title: A role for glutathione peroxidase in protecting pancreatic beta cells against oxidative stress in a model of glucose toxicity.
abstract: Antioxidant drugs have been reported to protect pancreatic islets from the adverse effects of chronic exposure to supraphysiological glucose concentrations. However, glucose has not been shown to increase intracellular oxidant load in islets, nor have the effects of increasing or inhibiting glutathione peroxidase (GPx) activity on islet resistance to sugar-induced oxidant stress been studied. We observed that high glucose concentrations increased intracellular peroxide levels in human islets and the pancreatic beta cell line, HIT-T15. Inhibition of gamma-glutamylcysteine synthetase (gammaGCS) by buthionine sulfoximine augmented the increase in islet peroxide and decrease in insulin mRNA levels, content, and secretion in islets and HIT-T15 cells induced by ribose. Adenoviral overexpression of GPx increased GPx activity and protected islets against adverse effects of ribose. These results demonstrate that glucose and ribose increase islet peroxide accumulation and that the adverse consequences of ribose-induced oxidative stress on insulin mRNA, content, and secretion can be augmented by a glutathione synthesis inhibitor and prevented by increasing islet GPx activity. These observations support the hypothesis that oxidative stress is one mechanism for glucose toxicity in pancreatic islets.
authors.affiliation: Pacific Northwest Research Institute and the Department of Medicine, University of Washington, Seattle, WA, 98122, USA.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Phuong Oanh T
authors.initials: PO
authors.lastname: Tran
authors.forename: Jamie
authors.initials: J
authors.lastname: Harmon
authors.forename: R Paul
authors.initials: RP
authors.lastname: Robertson
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D005947:Glucose / Q000633:toxicity*; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D012266:Ribose / Q000633:toxicity; D014162:Transfection
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; D007328:Insulin; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D019328:Buthionine Sulfoximine; D012266:Ribose; D005979:Glutathione Peroxidase; D005721:Glutamate-Cysteine Ligase; D005947:Glucose; D000111:Acetylcysteine