NITRIC-OXIDE AS AN INFLAMMATORY MEDIATOR IN INSULIN-DEPENDENT DIABETES-MELLITUS - A NEW THERAPEUTIC TARGET

Recent studies in vitro and in vivo have demonstrated that the cellular mediator nitric oxide (NO) is involved in the destruction of insulin-producing pancreatic beta-cells during the autoimmune pathogenesis of insulin-dependent diabetes mellitus. The primary source of islet cell toxic NO seems to be the inducible NO synthase of activated macrophages infiltrating the islets. NO rapidly induces the formation of DNA strand breaks in the islet cells. Consequently, the DNA repair enzyme poly(adenosine diphosphoribose) [poly(ADP-ribose)] polymerase (PARP) is activated to form ADP-ribose polymers from nicotinamide adenine dinucleotide (NAD+), thereby depleting the intracellular NAD+ pool to lethal levels. These findings give rise to the development of strategies aiming at the protection of islet cells from NO toxicity in diabetes-susceptible individuals. However, general suppression of NO formation has only limited effects and acute systemic adverse effects cannot be excluded. At present the most promising approach seems to be the reduction of islet PARP activity by well-tolerated inhibitory agents.