E-Cell Dysfunction, Glucose Intolerance, and Diabetes in the Polycystic Ovary Syndrome

Chapter 28 / Diabetes in PCOS 319

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From: Contemporary Endocrinology: Androgen Excess Disorders in Women:

Polycystic Ovary Syndrome and Other Disorders, Second Edition Edited by: R. Azziz et al. © Humana Press Inc., Totowa, NJ

28

E-Cell Dysfunction, Glucose Intolerance, and Diabetes in the Polycystic Ovary Syndrome

David A. Ehrmann

SUMMARY

Among women with polycystic ovary syndrome (PCOS), the prevalence of impaired glucose tolerance is estimated to be between 30 and 40%, whereas that of type 2 diabetes mellitus has been placed at 5–10%. These prevalences are among the highest known among women of reproductive age. The predisposition to glucose intolerance in PCOS may be influenced by antenatal events, including the rate of in utero growth and develop- ment as well as exposure to excess androgen concentrations from the maternal circulation. Once defects in insulin secretion develop in the setting of the characteristic insulin resistance of PCOS, glucose intolerance becomes evident. Provocative testing of pancreatic E-cell function may provide insights into the future risk for glucose intolerance among women with PCOS.

Key Words: Polycystic ovary syndrome; glucose tolerance; E-cell; insulin resistance.

1. INTRODUCTION

It is now well established that women with polycystic ovary syndrome (PCOS) are predisposed to develop a number of metabolic abnormalities, including impaired glucose tolerance (IGT) and type 2 diabetes mellitus (DM) (1,2). The prevalence of IGT has been estimated to be between 30 and 40%, whereas that of type 2 DM has been placed at 5–10% (1,2). Given that PCOS is thought to affect between 5 and 8% (5.7–9.1 million) of reproductive-aged women in the United States (3), it follows that at any given time an estimated 3 million women with PCOS will have IGT, whereas approxi- mately 1 million women with PCOS will have type 2 DM. This chapter focuses on the origins of glucose intolerance in PCOS, with an emphasis on the role of the pancreatic E-cell in this process.

2. BACKGROUND

2.1. Antecedents to Glucose Intolerance in PCOS

Recent attention has focused on developmental origins of adult diseases, including both PCOS and type 2 DM. Evidence exists to support the hypothesis that low (4,5) birthweight and/or size for gestational age may lead to insulin resistance, obesity, and type 2 DM in later life. The mechanisms underlying these associations are unknown, but alterations in birthweight (reflecting in utero growth/

nutritional status) have also been implicated in the pathogenesis of PCOS per se and its associated insulin resistance and glucose intolerance in some (6), but not all (7,8), studies.

Another developmental factor that has been proposed to influence the phenotypic expression of

PCOS is in utero androgen exposure (see Chapter 23). In nonhuman primates, fetal exposure to high

levels of androgen during early in utero development is associated with defects in insulin secretion

and action in adult life (9). Prenatally androgenized female rhesus monkeys exhibit glucoregulatory deficits similar to those seen in adult women with PCOS (10). Of interest, the timing of the androgen exposure appears to differentially affect glucose regulation: early androgen exposure has been asso- ciated with impaired pancreatic E-cell function, whereas exposure later in gestation appears to prima- rily alter insulin sensitivity. The extent to which these hormonal factors relate to the pathogenesis of PCOS in the human is not known.

It is now well documented that glucose intolerance in PCOS can occur as early as during the second decade of life (11–15). In one study, 27 adolescents with PCOS (mean age 16.7 r 1.6 years;

mean body mass index [BMI] 38.4 r 8.8 kg/m

) had an oral glucose tolerance test (OGTT): 8 (30%) were found to have IGT, 1 (4%) had undiagnosed DM, and the remaining 18 (66%) had normal glucose tolerance (11). Studies by Arslanian et al. (13) have shown that metabolic precursors to type 2 DM (decreased first-phase insulin secretion, decreased glucose disposition index, and increased hepatic glucose production) are evident among obese adolescents with PCOS.

2.2. Relationship of Insulin Secretion to Insulin Action

Glucose intolerance typically develops when defects in insulin secretion are superimposed upon a background of insulin resistance (16). Despite the fact that women with PCOS are characteristically insulin resistant, not all develop abnormalities in glucose tolerance. It has become evident that insu- lin secretory defects play an important role in the propensity to develop DM in PCOS.

Insulin secretion is most appropriately expressed in relation to the magnitude of ambient insulin

resistance. The product of these measures can be quantified (the so-called “disposition index”) and

related as a percentile to the hyperbolic relationship for these measures (Fig. 1) established in normal

subjects (17). We (18), as well as others (19), have found that a subset of subjects with PCOS has

E-cell secretory dysfunction. In absolute terms, women with PCOS had normal first-phase insulin

secretion compared to controls. In contrast, when first-phase insulin secretion was analyzed in

Fig. 1. Hyperbolic relationship between insulin secretion and insulin action in normoglycemic subjects stud-

ied with a frequently sampled intravenous glucose tolerance test reflecting the disposition index, based on data

of Kahn et al. (17). As insulin sensitivity (S

) declines, insulin secretion (acute insulin response to glucose [AIR

glucose]) must increase to maintain normal glucose tolerance. Shown are mean percentiles for PCOS subjects

previously reported (18) as well as mean summary data derived from the literature for women with a prior

history of gestational diabetes mellitus (Former GDMs) and subjects with a first-degree relative with type 2

diabetes mellitus. (From ref. 31.)

Chapter 28 / Diabetes in PCOS 321

relation to the degree of insulin resistance, women with PCOS exhibited a significant impairment in E-cell function. This reduction was particularly marked in women with PCOS who had a first- degree relative with type 2 DM: the mean disposition index of women with PCOS and a family history of type 2 DM was in the 8th percentile, while that of those without such a family history was in the 33rd percentile (p = 0.05) (Fig. 1). We have additionally quantified E-cell function in PCOS by examining the insulin secretory response to a graded increase in plasma glucose and by the ability of the E-cell to adjust and respond to induced oscillations in the plasma glucose level (18). Results from both provocative stimuli were consistent: when expressed in relation to the degree of insulin resis- tance; insulin secretion was impaired in PCOS subjects with a family history of type 2 DM when compared to controls.

Because these findings were consistent with studies showing a high degree of heritability of E-cell function (particularly when examined in relation to insulin sensitivity) among nondiabetic family members of individuals with type 2 DM (20), we sought to examine this further. Using the frequently sampled intravenous glucose tolerance test, insulin secretion (the acute insulin response to glucose [AIR

], insulin action (sensitivity to insulin [S

], and their product (disposition index [DI] = AIR

u S

) were quantified among women with PCOS (n = 33) and their nondiabetic first-degree relatives (n = 48) (21). Heritability of these measures was calculated from familial correlations estimated within a genetic model. The sibling correlation for AIR

was highly significant after adjustment for age and BMI, as was the disposition index, a measure of quantifying insulin secretion in relation to insulin sensitivity. This finding was supportive of a heritable component to E-cell dysfunction in families of women with PCOS.

Taken together, these results suggest that the risk imparted by insulin resistance to the develop- ment of type 2 DM in PCOS is enhanced by defects in insulin secretion. Furthermore, a history of type 2 DM in a first-degree relative appears to define a subset of PCOS subjects with the most pro- found defects in E-cell function.

Although nearly one-half of women with PCOS will ultimately develop glucose intolerance, most have been able to maintain glucose levels within the normal range at the time of initial clinical pre- sentation (1,2). This has been taken as evidence that their ability to adequately secrete insulin in compensation for the degree of insulin resistance is retained. However, most (1,22) but not all (23) studies have found that the rates of decline in glucose tolerance in PCOS are higher than expected compared to reference populations. This suggests that pancreatic E-cell dysfunction may supervene earlier in the evolution of glucose intolerance in women with PCOS compared to women without PCOS. The basis for this, however, remains unclear.

2.3. Provocative Assessment of Insulin Secretion

The development of transient DM in previously nondiabetic individuals treated with short-term glucocorticoids (“steroid diabetes”) has been recognized for many years. The potential of this finding as a predictor for subsequent development of DM was first described by Fajans et al. (24), who found that when normal glucose-tolerant individuals with a first-degree relative with DM were given small doses of cortisone acetate, 24% had IGT and 19% had DM on OGTT. In contrast, among those without a family history of DM, 3% developed IGT and 2% developed DM. In addition, an abnormal response to cortisone acetate was predictive of the subsequent development of DM over 7 years of follow-up: 35% of those with cortisone-induced glucose intolerance had developed DM compared with only 2% of those whose initial response was normal.

Henriksen et al. (25) have shown that nondiabetic first-degree relatives of type 2 diabetics with

evidence of mild alteration of E-cell function at baseline are unable to enhance their E-cell response to

dexamethasone-induced insulin resistance. Specifically, after treatment with dexamethasone (4 mg daily

for 5 days), normoglycemic subjects with or without a first-degree relative with DM increased their

first-phase insulin secretion to glucose on an intravenous glucose tolerance test. However, the dispo-

sition index (AIR

u S

) was significantly lower in the relatives (25).

The predominant mechanism responsible for glucocorticoid-induced glucose intolerance appears to be related to the induction or exacerbation of insulin resistance (26). Insulin-mediated peripheral glucose disposal is markedly impaired at a post-insulin receptor level (27). Both oxidative and nonoxidative pathways of glucose disposal are reduced by glucocorticoids (26), and muscle glycogen synthase activity is reduced (28,29). These alterations in insulin action resemble those observed in type 2 DM. Although insulin secretion may be altered by glucocorticoids, this appears to occur only at high doses (30).

We postulated that women with PCOS with normal glucose tolerance would differ from control women with normal glucose tolerance in their ability to secrete sufficient insulin and maintain nor- mal glucose tolerance after administration of dexamethasone (2 mg orally over 12 hours). In the baseline state (i.e., before the administration of dexamethasone), control women and women with PCOS had normal fasting glucose concentrations (94 r 2 vs 95 r 2 mg/dL) as well as similar glucose levels at 2 hours in response to a standard 75-g oral glucose load (120 r 7 vs 124 r 5 mg/dL).

However, when faced with a reduction in insulin sensitivity induced by the administration of dexam- ethasone, women with PCOS were significantly less able than control subjects to compensate with adequate insulin secretion. This was evidenced by a relative attenuation in C-peptide levels relative to plasma glucose during the OGTT (Fig. 2). These data suggest that short-term, low-dose glucocor- ticoid treatment augments insulin resistance sufficiently to reveal groups of patients in whom E-cell compensation is inadequate. Thus, glucocorticoid administration may be a useful means by which to determine whether the prevalence or magnitude of defects in insulin secretion differ between women with PCOS and their controls and, likewise, to determine whether such defects are more profound or present more often in a particular subset within a population of women with PCOS.

3. CONCLUSIONS

Women with PCOS have a substantial risk for the development of IGT and type 2 DM over their

life span. Several distinct genetic and environmental factors are emerging as important influences on

Fig. 2. C-peptide–to–glucose ratios obtained during the oral glucose tolerance test. When expressed in rela-

tion to the prevailing glucose concentration, those subjects with polycystic ovary syndrome (PCOS) were less

able than control subjects to mount a sufficient E-cell secretory response to an oral glucose load after dexam-

ethasone administration. The increment in the ratio of C-peptide to glucose is significantly lower in PCOS than

in control subjects. PCOS subjects at baseline ( 䊊) and postdexamethasone (䊉); control subjects at baseline (䉭)

and postdexamethasone ( 䉱). (From ref. 32.)

Chapter 28 / Diabetes in PCOS 323

this predisposition to glucose intolerance in PCOS. Environmental factors include the rate of in utero growth and development as well as exposure to excess androgen concentrations from the maternal circulation. Although it has been well established that insulin resistance contributes to the reproduc- tive and metabolic phenotypes of PCOS, the role of insulin secretory abnormalities in these pheno- types has received less attention. It is now known that the pancreatic E-cell does not respond normally to fluctuations in plasma glucose in a substantial subset of women with PCOS. Furthermore, these abnormalities appear to be heritable. Finally, although insulin-secretory defects may not be evident under basal conditions, with interventions such as the administration of low-dose glucocorticoids, latent defects can be demonstrated. Provocative testing of pancreatic E-cell function may provide insights into the future risk for glucose intolerance among women with PCOS.

4. FUTURE AVENUES OF INVESTIGATION

Future investigation into the pathogenesis of alterations in glucose tolerance in PCOS is likely to focus on genetic factors leading to specific defects in insulin secretion and insulin action. Through the identification of genetic markers, it may become possible to characterize those women with PCOS who are at high risk for the development of type 2 DM at a time when glucose tolerance is normal. In so doing, specific and targeted interventions may be used to minimize the risk for conversion from normal to abnormal glucose tolerance.

KEY POINTS

• IGT and type 2 DM occur with higher than expected frequency among women with PCOS.

• In utero growth retardation and exposure to excess levels of androgens may contribute to the subsequent development of glucose intolerance in PCOS.

• Defects in insulin action and insulin secretion contribute to glucose intolerance in PCOS and are evident as early as the second decade of life.

• Defects in insulin secretion appear to be heritable in families with PCOS and may identify those women with PCOS at highest risk for glucose intolerance.

• Provocative testing of E-cell function may identify a subset of women with PCOS at highest risk for future development of IGT and DM.

ACKNOWLEDGMENT

This work was supported by grants from the National Institutes of Health (M01-RR-00055, DK- 41814, AG-11412, HL-075079, and P60-DK20595), a Clinical Research Award (to D.A.E.) from the American Diabetes Association, and a gift from the Blum-Kovler Foundation.

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