Imeglimin amplifies glucose-stimulated insulin release from diabetic islets via a distinct mechanism of action

PLoS One. 2021 Feb 19;16(2):e0241651. doi: 10.1371/journal.pone.0241651. eCollection 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Calcium / metabolism
  • Cyclic ADP-Ribose / metabolism
  • Cytokines / metabolism
  • Diabetes Mellitus, Type 2 / metabolism*
  • Glucose / pharmacology*
  • Insulin Secretion / drug effects*
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism*
  • Islets of Langerhans / pathology
  • Male
  • Models, Biological
  • NAD / metabolism
  • Niacinamide / pharmacology
  • Nicotinamide Phosphoribosyltransferase / metabolism
  • Rats
  • Rats, Wistar
  • Ryanodine Receptor Calcium Release Channel / metabolism
  • Sulfonylurea Compounds / pharmacology
  • Triazines / pharmacology*


  • Cytokines
  • Ryanodine Receptor Calcium Release Channel
  • Sulfonylurea Compounds
  • Triazines
  • NAD
  • Cyclic ADP-Ribose
  • Niacinamide
  • Adenosine Triphosphate
  • Nicotinamide Phosphoribosyltransferase
  • nicotinamide phosphoribosyltransferase, rat
  • Glucose
  • Calcium
  • imeglimin

Grants and funding

Authors S H-B, PF, SB and DM are salaried employees of Poxel SA which funded the work described in this manuscript. The funder provided support in the form of research materials (supply of compound) and paying for research costs – including supplies and materials for animal care, equipment maintenance and reagents - paid according to a contract to Metabrain Research (Maisons Alfort, France). Author MK is a salaried employee of Metabrain Research; a portion of her salary was paid by the funder via the sponsored research contract between Poxel SA and Metabrain. The funder also provided salaries for authors S H-B, PF, SB and DM, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of each of these authors are articulated in the ‘author contributions’ section.