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

被引:93
作者
Wu, L
Nicholson, W
Knobel, SM
Steffner, RJ
May, JM
Piston, DW
Powers, AC
机构
[1] Vanderbilt Univ, Med Ctr, Dept Med, Div Endocrinol Diabet & Metab, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Med Ctr, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA
[3] Vet Affairs Tennessee Valley Healthcare Syst, Nashville, TN 37232 USA
关键词
D O I
10.1074/jbc.M307097200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:12126 / 12134
页数:9
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