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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.

POLYCYSTIC OVARY SYNDROME (PCOS) is a common hormonal disorder, affecting 5–10% of women of reproductive age (1). Characterized by ovarian androgen overproduction and anovulation (2, 3), PCOS is also associated with an increased risk of impaired glucose tolerance and an accelerated rate of conversion to type 2 diabetes mellitus (4, 5). Insulin resistance plays a central role in the pathogenesis of PCOS (6, 7) and administration of troglitazone, an insulin-sensitizing thiazolidinedione, improves not only insulin sensitivity, but also insulin secretion, ovarian androgen biosynthesis, and ovulatory function in those with the disorder (8, 9). These effects are mediated at least in part by the PPAR (10).

Genetic studies of the PPAR gene (PPARG) have identified a number of polymorphisms, including one generating an amino acid polymorphism, Pro¹²Ala. It has recently been shown that the Ala allele is associated with a lower body mass index (BMI), improved insulin sensitivity (11, 12), and a decreased risk of type 2 diabetes (13, 14). However, other studies suggest that the Ala allele is associated with a higher BMI (15, 16, 17, 18) and has no impact on diabetes risk (19).

The present study was undertaken to examine the relationship between the Pro¹²Ala polymorphism and clinical and hormonal characteristics in women with PCOS.

Subjects and Methods

Subjects

Subjects were recruited from the endocrinology clinics of the University of Chicago. All were at least 2 yr postmenarche and less than 40 yr of age. A diagnosis of PCOS required 1) the presence of oligo/amenorrhea; 2) hyperandrogenemia, defined by a supranormal plasma free T level (34.7 pmol/liter); 3) hyperandrogenism, as evidenced by infertility, hirsutism, acne, or androgenetic alopecia; and 4) exclusion of nonclassic 21-hydroxylase deficiency congenital adrenal hyperplasia, Cushing’s syndrome, hypothyroidism, or significant elevations in serum PRL (2). In addition to meeting these diagnostic criteria for PCOS, often referred to as the NIH consensus criteria (20), each subject had hormonal evidence of ovarian androgen overproduction documented by an abnormal 17-hydroxyprogesterone response to GnRH agonist administration or a supranormal plasma free T level after administration of dexamethasone (2). For at least 2 months before the study, subjects had not taken steroid preparations (including oral contraceptives) or medications known to alter insulin secretion and/or action. These studies were approved by the institutional review board of the University of Chicago, and written informed consent was obtained from each participant.

Oral glucose tolerance testing

All individuals, with the exception of those known to be diabetic, had an oral glucose tolerance test (OGTT). After an overnight 12-h fast, blood samples were obtained at -15 and 0 min. A glycohemoglobin level was also obtained at 0 min. Dextrose (75 g) was then administered orally, and blood samples were obtained at 30, 60, 90, and 120 min for measurement of glucose and insulin concentrations. Glucose tolerance status was based upon the plasma glucose concentration at 2 h using the criteria of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus of the American Diabetes Association (21). Specifically, a diagnosis of normal glucose tolerance, impaired glucose tolerance, or diabetes was assigned if the glucose level at 2 h was less than 7.8 mmol/liter, between 7.8–11.1 mmol/liter, or 11.1 mmol/liter or more, respectively.

Hormonal measures

Serum was obtained from each subject for measurement of total T, free T, SHBG, and dehydroepiandrosterone sulfate (DHAS).

Molecular genetic studies

Exon 2 of PPAR2 was amplified using PCR and the primers G2F (5'-CTGATGTCTTGACTCATGGG-3') and G2R (5' GGAAGACAAACTACAAGAGC-3'). The 295-bp PCR product was digested overnight with HgaI, which cleaves the Ala allele to generate DNA fragments 178 and 117 bp in size. The DNA fragments were separated on 3% agarose gel.

Assay methods

Plasma glucose was measured immediately using a glucose analyzer (model 2300 STAT, YSI, Inc., Yellow Springs, OH). The coefficient of variation of this method is less than 2%. Glycosylated hemoglobin was measured by boronate affinity chromatography with an intraassay coefficient of variation of 4% (Bio-Rad Laboratories, Inc., Hercules, CA). Serum insulin was assayed by a double antibody technique (22) with a lower limit of sensitivity of 20 pmol/liter and an average intraassay coefficient of variation of 6%. The cross-reactivity of proinsulin in the RIA for insulin is approximately 40%. Plasma C peptide was measured as previously described (22). The lower limit of sensitivity of the assay is 0.02 pmol/ml, and the intraassay coefficient of variation averaged 6%.

Plasma T was measured using a kit from Diagnostic Products (Los Angeles, CA). The free fraction of plasma T and the concentration of SHBG were measured by a competitive protein binding assay as previously described (23). The intra- and interassay coefficients of variation were 3.8% and 8.7%, respectively. DHAS was measured by RIA using a commercial kit (Diagnostics Systems Laboratories, Inc., Webster, TX).

Statistical analysis

All statistical analyses were performed using StatView software (SAS Institute, Inc., Cary, NC). Between-group comparisons were made using ANOVA or analysis of covariance with logarithmic transformation of data not normally distributed and post-hoc correction for multiple comparisons. P < 0.05 was considered significant. All data are presented as the mean ± SE.

Results

Clinical characteristics of the study population (Table 1)

Two hundred and eighteen PCOS subjects were examined: 130 (60%) Caucasian of European ancestry, 57 (26%) African-Americans, 13 (6%) Hispanics, 13 (6%) South Indians, and 5 (2%) of Middle Eastern ancestry. Twenty-two (10%) of the subjects were diabetic, consistent with the increased prevalence of diabetes in PCOS (4, 5). African-Americans accounted for 11 (50%) of the diabetes cases; the remaining half was comprised of 6 (27%) Caucasians, 3 (14%) Hispanics, 1 (5%) South Indian, and 1 (5%) Middle Eastern.

PPARG and PCOS

The Pro¹²Ala polymorphism was typed in all 218 PCOS subjects (Table 1). Twenty-eight had the Ala allele, all in the heterozygous state. The frequency of the Ala allele varied among the groups and ranged from 0.01 in African-Americans to 0.15 in Hispanics (Table 1). These values are similar to those determined in previous studies (13).

The effect of the Ala allele on clinical and hormonal measures was next analyzed in the nondiabetic Caucasian group (Table 2). There were too few subjects with the Ala allele to allow similar comparisons in the other groups. Diabetic subjects were excluded to eliminate the confounding effect of the diabetic state on the measures analyzed. There was no apparent effect of the Pro¹²Ala genotype on BMI. However, subjects with the Ala allele were more insulin sensitive, as evidenced by a significantly lower HOMA index (5.18 ± 1.33 vs. 6.54 ± 0.54; P < 0.05) as well as significantly 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) points during the OGTT (Table 2). This difference remained significant after adjusting for the effect of BMI.

Discussion

The etiology of PCOS is complex and incompletely understood (3, 7). However, it is generally recognized that insulin resistance is a key component in the pathogenesis of the disorder (7), and several reports have documented the association of PCOS with genes influencing insulin action (24, 25). The Pro¹²Ala polymorphism in PPARG has been implicated in the pathogenesis of other insulin-resistant conditions, including type 2 diabetes and obesity (13).

We found that Caucasian women with PCOS who had the Ala allele at Pro¹²Ala, although still substantially insulin resistant, were less insulin resistant than those with two Pro alleles. This difference could not be accounted for by a difference between groups in BMI, as both Pro/Ala and Pro/Pro subjects were similar in their degree of obesity (BMI, 33.9 ± 1.9 vs. 36.1 ± 0.8 kg/m²; P = 0.31). Further, when measures of insulin resistance were compared by analysis of covariance with BMI as a covariate, the results were similar.

These results are consistent with other studies in non-PCOS subjects, indicating that the presence of an Ala allele is associated with increased insulin sensitivity (11, 12). Our results suggest that the Pro¹²Ala polymorphism in PPARG is among the factors affecting insulin resistance in Caucasian women with PCOS. This polymorphism does not appear to contribute to the variation in insulin resistance among African-American women with PCOS because the frequency of the Pro allele approaches 1.0 in this population. Further studies are needed to define its role in other groups.

The Pro allele at Pro¹²Ala has been associated with a modest 1.25-fold increased risk of diabetes, but because the risk allele occurs with such high frequency, its modest effect translates into a large population-attributable risk, estimated to influence as much as 25% of type 2 diabetes in the general population (13). Studies of a larger group of PCOS women will be necessary to assess the effects of the Pro¹²Ala polymorphism on the risk of type 2 diabetes in this extremely insulin-resistant group of subjects.

Acknowledgments

We thank the patients for kindly agreeing to participate in these studies. In addition, the expert nursing care provided at University of Chicago Clinical Research Center is acknowledged.

Footnotes

This work was supported by USPHS grants (DK-20595, DK-44840, MH/DK-59522, DK-02315, and RR-00055), a Clinical Research Award (to D.A.E.) from the American Diabetes Association, and a gift from the Blum-Kovler Foundation.

Abbreviations: BMI, Body mass index; DHAS, dehydroepiandrosterone sulfate; HOMA, homeostasis model analysis; OGTT, oral glucose tolerance test; PCOS, polycystic ovary syndrome; PPARG, PPAR gene.

Received June 20, 2001.

Accepted November 5, 2001.

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