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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-0229
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 1 66-71
Copyright © 2005 by The Endocrine Society

Effects of Race and Family History of Type 2 Diabetes on Metabolic Status of Women with Polycystic Ovary Syndrome

David A. Ehrmann, Kristen Kasza, Ricardo Azziz, Richard S. Legro and Mahmoud N. Ghazzi for the PCOS/Troglitazone Study Group

Departments of Medicine (D.A.E.) and Health Studies (K.K.), University of Chicago Medical Center, Chicago, Illinois 60637; Department of Obstetrics and Gynecology, University of Alabama (R.A.), Birmingham, Alabama 35233; Department of Obstetrics and Gynecology, Pennsylvania State University (R.S.L.), Hershey, Pennsylvania 17033; and Pfizer Pharmaceuticals (M.N.G.), Ann Arbor, Michigan 48105

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


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Racial origin and family history of type 2 diabetes impact upon the risk of developing impaired glucose tolerance (IGT) and type 2 diabetes, both of which are common in women with polycystic ovary syndrome (PCOS). We examined the effects of race and family history of type 2 diabetes on the risk of IGT and type 2 diabetes in a large cohort of women with PCOS. Data obtained at baseline were analyzed from 408 premenopausal women with PCOS. Multivariate linear regression models were used to assess the impact of race (white, black, and other) and family history of type 2 diabetes on body mass index, waist circumference, and waist to hip ratio; glycemic measures (glucose and insulin levels obtained during a standard 75-g oral glucose tolerance test, fasting glucose to insulin ratio, and homeostasis model assessment model of insulin resistance derived from fasting levels of glucose and insulin), hemoglobin A1c, and SHBG, and dehydroepiandrosterone sulfate levels. Sixteen (4%) of the 408 patients had type 2 diabetes, 94 (23%) had IGT, and the remaining 298 (73%) had normal glucose tolerance. A history of type 2 diabetes in either parent (FHxPOS) was present in seven (44%) of the 16 diabetic women with PCOS, 37 (39%) of the 94 women with IGT, and 62 (21%) of those with normal glucose tolerance (P < 0.01, by {chi}2 test). The prevalences of IGT and type 2 diabetes were significantly higher in FHxPOS PCOS women compared with FHxNEG PCOS women, IGT evident in 37 (35%) FHxPOS compared with 57 (19%) FHxNEG women, and type 2 diabetes evident in seven (7%) FHxPOS compared with nine (3%) FHxNEG women. Among the 392 nondiabetic subjects, after adjustment for the effects of race, FHxPOS differed significantly from FHxNEG patients in having a higher mean waist to hip ratio, hemoglobin A1c level, 2-h glucose level, fasting glucose and insulin levels, glucose to insulin ratio, homeostasis model assessment model of insulin resistance, and areas under the glucose and insulin curves during the oral glucose tolerance test. A family history of type 2 diabetes was present with a significantly greater frequency among women with PCOS who had IGT or type 2 diabetes compared with those with normal glucose tolerance. Conversely, a family history of type 2 diabetes in a first-degree relative was associated with a significantly higher risk for IGT or type 2 diabetes in women with PCOS. Even among nondiabetic women with PCOS, a positive family history of type 2 diabetes was strongly associated with metabolic characteristics associated with an increased risk for type 2 diabetes. Finally, the fasting glucose concentration was poorly associated with 2-h glucose concentrations among PCOS women with IGT, suggesting that the fasting glucose concentration is inadequate to predict the presence of IGT in PCOS.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
POLYCYSTIC OVARY SYNDROME (PCOS) affects an estimated 5–8% of women in the United States (1). In addition to the reproductive consequences of PCOS, women with the disorder are at substantial risk for developing a number of metabolic abnormalities (2), most notably type 2 diabetes mellitus and its precursor, impaired glucose tolerance (IGT) (3, 4, 5). In most studies, type 2 diabetes is present in 5–10% of women with PCOS, whereas IGT is found in 30–40% (6, 7). These prevalences approximate those reported in Pima Indians, the population with the highest prevalence of type 2 diabetes in the world (8).

Defects in insulin action and insulin secretion are critical determinants in the pathogenesis of glucose intolerance in PCOS (9), and both are influenced by genetic (10, 11, 12, 13) and environmental factors (14). Recent studies have documented that insulin resistance (15) and pancreatic ß-cell dysfunction (16) have heritable components in PCOS families.

A family history of type 2 diabetes imparts an increased risk for the development of type 2 diabetes in individuals without PCOS; however, whether this is also true in PCOS has been evaluated in relatively few studies of limited sample size (17, 18, 19). In addition, the extent to which racial background modulates this risk in PCOS is not known. In the present study we therefore examined the effects of racial origin and family history of type 2 diabetes on the prevalence of IGT, type 2 diabetes, and metabolic risk factors for diabetes in a large cohort of untreated women with PCOS.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Details of the overall study design and methods have been reported previously (20). In brief, subjects were recruited prospectively during a multicenter controlled study designed to investigate the value of treating women with PCOS with the thiazolidinedione troglitazone. PCOS was diagnosed by the presence of 1) chronic ovulatory dysfunction (intermenstrual intervals of ≥45 d or a total of fewer than eight menses per year), 2) hyperandrogenemia (serum concentration of free testosterone greater than the upper normal limit used in the central laboratory used by this study, i.e. ≥6.3 pg/ml), and 3) the exclusion of other disorders, such as nonclassical congenital adrenal hyperplasia. These criteria are consistent with the suggestions arising from a conference sponsored by the NICHD, NIH, in April 1990 (21). Exclusionary criteria included evidence of unresolved medical conditions; hysterectomy, and/or oophorectomy; a prior diagnosis of type 1 or type 2 diabetes; significant cardiovascular disease; active cancer within the past 5 yr; and participation in another investigational study within the past 30 d. The use of medications known or suspected to affect reproductive or metabolic function within 60 d of study entry was prohibited. This study was approved by and conducted according to the guidelines of the institutional review boards of each of the participating centers. All subjects provided written informed consent.

Study protocol

Baseline demographic, anthropometric, and hormonal measurements were obtained for each subject (20). Blood samples were obtained for determination of total and free testosterone, dehydroepiandrosterone sulfate (DHEAS), androstenedione, FSH, LH, prolactin, estradiol, TSH, and 17-hydroxyprogesterone. The results of these measurements were reported previously (20, 22). In addition, blood was obtained for the measurement of SHBG and hemoglobin A1c. An oral glucose tolerance test (OGTT) was performed in each subject, with blood samples obtained 0, 30, 60, 90, and 120 min after the ingestion of 75 g glucose. Glucose and insulin were measured at all time points during the OGTT. 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 (23). A diagnosis of normal glucose tolerance, IGT, or diabetes was assigned if the glucose level at 2 h was less than 140 mg/dl (7.8 mmol/liter), between 140 and 200 mg/dl (7.8 and 11.1 mmol/liter), or 200 mg/dl (11.1 mmol/liter) or more, respectively.

Laboratory analysis

The assay methods for determining total and free testosterone, DHEAS, androstenedione, FSH, LH, prolactin, estradiol, TSH, and 17-hydroxyprogesterone have been previously reported (20, 22). The binding capacity of SHBG was directly measured in serum using a displacement technique that uses ammonium sulfate precipitation of free and protein-bound steroid. Glucose levels were measured by the hexokinase procedure (model 747-200, Hitachi, Tokyo, Japan), hemoglobin A1c levels by HPLC (Variant, Bio-Rad Laboratories, Inc., Hercules, CA), and insulin levels by RIA (Medical Research Laboratories, Inc., Highland Heights, KY).

Calculations and statistical analyses

The homeostasis model assessment of insulin resistance (HOMA-IR) was derived from the equation: HOMA-IR = (fasting plasma insulin concentration (mU/liter) x fasting plasma glucose concentration (mg/dl) ÷ 405 (24). Areas under the glucose and insulin response curves during the OGTT were calculated using the trapezoidal rule.

Pearson’s {chi}2 test was used to examine the association between categorical variables, such as glucose tolerance status and family history of type 2 diabetes. Univariate analyses of differences in the outcome measures by family history status and race were performed using two-sample t tests and ANOVA, respectively. Multivariate linear regression models were used to study the effects of both family history status and race simultaneously. A Bonferroni adjustment was made due to the multiple end points examined (adjusted {alpha} = 0.05/14 = 0.004). The strength of the association between fasting and 2-h glucose levels was assessed using Pearson’s correlation coefficient. Nonparametric tests were also performed, the results of which were comparable to those presented here and are not shown. All analyses were performed using SPSS version 11.5 (SPSS, Inc., Chicago, IL) or Stata version 8 (StataCorp LP, College Station, TX). All data are presented as the mean ± SE.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Baseline patient characteristics

Seven hundred and eighty-two women with known or suspected PCOS were screened for eligibility, 408 of whom qualified for the study. The baseline clinical and hormonal data obtained from these women are shown in Table 1Go. As expected, there was an elevated body mass index (BMI; 36.2 ± 0.4 kg/m2) in these women. An increased mean waist circumference (103.6 ± 0.9 cm) and waist to hip ratio (WHR; 0.9 ± 0.01) were indicative of upper body or android obesity.


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  		TABLE 1. Baseline clinical characteristics of 408 PCOS subjects

 
Sixteen (4%) of the 408 patients had type 2 diabetes, 94 (23%) had IGT, and the remaining 298 (73%) had normal glucose tolerance. Type 2 diabetes was present in a parent in seven (44%) of the 16 PCOS women discovered to be diabetic, in 37 (39%) of the 94 PCOS women found to have IGT, and in 62 (21%) of the remaining PCOS women with normal glucose tolerance, a significant difference (P < 0.01, by {chi}2 test; Table 2Go). In contrast, there was not a significant association between race and glucose tolerance status (P = 0.8).


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  		TABLE 2. Glucose tolerance status of PCOS subjects by presence of family history of type 2 diabetes

 
To avoid the confounding influence of the diabetic state on weight and glycemic measures, PCOS subjects with diabetes were eliminated from additional analysis. Among the 392 nondiabetic subjects, 303 (77%) were white, 51 (13%) were black, 20 (5%) were Hispanic, 4 (1%) were Asian/Pacific Islander, and 14 (4%) were other. Because the numbers of Hispanic and Asian/Pacific Islanders was small, these groups were combined with the group denoted "other" for all analyses. Compared with white PCOS women, black PCOS women had significantly higher fasting insulin levels (30.8 ± 4.4 vs. 20.7 ± 1.0 µU/ml) and area under the insulin curve during the OGTT (314.9 ± 25.1 vs. 224.1 ± 9.4), were more insulin resistant by HOMA-IR (7.5 ± 1.2 vs. 4.8 ± 0.2), and had higher hemoglobin A1c levels (5.5 ± 0.07 vs. 5.1 ± 0.03%; Table 3Go). As shown in Table 4Go, compared with the group of PCOS women without a family history of diabetes (n = 286), those in the family history-positive group (n = 99) had a significantly higher WHR (0.90 ± 0.01 vs. 0.87 ± 0.01 cm), hemoglobin A1c (5.3 ± 0.05 vs. 5.1 ± 0.03%), and 2-h glucose concentration (129.0 ± 3.6 vs. 114.5 ± 1.9 mg/dl) during the OGTT. The mean levels of both glucose and insulin at each time point during the OGTT are shown in Fig. 1Go by family history status. Of particular interest, there was a poor correlation (r = 0.115; P = 0.272) between fasting and 2-h glucose levels for women with IGT (Fig. 2Go). That is, IGT was poorly predicted by the fasting glucose concentration.


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  		TABLE 3. Baseline clinical characteristics in nondiabetic PCOS subjects by race

 

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  		TABLE 4. Baseline clinical characteristics in nondiabetic PCOS subjects by family history of type 2 diabetes

 


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  		FIG. 1. Glucose (top panel) and insulin (bottom panel) concentrations obtained during a 75-g OGTT in PCOS women with (•; FHxPOS) and without ({circ}; FHxNEG) a family history of type 2 diabetes. Compared with FHxNEG subjects, FHxPOS subjects had significantly higher mean glucose and insulin levels throughout the OGTT. Data are the mean ± SE.

 


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  		FIG. 2. Relationship between fasting plasma glucose and plasma glucose obtained 2 h after ingestion of 75 g dextrose in women with PCOS who have IGT (plasma glucose at 2 h, 140–200 mg/dl). Note the lack of a statistically significant relationship between these two measures (r = 0.115; P = 0.272).

 
Women with PCOS who had a positive family history of diabetes were more insulin resistant than those without such a family history, as reflected in a higher HOMA-IR index (6.6 ± 0.6 vs. 4.9 ± 0.3). Finally, SHBG levels were lower in the FHxPOS women (36.0 ± 1.7 nM) compared with FHxNEG women (41.1 ± 1.3 nM). SHBG has been reported as a surrogate marker of insulin resistance that is predictive of subsequent development of type 2 diabetes (25). The differences in insulin levels, insulin sensitivity, and SHBG are particularly striking given that the mean BMI was similar in those with and without a family history of diabetes (36.8 ± 0.8 vs. 35.9 ± 0.5 kg/m2, respectively).

To determine whether the effects of racial origin produced the observed differences between those with and without a family history of type 2 diabetes, multivariate linear regression models were used. In these models, both race (white/non-Hispanic, black/non-Hispanic, and other) and family history of type 2 diabetes served as independent variables (Table 5Go). After adjusting for race effects, family history of type 2 diabetes remained a significant determinant of waist circumference, WHR, DHEAS, hemoglobin A1c, HOMA-IR, and insulin and glucose levels during the OGTT. Measures for which race had a significant effect after adjustment for family history of type 2 diabetes included hemoglobin A1c levels, fasting insulin levels, and HOMA-IR.


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  		TABLE 5. Results of multivariate linear regression models

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
It is well established that women with PCOS are predisposed to develop IGT and type 2 diabetes (6, 7). Obesity, insulin resistance, and impaired pancreatic ß-cell function contribute to this predisposition (26, 27). In addition to these recognized factors, racial origin and the presence of type 2 diabetes in a first degree relative influence the risk of glucose intolerance, although this issue has been examined in a limited number of studies involving women with PCOS (17, 18, 19). The present study was therefore undertaken with the aim of characterizing the impact of both race and family history of diabetes on the metabolic characteristics and risk of IGT and type 2 diabetes in women with PCOS.

We found that the prevalences of both IGT (23%) and type 2 diabetes (4%) were elevated, although they were somewhat lower than those derived from the combined data available from 376 subjects reported previously (6, 7) in which 119 (31.6%) had IGT and 34 (9.0%) had type 2 diabetes. The lower prevalence of glucose intolerance reported here is probably due in part to the fact that preexisting type 2 diabetes was an exclusion criterion for enrollment in the original study design (20).

Our data also confirm and extend previous reports in which families of women with PCOS were found have a large number of individuals with type 2 diabetes (18, 19). Yildiz et al. (19) detected diabetes and IGT in 16% and 30% of mothers and in 27% and 31% of fathers, respectively, of women with PCOS. In addition, IGT was found in 5% of PCOS sisters. Sir-Petermann et al. (18) recently reported that insulin sensitivity was significantly lower and the prevalence of type 2 diabetes was 1.89-fold higher in the parents of PCOS women compared with the parents of controls even after adjustment for sex, age, and BMI. We found that type 2 diabetes in a first degree relative was evident in 44% of PCOS women with diabetes and 39% of those with IGT. In contrast, significantly fewer (21%) normal glucose-tolerant women with PCOS had a diabetic first degree relative. Conversely, the presence of type 2 diabetes in a first degree relative was associated with a significant increase in the risk of IGT (35% vs. 19%) and diabetes (7% vs. 3%) in women with PCOS. In the present study, because patient recall, rather than direct testing, was used as the method to obtain information regarding the presence of type 2 diabetes in family members, recall bias must be taken into consideration in the interpretation of our findings.

The racial disparity in the prevalence of type 2 diabetes has been well described (28) and attributed at least in part to the greater degrees of obesity and insulin resistance typically found in those groups with the higher prevalences. Likewise, in studies of women with PCOS, it has been shown that compared with white PCOS women of similar weight and BMI, African-American, Caribbean-Hispanic, and south Asian women with PCOS tend to have higher insulin levels and a greater degree of insulin resistance (11, 17, 29, 30). This finding is corroborated in the present study; black PCOS women had higher insulin levels and were more insulin resistant than white women with PCOS. These differences remained statistically significant even after taking the family history of diabetes into account.

When we analyzed the impact of family history in nondiabetic PCOS subjects alone (i.e. after excluding diabetic PCOS subjects from the analysis), a positive family history of diabetes was still associated with significantly higher levels of hemoglobin A1c as well as higher glucose and insulin levels during an OGTT. These findings are consistent with those indicating that impairment of both insulin action and insulin secretion, defects that are proximate to the development of type 2 diabetes, are heritable in PCOS families (15, 16). A significantly greater proportion of body fat was distributed to the upper body/abdomen in FHxPOS women, as reflected in a higher WHR (0.90 ± 0.01 vs. 0.87 ± 0.01), although the mean BMI was nearly identical in FHxPOS and FHxNEG women (36.8 ± 0.8 vs. 35.9 ± 0.5 kg/m2). An increased WHR has been highly correlated with insulin resistance and risk for development of diabetes (31). Indeed, FHxPOS women were more insulin resistant, as reflected in a significantly higher HOMA-IR (6.6 ± 0.6 vs. 4.9 ± 0.3).

Our finding of a poor correlation between the fasting and 2-h glucose concentrations during an OGTT in PCOS women with IGT (r = 0.115; P = 0.272) is particularly important given the high prevalence of IGT in this group and its association with a substantial rate of conversion to type 2 diabetes when untreated (7, 32). Given the additional recent evidence that treatment of IGT with lifestyle or metformin leads to a significant reduction in rates of conversion to type 2 diabetes (33, 34), it is reasonable to consider routinely performing an OGTT to identify those women with PCOS who would most benefit from intervention.

In conclusion, our results confirm that both race and family history of diabetes have a substantial impact on the metabolic and glycemic status of women with PCOS. A history of type 2 diabetes in a first degree relative appears to be an important factor in predicting the risks of metabolic abnormalities, IGT, and type 2 diabetes in women with PCOS.


   Acknowledgments
 
We recognize Shelly Cobb and Sankyo Ltd., Inc., for their contributions; Dr. Carlos Moran for his review and suggestions; and Drs. Bill Lasley and Andrea Dunaif for their advice and consultation. In addition to the authors, the following investigators participated in the PCOS/Troglitazone Study Group: Stephen Aronoff (Dallas, TX), Richard Bernstein (Greenbrae, CA), Donald Bodenner (Rochester, NY), Susan Braithwaite (Chicago, IL), Joshua Cohen (Washington, D.C.), David DePaolo (Boulder, CO), Daniel Einhorn (San Diego, CA), Jennifer Hone (Arvada, CO), Anne Kenshole (Toronto, Canada), Charles Kilo (St. Louis, MO), Siri Linda Kjos (Los Angeles, CA), Mary Korytkowski (Pittsburgh, PA), Diane Koster (Albuquerque, NM), Rebecca Lau (Indianapolis, IN), Rogerio Lobo (New York, NY), Jean Lucas (Atlanta, GA), Kathryn Martin (Boston, MA), William Meyer (Chapel Hill, NC), Sumer Pek (Ann Arbor, MI), Samantha Pfeifer (Philadelphia, PA), Robert Rebar (Cincinnati, OH), Geoffrey Redmond (Cleveland, OH), Roger Rittmaster (Halifax, Canada), Peter Ross (Fairfax, VA), Sherwyn Schwartz (San Antonio, TX), Robert Wild (Oklahoma City, OK), and Samuel S. C. Yen (La Jolla, CA).


   Footnotes
 
This work was supported by a grant from Pfizer/Parke-Davis Pharmaceutical Research, Inc., and University of Chicago General Clinical Research Center Grant M01-RR-00055.

Current address of R.A.: Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, California 90048.

First Published Online October 26, 2004

Abbreviations: BMI, Body mass index; DHEAS, dehydroepiandrosterone sulfate; HOMA-IR, homeostasis model assessment model of insulin resistance; IGT, impaired glucose tolerance; OGTT, oral glucose tolerance test; PCOS, polycystic ovary syndrome; WHR, waist to hip ratio.

Received February 9, 2004.

Accepted October 18, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Race and Family History Influence Risk of Polycystic Ovary Syndrome


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