Hypothesis
Androgen excess is a defining feature of polycystic ovary syndrome (PCOS), which affects 10% of women and confers a significant risk of type 2 diabetes mellitus. Classic androgens correlate with hyperglycaemia in PCOS, but the impact of the recently discovered 11-oxygenated androgens on diabetes risk is unknown. International consensus guidelines have highlighted an urgent need to develop novel biomarkers of diabetes risk in women with PCOS.
I hypothesise that 11-ketotestosterone, the predominant androgen in PCOS, is a major driver of diabetes risk through effects on skeletal muscle glucose metabolism.
Aims and Objectives
The objective of this proposal is to delineate the impact of 11-oxygenated androgens on diabetes risk in women with PCOS, focusing specifically on skeletal muscle glucose metabolism and mitochondrial function with an integrated physiology approach.
Methodology
I will test my hypothesis that 11-oxygenated androgens are independent drivers of hyperglycaemia in PCOS using a two-pronged approach. Firstly, I will investigate the impact of an oral 11-oxygenated androgen precursor challenge in comparison to a classic precursor on skeletal muscle insulin sensitivity in women with PCOS using hyperinsulinaemic-euglycaemic clamp and stable isotope studies. Secondly, I will phenotype a large cohort of women with PCOS, documenting clinical phenome and global metabolome characteristics to probe the relationship between 11-oxygenated androgens and diabetes risk in an approach suitable for clinical practice. I will utilise this cohort to establish a prospective database with the aim of extension to other Irish centres. Anticipated outcomes
This proposal will characterise the independent contribution of 11-oxygenated androgens to diabetes risk in PCOS by probing effects on skeletal muscle glucose and mitochondrial metabolism. Clinical phenome and global metabolome data in a large PCOS cohort will be used to stratify patients at highest metabolic risk, and to determine a possible role for 11-oxygenated androgens as novel biomarkers of diabetes risk.
