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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 6 2942-2945
Copyright © 2004 by The Endocrine Society

Insulin Sensitivity in Women with Polycystic Ovary Syndrome

Jana VrbÍková, David Cibula, Kateina Dvoáková, Sona Stanická, Gustav Sindelka1, Martin Hill, Michael Fanta, Karel Vondra and Jan Skrha

Institute of Endocrinology (J.V., K.D., S.S., M.H., K.V.), and Departments of Obstetrics and Gynecology (D.C., M.F.) and Internal Medicine (G.S., J.S.), Charles University in Prague, Prague, 116 94 Czech Republic

Address all correspondence and requests for reprints to: Jana Vrbíková, M.D., Institute of Endocrinology, Národní 8, Prague 1, 116 94 Czech Republic. E-mail: jvrbikova{at}endo.cz.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The aim of our study was to compare insulin sensitivity in lean and obese European polycystic ovary syndrome (PCOS) women with lean healthy women. We performed the euglycemic hyperinsulinemic clamp in 83 women with PCOS [53 lean with body mass index (BMI) of 21.5 ± 1.8 kg/m2 and 30 obese with BMI of 29.6 ± 3.7 kg/m2] and in 15 healthy women with BMI of 21.6 ± 1.8 kg/m2 to determine glucose disposal (M) and the insulin sensitivity index (ISI). Statistical evaluation was done using Kruskal-Wallis ANOVA followed by Kruskal-Wallis multiple-comparison z-value test. The basal blood glucose was significantly higher in lean and obese PCOS women than in controls (P < 0.02). Fasting insulin was significantly higher in both lean and obese PCOS women than in controls (P < 0.000001). Obese PCOS women were more insulin resistant than controls (P < 0.02 for M and P < 0.0008 for ISI); lean PCOS women did not differ from controls in M or ISI. Posthepatic insulin delivery was significantly higher in both lean and obese PCOS women compared with controls (P < 0.000008). We conclude that lean PCOS women are not more insulin resistant than healthy controls. Insulin hypersecretion, on the other hand, is present even in lean PCOS women.


   Introduction
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 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
IT IS GENERALLY accepted that women with polycystic ovary syndrome (PCOS) have a high prevalence of insulin resistance, with a consequent increased risk of metabolic diseases later in life. It is well established that obese PCOS women are insulin-resistant in excess of their adiposity (1, 2). In lean PCOS women, however, the situation is not so clear. To date, there have been two studies using the euglycemic hyperinsulinemic clamp that were not able to demonstrate a difference in insulin sensitivity between lean PCOS women and healthy controls in Europe (3, 4), whereas a study in the United States described significantly impaired insulin action in lean PCOS in comparison with healthy women matched for body fat and fat-free mass (2). Similar results were obtained by another group in Turkey (5). All these studies were conducted on small groups of lean women with PCOS (from 7–11 patients). These discrepancies are not easy to explain; ethnic origin of the patients could probably account for part of the differences.

In the present study, we thus examined large groups of both lean and obese women fulfilling the generally accepted diagnostic criteria of PCOS, using an euglycemic clamp, which is considered the gold standard in evaluating insulin sensitivity. The aim of our study was to compare insulin sensitivity in lean and obese European PCOS women with lean controls.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The study group consisted of 83 oligo/amenorrheic women with PCOS matching the National Institutes of Health criteria (6). All had clinical manifestation of hyperandrogenemia presenting as hirsutism and/or acne and with the elevation of the free testosterone (T) index more than six and/or androstenedione (A) above the upper limit of the normal range. Women were in good health condition, without any other serious disorder. Women with epilepsy or migraine were excluded. In all patients, 17-OH-progesterone was determined in the early follicular phase of their cycle, and if levels were between 5 and 10 nmol/liter, an ACTH test was undergone to exclude late-onset congenital adrenal hyperplasia. Hyperprolactinemia (prolactin levels), hypercortisolism (plasma cortisol, and, if necessary, urinary cortisol excretion per 24 h or short dexamethasone suppression test with 1 mg of dexamethasone at 2200–2300 h), and thyroid dysfunction (TSH, free T4, antithyroglobulin, and anti-thyroid-peroxidase antibodies) were excluded. In one patient, cytologically benign nodular goiter was present; she was on thyroid-suppressive medication with TSH, 0.04 mIU/liter; free T4, 19 pmol/liter (normal range, 12–22 pmol/liter), and T3, 1.83 nmol/liter (normal range, 1.30–3.10 nmol/liter). None of the patients had taken oral contraceptives or any other steroid or glucose-metabolism-affecting medication during the preceding 3 months.

The control group consisted of 15 healthy women with regular menstrual cycles (28–33 d) who also had not used oral contraceptives for at least the preceding 3 months and had no clinical signs of hyperandrogenemia. Their age and BMI were 27.6 ± 6.4 yr and 22.0 ± 2.7 kg/m2, respectively. The controls were recruited from the healthcare personnel of the hospital and their acquaintances.

The local ethical committees of the Institute of Endocrinology and the Faculty Hospital of Charles University in Prague (Prague, Czech Republic) approved the protocol of the study.

The patients and controls were evaluated at the clinical departments of both institutions as outpatients. After signing a written informed consent, they underwent blood sampling for hormonal and biochemical examinations between d 3 and 6 of the menstrual cycle or, in the case of secondary amenorrhea, at any time. After basal blood samples were taken, a 2-h euglycemic hyperinsulinemic (1 mIU/kg·min) clamp was performed as described previously (7). Insulin sensitivity was determined from the values obtained during the steady-state period, between the 100th and 120th minute. Target blood glucose level was 5.0 mmol/liter, with the coefficient of variance (CV) less than 5%.

The following parameters were calculated based on clamp results: glucose disposal rate (M) was defined as the amount of glucose supplied by the infusion to maintain the desired blood glucose level (M, µmol/kg·min), and the insulin sensitivity index (ISI) was defined as the ratio of M and the average insulin concentration during the observed period (ISI, µmol/kg·min per mIU/liter x 100). The posthepatic clearance rate of plasma insulin (MCRI, liter/kg·min) was calculated as the ratio of the insulin infusion rate by the steady-state plasma insulin. Fasting posthepatic insulin delivery (PHD, mIU/kg·min) was obtained as the product of MCRI and fasting plasma insulin (8).

Blood glucose was determined in whole blood by electrochemical method (Super GL; Dr. Muller Gerate Bau, Freital, Germany). Insulin was estimated by immunoradiometric assay kit (Immunotech, Marseille, France) or by RIA kits (CIS Bio International, Marseille, France) (interassay CV < 5%; intraassay CV < 8.5%; correlation coefficient between RIA and immunoradiometric assay was 0.92). T, A, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S), LH, and SHBG were determined as stated previously (9).

Statistical analysis

Kruskal-Wallis robust ANOVA was used for evaluation of the differences between controls, lean PCOS patients, and obese PCOS patients. The individual differences between the subgroups were evaluated by Kruskal-Wallis robust multiple-comparison z-value test. NCSS 2001 (Number Cruncher Statistical Systems, Kaysville, UT) was used for the calculations.


   Results
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 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The basal demographical, biochemical, and hormonal parameters in controls and lean and obese PCOS women are given in Table 1Go. As expected, significantly higher levels of T, A, and DHEA-S were found in both lean and obese PCOS compared with controls. SHBG levels were significantly lower in both lean and obese PCOS than in controls.


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  		TABLE 1. Differences between group of controls (C) and lean (L) and obese (O) PCOS women in anthropometric characteristics and biochemical markers

 
Basal blood glucose was significantly higher in lean and obese PCOS than in controls (P < 0.02). Basal insulin was significantly higher in obese and lean PCOS women than in controls (P < 0.000001). M was significantly lower in obese than in lean PCOS and controls (P < 0.02), and the same was observed for ISI (P < 0.0008). On the other hand, lean PCOS did not differ in M or ISI from controls. MCRI was significantly lower in obese than in lean PCOS (P < 0.03) and showed no difference between lean PCOS and controls. PHD was higher in both lean and obese PCOS compared with controls (P < 0.000008; Fig. 1Go).



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  		FIG. 1. Relationships between clamp indices and patient groups (C, controls; L, lean PCOS patients; O, obese PCOS patients). Dotted bars with error barsrepresent means with their 95% confidence intervals, whereas P<... denotes statistical significance of the overall trend as found by Kruskal-Wallis z-value test, multiple comparisons on the level of statistical significance of P< 0.05, were symbolized as follows: C-L, difference between controls and lean PCOS patients; C-O, difference between controls and obese PCOS patients; L-O, difference between lean and obese PCOS patients. The numbers in parenthesesat the end of the labels in the x-axis represent the numbers of subjects in the groups. G0, Basal blood glucose; IRI0, basal insulinemia.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
PCOS is a heterogeneous syndrome. In the phenotypic spectrum, we can find obese, invariably insulin-resistant women, and at the other extreme, lean PCOS patients with marked hyperandrogenemia but without insulin resistance. Nevertheless, until now, there have been few studies (3, 10) conducted on larger groups of PCOS women to evaluate whether insulin resistance is invariably connected with PCOS and, consequently, whether the majority of lean PCOS women is thus insulin resistant or whether insulin resistance is only an epiphenomenon related to body weight. Few studies found decreased insulin sensitivity only in association with abdominal obesity (3) or in lean PCOS women if they were also hyperinsulinemic (10).

Insulin resistance is a well-known risk factor for diabetes mellitus type 2. It is closely associated with syndrome X and is probably one of its central features (11). PCOS women show a pattern of cardiovascular risk factors (12) putting them at a greater risk of cardiovascular events. Thus, the early identification of insulin-resistant PCOS women could be advantageous from the perspective of possible early preventive measures.

In the present study, we documented that lean PCOS women are not insulin resistant in comparison with healthy controls. Lower insulin sensitivity was found only in obese PCOS women when compared with both controls and lean PCOS. This result is in accordance with others (3, 4) examining European PCOS women, who found no difference in insulin sensitivity between the PCOS women and healthy women with BMI of 21 kg/m2 but a significant reduction at BMI of about 28 and 35 kg/m2, respectively. After adjustment for truncoabdominal fat, both groups have similar insulin sensitivities over the whole range of BMI. On the contrary, there is good evidence in American or Asian PCOS women that they are insulin resistant independent of BMI (5) and body composition (2). These discrepancies cannot be easily explained and deserve future investigations. Probably, ethnic background, dietary composition, and a more sedentary lifestyle in the United States could play a role.

In addition to normal insulin sensitivity in lean PCOS, we found insulin hypersecretion in both lean and obese PCOS women compared with healthy women. Although basal insulin secretion was not measured directly in our study, our data accord well with the values obtained by others in general population using PHD as an estimate of insulin secretion (8) or with the results of C-peptide deconvolution analysis (13). The data related to insulin secretion in PCOS published so far are inconsistent. There is evidence supporting defective glucose-stimulated insulin secretion in PCOS using a minimal model and disposition index (1, 14). On the other hand, an increase in basal insulin secretion rate and a decrease in meal-stimulated pulses was found (15), as well as insulin hypersecretion independent of obesity (3). We have recently described increased glucose-stimulated ß-cell function even in lean individuals with PCOS (16). Using the oral glucose tolerance test and euglycemic clamp, insulin resistance and hypersecretion were found to be two distinct features of PCOS (10). Higher basal insulin levels described in lean PCOS women could thus be explained by basal insulin hypersecretion rather than by insulin resistance. The exact cause of basal insulin hypersecretion is not known. It could be speculated that hypersecretion could be determined genetically because heritability of fasting plasma insulin was found even after adjustment for BMI and insulin resistance (17). On the other hand, early phase of insulin secretion during iv glucose tolerance test was shown to be correlated with androgenicity (3) in PCOS, and thus, environmental factors also could play a role.

Decreased hepatic clearance of insulin may also influence basal insulinemia. We found lower hepatic clearance of insulin only in obese PCOS patients. This finding is in accordance with others (10), who found impaired insulin clearance defined by the ratio of basal C-peptide to insulin in obese but not in lean PCOS women. We are aware of the fact that the MCRI could be underestimated, especially in obese individuals when not corrected for the endogenous insulin secretion. Thus, to what extent basal insulin levels in obese PCOS patients are influenced by insulin resistance, defective hepatic insulin clearance, and increased insulin secretion remains to be established by other studies using direct measurement.

In conclusion, we were not able to confirm insulin resistance in lean PCOS women in comparison with lean healthy controls. On the other hand, lean PCOS women had higher basal insulin levels, probably caused by the increased basal insulin secretion. Obese PCOS women were more insulin resistant than both lean PCOS and lean controls.


   Footnotes
 
This work was supported by Grants NB/6696-3 and NH/6558-3 from the Internal Grant Agency of the Czech Ministry of Health.

J.V. and D.C. contributed equally to the study.

Abbreviations: A, Androstenedione; BMI, body mass index; CV, coefficient of variance; DHEA, dehydroepiandrosterone; DHEA-S, dehydroepiandrosterone sulfate; ISI, insulin sensitivity index; M, glucose disposal rate; MCRI, posthepatic clearance rate of plasma insulin; PCOS, polycystic ovary syndrome; PHD, posthepatic insulin delivery; T, testosterone.

1 G.S. died tragically in 2001. Back

Received August 18, 2003.

Accepted February 23, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Dunaif A, Finegood DT 1996 ß-Cell dysfunction independent of obesity and glucose intolerance in the polycystic ovary syndrome. J Clin Endocrinol Metab 81:942–947[Abstract]
  2. Dunaif A, Segal KR, Futterweit W, Dobrjansky A 1989 Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 38:1165–1174[Abstract]
  3. Holte J, Bergh T, Berne C, Berglund L, Lithell H 1994 Enhanced early insulin response to glucose in relation to insulin resistance in women with polycystic ovary syndrome and normal glucose tolerance. J Clin Endocrinol Metab 78:1052–1058[Abstract]
  4. Ovesen P, Moller J, Ingerslev HJ, Jorgensen JO, Mengel A, Schmitz O, Alberti KG, Moller N 1993 Normal basal and insulin-stimulated fuel metabolism in lean women with the polycystic ovary syndrome. J Clin Endocrinol Metab 77:1636–1640[Abstract]
  5. Toprak S, Yonem A, Cakir B, Guler S, Azal O, Ozata M, Corakci A 2001 Insulin resistance in nonobese patients with polycystic ovary syndrome. Horm Res 55:65–70[Medline]
  6. Dunaif A 1997 Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 18:774–800[Abstract/Free Full Text]
  7. DeFronzo RA, Tobin JD, Andres R 1979 Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237:E214–E223
  8. Ferrannini E, Natali A, Bell P, Cavallo-Perin P, Lalic N, Mingrone G 1997 Insulin resistance and hypersecretion in obesity. European Group for the Study of Insulin Resistance (EGIR). J Clin Invest 100:1166–1173[Medline]
  9. Vrbikova J, Hill M, Starka L, Cibula D, Bendlova B, Vondra K, Sulcova J, Snajderova M 2001 The effects of long-term metformin treatment on adrenal and ovarian steroidogenesis in women with polycystic ovary syndrome. Eur J Endocrinol 144:619–628[Abstract]
  10. Ciampelli M, Fulghesu AM, Cucinelli F, Pavone V, Caruso A, Mancuso S, Lanzone A 1997 Heterogeneity in ß cell activity, hepatic insulin clearance and peripheral insulin sensitivity in women with polycystic ovary syndrome. Hum Reprod 12:1897–1901[Abstract/Free Full Text]
  11. McFarlane SI, Banerji M, Sowers JR 2001 Insulin resistance and cardiovascular disease. J Clin Endocrinol Metab 86:713–718[Free Full Text]
  12. Wild RA 2002 Polycystic ovary syndrome: a risk for coronary artery disease? Am J Obstet Gynecol 186:35–43[CrossRef][Medline]
  13. Polonsky KS, Given BD, Van Cauter E 1988 Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects. J Clin Invest 81:442–448
  14. Ehrmann DA, Sturis J, Byrne MM, Karrison T, Rosenfield RL, Polonsky KS 1995 Insulin secretory defects in polycystic ovary syndrome. Relationship to insulin sensitivity and family history of non-insulin-dependent diabetes mellitus. J Clin Invest 96:520–527
  15. O’Meara NM, Blackman JD, Ehrmann DA, Barnes RB, Jaspan JB, Rosenfield RL, Polonsky KS 1993 Defects in ß-cell function in functional ovarian hyperandrogenism. J Clin Endocrinol Metab 76:1241–1247[Abstract]
  16. Vrbikova J, Bendlova B, Hill M, Vankova M, Vondra K, Starka L 2002 Insulin sensitivity and ß-cell function in women with polycystic ovary syndrome. Diabetes Care 25:1217–1222[Abstract/Free Full Text]
  17. Weyer C, Hanson RL, Tataranni PA, Bogardus C, Pratley RE 2000 A high fasting plasma insulin concentration predicts type 2 diabetes independent of insulin resistance: evidence for a pathogenic role of relative hyperinsulinemia. Diabetes 49:2094–2101[Abstract]



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