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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 6 3381-3386
Copyright © 2005 by The Endocrine Society

Preserved Insulin Sensitivity and ß-Cell Activity, but Decreased Glucose Effectiveness in Normal-Weight Women with the Polycystic Ovary Syndrome

G. Gennarelli, V. Rovei, R. F. Novi, J. Holte, F. Bongioanni, A. Revelli, G. Pacini, P. Cavallo-Perin and M. Massobrio

Departments of Obstetrics and Gynecology (G.G., V.R., F.B., A.R., M.M.) and of Internal Medicine (R.F.N., P.C.-P.), University of Torino, 10126 Torino, Italy; Carl Von Linne Kliniken (J.H.), 75183 Uppsala, Sweden; and Metabolic Unit (G.P.), Institute of Biomedical Engineering, National Research Council, 35127 Padova, Italy

Address all correspondence and requests for reprints to: Gianluca Gennarelli, Department of Obstetrics and Gynecology, via Ventimiglia 3, Torino 10100, Italy. E-mail: gennarelligl{at}libero.it.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Insulin resistance and hyperinsulinemia are often considered intrinsic features of the polycystic ovary syndrome (PCOS). Nevertheless, conflicting results of insulin sensitivity and secretion have been obtained in the subgroup of normal-weight women with PCOS. Differences in body composition, ethnicity, and diet composition and a family history of metabolic diseases may act as confounding variables in women with PCOS. In the present study, insulin sensitivity and secretion were estimated by an iv glucose tolerance test (IVGTT), analyzed by minimal models, in 20 normal-weight healthy women with PCOS and no family history of type 2 diabetes mellitus and in 20 normally ovulating women, matched for age and body mass index. Insulin sensitivity [mean (95% confidence intervals); PCOS 4.0 (2.8–5.1) vs. controls 4.5 (3.5–5.4) 10–4 min–1/µU·ml], and insulin secretion, expressed as the acute insulin response to glucose [PCOS 3.7 (3.3–4.2) vs. controls 3.7 (3.4–4.0) µU/ml] were similar in the two groups. The women with PCOS showed an increased proportion of total body fat (PCOS 29% vs. controls 27.2%; P < 0.01). They also showed decreased glucose effectiveness, i.e. the proportion of glucose uptake independent from insulin activity [PCOS 2.6 (2.1–3.0) vs. controls 3.8 (3.0–4.6) mg x 100 min–1; P = 0.01]. The levels of insulin sensitivity and of glucose effectiveness did not correlate in either group. Whether the isolated finding of decreased glucose effectiveness could reflect an early stage in the development of the metabolic aberrations often associated with the syndrome remains to be clarified.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
INSULIN RESISTANCE IS currently considered a predominant feature of the polycystic ovary syndrome (PCOS), the most common endocrine disturbance in women of reproductive age (1). However, although a general agreement has been reached on the constant association between insulin resistance and PCOS in obese women, data are conflicting for women with PCOS in the normal-weight range (2). The euglycemic hyperinsulinemic clamp (3) is the most sensitive method for measuring insulin sensitivity in vivo, and it is considered the gold standard for research purposes. As a matter of fact, about half of the published clamp studies found preserved insulin sensitivity in normal-weight women with PCOS (4, 5, 6, 7, 8, 9), when compared with weight-matched controls, whereas the remaining studies (in particular from North America) reported some degree of insulin resistance in these patients (10, 11, 12, 13).

However, the majority of previous studies failed to take into account the effect of confounding variables, such as ethnicity, dietary habits, a family history of type 2 diabetes mellitus, and body fat distribution (14), which could exert a strong impact on metabolism. In addition, the cutoff value in body mass index (BMI) for what is regarded as "normal weight" could vary between different studies, with important consequences on metabolic results (15).

It should be noted that the euglycemic clamp has been criticized, being unable to distinguish between insulin-dependent and insulin-independent glucose uptake. The latter, defined as glucose effectiveness (16), accounts for about 30% of glucose uptake in normal individuals, whereas it could significantly rise (up to 80%) in patients with disturbances of carbohydrate metabolism.

To understand why normal-weight women with PCOS show such heterogeneous levels of insulin sensitivity and to investigate whether other subtle anomalies of carbohydrate metabolism could be present in the PCOS is crucial from a clinical point of view. This is important in light of the spreading use of hypoglycemic drugs in these patients, who do not respond consistently to such therapy (17).

The present study investigated insulin sensitivity and secretion by means of an iv glucose tolerance test (IVGTT) followed by minimal model analysis in a selected group of normal-weight women with PCOS with no family history of type 2 diabetes mellitus. The results were compared with those obtained from a group of normally ovulating women with normal ovarian morphology, matched for age and weight, and who did not report a family history of metabolic diseases.


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

The study group included 20 women with PCOS enrolled at the Department of Obstetrics and Gynecology of Turin University Hospital and 20 healthy women with similar age and BMI, selected among hospital staff and medical students. The diagnosis of PCOS was based on the ultrasonographic evidence of polycystic ovaries (18), in association with a history of amenorrhea or menstrual irregularities indicating chronic ovulatory disturbances, according to the criteria of the recent Rotterdam Consensus Conference (19). The controls had regular menses and normal ovarian morphology according to ultrasonography. The ultrasound examination was performed transvaginally with an Ultramark 9 machine with HDI (high definition imaging) technology (ATL Ultrasound-Philips Medical Systems S.p.A., Milan, Italy; 5 MHz). The ovarian volume was calculated from the measurement of the three maximum diameters (D1, D2, D3), according to the following formula: {pi}/6 x D1 x D2 x D3.

Hirsutism was assessed by a modified version of the Ferriman and Gallwey protocol (20). Ten women with PCOS were hirsute (score, ≥7), whereas hirsutism was not found among control women.

All women were in good physical condition, nondiabetic, normotensive, with normal levels of prolactin, and did not suffer from any other metabolic diseases. Congenital adrenal hyperplasia was excluded in the women with PCOS by a normal morning serum concentration of 17{alpha}-hydroxyprogesterone (cutoff, 5 nmol/liter).

None of the women enrolled practiced a sport at a professional level. The degree of physical activity, assessed by a questionnaire, was comparable in the two groups. Six women with PCOS and seven controls smoked more than five cigarettes per day (the difference was not significant by {chi}2 analysis). None of the subjects had been taking any drug known to affect carbohydrate metabolism or any hormonal medication for at least 3 months before the study.

The metabolic and endocrine investigations were performed at any moment in amenorrheic and oligomenorrheic women, excluding recent ovulation by measuring plasma progesterone, and between the third and eighth days of the menstrual cycle in women with regular menstrual cycles.

The protocol received the approval of the Ethics Committee of the Medical Faculty, Turin University, and informed consent was obtained from all women.

Dietary composition

A specific questionnaire was administered under the supervision of an experienced dietician to estimate the total amount of calories per day and the proportion of total and saturated fats, proteins, and carbohydrates. The presence of binge-eating behavior was investigated by means of the Binge Eating Scale questionnaire (21). The Binge Eating Scale score considers two cutoff levels: between 18–26 (moderate) and above 27 (high binge-eating disorder).

Anthropometric variables

BMI was calculated as weight (kilograms) divided by height squared (meters2). The waist circumference was measured at a level midway between the lower rib margin and the iliac crest, and the hip circumference at the level of the great trochanters. The ratio between the waist and the hip girths (WHR) was then calculated. Skinfolds were measured in triplicate with a Harpenden skinfold caliper (British Indicator Ltd., Burgess Hill, West Sussex, UK) on the nondominant side of the body at the following sites: subscapularis, about 20 mm below the tip of the scapula; suprailiaca, about 20 mm above the iliac crest; umbilicalis, about 40 mm to the right of the umbilicus; triceps, halfway between the acromion process and olecranon process; and biceps, at the same level on the opposite side of the arm. Total body fat was estimated by a gender-specific equation (validated by comparison to hydrostatic weighing), which is based on age and the measurement of four skinfolds, namely biceps, triceps, subscapularis, and suprailiaca (22). The error in estimating body composition from anthropometry by this formula has been established to be approximately 5%, when compared with body densitometry.

Study protocol

The women were admitted to the hospital at 0700 h after an overnight fast. After an indwelling catheter was positioned in the antecubital vein, the patient rested for 15 min. The antecubital vein of the opposite arm was used for the infusion of glucose and insulin. At time –15 min, blood samples were drawn and collected for basal hormone analysis. Basal blood samples were collected at time –10 and –1 min. At time 0 min, a 33% glucose solution was infused (0.3 g/kg body weight, within 30 sec). At time 20 min, rapid insulin (Actrapid; Novo-Nordisk, Bagsvaerd, Denmark) 0.03 IU/kg body weight was administered iv within 10 sec.

Blood samples for the measurement of glucose, insulin, and C-peptide were collected at 3, 4, 5, 6, 8, 10, 14, 19, 22, 27, 30, 35, 40, 50, 70, 100, 140, and 180 min.

Hormone analyses

Blood samples for hormone determinations were collected in plain Vacutainer tubes SST-II and immediately stored in ice. The tubes were centrifuged at 3000 rpm for 20 min at 4 C, within 1 h from collection. Sera were stored in small aliquots at –80 C until analysis was performed.

Serum glucose was measured by enzymatic-colorimetric method (Glucose Liquid DPR; Sentinel CH., Milan, Italy); insulin and C-peptide were measured by RIA (Insulin Irma CT, RADIM, Pomezia, Rome, Italy; C-Peptide RIA CT, RADIM); fluoroimmunoassays were used for measuring LH, FSH, and SHBG (AutoDELFIA Hfsh Spec, PerkinElmer, Wallac Oy, Turku, Finland; AutoDELFIA Hlh Spec, PerkinElmer, Wallac Oy; AutoDELFIA SHBG, PerkinElmer, Wallac Oy); testosterone, androstenedione, and dehydroepiandrosterone sulfate (DHEA-S) were measured by RIA (Spectria Testosterone RIA, Orion Diagnostica, Espoo, Finland; Androstenedione DSL-4200, Diagnostic System Laboratories, Webster, TX).

The free androgen index (FAI) was calculated by the formula: (total T/SHBG) x 100. The within- and between-assay coefficients of variation for hormonal and metabolic variables were less than 9 and 14%, respectively.

Statistics and calculations

Data obtained from the IVGTT were evaluated by minimal model analysis (23). All variables were examined for normality of distribution with Kolmogorov-Smirnov goodness-of-fit test and, where necessary, log transformation was performed. Statistical analysis was performed by Student’s t test for unpaired data (two-tailed). In case of persistent skew of the distribution after log transformation, Wilcoxon’s rank sum test was used. Pearson’s product moment correlation was used to estimate linear relationships between variables. {chi}2 analyses were performed for categorical variables. The results are expressed as either arithmetic or geometric means, with 95% confidence intervals.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The clinical characteristics of the women with PCOS and controls are reported in Table 1Go. The groups were similar in age, BMI, and WHR. However, the women with PCOS showed a higher proportion of total body fat, as measured by the Durnin formula. Moreover, they had a tendency (not significant) to accumulate trunk-abdominal fat, as shown by skinfold measurement.


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  		TABLE 1. Clinical and anthropometric characteristics in normal-weight women with PCOS and in control women

 
No significant differences were registered in diet composition between the groups. The binge-eating questionnaire did not reveal any abnormal eating behavior in either group (data not shown).

The ovarian morphology and the hormonal profile in the study group showed a typical PCOS pattern, which strongly differed from that of the control women (Tables 1Go and 2Go). SHBG and DHEA-S did not differ between the groups.


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  		TABLE 2. Basal plasma hormone levels, LH/FSH ratio, FAI, and SHBG in 20 normal-weight women with PCOS and 10 control women

 
Fasting serum glucose, insulin, and C-peptide did not differ between the women with PCOS and the controls, nor did the level of insulin sensitivity (Table 3Go). Glucose effectiveness was significantly lower in the women with PCOS (Table 3Go). One control subject had a glucose effectiveness value that was outside the 95% confidence interval (Fig. 1Go). Therefore, statistical analysis was repeated after removing this outlier, but the difference between women with PCOS and controls persisted with a higher level of statistical significance [PCOS 2.6 (2.1–3.0) vs. controls 3.5 (3.0–4.0) mg x 100 min–1; P < 0.01]. No correlation between insulin sensitivity and glucose effectiveness was found for the two groups examined separately, nor when they were merged (Fig. 1Go). Furthermore, the level of glucose effectiveness did not correlate with any of the hormonal or anthropometric variables investigated.


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  		TABLE 3. Metabolic variables in 20 normal-weight women with PCOS and in 20 control women

 


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  		FIG. 1. Insulin sensitivity index (SI; 10–4 min–1/µU·ml) and glucose effectiveness (SG; mg x 100 min–1) during IVGTT in 20 women with PCOS (closed circles) and 20 control women (open circles).

 
ß-Cell activity, as measured by the acute insulin response to glucose (AIRg), was similar in patients and controls, even when analyzed in the context of prevailing insulin sensitivity, i.e. by calculating the disposition index (DI; Table 3Go and Fig. 2Go).



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  		FIG. 2. DI, i.e. correlation between the insulin sensitivity index (SI) and the AIRg in 20 women with PCOS (closed circles) and 20 control women (open circles).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The main finding of the present investigation was the lack of any significant difference in the levels of insulin sensitivity and secretion, as measured by the IVGTT and minimal model analysis, between women with PCOS and weight-matched controls. This result in Mediterranean women with PCOS is in line with previous findings obtained in Scandinavian women with PCOS (4, 7). Overall, these studies corroborate the notion that a substantial proportion of women with the full phenotypic expression of the PCOS have normal insulin sensitivity as measured by either the euglycemic clamp (5, 6, 8, 9) or the IVGTT (24), when the effect of confounding variables is excluded.

This goes against the concept of insulin resistance as a primary feature in all women with PCOS, a notion that was originally suggested by North American studies (10, 12). The lack of consistency in the available literature could partly depend on different diagnostic criteria. In most North American studies, the diagnosis of PCOS has been based on the findings of menstrual irregularities and hyperandrogenism (1990, National Institutes of Health Consensus), whereas in Europe the diagnosis has been traditionally based on ultrasound criteria. The latter method would probably allow the selection of a spread spectrum of clinical pictures, including those with more subtle abnormalities. However, it should be noted that the women with PCOS in the present study, selected on the basis of menstrual irregularities and ultrasound examination, also showed biochemical/clinical hyperandrogenism, thus fulfilling all possible diagnostic criteria for the syndrome. This makes it unlikely that this specific group of women with PCOS differs from other women with PCOS included in the majority of previous studies. Furthermore, the presence of polycystic ovaries in the control women was excluded at enrollment, thus avoiding the risk of selecting women with subtle forms of PCOS as controls.

On the other hand, the groups did not differ in several confounding variables known to affect the results of metabolic investigations (2), such ethnicity (25), diet (26), and a family history of type 2 diabetes mellitus or other metabolic diseases (24).

The women with PCOS showed an increased amount of total body fat, and a tendency (not significant) to accumulate more adipose tissue at sc truncal-abdominal sites (as shown by skinfold measurements) than their controls. This type of fat has been shown to be strongly associated with insulin resistance in women with PCOS (7, 27). However, the fact that BMI and WHR values were similar between the groups suggests that the differences could have been too subtle to determine changes in insulin metabolism in this selected group of women with PCOS.

Despite similar insulin sensitivity, the groups differed in the level of glucose effectiveness. In a previous study, Falcone et al. (28) found similarly decreased glucose effectiveness in women with PCOS. However, in that study, decreased insulin sensitivity and decreased glucose effectiveness coexisted in the women with PCOS. In the present study, decreased glucose effectiveness was an isolated finding, independent from the level of insulin sensitivity. Such a result is difficult to interpret. Glucose effectiveness is a determinant of glucose tolerance, together with insulin secretion and insulin sensitivity (29). It represents the ability of glucose per se to normalize its own concentration under basal insulin conditions (16); this action mostly occurs by the stimulation of glucose utilization, whereas only a small component reflects the inhibition of glucose production (30). It is estimated that in normal individuals between 30 and 50% of glucose disposal after an oral glucose load is due to glucose effectiveness (16). However, glucose effectiveness represents the major contributor to glucose disappearance in states of severe insulin resistance (31, 32, 33, 34).

Decreased glucose effectiveness has been associated with the development of impaired glucose tolerance or type 2 diabetes mellitus in different human populations (35, 36), or with a family history of type 2 diabetes mellitus (37). More recently, decreased glucose effectiveness (but not insulin sensitivity) has been found in patients with other features of the metabolic syndrome, such as increased blood pressure and an enlarged left ventricular mass (38). Furthermore, a cause-effect relationship between elevated free fatty acids and decreased glucose effectiveness has been recently suggested in diabetic individuals (29). Given that level of evidence, it is likely that decreased glucose effectiveness could represent a risk factor for, or an early stage in the development of disturbances of carbohydrate metabolism in women with PCOS, as well. Considering that the women with PCOS in the present study did not have a family history of metabolic diseases, in particular diabetes mellitus, it is tempting to speculate that decreased glucose effectiveness could be considered an intrinsic defect in at least some women with PCOS. Alternatively, it could be a consequence of an increased accumulation of total body fat. However, this hypothesis is not supported by the present data, considering the lack of linear correlation between glucose effectiveness and percent body fat.

ß-Cell activity, as measured by the AIRg, was definitely comparable between the groups. This holds true even when considering this variable in relation to the level of insulin sensitivity, i.e. when calculating the DI (39).

The DI, by including measurements of both insulin action and secretion, allows the analysis of the ß-cell function according to the ambient insulin resistance (40). When insulin resistance develops, insulin secretion should increase to compensate this impairment. As long as the DI is normal, glucose tolerance is also normal. When the increase in insulin secretion, i.e. ß-cell function, becomes inadequate in relation to insulin resistance (lower DI), glucose intolerance and eventually type 2 diabetes develop.

Previous North American studies suggested that defects in ß-cell function, clinically expressed as a reduction of DI, could be an intrinsic feature of the PCOS (24, 41, 42), whereas we and others showed either unchanged or even increased ß-cell activity in women with PCOS and normal glucose tolerance (4, 6), a variable that was independent from the level of insulin sensitivity. However, it should be noted that the patients included in the North American studies are often overweight/obese. It is possible that in those subjects increased and prolonged demands on the ß-cell could induce a precocious functional impairment, resulting in a decrease in DI. On the other hand, the predisposition to ß-cell dysfunction could vary considerably between subjects with or without a family history of diabetes mellitus. If this variable is not taken into account, the possibility exists that varying proportions of women with a genetic predisposition to diabetes, included in the PCOS groups, could be responsible for the heterogeneous results observed in different studies.

In summary, the results of the present study did not confirm the presence of abnormal insulin sensitivity and secretion in normal-weight women with PCOS and no family history of type 2 diabetes mellitus. These findings in a group of Mediterranean women with PCOS confirm previous results obtained in Scandinavian women with PCOS. However, a decreased activity of glucose per se on its own uptake was observed in the women with PCOS. It is tempting to speculate that among various factors, the reduced glucose effectiveness could be considered an additional feature of at least some women with PCOS, although more evidence should be acquired relating the role of glucose effectiveness in the disturbances of glucose metabolism in PCOS. Finally, whether these patients represent a subgroup of the general population of women with PCOS, or simply reflect an early stage in the development of the metabolic aberrations commonly associated with the syndrome, remains to be demonstrated.


   Footnotes
 
First Published Online March 8, 2005

Abbreviations: AIRg, Acute insulin response to glucose; BMI, body mass index; DHEA-S, dehydroepiandrosterone sulfate; DI, disposition index; FAI, free androgen index; IVGTT, iv glucose tolerance test; PCOS, polycystic ovary syndrome; WHR, waist to hip ratio.

Received October 6, 2004.

Accepted March 1, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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P. F. Svendsen, L. Nilas, K. Norgaard, J.-E. B. Jensen, and S. Madsbad
Obesity, body composition and metabolic disturbances in polycystic ovary syndrome
Hum. Reprod., September 1, 2008; 23(9): 2113 - 2121.
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