Metformin improves insulin resistance to enhance the glycolysis process by activating SIRT2 of granulosa cells in PCOS rats

What is the mechanism by which metformin enhances insulin sensitivity, improves granulosa cell glycolysis, and induces ovulation in PCOS rats? Analysis of the GSE168404 gene expression profile in the GEO database revealed increased IGF1 and decreased glycolytic enzyme levels (HK2, LDHA, PKM2) in granulosa cells of PCOS patients. To explore the effects of metformin on glycolysis imbalance induced by insulin resistance (IR), we conducted animal and cell experiments. Estrous cycles were monitored in control, PCOS model (induced by letrozole and a high-fat diet), and metformin-treated PCOS groups. Post-experiment, body weight, hormone levels, biochemical, histopathological, immunohistochemical, and glycolytic pathway analyses were performed. KGN cells were used to model IR with insulin, and AGK2 was used to inhibit SIRT2 specifically, while metformin was applied. Metformin significantly improved IR in PCOS rats, reduced IGF1 levels, and increased IGF1R. Insulin inhibited glycolytic activity in KGN cells, but metformin attenuated this effect. Metformin reversed the inhibition of SIRT2 in PCOS rat ovaries and restored glycolysis in KGN cells affected by AGK2. Metformin enhances insulin sensitivity and restores glycolysis by regulating SIRT2, which may improve follicular development and reduce ovarian damage in PCOS rats, offering a potential clinical treatment strategy for PCOS.