Imeglimin Ameliorates β-Cell Apoptosis by Modulating the Endoplasmic Reticulum Homeostasis Pathway
Imeglimin Ameliorates β-Cell Apoptosis by Modulating the Endoplasmic Reticulum Homeostasis Pathway
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DOI：
10.2337/db21-0123
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发表时间：
2022-03-01
期刊：
影响因子：
7.7
通讯作者：
Shirakawa, Jun
中科院分区：
文献类型：
--
作者：
Li, Jinghe;Inoue, Ryota;Shirakawa, Jun
新型抗糖尿病药物伊美利明对胰岛β细胞功能的影响尚不清楚。在这里，我们揭示了伊美利明对β细胞存活的影响。伊美格利明可增强线粒体功能，促进胰岛素分泌，促进β细胞增殖，并改善小鼠胰岛中的β细胞存活。Imeglimin上调内质网(ER)相关分子Chop(Ddit3)、Gadd34(Ppp1r15a)、ATF3和Sdf2l1的表达，并降低thapsigargin处理后eIF2α的磷酸化，恢复ER应激下β细胞的整体蛋白质合成。Imeglimin不能在CHOP缺乏的胰岛或在Gadd34抑制剂存在的情况下保护内质网应激诱导的β细胞凋亡。用伊美利明治疗后，秋田小鼠的β细胞凋亡率显著减少，而β细胞质量显著增加。Imeglimin还可以保护人类胰岛和人类多能干细胞来源的β-样细胞免受β细胞凋亡的影响。综上所述，伊美利明调节内质网稳态途径，从而在体外和体内都能阻止β细胞的凋亡。
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.