Introduction and Objective: Imeglimin, a drug for type 2 diabetes, reportedly promotes β-cell proliferation and β-cell survival; however, the underlying molecular mechanism remains unclear.Methods: We investigated The metabolites in islets after imeglimin treatment via LC-MS.Results: Treatment with imeglimin for one hour significantly altered the levels of 17 metabolites at 5.6 mM glucose and 11 metabolites at 11.1 mM glucose. After 24 hours of treatment, imeglimin changed the levels of 12 metabolites at 5.6 mM glucose and 28 metabolites at 11.1 mM glucose. The most significant changes in metabolic products were observed after 24 hours of stimulation in the presence of 11.1 mM glucose, which is the condition under which imeglimin promotes β-cell proliferation and improves survival. The metabolites altered by imeglimin under high glucose conditions are involved in NAD synthesis, amino acid metabolism and nucleic acid metabolism. Adenylosuccinate (S-AMP), produced by adenylosuccinate synthase (ADSS) from inosinic acid (IMP) and aspartate, was increased by 2.98-fold after treatment with imeglimin. The levels of aspartate and both the mRNA and protein levels of ADSS were significantly increased by imeglimin in islets. Integrated ontology analysis, which combines this metabolome analysis with gene expression microarray analyses under the same conditions, revealed that the levels of genes and metabolites involved in cell cycle progression and amino acid metabolism were altered by imeglimin. Alanosine, an inhibitor of ADSS, suppressed imeglimin-induced β-cell proliferation by approximately 50% in mouse islets. The inhibition of proliferation in imeglimin-treated β-cells by alanosine was also observed in human islets, human pluripotent stem cell-derived β-like cells, and porcine islets.Conclusion: Taken together, these findings suggest that chronic treatment with imeglimin promotes β-cell proliferation and survival partly through an increase in S-AMP production.
R. Inoue: None. J. Shirakawa: None.
Source link
Leave a Reply