2025年新着論文 26　生体機能学分野から論文が発表されました

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

Cell Rep Med. 2025 Jul 22:102254. doi: 10.1016/j.xcrm.2025.102254. Online ahead of print.

Authors

Takahiro Tsuno¹, Jinghe Li², Kuniyuki Nishiyama², Yuka Imamura Kawasawa³, Ryota Inoue², Esther Ong Yajima², Akira Nishiyama⁴, Shigeharu G Yabe⁵, Tatsuya Kin⁶, Hitoshi Okochi⁵, Tomohiko Tamura⁷, A M James Shapiro⁶, Seiichi Oyadomari⁸, Tadahiro Kitamura⁹, Yasuo Terauchi¹⁰, Jun Shirakawa¹¹

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

Free article

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.

Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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