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J. Biol. Chem., Vol. 279, Issue 13, 12126-12134, March 26, 2004

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Oxidative Stress Is a Mediator of Glucose Toxicity in Insulin-secreting Pancreatic Islet Cell Lines^*

Lan Wu, Wendell Nicholson, Susan M. Knobel¶, Robert J. Steffner, James M. May||, David W. Piston¶, and Alvin C. Powers¶||**

From the Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine and the ^¶Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232 and the ^||Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee 37232

Pancreatic cells secrete insulin in response to changes in the extracellular glucose. However, prolonged exposure to elevated glucose exerts toxic effects on cells and results in cell dysfunction and ultimately cell death (glucose toxicity). To investigate the mechanism of how increased extracellular glucose is toxic to cells, we used two model systems where glucose metabolism was increased in 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 cells generates oxidative stress and impairs cell function and survival; this may be a mechanism of glucose toxicity in cells. The level of cell GK may also be critical in this process.

Received for publication, July 3, 2003 , and in revised form, November 19, 2003.

^* This work was supported by a Merit Review Award from the VA Research Service, a postdoctoral fellowship grant from the Juvenile Diabetes Research Foundation International, Grants DK 55233, DK 64339, and DK50435 from the National Institutes of Health, the Vanderbilt Diabetes Research & Training Center, and the Vanderbilt Center in Molecular Toxicology (NIH DK20593, NIH P30ES00267). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence may be addressed: Division of Diabetes, Endocrinology, and Metabolism, Dept. of Medicine, 715 PRB, Vanderbilt University Medical Center, 2220 Pierce Ave., Nashville, TN 37232. Tel.: 615-936-1653; Fax: 615-936-1667; E-mail: lan.wu{at}vanderbilt.edu. ** To whom correspondence may be addressed: Division of Diabetes, Endocrinology, and Metabolism, Dept. of Medicine, 715 PRB, Vanderbilt University Medical Center, 2220 Pierce Ave., Nashville, TN 37232. Tel.: 615-936-1653; Fax: 615-936-1667; E-mail: al.powers{at}vanderbilt.edu.

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