RT Journal Article SR Electronic T1 Imeglimin Amplifies Glucose-Stimulated Insulin Release from Diabetic Islets via a Distinct Mechanism of Action JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.10.20.346841 DO 10.1101/2020.10.20.346841 A1 Sophie Hallakou-Bozec A1 Micheline Kergoat A1 Pascale Fouqueray A1 Sébastien Bolze A1 David E. Moller YR 2020 UL http://biorxiv.org/content/early/2020/10/20/2020.10.20.346841.abstract AB Pancreatic islet β-cell dysfunction is characterized by defective glucose-stimulated insulin secretion (GSIS) and is a predominant component of the pathophysiology of diabetes. Imeglimin, a novel first-in-class small molecule tetrahydrotriazine drug candidate, improves glycemia and GSIS in preclinical models and clinical trials in patients with type 2 diabetes; however, the mechanism by which it restores β-cell function is unknown. Here, we show that Imeglimin acutely and directly amplifies GSIS in islets isolated from rodents with Type 2 diabetes via a mode of action that is distinct from other known therapeutic approaches. The underlying mechanism involves increases in the cellular nicotinamide adenine dinucleotide (NAD+) pool – potentially via the salvage pathway and induction of nicotinamide phosphoribosyltransferase (NAMPT) along with augmentation of glucose-induced ATP levels. Further, additional results suggest that NAD+ conversion to a second messenger, cyclic ADP ribose (cADPR), via cyclic ADP ribose hydrolase (CD38) is required for Imeglimin’s effects in islets, thus representing a potential link between increased NAD+ and enhanced glucose-induced Ca2+ mobilization which - in turn - is known to drive insulin granule exocytosis. Collectively, these findings implicate a novel mode of action for Imeglimin that explains its ability to effectively restore β-cell function and provides for a new approach to treat patients suffering from Type 2 diabetes.