EFFECT OF TROGLITAZONE ON INSULIN SENSITIVITY AND PANCREATIC BETA-CELL FUNCTION IN WOMEN AT HIGH-RISK FOR NIDDM

We conducted a randomized placebo-controlled study to determine the ef fects of the thiazolidinedione compound troglitazone on whole-body ins ulin sensitivity (S-I), pancreatic beta-cell function, and glucose tol erance in 42 Latino women with impaired glucose tolerance (IGT) and a history of gestational diabetes mellitus (GDM), characteristics that c arry an 80% risk of developing NIDDM within 5 years. After baseline or al (OGTT) and intravenous (IVGTT) glucose tolerance testing, subjects were assigned to take placebo or 200 or 400 mg troglitazone daily for 12 weeks (14 subjects per treatment; group). An OGTT and IVGTT were re peated during the 12th week of treatment. Five subjects failed to comp lete the trial for personal reasons, and medication compliance average d 90% in the remaining subjects, none of whom experienced a serious ad verse event. S-I, calculated by minimal model analysis of IVGTT result s, changed by only 4 +/- 14% during 12 weeks of placebo administration , but increased 40 +/- 22 and 88 +/- 22% above basal during treatment with 200 and 400 mg troglitazone, respectively (P = 0.01 among groups) , troglitazone administration was also associated with a dose-dependen t reduction in the total insulin area during IVGTTs, which was highly significant: (P < 0.001), and with a reduction during OGTTs, which app roached statistical significance (P = 0.09). Glucose tolerance improve d slightly in all groups, but the magnitude of change did not differ s ignificantly among groups, whether it was assessed as the number of su bjects who continued to manifest IGT at 12 weeks (P = 0.64 among group s), the change in total glucose area during OGTTs (P = 0.58), or the c hange in fractional glucose disappearance rates during IVGTTs (P = 0.2 8). Among the women who received troglitazone, the greatest improvemen t in S, occurred in the women who had the highest diastolic blood pres sures and the best IVGTT insulin responses during baseline testing. Ou r findings indicate that troglitazone improved whole-body insulin sens itivity and lowered circulating insulin concentrations in women with p rior GDM who are at very high risk for NIDDM. The lack of improvement in glucose tolerance despite improved insulin sensitivity may be a man ifestation of the beta-cell defect that predisposes the women to NIDDM , The overall pattern of response to troglitazone in our high-risk pat ients indicates that the drug is an ideal agent with which to test whe ther the amelioration of insulin resistance can delay or prevent diabe tes in women with limited beta-cell reserve.