2. Academic Validation
  3. Metformin alleviates glucolipotoxicity-induced pancreatic β cell ferroptosis through regulation of the GPX4/ACSL4 axis

Metformin alleviates glucolipotoxicity-induced pancreatic β cell ferroptosis through regulation of the GPX4/ACSL4 axis

  • Eur J Pharmacol. 2023 Aug 5;175967. doi: 10.1016/j.ejphar.2023.175967.
Yue Sun 1,  Li-Qun Guo 2,  De-Guo Wang 3,  Yu-Jie Xing 4,  Ya-Ping Bai 5,  Teng Zhang 6,  Wen Wang 7,  Si-Min Zhou 8,  Xin-Ming Yao 9,  Jin-Han Cheng 10,  Wei-Wei Chang 11,  Kun Lv 12,  Chun-Xiao Li 13,  Xiang Kong 14
Affiliations

Affiliations

  • 1 Department of Gerontology, Geriatric Endocrinology Unit, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, 241001, China; Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, 241002, China. Electronic address: sunyuetbc@163.com.
  • 2 Department of Pharmacology, Wannan Medical College, Wuhu, 241002, China. Electronic address: wy_glq@163.com.
  • 3 Department of Gerontology, Geriatric Endocrinology Unit, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, 241001, China. Electronic address: wangdeguo@medmail.com.cn.
  • 4 Department of Gerontology, Geriatric Endocrinology Unit, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, 241001, China; Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, 241002, China. Electronic address: yujiexing0510@163.com.
  • 5 Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, 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. Electronic address: ya19855363005@163.com.
  • 6 Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, 241002, China. Electronic address: zt18895380684@163.com.
  • 7 Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, 241002, China. Electronic address: 403215973@qq.com.
  • 8 Department of Gerontology, Geriatric Endocrinology Unit, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, 241001, China; Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, 241002, China. Electronic address: Zsimin9602@163.com.
  • 9 Department of Endocrinology, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, 241001, China. Electronic address: yxm6965@sina.com.
  • 10 Department of Endocrinology, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, 241001, China. Electronic address: 1749444722@qq.com.
  • 11 Department of Epidemiology and Health Statistics, School of Public Health, Wannan Medical College, Wuhu, 241002, Anhui, China. Electronic address: xiaowei8601@163.com.
  • 12 Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, 241002, China; Central Laboratory of Yijishan Hospital, Wuhu, 241001, China; Anhui Provincial Key Laboratory of Molecular Enzymology and Mechanism of Major Diseases, College of Life Sciences, Anhui Normal University, Wuhu, 241000, China. Electronic address: lvkun315@126.com.
  • 13 Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China. Electronic address: lichunxiao8387@xinhuamed.com.cn.
  • 14 Department of Gerontology, Geriatric Endocrinology Unit, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, 241001, China; Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, 241002, China; Central Laboratory of Yijishan Hospital, Wuhu, 241001, China; Anhui Provincial Key Laboratory of Molecular Enzymology and Mechanism of Major Diseases, College of Life Sciences, Anhui Normal University, Wuhu, 241000, China. Electronic address: wnmcyaolikx@sina.com.
PMID: 37549729 DOI: 10.1016/j.ejphar.2023.175967
Abstract

Ferroptosis, a new type of cell death, is associated with pancreatic β cell damage. However, the role of glucolipotoxicity in inducing β cell Ferroptosis remains unclear. Metformin (Met), exenatide (Exe), and saxagliptin (Sax) are frequently used anti-hyperglycaemic drugs. However, their protective effects on β cells through Ferroptosis modulation are not well-established. In this study, we observed significant Ferroptosis in NIT-1 cells and primary mouse islets after exposure to high glucose and palmitate (HG/PA). Compared to Exe and Sax, Met significantly alleviated glucolipotoxicity-induced pancreatic β cell Ferroptosis. Blocking the activity of Glutathione Peroxidase 4 (GPX4) with Ras-selective lethal 3 or inhibiting its expression by small interfering RNA transfection significantly attenuated the anti-ferroptosis effects of Met. Mechanistically, Met alleviates HG/PA-induced β cell Ferroptosis by regulating the GPX4/ACSL4 axis. Collectively, our findings highlight the significance of Ferroptosis in pancreatic β cell glucolipotoxicity-induced injury and provide novel insights into the protective effects of Met on islet β cells.

Keywords

Ferroptosis; GPX4; Metformin; Pancreatic β cell.

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