The Mechanism Of Androgen Receptor Splice Variants In The Development Of Insulin Resistance In Polycystic Ovary Syndrome

OBJECTIVE:To investigate the role of androgen receptor(AR)splice variants in the development of insulin resistance in patients with PCOS and to elucidate its mechanism.DESIGN:Clinical correlation analysis,animal model phenotype exploration,in vivo mechanism verification.MATERIALS AND METHODS:1)Recruit PCOS women and control women to collect their personal information and endocrine data.Identification of granulosa cells for the presence of AR splice variants,detection of insulin and androgen-related hormone levels in serum and follicular fluid.2)Construct a mouse model of AR splice variant for phenotypic observation,including:growth,body weight,fasting blood glucose,glucose tolerance,insulin tolerance,body composition,and estrous cycle.Peripheral blood of mice was collected and the levels of fasting blood insulin,leptin,T,E2,LH and FSH were determined.The mouse ovary,liver and fat sections were stained.3)Construction of AR splice variant overexpression cell model to detect cellular glucose uptake and insulin utilization.GLUT4 protein expression and membrane translocation were examined.INS,IRS1,AKT and their phosphorylated protein expression were examined.RESULTS:1)PCOS patients with AR splice variants had local high androgen and high insulin in the ovary.2)AR splicing variant mice showed abnormal glucose tolerance,insulin resistance,and obesity phenotype,and the reproductive phenotype was highly similar to PCOS women.3)The phosphorylation level of IRS1 in AR splice variant cells was changed,AKT phosphorylation was weakened,and GLUT4 membrane expression was decreased.CONCLUSION:AR splicing variants inhibit the intracellular signaling pathway of insulin by altering the phosphorylation level of IRS1/AKT signaling,resulting in decreased GLUT4 membrane translocation,impaired glucose uptake,and insulin resistance.