title: Oxidative stress is a mediator of glucose toxicity in insulin-secreting pancreatic islet cell lines.
abstract: 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.
authors.affiliation: Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, 715 PRB, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, TN 37232, USA. lan.wu@vanderbilt.edu
authors.forename: Lan
authors.initials: L
authors.lastname: Wu
authors.forename: Wendell
authors.initials: W
authors.lastname: Nicholson
authors.forename: Susan M
authors.initials: SM
authors.lastname: Knobel
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Steffner
authors.forename: James M
authors.initials: JM
authors.lastname: May
authors.forename: David W
authors.initials: DW
authors.lastname: Piston
authors.forename: Alvin C
authors.initials: AC
authors.lastname: Powers
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D016923:Cell Death; D002460:Cell Line; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D005941:Glucokinase / Q000096:biosynthesis; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology*; D050356:Lipid Metabolism; D009249:NADP / Q000378:metabolism; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species; D013997:Time Factors
chemical_list: D018076:DNA, Complementary; D016166:Free Radical Scavengers; D007328:Insulin; D017382:Reactive Oxygen Species; D009249:NADP; D000255:Adenosine Triphosphate; D005941:Glucokinase; D005947:Glucose; D004318:Doxycycline; D010100:Oxygen