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

Autor: Li, Jinghe, Inoue, Ryota, Togashi, Yu, Okuyama, Tomoko, Satoh, Aoi, Kyohara, Mayu, Nishiyama, Kuniyuki, Tsuno, Takahiro, Miyashita, Daisuke, Kin, Tatsuya, Shapiro, A.M. James, Chew, Resilind Su Ern, Teo, Adrian Kee Keong, Oyadomari, Seiichi, Terauchi, Yasuo, Shirakawa, Jun
Předmět:
Zdroj: Diabetes; Mar2022, Vol. 71 Issue 3, p424-439, 16p
Abstrakt: The effects of imeglimin, a novel antidiabetes agent, on β-cell function remain unclear. Here, we unveiled the impact of imeglimin on β-cell survival. Treatment with imeglimin augmented mitochondrial function, enhanced insulin secretion, promoted β-cell proliferation, and improved β-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 eIF2α phosphorylation after treatment with thapsigargin and restored global protein synthesis in β-cells under ER stress. Imeglimin failed to protect against ER stress-induced β-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 β-cells and increased β-cell mass in Akita mice. Imeglimin also protected against β-cell apoptosis in both human islets and human pluripotent stem cell-derived β-like cells. Taken together, imeglimin modulates the ER homeostasis pathway, which results in the prevention of β-cell apoptosis both in vitro and in vivo. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index