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 a nd lipid metabolism in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS - A total of 23 diabetic patients (age 30-70 ye ars. BMI < 36 kg/m(2)) who were being treated with a stable dose of sulfony lurea were randomly assigned to receive either placebo (n = 11) or pioglita zone (45 mg/day) (n = 12) for 16 weeks. Before and after 16 weeks of treatm ent, all subjects received a 75-g oral glucose tolerance test (OGTT); and h epatic and peripheral insulin sensitivity was measured with a two-step eugl ycemic insulin (40 and 169 mU . min(-1) . m(-2)) clamp performed with 3-[H- 3]glucose and indirect calorimetry. HBA(1c) was measured monthly throughout the study period. RESULTS - After 16 weeks of pioglitazone treatment, the fasting plasma gluc ose (FPG; 184 <plus/minus> 15 to 135 +/- 11 mg/dl. P<0.01), mean plasma glu cose during OGTT (293 <plus/minus> 12 to 225 +/- 14 mg/dl. P < 0.01), and H BA(1c) (8.9 <plus/minus> 0.3 to 7.2 +/- 0.5%, P < 0.01) decreased significa ntly without change in fasting or glucose-stimulated insulin/C-peptide conc entrations. Fasting plasma free fatty acid (FFA; 647 <plus/minus> 39 to 478 +/- 49 mu Eq/1, P < 0.01) and mean plasma FFA during OGTT (485 <plus/minus > 30 to 347 +/- 33 mu Eq/1, P < 0.01) decreasd significantly after pioglita zone treatment. Before and after pioglitazone treatment, basal endogenous g lucose production (EGP) and FPG were strongly correlated (r = 0.67, P < 0.0 1). EGP during the first insulin clamp step was significantly decreased aft er 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 plasma glucose concentration during the OGTT was strongly related to the change in total body glucose di sposal during the second insulin clamp step. CONCLUSIONS - These results suggest that pioglitazone therapy in type 2 dia betic patients decreases fasting and postprandial plasma glucose levels by improving hepatic and peripheral (muscle) tissue sensitivity to insulin.