title: Suppression of NADPH oxidase 2 substantially restores glucose-induced dysfunction of pancreatic NIT-1 cells.
abstract: 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.
authors.affiliation: Peking University Fifth School of Clinical Medicine (Beijing Hospital), Beijing, China.
authors.forename: Huiping
authors.initials: H
authors.lastname: Yuan
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Lu
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Huang
authors.forename: Qinghua
authors.initials: Q
authors.lastname: He
authors.forename: Yong
authors.initials: Y
authors.lastname: Man
authors.forename: Yingsheng
authors.initials: Y
authors.lastname: Zhou
authors.forename: Shu
authors.initials: S
authors.lastname: Wang
authors.forename: Jian
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007328:Insulin; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; D005947:Glucose