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A Fasting Glucose to Insulin Ratio Is a Useful Measure of Insulin Sensitivity in Women with Polycystic Ovary Syndrome¹

Department of Obstetrics and Gynecology, Pennsylvania State University College of Medicine (R.S.L.), Hershey Pennsylvania 17033; the Diabetes Research Laboratory, Simon Fraser University School of Kinesiology (D.F.), Burnaby, British Columbia, Canada V5A 1S6; and the Division of Women’s Health, Brigham and Women’s Hospital (A.D.), Boston, Massachusetts 02115.

Address all correspondence and requests for reprints to: Andrea Dunaif, M.D., Division of Women’s Health, Brigham and Women’s Hospital, PBB-Admin-5, 75 Francis Street, Boston, Massachusetts 02115.

	Abstract

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Women with polycystic ovary syndrome (PCOS) are profoundly insulin resistant, and the resultant hyperinsulinemia exacerbates the reproductive abnormalities of the syndrome. Agents that ameliorate insulin resistance and reduce circulating insulin levels could provide a new therapeutic modality for PCOS. Identifying the subset of PCOS women who are most insulin resistant may therefore be useful for selecting women who will respond to this therapy. We examined the correlation of basal and oral glucose-stimulated glucose and insulin levels and fasting and stimulated glucose/insulin (G:I) ratios with parameters of insulin sensitivity obtained by frequently sampled iv glucose tolerance test (FSIGT) to assess whether there is a simple screening test for insulin resistance in PCOS. Forty PCOS women (aged 18–40 yr; body mass index, >26 kg/m²) and 15 control women matched for age, weight, and ethnicity underwent both a 75-g oral glucose tolerance test (OGTT) and a FSIGT. The insulin sensitivity index (S_I) was calculated by application of the minimal model of glucose kinetics to the dynamics of plasma glucose and insulin levels during the FSIGT. The best correlation in PCOS between S_I and a fasting level was found with fasting G:I ratios (r = 0.73; P < 0.0001). A less substantial, but significant, correlation was found with fasting insulin levels (r = 0.50; P < 0.001), and no significant correlation was found with fasting glucose levels (r = 0.24; P = NS). The fasting G:I was more strongly correlated with S_I than with integrated glucose and insulin responses during the OGTT. The only stronger correlation was with the OGTT 2 h G:I ratio (r = 0.74; P < 0.001). Stepwise regression analysis with S_I as the dependent variable and fasting glucose and insulin levels, area under the curve for glucose and insulin, and a fasting G:I ratio showed that only the fasting G:I ratio was significantly predictive of S_I in the model (F to remove value = 38.1; P < 0.001). When viewed as a screening test for insulin resistance in PCOS, setting a value of the fasting G:I ratio of less than 4.5 as abnormal (using an S_I value below the 10th percentile of our control population as evidence for insulin resistance), the sensitivity of a fasting G:I ratio was 95%, the specificity was 84%, the positive predictive value was 87%, and the negative predictive value was 94%. Receiver operator curve analysis showed that this fasting G:I ratio was the single best screening measure for detecting insulin resistance. We conclude that a fasting G:I ratio may be useful as a screening test for insulin resistance in obese non-Hispanic white PCOS women. This may be a clinically useful parameter for selecting PCOS women most likely to respond to therapeutic interventions that improve insulin sensitivity.

	Introduction

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POLYCYSTIC ovary syndrome (PCOS) is the most common endocrine disorder of premenopausal women, characterized by hyperandrogenic chronic anovulation (1). Women with PCOS are profoundly insulin resistant, and the resulting hyperinsulinemia plays a role in the pathogenesis of the reproductive disturbances (2, 3, 4). Abnormalities in insulin action are poorly detected by a single determination of either glucose or insulin levels (5, 6). This diagnosis requires iv administration of glucose, insulin, and/or other substances in a research setting. Such tests are time, labor, and, above all, cost-intensive and are not feasible for large scale screening of populations or routine interval assessment of individuals at risk.

Initial studies have shown that agents that ameliorate insulin resistance and reduce circulating insulin levels, such as troglitazone (7, 8) or metformin (9, 10), may provide a new therapeutic modality in PCOS. Thus, identifying the subset of PCOS women who are the most insulin resistant with a simple test may become more relevant as therapeutic interventions that improve insulin sensitivity in PCOS women are identified. We sought, therefore, to assess whether there was a simple fasting measure of insulin resistance in PCOS women that correlated well with more involved dynamic tests of insulin action.

	Subjects and Methods

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Subjects

We studied 40 PCOS and 15 control women. All were non-Hispanic white women from the south central Pennsylvania area. This study was approved by the institutional review board of the Milton S. Hershey Medical Center (Hershey, PA), and all subjects gave written informed consent. The women had a body mass index greater than 26 kg/m² and were between 18–40 yr of age. All women were in good health, euthyroid, and, for at least 1 month before each study, were not taking any medication (except for oral contraceptive agents, which were stopped for 3 months before the study) known to affect sex hormone or carbohydrate metabolism. The diagnosis of PCOS was made by the finding of an elevation of either total testosterone or biologically available testosterone levels associated with chronic oligomenorrhea (6 or fewer menses/yr). Nonclassical 21-hydroxylase deficiency, hyperprolactinemia, and androgen-secreting tumors were excluded by appropriate tests before the diagnosis of PCOS was made. Control women were matched for age, weight, and ethnicity to the women with PCOS. They did not engage in regular aerobic activity, nor did they have a history of diabetes mellitus or hypertension. There was no history of diabetes mellitus in the first degree relatives of the control women. Control women had regular menses every 27–32 days and were not hirsute. Androgen levels in control women were determined without regard to cycle day.

Study protocol

All studies were performed after a 3-day 300-g carbohydrate diet and an overnight fast. Each woman was allowed to rest for 0.5 h after insertion of an iv catheter before the oral glucose tolerance test (OGTT). A 75-g oral glucose load was administered, and blood was obtained for glucose and insulin determinations at 0, 30, 60, 90, and 120 min through the catheter. In two PCOS women we were unable to obtain a sample at 30 min during the OGTT because of technical problems with access. Glucose tolerance was assessed by WHO criteria (11). Forty-three percent of the PCOS women (17 of 40) were glucose intolerant, and all of the control women had normal glucose tolerance.

Insulin action was determined by a frequently sampled iv glucose tolerance test (FSIGT) (12, 13, 14). These tests were performed without regard to the phase of the menstrual cycle to assess whether it would still be possible to detect insulin resistance with this simplified study design (14). The FSIGTs were performed after a standard overnight fast of 10 h on a separate day after the OGTT. Women had two iv catheters inserted, one in each arm, and then were allowed to rest for 30 min. At 0 min, 0.3 g/kg glucose was injected over 1 min, and at 20 min, 500 mg tolbutamide (Upjohn Co., Kalamazoo, MI) were injected over 20 s. Blood samples were drawn at -15, -10, -5, -1, 0, 2, 3, 4, 5, 8, 10, 12, 14, 16, 19, 22, 23, 24, 25, 27, 30, 40, 50, 60, 70, 90, 100, 120, 140, 160, and 180 min. The insulin sensitivity index (S_I) and glucose effectiveness (S_G; MINMOD computer program version NUDEMM1, R. Bergman, Los Angeles, CA) as well as the acute insulin response to glucose (AIRg) and the disposition index (the product of S_I x AIRg) were calculated as previously reported (14).

Assays

A single fasting blood sample obtained at 0 min of the OGTT was used for the androgen assays. Assays for testosterone, biologically available, and dehyroepiandrosterone sulfate were performed as previously reported (7). Glucose was measured by the glucose oxidase technique with a Beckman Glucose Analyzer 2 (Fullerton, CA), and insulin levels were measured using Diagnostic Products Corp. kits (Los Angeles, CA) as previously reported (7). The cross-reactivity with proinsulin at the midcurve of the assay is approximately 40%.

Definition of insulin resistance

S_I values from the age-, weight-, and ethnicity-matched control group were used to define the normal distribution; the tenth percentile for S_I was less than 1.12 x 10^-4 min^-1/(µU/mL). We have previously found that this sample size is adequate to define the variance in this normal population (14). Insulin resistance was then defined in PCOS women as an S_I value less than this.

Data analysis

Continuous data were compared between the two groups (PCOS and controls) using unpaired t tests. The integrated area under the curve (AUC) analysis for glucose and insulin was determined according to the formula of Tai et al. (15). Regression analysis was performed using S_I as the dependent variable and OGTT fasting and stimulated glucose and insulin levels as independent parameters. Stepwise regression analysis was performed with S_I as the dependent variable and fasting glucose and insulin levels, AUC for glucose and insulin, and fasting G:I ratio. Data were analyzed using StatView 4.5 for the Macintosh (Abacus Concepts, Berkeley, CA). Receiver operator curves (ROCs) were created by calculating the sensitivity and specificity of fixed cut-off points of the various parameters examined. Values are reported as the mean ± SD. P < 0.05 was considered statistically significant.

	Results

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The clinical features of the PCOS women and control women are summarized in Table 1. By design, there were no significant differences between the two groups in age or weight. Waist/hip girth ratios were significantly higher in the PCOS women than in the control women (0.84 ± 0.08 vs. 0.78 ± 0.05; P < 0.05). PCOS women also had significantly higher levels of circulating testosterone (86.2 ± 34.5 vs. 33.4 ± 9.7 ng/dL; P < 0.0001), biologically available testosterone (31.2 ± 12.5 vs. 8.3 ± 3.8 ng/dL; P < 0.0001), and dehyroepiandrosterone sulfate (2472 ± 1570 vs. 1501 ± 553 ng/mL; P < 0.001). Fasting glucose levels did not differ, but PCOS women had significantly higher fasting insulin levels than control women (27.0 ± 18.1 vs. 13.3 ± 10.1 µU/mL; P < 0.001). S_I was significantly lower in PCOS than in control women [1.81 ± 1.82 vs. 4.37 ± 2.60 x 10^-4 min^-1/(µU/mL); P < 0.0001].

View larger version (18K): [in this window] [in a new window]   Figure 1. Regression plots of fasting glucose, fasting insulin, and fasting G:I ratio to SI (10-4 min-1/(µU/mL), as determined by FSIGT in PCOS women (n = 40).

View larger version (27K): [in this window] [in a new window]   Figure 2. ROC curves for fasting values (A) and OGTT values (B) for detecting insulin resistance in PCOS women. Sensitivity is plotted against 1 - specificity (or the false positive rate) for various cut-off values. The ideal test is one that approaches or reaches the upper left corner of the graph (100% sensitivity and 100% specificity). A test that approximates a coin flip yields a diagonal from the lower left to the upper right corner of the graph. The cut-off point that has the best combination is located at the "knee" of the graph and is labeled for each parameter (A–G). The cut-off values of the test are given in Table 3.

	Discussion

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Our results indicate that a fasting G:I ratio is a good measure of insulin sensitivity in obese PCOS women and has both high sensitivity and specificity for detecting insulin-resistant women. Fasting hyperinsulinemia has been used as a measure of insulin action (5, 6). Basal and glucose-stimulated hyperinsulinemia are well reported in obese PCOS women (2, 16). This is secondary to profound peripheral insulin resistance (4, 14). Fasting glucose levels are also higher in obese PCOS women secondary to increased basal hepatic glucose production (4, 17), which reflects hepatic insulin resistance, but this usually does not achieve statistical significance, as is the case in the present study. The fasting G:I ratio reflects both of these abnormalities and could be predicted to be a more sensitive marker for insulin resistance than either value alone, consistent with our findings. The fasting G:I ratio would not be predicted to be a good measure of insulin resistance in nonobese PCOS women because they have neither fasting hyperinsulinemia (3, 4, 16) nor increased basal hepatic glucose production (4, 17). As nonobese PCOS women were not included in the present study, we can not directly confirm this.

Insulin resistance and the resulting hyperinsulinemia contribute to the reproductive abnormalities of PCOS women (2, 18). Lowering circulating insulin levels by a variety of mechanisms has resulted in decreased androgen levels in PCOS women. As little as a 7% decrease in body weight has significantly improved hyperandrogenism (19). The short term use of agents that lower insulin secretion, such as diazoxide or somatostatin, produces similar effects (20, 21). Therapy with metformin, which acts primarily by suppressing hepatic gluconeogenesis, when accompanied by a reduction in circulating insulin levels, can decrease androgen levels in PCOS (9, 10, 22). In two small studies, the administration of troglitazone, an agent that directly reduces target tissue insulin resistance and, accordingly, circulating insulin levels, also resulted in a decrease in circulating androgen levels in PCOS women (7, 8). A baseline fasting G:I ratio has been shown to have good correlation with the clinical efficacy of troglitazone on hyperglycemia in Japanese patients with type 2 diabetes (23).

We have chosen the lower decile of insulin sensitivity from an age-, weight-, and ethnicity-matched control group to define insulin resistance. If we had selected a less stringent criterion that reflects the prevalence of insulin resistance in the larger population (24), such as a value below the 25th percentile of the control population, 80% of PCOS women would have been designated insulin resistant. For the purposes of evaluating the usefulness of the fasting G:I ratio as well as other OGTT parameters as screening tests for insulin action, we used the more stringent criterion of the lowest decile of insulin sensitivity as the cut-off point. Other groups have defined insulin resistance as a measure of insulin action in the lower decile of insulin sensitivity in lean subjects (25). By using obese women to define the normal range of insulin sensitivity, we were assessing insulin resistance that was beyond that due to obesity per se.

A brief report by Parra and colleagues suggested that a fasting G:I ratio might be a useful measurement for predicting glucose-stimulated hyperinsulinemia in PCOS women (26). We have shown for the first time that the fasting G:I ratio is a sensitive and specific marker of insulin sensitivity in PCOS. S_I as determined by FSIGT has been shown to be highly correlated with insulin action determined by the euglycemic glucose clamp technique in many insulin-resistant states, including PCOS (27, 28). We have also controlled for the effects of age, weight, and ethnicity in PCOS women on insulin sensitivity by using an appropriate control group (4, 29, 30, 31).

We chose ROC curve analysis to graphically portray the trade-off involved in improving a test’s sensitivity at a cost of lower specificity and to select the best cut-off value. The fasting G:I ratio offered the best single cut-off measure (including sensitivity, specificity, positive predictive value, negative predictive value, and 95% confidence intervals), had a better correlation with S_I by simple regression than fasting insulin level, and was a better fasting predictor of S_I by our stepwise regression model. We do not have an adequate sample size to assess statistically whether the fasting G:I ratio is superior to a fasting insulin level by comparison of ROC AUC analysis. A power analysis based on our preliminary findings suggests that we would need 4 times as many PCOS women in the insulin-resistant group to detect a difference in the sensitivity of the two measures.

Our results indicate that a fasting G:I ratio is an easily obtainable, safe, highly sensitive, and specific measure of insulin sensitivity in obese non-Hispanic white PCOS women. The predictive power of both a positive and a negative test is excellent. Further studies will be needed to validate this measure in other populations. We suggest that the fasting G:I ratio may be a useful test for identifying PCOS women with insulin resistance. These women may be more likely to benefit from therapies that lower circulating insulin levels.

	Acknowledgments

 
We thank Allan Kunselman, M.A., from the Department of Health Evaluation Sciences at the Milton S. Hershey Medical Center for his help with the data analysis. Additionally, we thank the nurses and staff of the General Clinical Research Center at the Milton S. Hershey Medical Center for their outstanding patient care, and Sharon Ward for her excellent coordination of the study.

	Footnotes

 
¹ This work was supported by the National Cooperative Program for Infertility Research at University of Pennsylvania-Brigham and Women’s Hospital-University of California at San Francisco-Pennsylvania State University U54-HD-34449, USPHS Grants RO1-DK-40605 (to A.D.) and K08-HD-0118 (to R.S.L.), General Clinical Research Center Grant MO1-RR-10732 (to Pennsylvania State University College of Medicine), as well as grants from the American Diabetes Association (to A.D.) and the CROWN Foundation (to R.S.L.).

Received March 4, 1998.

Revised May 6, 1998.

Accepted May 8, 1998.

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