Intracellular targets for nitric oxide toxicity to pancreatic beta-cells.
The radical nitric oxide (NO) may be a mediator of pancreatic beta-cell damage in early insulin-dependent diabetes mellitus (IDDM). Under the stimulus of cytokines, invading macrophages and the beta-cell themselves may produce large amounts of NO, leading to beta-cell dysfunction and death. It still remains to be determined which are the intracellular targets for NO-induced damage. Available data from rat islets indicate that the radical inactivates the mitochondrial enzyme aconitase, impairing substrate oxidation and ATP production. Ionic channels and complexes I and II of the mitochondrial electron transport chain are two other possible targets for NO effects which may impair insulin secretion. NO also leads to nuclear DNA damage in both rat and human pancreatic beta-cells, as evaluated by the 'comet assay'. The effects of NO at the DNA level are complex, and involve formation of N-nitrosoamines, deamination of purines and pyrimidines, or damage induced by peroxynitrite. Besides inducing over DNA damage. NO may also inactivate DNA repair/replication enzymes. The outcome of NO-induced beta-cell DNA damage can be cell death by apoptosis or, in some cases, necrosis. Upon cell damage beta-cells trigger cell repair mechanisms. This seems also to be the case following NO exposure, and insulin-producing cells are able to regain their function following treatment with non-lethal concentrations of NO. A better understanding of the mechanisms involved in NO-induced beta-cell damage and repair may be instrumental in developing new strategies for IDDM prevention.
Delaney
C A
CA
Department of Medical Cell Biology, Uppsala University, Sweden.
Eizirik
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DL
D000818:Animals; D016923:Cell Death; D004249:DNA Damage / Q000187:drug effects*; D003922:Diabetes Mellitus, Type 1; D006801:Humans; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects*; D008264:Macrophages / Q000502:physiology; D009569:Nitric Oxide / Q000633:toxicity*; D051381:Rats
D009569:Nitric Oxide