Supplementation of N-acetylcysteine inhibits NFkappaB activation and protects against alloxan-induced diabetes in CD-1 mice.
Reactive oxygen species (ROS) are involved in the destruction of pancreatic beta cells and the development of insulin-dependent diabetes mellitus (IDDM). However, the cellular mechanism responsible for beta cell death is still unclear. We hypothesize that activation of NFkappaB by ROS is the key cellular signal in initiating a cascade of events leading to beta cell death. Thus, enhancement of pancreatic GSH, a known antioxidant and key regulator of NF-kappaB, should protect against IDDM. Weanling CD1 mice (n=5) were injected with alloxan (50 mg/kg i.v.) to induce IDDM. Using EPR spin trapping techniques, we demonstrated that alloxan generated ROS in the pancreas 15 min after administration. Activation of NFkappaB in pancreatic nuclear extracts was observed 30 min after alloxan injection, as assessed by an electrophoretic mobility shift assay. Fasting blood glucose levels were monitored for 14 days. Supplementation with N-acetylcysteine (NAC, 500 mg/kg), a GSH precursor, inhibited alloxan-induced NFkappaB activation and reduced hyperglycemia. Thus, NFkappaB activation by ROS may initiate a sequence of events leading to IDDM. Inhibition of NF-kappaB activation by NAC attenuated the severity of IDDM. This research will contribute to the understanding of the etiology of IDDM and may lead to the development of better strategies for disease prevention.
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Department of Human Nutrition, The Ohio State University, Columbus, Ohio 43210-1295, USA.
Chen
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Bray
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D000111:Acetylcysteine / Q000627:therapeutic use*; D000284:Administration, Oral; D000496:Alloxan / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003497:Cyclic N-Oxides; D003921:Diabetes Mellitus, Experimental / Q000517:prevention & control*; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology*; D004305:Dose-Response Relationship, Drug; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals; D005978:Glutathione / Q000494:pharmacology; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000032:analysis; D052247:Nitric Oxide Synthase Type II; D009589:Nitrogen Oxides / Q000494:pharmacology; D010179:Pancreas / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism
D001786:Blood Glucose; D003497:Cyclic N-Oxides; D005609:Free Radicals; D016328:NF-kappa B; D009589:Nitrogen Oxides; D009569:Nitric Oxide; C029217:phenyl-N-tert-butylnitrone; D000496:Alloxan; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D005978:Glutathione; D000111:Acetylcysteine