Imeglimin amplifies glucose-stimulated insulin release from diabetic islets via a distinct mechanism of action.
Sophie Hallakou-BozecMicheline KergoatPascale FouqueraySébastien BolzeDavid E MollerPublished in: PloS one (2021)
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 ADP ribosyl cyclase/cADPR 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.
Keyphrases
- type diabetes
- glycemic control
- blood glucose
- small molecule
- clinical trial
- end stage renal disease
- high glucose
- cardiovascular disease
- diabetic rats
- drug induced
- ejection fraction
- chronic kidney disease
- newly diagnosed
- cell therapy
- insulin resistance
- single cell
- oxidative stress
- peritoneal dialysis
- prognostic factors
- adipose tissue
- randomized controlled trial
- weight loss
- sensitive detection
- stress induced