Oxidative stress is a mediator of glucose toxicity in insulin-secreting pancreatic islet cell lines.

Wu L, Nicholson W, Knobel SM, Steffner RJ, May JM, Piston DW, Powers AC
J Biol Chem. 2004 279 (13): 12126-34

PMID: 14688272 · DOI:10.1074/jbc.M307097200

Pancreatic beta cells secrete insulin in response to changes in the extracellular glucose. However, prolonged exposure to elevated glucose exerts toxic effects on beta cells and results in beta cell dysfunction and ultimately beta cell death (glucose toxicity). To investigate the mechanism of how increased extracellular glucose is toxic to beta cells, we used two model systems where glucose metabolism was increased in beta cell lines by enhancing glucokinase (GK) activity and exposing cells to physiologically relevant increases in extracellular glucose (3.3-20 mm). Exposure of cells with enhanced GK activity to 20 mm glucose accelerated glycolysis, but reduced cellular NAD(P)H and ATP, caused accumulation of intracellular reactive oxygen species (ROS) and oxidative damage to mitochondria and DNA, and promoted apoptotic cell death. These changes required both enhanced GK activity and exposure to elevated extracellular glucose. A ROS scavenger partially prevented the toxic effects of increased glucose metabolism. These results indicate that increased glucose metabolism in beta cells generates oxidative stress and impairs cell function and survival; this may be a mechanism of glucose toxicity in beta cells. The level of beta cell GK may also be critical in this process.

MeSH Terms (21)

Adenosine Triphosphate Animals Blotting, Western Cell Death Cell Line DNA, Complementary Dose-Response Relationship, Drug Doxycycline Free Radical Scavengers Glucokinase Glucose Insulin Insulin Secretion Islets of Langerhans Lipid Metabolism NADP Oxidative Stress Oxygen Rats Reactive Oxygen Species Time Factors

Connections (2)

This publication is referenced by other Labnodes entities: