Suppression of NADPH oxidase 2 substantially restores glucose-induced dysfunction of pancreatic NIT-1 cells

FEBS J. 2010 Dec;277(24):5061-71. doi: 10.1111/j.1742-4658.2010.07911.x. Epub 2010 Nov 12.


Defects in insulin secretion by pancreatic cells and/or decreased sensitivity of target tissues to insulin action are the key features of type 2 diabetes. It has been shown that excessive generation of reactive oxygen species (ROS) is linked to glucose-induced β-cell dysfunction. However, cellular mechanisms involved in ROS generation in β-cells and the link between ROS and glucose-induced β-cell dysfunction are poorly understood. Here, we demonstrate a key role of NADPH oxidase 2 (NOX2)-derived ROS in the deterioration of β-cell function induced by a high concentration of glucose. Sprague-Dawley rats were fed a high-fat diet for 24 weeks to induce diabetes. Diabetic rats showed increased glucose levels and elevated ROS generation in blood, but decreased insulin content in pancreatic β-cells. In vitro, increased ROS levels in pancreatic NIT-1 cells exposed to high concentrations of glucose (33.3 mmol·L(-1)) were associated with elevated expression of NOX2. Importantly, decreased glucose-induced insulin expression and secretion in NIT-1 cells could be rescued via siRNA-mediated NOX2 reduction. Furthermore, high glucose concentrations led to apoptosis of β-cells by activation of p38MAPK and p53, and dysfunction of β-cells through phosphatase and tensih homolog (PTEN)-dependent Jun N-terminal kinase (JNK) activation and protein kinase B (AKT/PKB) inhibition, which induced the translocation of forkhead box O1 and pancreatic duodenal homeobox-1, followed by reduced insulin expression and secretion. In conclusion, NOX2-derived ROS could play a critical role in high glucose-induced β-cell dysfunction through PTEN-dependent JNK activation and AKT inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / analysis
  • Cell Line
  • Diabetes Mellitus, Experimental / enzymology
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Glucose / pharmacology*
  • Insulin / metabolism
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / enzymology
  • Islets of Langerhans / pathology
  • NADPH Oxidases / antagonists & inhibitors*
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism


  • Blood Glucose
  • Insulin
  • Reactive Oxygen Species
  • NADPH Oxidases
  • Glucose