Human Reproduction vol.7 no.7 pp.922-925, 1992

Impaired glucose effectiveness in patients with polycystic ovary syndrome

Tommaso Falcone2, A.Brian Little2 and David Morris1 Departments of Medicine and 2Obstetrics and Gynaecology, Division of Endocrinology, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec H3A 1A1, Canada 'To whom correspondence should be addressed

Insulin resistance and glucose intolerance are common features of polycystic ovary syndrome (PCOS). We have investigated the effect of glucose on the fractional glucose disappearance in patients with PCOS and in age- and weightmatched control subjects. The minimal model method as applied to a frequently sampled intravenous ghicose tolerance test was employed. The insulin sensitivity index (Si) and ghicose effectiveness (SG) were calculated with the IVflNMOD program. Testosterone, androstenedione and free testosterone concentrations were significantly higher in PCOS subjects. Glucose-induced ghicose clearance (SG) and insulin sensitivity were significantly lower hi PCOS subjects than controls [SG: 2.7 ± 0.3 versus 1.8 ± 0.1 x 100/min; P < 0.01; S,: 133.4 ± 20.0 versus 65.6 ± 6.4/min (nmol/ml)]. Six PCOS women had an SG value within the normal range (> 2.0 x 100/min) but had a similar S] to that found in PCOS women with abnormal SG. We suggest that independent alterations in both glucose- and insulin-mediated glucose uptake occur in patients with PCOS. The underlying disturbance in glucose effectiveness may be similar to that found in familial non-insulin dependent diabetes mellitus. Key words: glucose effectiveness (SG)/insulin sensitivity (S,)

Introduction Insulin resistance is a common feature of both type II diabetes and polycystic ovary syndrome (PCOS) (Falcone et al., 1990; Welch et al., 1990; Warram et al., 1990). Insulin-dependent utilization of peripheral glucose is diminished in patients with hyperandrogenism (Peiris et al., 1989; Dunaif et al., 1989). Glucose-induced glucose disposal is reduced in type II diabetic subjects (Welch et al., 1990). Similar findings have been reported in the normal offspring of two parents with type II diabetes (Warram et al., 1990). These findings suggest that hyperandrogenic woman may show an impaired peripheral response to both insulin and glucose, comparable to that seen in type II diabetics and their offspring. The androgen excess found in PCOS subjects with reduced insulin sensitivity may in part reflect the insulin resistance, since 922 Downloaded from https://academic.oup.com/humrep/article-abstract/7/7/922/643233 by University of California, Santa Barbara user on 11 April 2018

we have shown that suppression of the dehydroepiandrosterone (DHEA) concentration normally caused by insulin is impaired (Falcone et al., 1990). We have therefore investigated the effect of glucose on fractional glucose disappearance and its relationship to insulin sensitivity using the minimal model approach in patients with PCOS. The patients and controls in this study have been previously reported (Falcone et al., 1990). This previous study dealt with the androgen response to a frequently sampled intravenous glucose tolerance test. This is the first report on the effect of glucose on the fractional glucose disappearance in patients with PCOS. Materials and methods The study was approved by the Ethics Committee of the Department of Obstetrics and Gynaecology of the Royal Victoria Hospital. Women were recruited from the population of the Reproductive Medicine Clinic and gave fully informed consent for the investigation. They were included as PCOS subjects if they had amenorrhoea or oligomenorrhoea associated with hirsutism (grade 2 or greater on the face and abdomen) (Ferriman, 1971), and circulating testosterone and androstenedione concentrations 1.5 SD above those of a group of 55 normal women with proven fertility [normal values (mean ± SD): testosterone, 1.4 ± 0.6 nmol/1; androstenedione, 7.4 ± 1.2 nmol/1]. An adrenocorticotrophic hormone (ACTH) test was performed in all subjects to exclude non-classical 21-hydroxylase deficiency (New et al., 1983). Control subjects were healthy volunteers with no history or clinical evidence of any endocrine or reproductive abnormality. Twenty women with PCOS and nine age- and weight-matched controls were investigated. Their clinical details and serum hormone concentrations are shown in Table I, and have been reported previously (Falcone et al., 1990). Their body mass index was calculated by dividing the weight in kilograms by the square of the height in metres. After initial evaluation and informed consent being given, the women were placed on a diet which included 300 g of carbohydrate for a period of 3 days. They were then admitted, after a 12 h fast, to the Metabolic Day Centre. In women with known menstrual cycles, the studies were performed in the midfollicular phase (days 6 — 7). Two antecubital venous catheters were inserted, and four basal blood samples were collected over a 20 min period at 5 min intervals. A frequently sampled intravenous glucose tolerance test was then performed as previously described (Berman et al., 1987). Glucose (300 mg/kg, i.v. was followed 20 min later by tolbutamide (300 mg for women with a body mass index < 30 kg/m2 and 500 mg for © Oxford University Press

Impaired glucose effectiveness in PCOS patients

those with a body mass index >30 kg/m2) infused i.v. as a bolus. Glucose and insulin samples were obtained at 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 19, 22, 24, 25, 27, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160 and 180 min. Baseline insulin and glucose levels were defined as the mean levels in samples obtained during the initial 20 min period prior to the administration of glucose. Hormone measurements All samples from one experiment were measured in a single assay. Serum glucose concentrations were determined by the glucose oxidase method (Beckman Glucose Analyser, Fullerton, CA). Serum insulin levels were determined by a double antibody radioimmunoassay (Fantus and Brosseau, 1986), with an intraassay coefficient of variation of 4.5-5.5% and an inter-assay coefficient of variation of 7.6%. Serum testosterone, androstenedione, free testosterone and DHEA were measured by radioimmunoassay (Radioassay Systems Laboratories, Inc., Carson, CA). The intra- and inter-assay coefficients of variation were as follows: androstenedione (10.6%, 13.8%), testosterone (4.4%, 13.0%), free testosterone (6.9%, 12.1%), and DHEA (9.8%, 12.4%).

AT. Details of this analysis have been previously described (Welch et al., 1990). In brief, the minimal model of glucose kinetics describes the relationship between the plasma insulin level and the fall in the plasma glucose level after an i.v. glucose injection. Insulin is said to enter a remote compartment from which insulin action occurs. S, is a measure of the effect of insulin concentration above the basal level to enhance glucose disappearance. SG is the total effect of glucose on fractional glucose disappearance independent of an increase in insulin, but including the contributions of basal insulin (Welch et al., 1990). Statistical analysis Student's r-test was used for inference on means (using pooled estimate of common variance), while the chi-square test (with continuity correction) was used to determine statistical differences in categorical variables between cases and controls. Correlation coefficients were calculated using Pearson's coefficient of correlation. Spearman's rank correlation test was used for analysis of non-parametrically distributed variables. To test the significance of the correlation coefficient, we used the /-distribution to calculate critical values. Analysis of variance was computed using a two-tailed test.

Minimal model analysis Insulin sensitivity (S,) and glucose effectiveness (SG) were determined using the MINMOD computer program (Pacini and Bergman, 1986; copyright R.N.Bergman) run on an IBM PC-

Results The patients and control subjects were similar in age and weight (Table I). A similar proportion of both PCOS and control women

TaWe I. Clinical details and serum hormone concentrations (mean ± SE) of 20 women with polycystic ovary disease syndrome (PCOS) and nine age- and weightmatched controls Variable

Controls (n = 9)

Age (years) BMI (kg/m2) Insulin (pmol/1) Glucose (mmol/l) Androstenedione (nmol/1) Testosterone (nmol/1) Free testosterone (pmol/1) DHEA (nmol/1)

29.3 26.7 59 5 4.8 6.1 1.9 9.0 28 4

Glucose effectiveness (SG) (x 100/min) Insulin sensitivity (S,) (nmol/ml/min)

2.7 ± 0 3 33.4 ± 20.0

± ± ± ± ± ± ± ±

PCOS (n = 20)

2.5 15 7.1 0.1 06 0.3 1 1 3.0

26 .2 27 .2 81 .1 4 .8 8 .7 3 .1 13.3 29 .1

± ± ± ± ± ±

1.2 NS 1 4 NS 7.7 * 0.1 NS 0.6 0.3 • • 1.0 * * ± 5.1 NS

1 8 ± 0.1 ** 65 .6 ± 6.4 **

*P < 0.05; **P < 0.01; NS = non-significant; BMI = body mass index, DHEA = dehydroepiandrosterone Data previously reported by Falcone el al. (1990).

Table II. Findings (mean ± SE) in women with polycystic ovary syndrome (PCOS) stratified by normal (N) glucose effectiveness (SG) and reduced (R) SG Variable

SG-N (n = 6)

SG-R (n = 14)

Age (years) BMI (kg/m2) Insulin (pmol/1) Glucose (mmol/l) Androstenedione (nmol/1) Testosterone (nmol/1) Free testosterone (pmol/1) DHEA (nmol/1)

28.3 26.1 56.0 5.0 8.2 3.2 13.9 27.8

25 2 27 .6 83 .3 4 .7 8 .9 3 .1 12.9 29 .7

± 19 ± 2.3 ± 11 3 ± 0.18 ± 0.7 ± 0.3 ± 1.3 ± 11.4

Glucose effectiveness (SG) (X 100/min) 2 8 ± Insulin sensitivity (S,) (nmol/ml/min) 78.4 ±

01 9.6

± 1.6 NS ± 1.8 NS ± 10.4 NS ± 0.22 NS ± 0.8 NS ± 0.4 NS ± 1.3 NS ± 5.7 NS

1.4 ± 60.0 ±

0 07»* 9 6 NS

BMI = body mass index, DHEA = dehydroepiandrosterone; NS = Non-significant, **P < 0.01.

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T.Falcone, A.B.Uttle and D.Morris

Controls 200

SI (min-1/nmol/ml)

with reduced glucose effectiveness (SG) in any other clinical or endocrine parameter (Table II). Discussion

150

100

2

3

SQ (X100 min-1)

PCOS 200

SI (min-1/nmol/ml)

140

2

3

SQ (X100 min-1)

Fig. 1. Relationship between the insulin sensitivity index (S,) and glucose effectiveness (SG) in 20 women with polycystic ovary syndrome (PCOS) and nine age- and weight-matched controls. were obese, with a body mass index >27 (57% of the PCOS and 55% of the control subjects). The fasting concentrations of insulin, androstenedione, testosterone and free testosterone were significantly higher in the women with PCOS. No difference in fasting glucose or DHEA concentrations was found between the groups. Glucose effectiveness SG and insulin sensitivity S, were significantly lower in the PCOS subjects than in the controls (Table I). A positive relationship between body mass index and fasting insulin was noted in both PCOS cases (r = 0.75, P < 0.001) and controls (r = 0.67, P < 0.05). No relationship was found between glucose effectiveness SG and insulin, glucose, androstenedione, testosterone, free testosterone or DHEA in control or PCOS subjects. In the controls, S, was related to SG (r = 0.70, P < 0.01) (Figure 1), insulin (r = - 0 . 7 6 , P < 0.05) and body mass index 0.63, P < 0.01). In the PCOS group, Si was not significandy related to SG (Figure 1), but was related to insulin (r = - 0 . 6 7 , P < 0.01) and body mass index (r = 0.63, P < 0.01). Analysis of the PCOS subjects revealed that six had SG values within one standard deviation of the control group mean ( > 2 x 100/min). There was no significant difference between this subgroup of PCOS patients with normal glucose effectiveness (SG) and those 924 Downloaded from https://academic.oup.com/humrep/article-abstract/7/7/922/643233 by University of California, Santa Barbara user on 11 April 2018

We have demonstrated that in patients with PCOS there is a significant reduction of glucose-induced glucose disposal, independent of body weight. Values of glucose effectiveness (SG) obtained in our PCOS patients are similar to those in diabetics (Welch et al., 1990). Subgroups of patients may have one defect, i.e. normal glucose effectiveness and reduced insulin sensitivity, while others may have both reduced glucose and insulin sensitivity. Although insulin sensitivity appears to be correlated with glucose effectiveness in controls, this does not appear to be the case in PCOS subjects. This suggests that insulin resistance and impaired glucose effectiveness may be independent of one another in PCOS patients. These findings are similar to those in the apparently normal offspring of type II diabetic parents in whom reduced glucose clearance and fasting hyperinsulinaemia is present long before the diagnosis of type II diabetes is made (Warram et al., 1990). It is thought that reduced glucose clearance is associated with compensatory hyperinsulinaemia, which in turn can lead to defects in insulin action at receptor and post-receptor sites (Garvey et al., 1986) and thus insulin resistance (Rizza etal, 1985). The metabolic disturbances in PCOS are obviously complex and inter-related. Although the severe insulin resistance in a few women with the syndrome reflects genetically abnormal insulin receptor genes (Moller and Flier, 1988), this is a rare finding, which could be due to the limited technology available. Since suppression of androgen secretion does not alter insulin resistance, it is likely that these defects contribute to the development of androgen excess. The abnormality in glucose effectiveness may reflect a similar disturbance to that found in early non-insulin dependent diabetes mellitus. This syndrome thus provides an excellent experimental model to study the progress of the metabolic abnormalities found in non-insulin dependent diabetes mellitus. Acknowledgements This work was supported by a grant from the Royal Victoria Hospital Foundation and was presented at the 38th Annual Meeting of the Society for Gynecologic Investigation, San Antonio, Texas, March 1991. References Berman,R.N., Prager.R., Volund,A. and Olefsky.J.M. (1987) Equivalence of the insulin sensitivity index in man derived by the minimal model method and the euglycemic clamp. J. Clin. Invest., 79, 790-800. Dunaif.A., Segal,K., Futterweh,W. and DobrjanskyJ. (1989) Profound periphera) resistance independent of obesity in polycystic ovary syndrome. Diabetes, 38, 1165-1174. Falcone,T., Finegood.D.T., Fantus,l.G. and Morris,D. (1990) Androgen response to endogenous insulin secretion during the frequently sampled intravenous glucose tolerance test in normal and hyperandrogenic women. J. Clin. Endocrinol. Metab., 71, 1653-1657. Fantus.I.G. and Brosseau.N. (1980) Mechanism of action of metformin: insulin receptor and post receptor effects in vitro and in vivo. J. Clin. Endocrinol. Metab., 63, 898-905.

Impaired glucose effectiveness in PCOS patients

Fernman.D. (1971) Human Hair Growth in Health and Disease. Thomas, Springfield. Garvey.W.T., Olefsky.J.M. and Marshall.S. (1986) Insulin induces progressive insulin resistance in cultured rat adipocytes. Sequential effects at receptor and multiple postreceptor shes. Diabetes, 258, 267. Moller.D.E. and FlierJ.S. (1988) Detection of an alteration in the insulin receptor gene in a patient with insulin resistance, acanthosis nigricans, and the poly cystic ovary syndrome (type A insulin resistance). N. Engl. J. Med., 319, 1526-1529. New.M.I., Lorenzen,F. and Lerner.A.J. (1983) Genotyping steroid 21-hydroxylase deficiency: hormonal reference data. J. Clin. Endocrinol. Metab., 57, 320-326. Pacini.G. and Bergman,R.N. (1986) MINMOD: a computer program to calculate insulin sensitivity and pancreatic responsivity from the frequently sampled intravenous glucose tolerance test. Comput. Methods Progr. Biomed., 23, 113-122. Peiris,A.N., Aiman.EJ., Drucker.W.D. and Kissebah,A.H. (1989) The relative contributions of hepatic and peripheral tissues to insulin resistance in hyperandrogenic women. J. Clin. Endocrinol. Metab., 68, 715-720. Rizza,R.A., Mandarino.L.J., Genest.J., Baker.B.A. and Gerich.J.E. (1985) Production of insulin resistance by hyperinsulinemia in man. Diabetologia, 28, 70-75. Warram,J.H., Martin,B.C, Krowlewski,A.S., SoeldnerJ.S. and Kahn.R.C. (1990) Slow glucose removal and hyperinsulinemia precede the development of type II diabetes in offspring of diabetic parents. Ann. Intern. Med., 113, 909-915. Welch,S., Gebhart.S.S.P., Bergman,R.N. and Phillips,L.S. (1990) Minimal model analysis of intravenous glucose tolerance test-derived insulin sensitivity in diabetic subjects. J. Clin. Metab., 71, 1509-1518. Received on January 23, 1992; accepted on March 16, 1992

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Impaired glucose effectiveness in patients with polycystic ovary syndrome.

Insulin resistance and glucose intolerance are common features of polycystic ovary syndrome (PCOS). We have investigated the effect of glucose on the ...
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