2. Academic Validation
  3. Imeglimin Ameliorates β-Cell Apoptosis by Modulating the Endoplasmic Reticulum Homeostasis Pathway

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.
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

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.
PMID: 34588186 DOI: 10.2337/db21-0123
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.

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