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

<jats:p>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. <jats:italic>In vitro</jats:italic>, increased ROS levels in pancreatic NIT‐1 cells exposed to high concentrations of glucose (33.3 mmol·L<jats:sup>−1</jats:sup>) 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.</jats:p>