Metformin activates SIRT2 to improve insulin resistance and promote granulosa cell glycolysis in a rat model of polycystic ovary syndrome
Abstract
RESEARCH QUESTION
What is the mechanism by which metformin enhances insulin sensitivity, improves granulosa cell glycolysis and induces ovulation in a rat model of polycystic ovary syndrome (PCOS)?
DESIGN
Analysis of the GSE168404 gene expression profile in the Gene Expression Omnibus database revealed increased levels of IGF1 and decreased levels of glycolytic enzymes (HK2, LDHA, PKM2) in the granulosa cells of PCOS patients. To explore the effects of metformin on the imbalance in glycolysis induced by insulin resistance (IR), experiments were conducted using Sprague-Dawley rats and KGN cells (human ovarian granulosa cells). Oestrous cycles were monitored in control, PCOS model (induced by letrozole and a high-fat diet) and metformin-treated PCOS groups. Analyses of body weight, hormone concentrations and biochemical, histopathological, immunohistochemical and glycolytic pathways were performed. KGN cells were used to model insulin resistance with insulin, and AGK2 was used specifically to inhibit sirtuin 2 (SIRT2), while metformin was applied.
RESULTS
Metformin significantly improved insulin resistance in PCOS rats, reduced insulin-like growth factor 1 (IGF1) protein and mRNA expression (all P ≤ 0.0348) and increased IGF1 receptor (IGF1R) impression (all P ≤ 0.0361). Insulin inhibited glycolytic activity in KGN cells, but metformin attenuated this effect (all P ≤ 0.0255). Metformin reversed the inhibition of SIRT2 in PCOS rat ovaries (all P ≤ 0.0483) and restored…
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