Nicotinamide Riboside Kinase 1 protects against diet and age-induced pancreatic beta-cell failure

Objective: Disturbances in NAD+ metabolism have been described as a hallmark for multiple metabolic and age-related diseases, including type 2 diabetes. While alterations in pancreatic ?-cell function are critical determinants of whole-body glucose homeostasis, the role of NAD+ metabolism in the endocrine pancreas remains poorly explored. Here, we aimed to evaluate the role of nicotinamide riboside (NR) metabolism in maintaining NAD+ levels and pancreatic ?-cell function in pathophysiological conditions. Methods: Whole body and pancreatic ?-cell-specific NRK1 knockout (KO) mice were metabolically characterized in situations of high-fat feeding and aging. We also analyzed pancreatic ?-cell function and gene expression. Results: We first demonstrate that NRK1, the essential enzyme for the utilization of NR, is substantially expressed in pancreatic ?-cells. While NR treatment did not alter glucose-stimulated insulin secretion in pancreatic islets from young healthy mice, NRK1 knockout mice displayed glucose intolerance and compromised ?-cells response to a glucose challenge upon high-fat feeding or aging. Interestingly, ß cells dysfunction stemmed from the functional failure of other organs, such as liver and kidney, and the associated changes in circulating peptides and hormones, as mice lacking NRK1 exclusively in ß-cells did not show altered glucose homeostasis. Conclusions: This work unveils a new physiological role for NR metabolism in the maintenance of glucose tolerance and pancreatic ?-cell function in high-fat feeding or aging conditions. Overall design: Both WT and NRK1 ins1Cre KO mice were submitted on HFD for 12 weeks and pancretic islets were collected at the sacrifice.