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

J Diabetes Investig. 2022 Jan;13(1):34-41. doi: 10.1111/jdi.13669. Epub 2021 Sep 27.

Abstract

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.

Keywords: Cyclic ADP ribose; Imeglimin; Transient receptor potential melastatin 2.

MeSH terms

  • ADP-ribosyl Cyclase / metabolism*
  • Animals
  • Blood Glucose / drug effects
  • Hypoglycemic Agents / pharmacology*
  • Insulin Secretion / drug effects*
  • Islets of Langerhans / drug effects
  • Male
  • Mice
  • Signal Transduction / drug effects
  • TRPM Cation Channels / metabolism*
  • Triazines / pharmacology*

Substances

  • Blood Glucose
  • Hypoglycemic Agents
  • TRPM Cation Channels
  • TRPM2 protein, mouse
  • Triazines
  • ADP-ribosyl Cyclase
  • imeglimin