The insulin signaling pathway is dysregulated in cumulus cells from obese, infertile women with polycystic ovarian syndrome with an absence of clinical insulin resistance

Methods: This is a cohort study, conducted at a university-based reproductive medicine center and private reproductive medicine center that aimed to evaluate granulosa cumulus cell gene expression in the insulin signaling pathway in Polycystic Ovary Syndrome (PCOS) patients undergoing in vitro fertilization (IVF) treatment and to compare the cumulus gene expression between normal weight and obese women without clinical insulin resistance. Fifteen PCOS patients, nine normal weight patients and six obese patients presenting normal HOMA IR (Homeostasis Model Assessment-Insulin Resistance), participated. Patients underwent oocyte retrieval for IVF and after the procedure, granulosa cumulus cells were removed from the oocytes for RNA extraction. Quantitative polymerase chain reaction (PCR) array analysis of 84 genes from insulin signaling pathway was conducted. The results were expressed as fold up- or fold down-expression in obese patients compared with normal weight patients. Any fold change >= 3 or <= 3 and anyp <= 0.05 were considered statistically significant. Results: There were 10 genes that were overexpressed in obese compared with normal weight women, BCL2L1, BRAF, CBL, DOK1, FBP1, FRS2, MTOR, PCK2, RPS6KA1, and SORBS1, that had a fold change >= 3 and p <= 0.05. Discussion: In the obese group, the overexpressed genes are mainly responsible for the proliferation and differentiation of cumulus cells during oocyte maturation, insulin resistance, apoptosis regulation, and glucose metabolism during early embryogenesis, suggesting that in the follicular environment, insulin resistance is present even in the absence of clinical signs. Conclusion: Together, our findings and the related literature suggest that those alterations may be associated with the worse prognosis of follicular development and oocyte maturation observed in PCOS obese women.