A novel mechanism of imeglimin‐mediated insulin secretion via the cADPR‐TRP channel pathway

AIMS/INTRODUCTION: Imeglimin is a novel oral hypoglycemic agent that improves blood glucose levels through multiple mechanisms of action including the enhancement of glucose‐stimulated insulin secretion (GSIS), however, the details of this mechanism have not been clarified. In the process of GSIS, activation of the transient receptor potential melastatin 2 (TRPM2) channel, a type of non‐selective cation channel (NSCCs) in β‐cells, promotes plasma membrane depolarization. The present study aimed to examine whether imeglimin potentiates GSIS via the TRPM2 channel in β‐cells. MATERIALS AND METHODS: Pancreatic islets were isolated by collagenase digestion from male wild‐type and TRPM2‐knockout (KO) mice. Insulin release and nicotinamide adenine dinucleotide (NAD(+)) production in islets were measured under static incubation. NSCC currents in mouse single β‐cells were measured by patch‐clamp experiments. RESULTS: Batch‐incubation studies showed that imeglimin enhanced GSIS at stimulatory 16.6 mM glucose, whereas it did not affect basal insulin levels at 2.8 mM glucose. Imeglimin increased the glucose‐induced production of NAD(+), a precursor of cADPR, in islets and the insulinotropic effects of imeglimin were attenuated by a cADPR inhibitor 8‐Br‐cADPR. Furthermore, imeglimin increased NSCC current in β‐cells, and abolished this current in TRPM2‐KO mice. Imeglimin did not potentiate GSIS in the TRPM2‐KO islets, suggesting that imeglimin’s increase of NSCC currents through the TRPM2 channel is causally implicated in its insulin releasing effects. CONCLUSIONS: Imeglimin may activate TRPM2 channels in β‐cells via the production of NAD(+)/cADPR, leading to the potentiation of GSIS. Developing approaches to stimulate cADPR‐TRPM2 signaling provides a potential therapeutic tool to treat type 2 diabetes.