PR000652 (Project)

Description:Polycystic Ovary Syndrome (PCOS), a condition of androgen excess, infrequent ovulation, and insulin resistance is the most common endocrine disorder among premenopausal women. Little is known about the exact mechanisms of insulin resistance in PCOS and how metformin can improve insulin sensitivity, increase the frequency of ovulation and lower androgens in PCOS. Preliminary data from metabolomic analyses of amino acids demonstrate increased concentrations of lysine and its metabolite, a-aminoadipic acid (AAA), in PCOS versus obese controls. Interestingly, greater AAA concentrations predicted the development of type 2 diabetes in the Framingham epidemiologic cohort, experimentally lowers glucose in animal models and increases insulin secretion in vitro. To date, the mechanism for increased circulating concentrations of lysine and AAA in insulin-resistant individuals is not known. Building upon these findings, we have initiated a project to simultaneously study lysine and AAA kinetics for the first time in insulin-resistant individuals using stable isotope tracer methodology. We will evaluate: 1) whether lysine and AAA kinetics are altered in PCOS versus healthy controls; 2) the effect of hyperinsulinemia on lysine and AAA kinetics in PCOS versus controls; 3) whether treatment to improve insulin sensitivity changes lysine and AAA kinetics in PCOS. The long-term goal is to target pathways for the treatment of PCOS and the prevention of type 2 diabetes in PCOS and other insulin-resistant individuals at greater risk for type 2 diabetes.