2022年4月1日 / 最終更新日 : 2022年11月22日 ad_y ニュース

2022年 新着論文 11　生体機能学分野から論文が発表されました

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

Diabetes. 2022 Mar 1;71(3):424-439. doi: 10.2337/db21-0123.

Authors

Jinghe Li  1   2 , Ryota Inoue  1   2 , Yu Togashi  2 , Tomoko Okuyama  2 , Aoi Satoh  1 , Mayu Kyohara  2 , Kuniyuki Nishiyama  1   2 , Takahiro Tsuno  1   2 , Daisuke Miyashita  2 , Tatsuya Kin  3 , A M James Shapiro  3 , Resilind Su Ern Chew  4 , Adrian Kee Keong Teo  4   5 , Seiichi Oyadomari  6 , Yasuo Terauchi  2 , Jun Shirakawa  1   2

Affiliations

  • 1 Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan.
  • 2 Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
  • 3 Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, Alberta, Canada.
  • 4 Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology, A*STAR, Proteos, Singapore.
  • 5 Departments of Biochemistry and Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
  • 6 Division of Molecular Biology, Institute of Advanced Medical Sciences, Tokushima University, Kuramoto, Tokushima, Japan.

Abstract

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.

© 2022 by the American Diabetes Association.

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