1757-P: Imeglimin Enhances Glucose-Induced Insulin Secretion with Activating Mitochondrial Function

The underlying pathology of diabetes mellitus is inadequate insulin secretion and resistance. The resulting hyperglycemia leads to complications, decreased quality of life and shortened life span. New drugs to reduce blood glucose are still required. Imeglimin has a chemical structure derived from the antidiabetic compound metformin, and now is clinically used as an oral hypoglycemic agent with a tetrahydro-triazin structure in Japan. Several studies reported that imeglimin promotes glucose-stimulated insulin secretion (GSIS) in diabetic mouse models and protects pancreatic beta cells from inflammation and ROS-induced apoptosis, however, the underlying mechanism of enhanced GSIS has not been fully elucidated yet. The aim of this study is to investigate the effect of imeglimin on insulin secretion. First, we found that the in vivo administration of imeglimin to C57Bl/6 mice enhanced GSIS with increase of insulin secretion. Next, we investigated the effect of imeglimin on isolated islets from C57Bl/6 mice. Ten µM imeglimin, which is equivalent to the clinically used dose for 24 hours stimulated GSIS from isolated islets, however, 1000 µM imeglimin does not enhance GSIS. Intriguingly, 10 µM but not 1000 µM imeglimin enhanced mitochondrial oxygen consumption rate and membrane potential. While it has been reported that the imeglimin-induced increase in GSIS in streptozotocin-treated mice is attributed to an increase in NAD⁺ and enhanced calcium influx by activating NAMPT expression, no change in NAD⁺ levels by imeglimin was observed in C57Bl/6 mice. Our data showed that a clinical relevant dose of imeglimin enhanced GSIS with enhanced mitochondrial function in islets isolated from C57Bl/6 mice.