Adenylosuccinate Mediates Imeglimin-Induced Proliferative and Antiapoptotic Effects in β-Cells

Imeglimin, a drug for type 2 diabetes, reportedly promotes β-cell proliferation and increases β-cell survival; however, the detailed underlying molecular mechanism remains unclear. Here, we investigated metabolites in pancreatic islets after imeglimin treatment via liquid chromatography with tandem mass spectrometry. Treatment with imeglimin for 1 h significantly altered the levels of 17 metabolites at 5.6 mmol/L glucose and 11 metabolites at 11.1 mmol/L glucose. After 24 h of treatment, imeglimin changed the levels of 12 metabolites at 5.6 mmol/L glucose and 28 metabolites at 11.1 mmol/L glucose. The metabolites altered by imeglimin under high-glucose conditions were involved in NAD synthesis, amino acid metabolism, and nucleic acid metabolism. Adenylosuccinate (S-AMP), produced by adenylosuccinate synthase (ADSS) from inosine monophosphate (IMP) and aspartate, increased 2.98-fold after treatment with imeglimin. The levels of IMP and aspartate and both the mRNA and protein levels of ADSS were elevated following imeglimin treatment in islets. Alanosine, an inhibitor of ADSS, suppressed imeglimin-induced β-cell proliferation and survival in mouse islets, human islets, human pluripotent stem cell–derived β-cells, and porcine islets. Taken together, these findings suggest that chronic treatment with imeglimin promotes β-cell proliferation and survival partly through an increase in S-AMP production. ARTICLE HIGHLIGHTS Although imeglimin promotes β-cell proliferation and ameliorates β-cell apoptosis, the detailed metabolic changes induced by imeglimin in β-cells are unknown. Imeglimin increases adenylosuccinate (S-AMP), which is produced by adenylosuccinate synthase (ADSS) from inosine monophosphate and aspartate, and imeglimin also increases amino acid content, including aspartate, in mouse islets. Inhibition of S-AMP production by an ADSS inhibitor reduces the ability of imeglimin to increase β-cell proliferation and ameliorate β-cell apoptosis in mouse islets, human islets, porcine islets, and human pluripotent stem cell–derived β-cells. Imeglimin increases S-AMP to promote β-cell proliferation and ameliorate β-cell apoptosis.