Zhang Zhihan, Huo Peng, Lei Xiaocan, Xue Haoxuan, Yang Xiuli, Le Jianghua, Zhang Shun
Department of Reproductive Medical Center, The Affiliated Hospital of Guilin Medical University, Guilin, China.
Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, Guilin Medical University, Guilin, Guangxi, China.
Reprod Biomed Online. 2025 May;50(5):104750. doi: 10.1016/j.rbmo.2024.104750. Epub 2024 Dec 12.
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)?
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.
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 glycolysis in KGN cells treated by AGK2 (all P ≤ 0.0369).
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.
在多囊卵巢综合征（PCOS）大鼠模型中，二甲双胍增强胰岛素敏感性、改善颗粒细胞糖酵解并诱导排卵的机制是什么？
对基因表达综合数据库中GSE168404基因表达谱的分析显示，PCOS患者颗粒细胞中胰岛素样生长因子1（IGF1）水平升高，糖酵解酶（己糖激酶2、乳酸脱氢酶A、丙酮酸激酶M2）水平降低。为了探究二甲双胍对胰岛素抵抗（IR）诱导的糖酵解失衡的影响，使用了斯普拉格-道利大鼠和KGN细胞（人卵巢颗粒细胞）进行实验。对对照组、PCOS模型组（由来曲唑和高脂饮食诱导）和二甲双胍治疗的PCOS组的发情周期进行监测。对体重、激素浓度以及生化、组织病理学、免疫组织化学和糖酵解途径进行分析。用胰岛素使KGN细胞模拟胰岛素抵抗，用AGK2特异性抑制沉默调节蛋白2（SIRT2），同时应用二甲双胍。
二甲双胍显著改善了PCOS大鼠的胰岛素抵抗，降低了胰岛素样生长因子1（IGF1）蛋白和mRNA表达（所有P≤0.0348），并增加了IGF1受体（IGF1R）表达（所有P≤0.0361）。胰岛素抑制了KGN细胞中的糖酵解活性，但二甲双胍减弱了这种作用（所有P≤0.
