| First Author | Zheng H | Year | 2015 |
| Journal | Antioxid Redox Signal | Volume | 22 |
| Issue | 10 | Pages | 819-31 |
| PubMed ID | 25556857 | Mgi Jnum | J:346566 |
| Mgi Id | MGI:6877955 | Doi | 10.1089/ars.2014.6017 |
| Citation | Zheng H, et al. (2015) CNC-bZIP protein Nrf1-dependent regulation of glucose-stimulated insulin secretion. Antioxid Redox Signal 22(10):819-31 |
| abstractText | AIMS: The inability of pancreatic beta-cells to secrete sufficient insulin in response to glucose stimulation is a major contributing factor to the development of type 2 diabetes (T2D). We investigated both the in vitro and in vivo effects of deficiency of nuclear factor-erythroid 2-related factor 1 (Nrf1) in beta-cells on beta-cell function and glucose homeostasis. RESULTS: Silencing of Nrf1 in beta-cells leads to a pre-T2D phenotype with disrupted glucose metabolism and impaired insulin secretion. Specifically, MIN6 beta-cells with stable knockdown of Nrf1 (Nrf1-KD) and isolated islets from beta-cell-specific Nrf1-knockout [Nrf1(b)-KO] mice displayed impaired glucose responsiveness, including elevated basal insulin release and decreased glucose-stimulated insulin secretion (GSIS). Nrf1(b)-KO mice exhibited severe fasting hyperinsulinemia, reduced GSIS, and glucose intolerance. Silencing of Nrf1 in MIN6 cells resulted in oxidative stress and altered glucose metabolism, with increases in both glucose uptake and aerobic glycolysis, which is associated with the elevated basal insulin release and reduced glucose responsiveness. The elevated glycolysis and reduced glucose responsiveness due to Nrf1 silencing likely result from altered expression of glucose metabolic enzymes, with induction of high-affinity hexokinase 1 and suppression of low-affinity glucokinase. INNOVATION: Our study demonstrated a novel role of Nrf1 in regulating glucose metabolism and insulin secretion in beta-cells and characterized Nrf1 as a key transcription factor that regulates the coupling of glycolysis and mitochondrial metabolism and GSIS. CONCLUSION: Nrf1 plays critical roles in regulating glucose metabolism, mitochondrial function, and insulin secretion, suggesting that Nrf1 may be a novel target to improve the function of insulin-secreting beta-cells. |
