Protective effects of metformin on pancreatic β-cell ferroptosis in type 2 diabetes in vivo

作者：Yue Sun, Ya-Ping Bai, Deguo Wang, Yujie Xing, Teng Zhang, Wen Wang, Si-min Zhou, Jinhan Cheng, Weiwei Chang, Xiang Kong, Xin-ming Yao, Liqun Guo · 发表于：Biomedicine & Pharmacotherapy · 年份：2023 · DOI：10.1016/j.biopha.2023.115835 · 被引用次数：24 · 研究领域：Epigenetics and DNA Methylation、Ferroptosis and cancer prognosis、RNA modifications and cancer

Metformin (Met) is the recommended first-line therapeutic drug for type 2 diabetes mellitus (T2DM) and exerts protective effects on β-cell damage. Ferroptosis, a new form of cell death, is associated with pancreatic islet injury in patients with T2DM. However, the protective effects of Met treatment against β-cell damage through ferroptosis modulation remain under-reported. This study investigated the in vivo effects of Met treatment on pancreatic β-cell ferroptosis using two different diabetic mouse models, namely, low-dose streptozotocin (STZ) and high-fat diet (HFD)-induced diabetic mice and db/db mice. Met treatment significantly restored insulin release, reduced cell mortality, and decreased the overproduction of lipid-related reactive oxygen species in the islets of both STZ/HFD-induced diabetic mice and db/db mice. Administration of the Ras-selective lethal 3 injection significantly attenuated the antiferroptosis effects of Met. Mechanistically, Met treatment alleviated β-cell ferroptosis in T2DM, which was associated with the regulation of the GPX4/ACSL4 axis in the islets. In conclusion, our findings highlight the significance of ferroptosis in T2DM β-cell damage and provide novel insights into the protective effects of Met against islet β cells.