The Effect of Metformin, Flutamide and Dietary Nicotinic Acid on Dyslipidemia and Cardiometabolic Risk in the JCR:LA-­cp Rodent Model of PCOS

Abstract

Polycystic ovary syndrome (PCOS) is a highly prevalent metabolic-endocrine disorder affecting up to 18% of adolescent and adult females in their reproductive years. PCOS is associated with an increased risk of cardiovascular disease (CVD) and type 2 diabetes. Atherogenic dyslipidemia occurs in 70% of PCOS patients, however at present the independent role of testosterone and insulin in modulating lipid metabolism in PCOS is not understood. Currently, there is no single therapy that is safe and effective to improve plasma lipids and cardiometabolic risk in PCOS. The primary aim of this thesis was to determine the effect of the insulin sensitizer, metformin, and the androgen receptor blocker, flutamide, and a lipid-lowering vitamin, nicotinic acid, on insulin and glucose, lipid and apoB-lipoprotein metabolism in the JCR:LA-cp rodent model of PCOS. The results showed metformin improved fasting plasma insulin and HOMA-IR, and attenuated intestinal chylomicron-cholesterol secretion and this was concomitant with changes in insulin signaling and lipogenic gene expression. Flutamide reduced fasting plasma TG, apolipoprotein (apo) B48 and apoB100, as well as intestinal TG secretion, but there was no effect on mRNA expression of lipogenic genes. Nicotinic acid treatment alone improved postprandial plasma insulin concentrations and tended to decrease intestinal chylomicron-apoB48 secretion. Addition of metformin reduced fasting plasma insulin, glucose and HOMA-IR, insulin and glucose response to a ‘meal tolerance test’ and tended to lower fasting plasma TG and apoB48 concentrations. Collectively, the results from these studies demonstrate: i) the androgen receptor and testosterone mediate regulation of lipid and lipoprotein metabolism in the liver and intestine and this is independent of insulin, ii) nicotinic acid has beneficial effects on insulin-glucose metabolism and may have the potential to target dyslipidemia in PCOS conditions, as demonstrated in the JCR:LA-cp rodent model of PCOS.