Metformin activates SIRT2 to improve insulin resistance and promote granulosa cell glycolysis in a rat model of polycystic ovary syndrome

IF 3.7 2区医学 Q1 OBSTETRICS & GYNECOLOGY

Reproductive biomedicine online Pub Date : 2025-05-01 DOI:10.1016/j.rbmo.2024.104750

Zhihan Zhang , Peng Huo , Xiaocan Lei , Haoxuan Xue , Xiuli Yang , Jianghua Le , Shun Zhang

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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 glycolysis in KGN cells treated by AGK2 (all P ≤ 0.0369).

Conclusion

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.

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在多囊卵巢综合征大鼠模型中，二甲双胍激活SIRT2改善胰岛素抵抗并促进颗粒细胞糖酵解。

研究问题：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和诱导排卵的机制是什么？设计：分析基因表达综合数据库中的GSE168404基因表达谱，发现PCOS患者颗粒细胞中IGF1水平升高，糖酵解酶（HK2、LDHA、PKM2）水平降低。为了探讨二甲双胍对胰岛素抵抗（insulin resistance， IR）所致糖酵解失衡的影响，我们采用Sprague-Dawley大鼠和KGN细胞（人卵巢颗粒细胞）进行了实验。对照组、PCOS模型组（来曲唑+高脂饮食）和二甲双胍治疗PCOS组监测发情周期。进行了体重、激素浓度和生化、组织病理学、免疫组织化学和糖酵解途径的分析。KGN细胞用胰岛素模拟胰岛素抵抗，AGK2特异性抑制sirtuin 2 (SIRT2)，同时使用二甲双胍。结果：二甲双胍显著改善PCOS大鼠胰岛素抵抗，降低胰岛素样生长因子1 （IGF1）蛋白和mRNA表达（P均≤0.0348），增加IGF1受体（IGF1R）印象（P均≤0.0361）。胰岛素抑制KGN细胞的糖酵解活性，但二甲双胍减弱了这种作用（P≤0.0255）。二甲双胍逆转了PCOS大鼠卵巢对SIRT2的抑制（均P≤0.0483），恢复了AGK2处理的KGN细胞的糖酵解（均P≤0.0369）。结论：二甲双胍通过调节SIRT2增强胰岛素敏感性，恢复糖酵解，可能改善PCOS大鼠卵泡发育，减轻卵巢损伤，为PCOS临床治疗提供了一种潜在的治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Reproductive biomedicine online 医学-妇产科学

CiteScore

7.20

自引率

7.50%

发文量

391

审稿时长

50 days

期刊介绍： Reproductive BioMedicine Online covers the formation, growth and differentiation of the human embryo. It is intended to bring to public attention new research on biological and clinical research on human reproduction and the human embryo including relevant studies on animals. It is published by a group of scientists and clinicians working in these fields of study. Its audience comprises researchers, clinicians, practitioners, academics and patients. Context: The period of human embryonic growth covered is between the formation of the primordial germ cells in the fetus until mid-pregnancy. High quality research on lower animals is included if it helps to clarify the human situation. Studies progressing to birth and later are published if they have a direct bearing on events in the earlier stages of pregnancy.