Dysregulated α-cell function contributes to the development of diabetes. In this study, we found 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 EPAC2-mediated secretion of glucagon induced by low glucose, 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 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.

・Cell Reports Medicine
・2025/7/25
・Imeglimin suppresses glucagon secretion and induces a loss of α-cell identity.

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