Molecular Defects of Insulin Signaling in PCOS

DESCRIPTION (provided by applicant): The polycystic ovary syndrome (PCOS) affects about 4% of reproductive-aged women, and is one of the most common causes of oligo-ovulatory infertility. Between 50% and 70% of women with PCOS demonstrate insulin resistance, independent of body weight, and the resulting compensatory hyperinsulinemia leads to the hyperandrogenic features of the disorder. Overall, little is know about the molecular aspects of the insulin signaling defects of PCOS. Previous studies have indicated that insulin-stimulated glucose transport is deficient, suggesting an alteration along the PI-3 kinase/Akt/GLUT-4 cascade. Alternatively, mitogenic activity in response to insulin appears to be normal in the fibroblasts of these patients, suggesting that the MAPK pathway may be unaffected in PCOS. Based on these observations we have hypothesized that abnormal insulin receptor (IR) signaling in adipose tissues is a frequent abnormality in women with PCOS; and that the defect is present downstream from the IR, affecting the PI-3 kinase/Akt/GLUT-4, but not the MAPK, pathway. We have also hypothesized that the insulin resistance of PCOS may be more closely related to abnormalities of visceral (omental) than subcutaneous fat. Our Specific Aim is to determine whether abnormal IR signaling is present in the adipocytes of patients with PCOS. Specifically, we will test our hypothesis by studying the abdominal subcutaneous and omental adipose tissues of 10 normal-weight or pre-obese PCOS patients and 10 age/race/body massmatched controls. In these tissues we will determine: i) the total amount and the degree of phosphorylation in response to insulin of the IR, the IR substrate-1 and 2 proteins (IRS-1/2), and of critical intermediate proteins (i.e., Akt, GSK-3, and FKHR of the PI-3 kinase/Akt cascade; c-Raf, MEK-1, ERKI/2, and p90RSK of the ERKI/2 cascade; JNK of the SAPK/JNK cascade; and p38 MAPK of the cascade of the same name) and the translational regulator p70 S6; and ii) the total amounts of GLUT-4 and IRS-associated PI-3 kinase. We should note that this systematic approach to investigating insulin signaling is critical at this early stage in the study of the mechanisms underlying insulin resistance in PCOS. Long term, these studies have the potential of eventually elucidating the etiologic mechanism(s) in some, or most, patients; helping to develop targeted therapies; and guiding the search for molecular markers for PCOS.