期刊
DIABETES
卷 71, 期 3, 页码 424-439出版社
AMER DIABETES ASSOC
DOI: 10.2337/db21-0123
关键词
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资金
- MEXT of Japan [18K16240]
- Novo Nordisk Pharma Ltd.
- Kanae Foundation for the Promotion of Medical Science
- Suzuken Memorial Foundation
- Japan Foundation for Applied Enzymology
- Ono Medical Research Foundation
- Kamome Memorial Foundation of Yokohama City University
- Japan IDDM Network
- Takeda Science Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- AMED-A*STAR SCICOP Joint Grant [192B9002]
Imeglimin protects beta-cell survival by enhancing function, promoting proliferation, and preventing apoptosis, thereby improving islet survival and mass.
The effects of imeglimin, a novel antidiabetes agent, on beta-cell function remain unclear. Here, we unveiled the impact of imeglimin on beta-cell survival. Treatment with imeglimin augmented mitochondrial function, enhanced insulin secretion, promoted beta-cell proliferation, and improved beta-cell survival in mouse islets. Imeglimin upregulated the expression of endoplasmic reticulum (ER)-related molecules, including Chop (Ddit3), Gadd34 (Ppp1r15a), Atf3, and Sdf2l1, and decreased eIF2 alpha phosphorylation after treatment with thapsigargin and restored global protein synthesis in beta-cells under ER stress. Imeglimin failed to protect against ER stress-induced beta-cell apoptosis in CHOP-deficient islets or in the presence of GADD34 inhibitor. Treatment with imeglimin showed a significant decrease in the number of apoptotic beta-cells and increased beta-cell mass in Akita mice. Imeglimin also protected against beta-cell apoptosis in both human islets and human pluripotent stem cell-derived beta-like cells. Taken together, imeglimin modulates the ER homeostasis pathway, which results in the prevention of beta-cell apoptosis both in vitro and in vivo.
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