean plasma FFA during OGTT (485 ± 30 to 347 ± 33 μEq/l, P < 0.01) decreased significantly after pioglitazone treatment. Before and after pioglitazone treatment, basal endogenous glucose production (EGP) and FPG were strongly correlated (r = 0.67, P < 0.01). EGP during the first insulin clamp step was significantly decreased after pioglitazone treatment (P < 0.05), whereas insulin-stimulated total and nonoxidative glucose disposal during the second insulin clamp was increased (P < 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 plasrna 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.