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

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 b-cells, promotes plasma membrane depolarization. The present study aimed to examine whether imeglimin potentiates GSIS via the TRPM2 channel in b-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 b-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 b-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 b-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.

Clinical Efficacy of Imeglimin (Twymeeg) for Elderly Patient with Type 2 Diabetes Mellitus (T2DM)

“…This GSIS process includes activated transient receptor potential melastatin 2 (TRPM2) channels. As a result, it can promote the plasma membrane depolarization, which is one of non-selective cation channels (NSCCs) of beta-cells [11]. Moreover, imeglimin can be involved in the calcium mobilization for the amplification pathway during insulin secretion process [12].…”

A Review on the Role of TRP Channels and Their Potential as Drug Targets_An Insight Into the TRP Channel Drug Discovery Methodologies

“…In the process, the entry of glucose and activation of TRP channels causes depolarization of the cell and insulin release ( Yamada et al, 2016 ). Similarly, Funazaki et al also showed that the supporting activation of TRPM2 by Imeglimin enhanced the release of insulin secretion and showed it to be a possible tool for type 2 diabetes ( Funazaki et al, 2022 ). Also, there are several other forms of TRP channels such as TRPC, TRPM, TRPV, and TRPML in blood vessels, endothelial cells, vascular smooth muscles, and perivascular adipose tissue.…”

Pharmacokinetics of Imeglimin in Caucasian and Japanese Healthy Subjects

“…Imeglimin or placebo was administered to Caucasian and Japanese subjects in single oral doses of 250 (Caucasian only), 500, 1000, 1500, 2000, 4000, 6000, and 8000 (Caucasian only) mg on the morning of Day 1 after an overnight fasting period. Blood samples (6 mL) for plasma pharmacokinetic assessments were collected into a lithium heparinate tube on Day 1 at the following time points: pre-dose, 0.5, 1, 1.5, 2, 3,4,6,8,10,12,16,24,36,48, and 72 h post-dose, except for Caucasians at 1000, 1500, 2000, and 4000 mg where the following timepoints were used: pre-dose, 1, 2, 3, 3.5, 4, 4.5, 5, 6, 8, 12, 16, 24, 36, 48, and 72 h post-dose. Urine samples were collected for each cohort: before drug administration, and at the following intervals 0-4, 4-8, 8-12, 12-24, and 24-48 h after drug administration.…”

“…Biochemical and molecular investigations have shown that the effect of imeglimin on insulin secretion was mediated by improvement of glucose-stimulated ATP generation and by an increase in NAD + synthesis in (rodent) islets [1,2,4]. More recently it was suggested that this production of NAD + /cADPR by imeglimin may activate transient receptor potential melastatin 2 (TRPM2) channels in β-cells, leading to the potentiation of glucose-stimulated insulin secretion (GSIS) [10]. In parallel, imeglimin restores mitochondrial function by modulating the respiratory chain complex activities through partial inhibition of Complex I and rescue of Complex III activity, decreasing reactive oxygen species production and preventing cell death by delaying the mitochondrial permeability transition pore's opening [11][12][13].…”