PMID- 37924788 OWN - NLM STAT- MEDLINE DCOM- 20231115 LR - 20231115 IS - 1950-6007 (Electronic) IS - 0753-3322 (Linking) VI - 168 DP - 2023 Dec TI - Protective effects of metformin on pancreatic beta-cell ferroptosis in type 2 diabetes in vivo. PG - 115835 LID - S0753-3322(23)01633-5 [pii] LID - 10.1016/j.biopha.2023.115835 [doi] AB - Metformin (Met) is the recommended first-line therapeutic drug for type 2 diabetes mellitus (T2DM) and exerts protective effects on beta-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 beta-cell damage through ferroptosis modulation remain under-reported. This study investigated the in vivo effects of Met treatment on pancreatic beta-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 beta-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 beta-cell damage and provide novel insights into the protective effects of Met against islet beta cells. CI - Copyright (c) 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved. FAU - Sun, Yue AU - Sun Y AD - Department of Gerontology, Geriatric endocrinology unit, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu 241001, China; Anhui Provincial Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wannan Medical College, Wuhu 241002, China. FAU - Bai, Ya-Ping AU - Bai YP AD - Anhui Provincial Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wannan Medical College, Wuhu 241002, China; Anhui Provincial Key Laboratory of Molecular Enzymology and Mechanism of Major Diseases, College of Life Sciences, Anhui Normal University, Wuhu 241000, China. FAU - Wang, De-Guo AU - Wang DG AD - Department of Gerontology, Geriatric endocrinology unit, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu 241001, China; Anhui Provincial Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wannan Medical College, Wuhu 241002, China. FAU - Xing, Yu-Jie AU - Xing YJ AD - Department of Gerontology, Geriatric endocrinology unit, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu 241001, China; Anhui Provincial Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wannan Medical College, Wuhu 241002, China. FAU - Zhang, Teng AU - Zhang T AD - Anhui Provincial Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wannan Medical College, Wuhu 241002, China. FAU - Wang, Wen AU - Wang W AD - Anhui Provincial Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wannan Medical College, Wuhu 241002, China. FAU - Zhou, Si-Min AU - Zhou SM AD - Department of Gerontology, Geriatric endocrinology unit, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu 241001, China; Anhui Provincial Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wannan Medical College, Wuhu 241002, China. FAU - Cheng, Jin-Han AU - Cheng JH AD - Department of Endocrinology, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu 241001, China. FAU - Chang, Wei-Wei AU - Chang WW AD - Department of Epidemiology and Health statistics, School of public health, Wannan Medical College, Wuhu 241002, Anhui, China. FAU - Kong, Xiang AU - Kong X AD - Department of Gerontology, Geriatric endocrinology unit, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu 241001, China; Anhui Provincial Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wannan Medical College, Wuhu 241002, China; Anhui Provincial Key Laboratory of Molecular Enzymology and Mechanism of Major Diseases, College of Life Sciences, Anhui Normal University, Wuhu 241000, China; Central Laboratory of Yijishan Hospital, Wuhu 241001, China. Electronic address: wnmcyaolikx@sina.com. FAU - Yao, Xin-Ming AU - Yao XM AD - Department of Endocrinology, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu 241001, China. Electronic address: yxm6965@sina.com. FAU - Guo, Li-Qun AU - Guo LQ AD - School of Pharmacy, Anhui Innovative Center for Drug Basic Research of Metabolic Diseases, Wannan Medical College, Wuhu 241002, China. Electronic address: wy_glq@163.com. LA - eng PT - Journal Article DEP - 20231103 PL - France TA - Biomed Pharmacother JT - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie JID - 8213295 RN - 9100L32L2N (Metformin) RN - 0 (Insulin) SB - IM MH - Humans MH - Mice MH - Animals MH - *Diabetes Mellitus, Type 2/drug therapy/metabolism MH - *Metformin/pharmacology/therapeutic use/metabolism MH - *Diabetes Mellitus, Experimental/drug therapy/metabolism MH - *Ferroptosis MH - *Insulin-Secreting Cells/metabolism MH - Insulin/metabolism OTO - NOTNLM OT - Ferroptosis OT - Islets OT - Metformin OT - Type 2 diabetes mellitus COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/11/05 00:42 MHDA- 2023/11/15 06:42 CRDT- 2023/11/04 19:12 PHST- 2023/08/16 00:00 [received] PHST- 2023/10/26 00:00 [revised] PHST- 2023/11/01 00:00 [accepted] PHST- 2023/11/15 06:42 [medline] PHST- 2023/11/05 00:42 [pubmed] PHST- 2023/11/04 19:12 [entrez] AID - S0753-3322(23)01633-5 [pii] AID - 10.1016/j.biopha.2023.115835 [doi] PST - ppublish SO - Biomed Pharmacother. 2023 Dec;168:115835. doi: 10.1016/j.biopha.2023.115835. Epub 2023 Nov 3.