Introduction: Insulin resistance (IR) and obesity coexist in polycystic ovary syndrome (PCOS) and contribute to increased risk of diabetes and cardiovascular disease. An intrinsic insulin signalling defect is present in skeletal muscle of PCOS and it affects insulin mediated glucose transport in the presence of lipid in vitro studies.Methods: The effect of non-esterified fatty acids (NEFA) on IR, postprandial lipids and cardiovascular risk in obese women with PCOS compared to controls was examined by lowering NEFA levels with acute overnight acipimox and chronic 12 week tredaptive therapy. Additional studies included elevating NEFA by lipid infusions and improving NEFA metabolism by moderate intensity exercise.Results: Effective lowering of NEFA with overnight acipimox therapy improved fasting and postprandial IR in PCOS. It enhanced chylomicron clearance with reduced overnight VLDL production. A rebound rise in NEFA following chronic tredaptive therapy worsened fasting and postprandial IR. However, despite this, tredaptive had the counterintuitive effect of lowering fasting and postprandial triglycerides without effecting endothelial function and hsCRP.PCOS women were found to be less tolerant to acutely induced lipaemia than controls with an exaggerated fall in their rate of glucose disposal during a hyperinsulinaemic euglycaemic clamp. Exercise improved cardiovascular fitness and cardiovascular risk in PCOS. Exercise enhanced fasting insulin sensitivity and the rate of glucose disposal during the saline and hyperlipidaemia. Unlike controls, the platelets from PCOS subjects were more susceptible to platelet agonists and less responsive to platelet antagonists in induced hyperlipidaemia, triggering platelet hyper-activation that was not corrected by a supraphysiological dose of insulin.Conclusions: These studies demonstrate the definite role of NEFA in the pathophysiology of IR in PCOS and support the in vitro findings of high NEFA reducing insulin mediated glucose transport. This work also supports the concept that platelet insulin resistance in PCOS during lipaemia might increase cardiovascular risk in these patients
