Imeglimin at clinical doses promotes glucose-stimulated insulin secretion and mitochondrial supercomplex formation

Abstract

Imeglimin is a novel antidiabetic agent that improves glycemic control by enhancing glucose-stimulated insulin secretion (GSIS). Although previous studies have suggested that imeglimin acts through increased NAD+ production and CD38-dependent calcium signaling, the mechanism responsible for its insulinotropic effect at clinically relevant concentrations remains incompletely understood. In particular, how clinically relevant concentrations of imeglimin affect mitochondrial bioenergetics in pancreatic beta cells remains unclear. To address this question, we examined the effects of imeglimin in normal glucose-tolerant C57BL/6 mice and isolated mouse islets using concentrations corresponding to clinically achieved plasma levels. Chronic administration of imeglimin at a pharmacological dose corresponding to clinically relevant exposure enhanced GSIS without affecting insulin sensitivity in vivo. In isolated islets, continuous exposure to imeglimin at a clinically relevant concentration (10 μmol/l) significantly enhanced GSIS, whereas supraphysiological imeglimin (1000 μmol/l) reduced GSIS. Mechanistically, 10 μmol/l imeglimin increased mitochondrial respiration, mitochondrial membrane potential, and ATP production while suppressing glucose-induced reactive oxygen species generation. Notably, blue native polyacrylamide gel electrophoresis revealed that clinically relevant concentrations of imeglimin promoted mitochondrial respiratory supercomplex formation, whereas supraphysiological concentrations did not.

These findings suggest that mitochondrial respiratory supercomplex formation may contribute to the insulinotropic action of imeglimin. Our results provide new insight into mitochondrial regulation of pancreatic beta cell function and suggest that enhancement of mitochondrial supercomplex assembly represents a potential mechanism by which clinically relevant imeglimin improves beta cell function, in addition to previously proposed NAD+-dependent pathways.