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.
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.