Imeglimin Ameliorates beta-Cell Apoptosis by Modulating the Endoplasmic Reticulum Homeostasis Pathway

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.