2130-P: Imeglimin Modulated ER Stress to Prevent ß-Cell Apoptosis Induced by High Glucose or Thapsigargin

Abstract

Imeglimin, a tetrahydrotriazine anti-hyperglycemic agent, is thought to have effects on mitochondrial function of the liver, skeletal muscle, and pancreatic β-cells. However, the molecular mechanisms of imeglimin action have been still unclear. Treatment of mouse islets with 1.0 mM imeglimin significantly increased insulin release in response to glucose (2.1-fold, p<0.01 at 11.1 mM glucose; 1.9-fold, p<0.05 at 16.7 mM glucose, compared to 3.9 mM glucose). Treatment with a combination of liraglutide (100 nM) and imeglimin did not show an additional increase in insulin secretion compared to the treatment with liraglutide alone. Liraglutide and imeglimin significantly increased EdU-incorporated proliferating β-cells in the islets under 11.1 mM glucose (1.02% in vehicle control; 2.21% in liraglutide, p<0.01 vs. vehicle; 1.46% in 1.0 mM imeglimin, p<0.01 vs. vehicle). Imeglimin prevented β-cell apoptosis induced by high glucose (32% of control in imeglimin, p<0.01; 57% of control in liraglutide, p=0.068). We conducted gene expression microarray analysis of islets treated with imeglimin under high glucose and some ER stress-related gene expression were altered by imeglimin. Then, we examined the effects of imeglimin on ER stress-induced β-cell apoptosis in mouse islets. Imeglimin significantly reduced β-cell apoptosis induced by thapsigargin at 5.6 mM glucose (29% of thapsigargin, p<0.01). Imeglimin further upregulated the expression of C/EBP homologous protein (CHOP) under thapsigargin treatment and tended to decrease phosphorylation of eIF2-α. We also confirmed that imeglimin improved β-cell apoptosis induced by high glucose or thapsigargin in human islets. Collectively, imeglimin prevented β-cell apoptosis induced by high glucose or thapsigargin, in addition to increase in insulin secretion and β-cell proliferation. Imeglimin seemed to regulate CHOP/GADD34-mediated dephosphorylation of eIF2-α to recover from translational inhibition. Disclosure J. Li: None. J. Shirakawa: None. Y. Togashi: None. Y. Terauchi: Advisory Panel; Self; AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Sanofi. Research Support; Self; Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd.

Imeglimin preserves islet β‐cell mass in Type 2 diabetic ZDF rats

“…Moreover, the molecule was shown to prevent the death of cultured rat β cells and INS‐1 cells when exposed to pro‐inflammatory cytokines and high glucose, respectively 12 . Similarly, a preliminary report revealed that imeglimin prevents β‐cell apoptosis induced by high glucose in both rat and human isolated islets 31 . These findings and the current results beg the following question: What mechanism(s) may underlie the ability of imeglimin to reduce β‐cell apoptosis and preserve mass?…”

Mechanism of action of Imeglimin: A novel therapeutic agent for type 2 diabetes

“…In addition to direct effects to amplify GSIS, previous in vitro studies performed with isolated human or rat islets or cultured rat insulinoma (INS1) cells showed a protective effect of Imeglimin to reduce cell death in response to cytokines or high glucose incubation 41,46 . These effects suggested that Imeglimin might have longer term benefits to prevent the loss of functional β‐cell mass in T2D.…”

Molecular Mechanisms by Which Imeglimin Improves Glucose Homeostasis

“…They also suggested that imeglimin increases beta cell mass by inhibitory impacts on permeability transition pores (PTP) of mitochondria [25]. There is a growing evidence confirming the protecting roles of imeglimin on beta cells [9,26]. The above mentioned evidence suggests that imeglimin improves glucose homeostasis partly via promoting beta-cell function.…”

“…Beyond the above described metabolic effects, imeglimin can provide additional pharmacologic effects [26]. For example, it improves endoplasmic reticulum stress and in turn inhibits various downstream pathophysiologic pathways [26].…”

“…Beyond the above described metabolic effects, imeglimin can provide additional pharmacologic effects [26]. For example, it improves endoplasmic reticulum stress and in turn inhibits various downstream pathophysiologic pathways [26]. It could also potentially act as a protective agent against vascular dysfunction in diabetic complications [13,31].…”