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.
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.