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
  • 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: [email protected].
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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