Obesity is a well-recognized risk-factor for development of type 2 diabetes, but alone is insufficient to cause glucose intolerance. Thus, while it is generally accepted that women with PCOS are predisposed to type 2 diabetes (13,14), the development of diabetes cannot be attributed solely to the obesity that typically accompanies PCOS.
Initial studies placed the prevalence of diabetes in PCOS at approximately 20% (8). More recent data have established that the prevalence of impaired glu- -o cose tolerance and type 2 diabetes mellitus among women with PCOS is even higher, with consistency across populations of varied ethnic and racial backgrounds (14,15). In two recent, large prospective studies, the prevalence of IGT g was between 30 to 40% and that of type 2 diabetes between 5 to 10% (14,15). <j These prevalences approximate those in Pima Indians who have one of the highest Ji rates of diabetes in the world (16). Evidence for an enhanced rate of development J of diabetes is also evident from long-term follow-up of women with PCOS (17). a
More recently, we have found a nearly five- to tenfold increase in the expected conversion rate from IGT to type 2 diabetes in PCOS (14,18).
What factors underlie this predisposition to type 2 diabetes in PCOS? There is much to support a key role for insulin resistance. As noted, the magnitude of insulin resistance is greater in women with PCOS than in carefully matched controls (19-21). A distinct, and possibly selective (22), form of insulin resistance may account for these findings. Fibroblasts isolated from women with PCOS exhibit decreased insulin receptor autophosphorylation, both basally and in response to insulin stimulation (23). Phosphoaminoacid analysis has revealed a decrease in insulin-dependent receptor tyrosine phosphorylation and increased insulin-dependent receptor serine phosphorylation (23). The relative increase in serine phosphorylation could account, at least in part, for the post-receptor defect in insulin action since it has been shown that insulin receptor serine phosphoryla-tion decreases the receptor's tyrosine kinase activity (24). In addition, it has been proposed that the presence of such defects in ex vivo cell culture of fibroblasts supports a genetic, rather than acquired, basis for insulin resistance (21).
Even though a substantial proportion of women with PCOS develop glucose intolerance, the majority do not, thus making it reasonable to ask whether the defects in insulin action described above are sufficient to account for the high prevalence of diabetes in this population. Specifically, what factors distinguish insulin-resistant women with PCOS who develop glucose intolerance from those who are able to maintain normoglycemia?
Insulin secretory defects play an important role in the propensity to develop diabetes in PCOS. Initial evidence for P-cell dysfunction in PCOS was derived from analyses of basal and postprandial insulin secretory responses in women with PCOS relative to weight-matched controls with normal androgen levels (25). The incremental insulin secretory response to meals was markedly reduced in women with PCOS, resulting from a reduction in the relative amplitude of meal-related secretory pulses rather than from a reduction in the number of pulses present. This pattern, which resembled that of type 2 diabetes more than that of simple obesity (26,27), was striking in that it was evident in these nondiabetic women with PCOS.
It was subsequently reported that women with PCOS had similar, or even exaggerated (28), acute insulin responses during a modified IVGTT, leading some to conclude that P-cell function was normal in PCOS. However, insulin secretion -o a is most appropriately expressed in relation to the magnitude of ambient insulin resistance. The product of these measures can be quantitated (the so-called ''dis- £
position index'') and related as a percentile to the hyperbolic relationship for g these measures established in normal subjects (29). In so doing, we (13), as well <j as others (30), have found that a subset of PCOS subjects has P-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 a
& u was analyzed in relation to the degree of insulin resistance, women with PCOS exhibited a significant impairment in P-cell function. This reduction was particularly marked in women with PCOS who had a first-degree relative with type 2 diabetes: the mean disposition index of women with PCOS and a family history of type 2 diabetes was in the eighth percentile, while that of those without such a family history was in the thirty-third percentile (p < 0.05). We have additionally quantitated P-cell function in PCOS by examining the insulin secretory response to a graded increase in plasma glucose and by the ability of the P-cell to adjust and respond to induced oscillations in the plasma glucose level (13). Results from both provocative stimuli were consistent: when expressed in relation to the degree of insulin resistance, insulin secretion was impaired in PCOS subjects with a family history of type 2 diabetes when compared to controls.
These results suggest that the risk imparted by insulin resistance to the development of type 2 diabetes in PCOS is enhanced by defects in insulin secretion. Further, a history of type 2 diabetes in a first-degree relative appears to define a subset of PCOS subjects with the most profound defects in P-cell function. Taken together, these findings are in accord with studies showing a high degree of heritability of P-cell function, particularly when examined in relation to insulin sensitivity (31), and among nondiabetic members of familial type 2 diabetic kindreds (32).
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