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

Abstract

OBJECTIVE -We have tested whether the Pro12Ala variant of the peroxisome proliferatoractivated receptor (PPAR)-␥ 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-␥ 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 Ϫ0.21 Ϯ 0.57, 0.91 Ϯ 0.26, and 2.58 Ϯ 1.32 min Ϫ1 per U/ml ⅐ 10 Ϫ4 , respectively. Frequencies of the Ala/Ϫ genotype were 30, 22, and 26% in the same three tertiles (P ϭ 0.77). Analysis of phenotypes by genotype revealed only small differences between the Pro/Pro and Ala/Ϫ groups, respectively, in baseline S i (2.76 Ϯ 0.19 vs. 2.33 Ϯ 0.33 ϫ 10 Ϫ4 min Ϫ1 per U/ml; P ϭ 0.27), the change in S i after 3 months of troglitazone treatment (1.19 Ϯ 0.17 vs. 0.93 Ϯ 0.30; P ϭ 0.46), and the cumulative incidence of diabetes during a median follow-up of 30 months (13 vs. 17%; P ϭ 0.66).CONCLUSIONS -Among young Hispanic women at high risk for type 2 diabetes, the Pro12Ala variant of the PPAR-␥ receptor gene did not explain the failure of ϳ1/3 of subjects to increase their insulin sensitivity when placed on troglitazone at a dose of 400 mg/day.

Retinoid X Receptor Heterodimer Variants and Cardiovascular Risk Factors

“…With regard to the response to TZD treatment, subjects with the Ala12 allele showed a better response to therapy than those with Pro12 homozygotes in one study 89) , and no difference was observed between the two genotypes in another 90) ; however, the Ala12 allele was the most important risk factor for TZD-induced edema 91) . As PPAR plays an important role in osteocyte differentiation 66,67) , it is possible to speculate on its association with bone metabolism.…”

Peroxisome proliferator-activated receptors: Targets for the treatment of metabolic illnesses (Review)

“…Later, studies on pioglitazone and rosiglitazone found no hepatotoxicity, confirming that this was not a class effect (57)(58)(59); however, similar metabolic effects were found. In a study using pioglitazone and a placebo control, HbA IC , fasting glycemia, fasting insulin, C peptide and triglycerides were reduced while HDL cholesterol was increased.…”

Genetic variants affecting incretin sensitivity and incretin secretion

“…Response to thiazolidinedione therapy has been associated with PPARG (peroxisome proliferator-activated receptor-gamma) variation [90,91], though not by all studies [92][93][94]. Literature on the impact of the KCNJ11 risk variant E23K on treatment response to sulfonylureas is similarly controversial.…”