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
  • 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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