Insulin resistance and the polycystic ovary syndrome
It is now clear that PCOS is often associated with profound insulin resistance as well as with defects in insulin secretion. These abnormalities, together with obesity, explain the substantially increased prevalence of glucose intolerance in PCOS. Moreover, since PCOS is an extremely common disorder, PCOS-related insulin resistance is an important cause of NIDDM in women (Table 3). The insulin resistance in at least 50% of PCOS women appears to be related to excessive serine phosphorylation of the insulin receptor. A factor extrinsic to the insulin receptor, presumably a serine/threonine kinase, causes this abnormality and is an example of an important new mechanism for human insulin resistance related to factors controlling insulin receptor signaling. Serine phosphorylation appears to modulate the activity of the key regulatory enzyme of androgen biosynthesis, P450c17. It is thus possible that a single defect produces both the insulin resistance and the hyperandrogenism in some PCOS women (Fig. 19). Recent studies strongly suggest that insulin is acting through its own receptor (rather than the IGF-I receptor) in PCOS to augment not only ovarian and adrenal steroidogenesis but also pituitary LH release. Indeed, the defect in insulin action appears to be selective, affecting glucose metabolism but not cell growth. Since PCOS usually has a menarchal age of onset, this makes it a particularly appropriate disorder in which to examine the ontogeny of defects in carbohydrate metabolism and for ascertaining large three-generation kindreds for positional cloning studies to identify NIDDM genes. Although the presence of lipid abnormalities, dysfibrinolysis, and insulin resistance would be predicted to place PCOS women at high risk for cardiovascular disease, appropriate prospective studies are necessary to directly assess this.
Insulin action in vivo in PCOSAlthough insulin has a number of actions, in addition tothose regulating glucose metabolism, such as inhibition oflipolysis and stimulation of amino acid transport (51), theeffects of insulin on glucose metabolism are usually exam-ined in studies of insulin resistance (60). This can be studiedquantitatively in humans with the euglycemic glucose clamptechnique: a desired dose of insulin is administered andeuglycemia is maintained by a simultaneous variable glucoseinfusion whose rate is adjusted based on frequent arterial-ized blood glucose determinations and a negative feedbackprinciple (60 – 62). At steady state, the amount of glucose thatis infused equals the amount of glucose taken up by theperipheral tissues and can be used as a measure of peripheralsensitivity to insulin, known as insulin-mediated glucosedisposal (IMGD) or M (61, 62). The suppression of hepaticglucose production by insulin can be assessed by the use ofa simultaneous infusion of isotopically labeled glucose.Insulin-mediated glucose disposal occurs only in muscle(skeletal and cardiac) and in fat; muscle accounts for about85% of this (60)
Hypotheses Explaining the Association of InsulinResistance and PCOSA. Causal association1. Do androgens cause insulin resistance?If glucose utilizationis expressed as a function of muscle mass rather than totalbody mass, women do appear to be more insulin sensitivethan men (158, 159). Moreover, when isolated fat cells arecompared, female adipocytes are more sensitive than maleadipocytes to insulin-mediated glucose uptake (160). Theseare subtle differences, however, and do not approach thedegree of impairment in insulin sensitivity observed in PCOS(54, 55). Finally, in the rare syndromes of extreme insulinresistance and hyperandrogenism, specific molecular defectsin insulin action have been clearly identified as the cause ofinsulin resistance (19, 161).It is possible, however, that androgens may produce mildinsulin resistance. Women receiving oral contraceptives con-taining “androgenic” progestins can experience decompen-sations in glucose tolerance, as can individuals receivingsynthetic anabolic steroids
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- PMID: 9408743
- DOI: 10.1210/edrv.18.6.0318