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Diabetes Care 25:517-523, 2002
© 2002 by the American Diabetes Association, Inc.

Emerging Treatments and Technologies
Original Article

Dose-Response Effect of Pioglitazone on Insulin Sensitivity and Insulin Secretion in Type 2 Diabetes

Yoshinori Miyazaki, MD, PHD, Masafumi Matsuda, MD, PHD and Ralph A. DeFronzo, MD

University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas

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± 0.6 kg/m2) were randomly assigned to receive placebo (n=11) or 7.5 mg (n=13), 15 mg (n=12), 30 mg (n=11), or 45 mg (n=11) of pioglitazone per day for 26 weeks. Before and after 26 weeks, subjects underwent a 75-g oral glucose tolerance test (OGTT).

RESULTS—Patients treated with 7.5 or 15 mg/day of pioglitazone had no change in fasting plasma glucose (FPG) and fasting plasma insulin (FPI) concentrations or in plasma glucose (PG) and insulin concentrations during the OGTT. Patients treated with 30 and 45 mg/day of pioglitazone, respectively, had significant decreases from placebo in HbA1c ({Delta}=-2.0 and -2.9%), FPG ({Delta}=-66 and -97 mg/dl), and mean PG during OGTT ({Delta}=-84 and -107 mg/dl). Fasting plasma insulin decreased significantly in the 45-mg/day pioglitazone group, but the mean plasma insulin during the OGTT did not change. The insulinogenic index ({Delta} area under the curve [AUC] insulin/{Delta}AUC glucose) during the OGTT increased significantly in the 30- and 45-mg/day pioglitazone groups (0.13± 0.03 to 0.27± 0.05, P < 0.05). From the OGTT, we previously have derived a composite whole-body insulin sensitivity index (ISI) that correlates well with that measured directly with the insulin clamp technique. Whole-body ISI [ISI=10,000 , where and equal mean plasma glucose and insulin concentrations during OGTT] increased significantly in patients treated with 30 mg (1.8± 0.3 to 2.5± 0.3, P < 0.05) or 45 mg (1.6± 0.2 to 2.7± 0.6, P < 0.05) per day of pioglitazone. In the basal state, the hepatic ISI [k/(FPG x FPI)[k/(FPG x FPI)], which agrees closely with that measured directly with tritiated glucose, increased in patients treated with 30 mg (0.13± 0.02 to 0.21± 0.03, P < 0.05) and 45 mg (0.11± 0.02 to 0.24± 0.06, P < 0.05) per day of pioglitazone. Significant correlations between the dose of pioglitazone and the changes in HbA1c (r=-0.58), FPG (r=-0.47), mean PG during the OGTT (r=-0.46), insulinogenic index (r=0.34), hepatic ISI (r=0.44), and whole-body ISI (r=0.36) were observed.

CONCLUSIONS—Pioglitazone improves glycemic control through the dose-dependent enhancement of ß-cell function and improved whole-body and hepatic insulin sensitivity.

Abbreviations: AUC, area under the curve • FPG, fasting plasma glucose • FPI, fasting plasma insulin • ISI, insulin sensitivity index • OGTT, oral glucose tolerance test • PG, plasma glucose • PPAR{gamma}, peroxisome proliferator–activated receptor-{gamma}


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