2. Academic Validation
  3. Imeglimin suppresses glucagon secretion and induces a loss of α cell identity

Imeglimin suppresses glucagon secretion and induces a loss of α cell identity

  • Cell Rep Med. 2025 Aug 19;6(8):102254. doi: 10.1016/j.xcrm.2025.102254.
Takahiro Tsuno 1,  Jinghe Li 2,  Kuniyuki Nishiyama 2,  Yuka Imamura Kawasawa 3,  Ryota Inoue 2,  Esther Ong Yajima 2,  Akira Nishiyama 4,  Shigeharu G Yabe 5,  Tatsuya Kin 6,  Hitoshi Okochi 5,  Tomohiko Tamura 7,  A M James Shapiro 6,  Seiichi Oyadomari 8,  Tadahiro Kitamura 9,  Yasuo Terauchi 10,  Jun Shirakawa 11
Affiliations

Affiliations

  • 1 Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi 371-8512, Japan; Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan.
  • 2 Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi 371-8512, Japan.
  • 3 Penn State University College of Medicine, Hershey, PA 17033, USA; Animal Genome Institute, Palmyra, PA 17010, USA.
  • 4 Department of Immunology, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan.
  • 5 Department of Regenerative Medicine, National Center for Global Health and Medicine (NCGM), Tokyo 162-8655, Japan.
  • 6 Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, AB T6G 2G5, Canada.
  • 7 Department of Immunology, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan; Advanced Medical Research Center, Yokohama City University, Yokohama 236-0004, Japan.
  • 8 Division of Molecular Biology, Institute of Advanced Medical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, Japan.
  • 9 Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi 371-8512, Japan.
  • 10 Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan.
  • 11 Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi 371-8512, Japan; Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan. Electronic address: jshira@gunma-u.ac.jp.
PMID: 40713970 DOI: 10.1016/j.xcrm.2025.102254
Abstract

Dysregulated α cell function contributes to the development of diabetes. In this study, we find that treatment with imeglimin, an antidiabetic drug, prevents glucagon release and induces a loss of α cell identity through direct action on α cells. Mechanistically, imeglimin reduces Gsα expression to inhibit the exchange protein directly activated by cyclic adenosine monophosphate 2 (EPAC2)-mediated secretion of glucagon induced by low glucose, gastric inhibitory polypeptide (GIP), or adrenaline in an insulin-independent manner. Imeglimin also attenuates α cell CA2+ oscillations. MafB expression is downregulated by imeglimin to induce α cell dedifferentiation. In addition, imeglimin upregulates C/EBP homologous protein (CHOP) expression, which partly contributes to the reduction in Gsα and MafB expression to reduce glucagon secretion and induce α cell reprogramming without altering protein translation. These pleiotropic effects of imeglimin on glucagon secretion and α cell identity can be recapitulated in mouse models of diabetes in vivo. These data suggest that the imeglimin-mediated regulation of α cell plasticity, particularly via glucagon suppression, may contribute to glucose homeostasis.

Keywords

C/EBP homologous protein; G protein-coupled receptor signaling; Gsα; MafB; dedifferentiation; diabetes; glucagon; human islets; imeglimin; α cells.

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