Antioxidants, NFkappaB activation, and diabetogenesis.
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 review will focus on the role of antioxidant defense systems in the susceptibility to IDDM and on ROS as cellular messengers that 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 study. It is suggested that pancreas-specific ROS productions play a critical role in signaling the cellular autoimmune/inflammatory response 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. It is believed that this cascade results in a cyclic amplification of ROS and eventually leads to apoptosis and/or necrosis of beta cells. 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.
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Department of Human Nutrition, The Ohio State University, Columbus, OH 43210-1295, USA.
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D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000209:etiology; D007515:Islets of Langerhans / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology*; D017382:Reactive Oxygen Species
D000975:Antioxidants; D016328:NF-kappa B; D017382:Reactive Oxygen Species