Supplementation of N-acetylcysteine inhibits NFκB 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 NF kappa B 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-KB, 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 NF kappa B 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 NF kappa B activation and reduced hyperglycemia, Thus, NF kappa B activation by ROS may initiate a sequence of events leading to IDDM, Inhibition of NF-kappa B 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.