Changes in Insulin Sensitivity in Response to Troglitazone Do Not Differ Between Subjects With and Without the Common, Functional Pro12Ala Peroxisome Proliferator–Activated Receptor-γ2 Gene Variant: Results from the Troglitazone in Prevention of Diabetes (TRIPOD) study

OBJECTIVE —We have tested whether the Pro12Ala variant of the peroxisome proliferator–activated receptor (PPAR)-γ nuclear receptor involved in thiazolidinedione (TZD) action accounted for the failure of troglitazone to increase insulin sensitivity in nondiabetic Hispanic women with previous gestational diabetes treated in the Troglitazone in Prevention of Diabetes (TRIPOD) study. RESEARCH DESIGN AND METHODS —Ninety-three women assigned to troglitazone had intravenous glucose tolerance tests at randomization and after 3 months of treatment with troglitazone, 400 mg/day, and were genotyped for the Pro12Ala variant of the PPAR-γ gene. Subjects were divided into tertiles based on their change in minimal model insulin sensitivity ( S i ) during the first 3 months of troglitazone treatment. RESULTS —The mean changes in S i in the bottom, middle, and top tertiles of S i response were −0.21 ± 0.57, 0.91 ± 0.26, and 2.58 ± 1.32 min −1 per μU/ml · 10 −4 , respectively. Frequencies of the Ala/− genotype were 30, 22, and 26% in the same three tertiles ( P = 0.77). Analysis of phenotypes by genotype revealed only small differences between the Pro/Pro and Ala/− groups, respectively, in baseline S i (2.76 ± 0.19 vs. 2.33 ± 0.33 × 10 −4 min −1 per μU/ml; P = 0.27), the change in S i after 3 months of troglitazone treatment (1.19 ± 0.17 vs. 0.93 ± 0.30; P = 0.46), and the cumulative incidence of diabetes during a median follow-up of 30 months (13 vs. 17%; P = 0.66). CONCLUSIONS —Among young Hispanic women at high risk for type 2 diabetes, the Pro12Ala variant of the PPAR-γ receptor gene did not explain the failure of ∼1/3 of subjects to increase their insulin sensitivity when placed on troglitazone at a dose of 400 mg/day.