Antioxidants, NF(kappa)B activation and the development of insulin-dependent diabetes mellitus

Although many risk factors can trigger the development of insulin-dependent diabetes (IDDM), it is likely that reactive oxygen species (ROS) play a central role in beta cell death and disease progression. This dissertation work focuses on the role of antioxidant defense systems in the susceptibility to IDDM and the cellular mechanisms by which ROS and antioxidants regulate the expression of genes leading to beta cell death. Accumulating evidence indicates that increased antioxidant defense systems reduce the susceptibility to IDDM in animal models or in human studies. We hypothesize that pancreas-specific ROS production plays a critical role in signaling the cellular autoimmune/inflammatory response in IDDM by activating the transcription factor, NFkappaB. Various diabetogenic factors may lead to an increase in ROS production, which activates the redox-sensitive NFkappaB. This may be the initial event for the expression of cytokines and chemotactic agents involved in the autoimmune/inflammatory response. To test this hypothesize we have examined pancreatic NFkappaB activation in two different chemically induced models for IDDM using the drugs alloxan and streptozotocin (STZ). We have also investigated the role of various antioxidants, including N-acetylcysteine (NAC), alpha-phenyl-t-butyl-nitrone (PBN), zinc and vitamin E, on the ability to inhibit pancreatic NFkappaB activation and prevent the development of diabetic symptoms. We found a specific activation of NFkappaB in the pancreas with both diabetogenic agents. In addition, classes of antioxidants which effectively inhibited NFkappaB activation were potent in inhibiting the development of the disease. The specificity of antioxidants to inhibit NFkappaB activation and the hyperglycemic response emphasizes the importance of selectivity in antioxidant therapy. Research in this area will contribute significantly to our understanding of the cellular and mechanistic role of ROS in the etiology of IDDM and will lead to the development of better prevention strategies.