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Insulin Resistance Is Attenuated in Women with Polycystic Ovary Syndrome with the Pro¹²Ala Polymorphism in the PPAR Gene

Departments of Medicine (M.H., A.Q., K.K.B., N.J.C., D.A.E.), Biochemistry and Molecular Biology (S.Y.A.), and Human Genetics (N.J.C.), University of Chicago, Chicago, Illinois 60637

Address all correspondence and requests for reprints to: David A. Ehrmann, M.D., Department of Medicine, Section of Endocrinology, University of Chicago Pritzker School of Medicine, 5841 South Maryland Avenue, MC 1027, Chicago, Illinois 60637. E-mail: dehrmann{at}medicine.bsd.uchicago.edu

Abstract

Polycystic ovary syndrome (PCOS) is common in women of reproductive age and is associated with a high risk for development of type 2 diabetes. Insulin resistance, a key component in the pathogenesis of PCOS and glucose intolerance, is ameliorated by the thiazolidinediones, synthetic ligands for the PPAR. In the present study we have examined the relationship of the Pro¹²Ala polymorphism in the PPAR gene (PPARG) to clinical and hormonal features of PCOS.

Two hundred and eighteen women with PCOS had a 75-g oral glucose tolerance test, and blood was obtained for measurement of serum androgen levels. Sixty percent of the subjects were Caucasian, 26% were African-American, 6% were Hispanic, 6% were South Asian, and 2% were Middle-Eastern. Compared with Caucasians, the African-American group had a higher prevalence of diabetes (19% vs. 5%, respectively), were more obese (body mass index, 40.9 ± 1.8 vs. 36.3 ± 0.8 kg/m²; P < 0.05), and were more insulin resistant.

Twenty-eight of 218 subjects had the Ala allele, all in the heterozygous state. The frequency of the Ala allele varied among the groups: 0.01 in African-Americans, 0.08 in Caucasians, and 0.15 in Hispanics. Nondiabetic Caucasians with an Ala allele (Pro/Ala group) were more insulin sensitive than those in the Pro/Pro group, as evidenced by a lower homeostasis model assessment index (5.18 ± 1.33 vs. 6.54 ± 0.54; P < 0.05) and lower levels of insulin at both the fasting (132 ± 27 vs. 165 ± 12 pmol/liter; P = 0.03) and 2 h (688 ± 103 vs. 10190 ± 99 pmol/liter; P = 0.04) time points during the oral glucose tolerance test. We conclude that Pro¹²Ala in PPARG is a modifier of insulin resistance in Caucasian women with PCOS.

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