Single-cell gene expression profile of cultured mouse islet cells

Dysregulated a-cell function contributes to the onset and progression of diabetes. Here, we report that the treatment with imeglimin, an anti-diabetes drug, prevents glucagon release and promotes a-to-ß cell transdifferentiation through direct action on a-cells. Mechanistically, imeglimin reduces Gsa expression to attenuate EPAC2-mediated glucagon secretion induced by glucose or GIP in an insulin-independent fashion. MafB expression is downregulated by imeglimin to make a-cell transdifferentiate to ß-cell. Imeglimin also upregulates CHOP expression, which partly contributes to the reduction in both Gsa and MafB expression to reduce glucagon secretion and induce a-cell dedifferentiation, without alteration of protein translation. Those pleiotropic effects of imeglimin on glucagon secretion and a-cell identity can be recapitulated by mouse models of diabetes in vivo. These data implicate the imeglimin-mediated regulation of a-cell plasticity as a novel component in diabetes therapy to correct islet functions. Overall design: Pancreatic islets were isolated from 8 weeks old male C57BL6J mice. The islets were cultured for 24 hours with or without 1 mM imeglimin under 3.9 mM or 11.1 mM glucose.