title: CNC-bZIP protein Nrf1-dependent regulation of glucose-stimulated insulin secretion.
abstract: OBJECTIVE
  The inability of pancreatic β-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 β-cells on β-cell function and glucose homeostasis.
  
  
  RESULTS
  Silencing of Nrf1 in β-cells leads to a pre-T2D phenotype with disrupted glucose metabolism and impaired insulin secretion. Specifically, MIN6 β-cells with stable knockdown of Nrf1 (Nrf1-KD) and isolated islets from β-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.
  
  
  METHODS
  Our study demonstrated a novel role of Nrf1 in regulating glucose metabolism and insulin secretion in β-cells and characterized Nrf1 as a key transcription factor that regulates the coupling of glycolysis and mitochondrial metabolism and GSIS.
  
  
  CONCLUSIONS
  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 β-cells.
authors.affiliation: 1 The First Affiliated Hospital, China Medical University , Shenyang, China .
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Zheng
authors.forename: Jingqi
authors.initials: J
authors.lastname: Fu
authors.forename: Peng
authors.initials: P
authors.lastname: Xue
authors.forename: Rui
authors.initials: R
authors.lastname: Zhao
authors.forename: Jian
authors.initials: J
authors.lastname: Dong
authors.forename: Dianxin
authors.initials: D
authors.lastname: Liu
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Qingchun
authors.initials: Q
authors.lastname: Tong
authors.forename: Weiping
authors.initials: W
authors.lastname: Teng
authors.forename: Weidong
authors.initials: W
authors.lastname: Qu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Melvin E
authors.initials: ME
authors.lastname: Andersen
authors.forename: Jingbo
authors.initials: J
authors.lastname: Pi
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D002460:Cell Line; D005947:Glucose / Q000378:metabolism*; D006946:Hyperinsulinism / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics* / Q000378:metabolism*; D018384:Oxidative Stress
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D007328:Insulin; C495634:Nrf1 protein, mouse; D051266:Nuclear Respiratory Factor 1; D005947:Glucose