Li Wei Cho et al It has now been recognized that the diagnosis of metabolic syndrome identiﬁes patients at increased risk of developing cardiovascular disease, and attempts have been made to de- velop the most convenient and useful criteria for the diagnosis of this condition in clinical practice. With the pathogenesis of metabolic syndrome not well understood, central obesity and insulin resistance are acknowledged as important causative factors (Anderson et al 2001; Carr et al 2004; Nesto 2003). The most recent International Diabetes Federation consensus, however, has developed a new deﬁnition emphasizing the importance of central obesity with modiﬁcations according to ethnic groups (Alberti et al 2006). Previous deﬁnitions from the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III), USA (NCEP/ATPIII 2001) and the World Health Organization (WHO) had emphasized insulin resistance (Alberti and Zimmet 1998; Grundy et al 2004). It would appear that many women with PCOS fulﬁl the criteria for the metabolic syndrome in view of a higher reported incidence of hypertension, dyslipidemia, visceral obesity, insulin resistance and hyperinsulinemia in this population (Glueck et al 2003). It is recognized that insulin resistance and compensatory hyperinsulinemia not only contribute to hyperglycemia, but they also have a pathophysi- ological role in the development of the cardio-metabolic state (Mather et al 2000). Metabolic abnormalities of PCOS Hyperinsulinemia and insulin resistance Insulin binds to its receptor on the cell membrane facilitating the delivery of glucose across the membrane by enhancing the expression of GLUT transporters (Stephens and Pilch 1995). Disturbance in insulin’s ability to bind to its receptor, or the transport mechanism across the cell membrane may lead to a state of reduced sensitivity to insulin, or insulin resistance. Studies suggest that insulin induced receptor autophosphorylation is markedly diminished in approxi- mately 50% of PCOS women. In those PCOS women who have normal receptor autophosphorylation, it remains likely that signalling mechanism downstream of the receptor are abnormal (Dunaif 1995). In addition to decreased insulin sensitivity, pancreatic β-cell secretory dysfunction has also been reported (Ehrmann et al 1995; Dunaif and Finegood 1996). Furthermore, a reduction in hepatic insulin extraction resulting in a reduction of insulin clearance rate may also contribute to the high insulin levels (Mahabeer et al 1989; O’Meara et al 1993). 56 Insulin stimulates lipogenesis in arterial tissue and adi- pose tissue via an increased production of acetyl-Co A, and the entry of glucose and triglycerides (Pekala et al 1983). Dyslipidemia associated with high levels of triglycerides and low levels of HDL cholesterol in cardiometabolic syndrome are attributed to the effect of insulin on cholesterol ester transfer protein that promotes the transfer of cholesterol from HDL to VLDL and resultant catabolism of Apo lipoprotein A (Swenson 1991; Chen et al 1991). As insulin increases the levels of HMG Co A reductase, the rate-limiting enzyme in the synthesis of cholesterol, it may contribute to the raised cholesterol level that is also a feature of hyperinsulinemia (Dietschy and Brown 1974). Loss of peroxisome proliferator activated nuclear recep- tor (PPAR) gamma has been linked to the development of severe insulin resistance, diabetes, and hypertension (Celi and Shuldiner 2002). Although both metformin and the thiazolidinediones act as insulin sensitizers, one recent study suggested that only rosiglitazone, but not metformin, increased the expression of PPAR gamma in peripheral tis- sue (Tiikkainen et al 2004) thereby increasing peripheral insulin sensitivity. This may suggest that the thiazolidin- ediones may have additional peripheral beneﬁts compared with metformin. Visceral obesity The prevalence of obesity in PCOS varies widely, between approximately 10–50% (Balen et al 1995; Carmina et al 1992). Obese PCOS have lower levelsof luteinizing hormone (LH), sex hormone binding globulin (SHBG), dehydroepi- androsterone (DHEAS), dihydrotestosterone, free insulin-like growth Factor (IGF)-I, high-density lipoprotein, and higher low-density lipoprotein, compared with the nonobese PCOS group (Silfen et al 2003). However, the situation is complex; not all obese people are insulin resistant and not all who are insulin resistant are obese. Gluteo-femoral obesity is less associated with insulin resistance than is central or android obesity (Basdevant et al 1987). A state of hyperinsulinemia may itself contribute to obesity by the anabolic effect on fat metabolism through adipogenesis with increased uptake of glucose into adipocytes, the production of triglycerides and inhibition of hormone sensitive lipase (Arner 2005). Hypertension Hyperinsulinemia may contribute to the hypertension of the cardiometabolic syndrome by enhanced sodium retention (Zavaroni et al 1995), causing an increased intracellular sodium and calcium (Resnick 1992), and stimulation of the Vascular Health and Risk Management 2007:3(1)