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 cellula r 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 macrophag es infiltrating the islets. NO rapidly induces the formation of DNA st rand breaks in the islet cells. Consequently, the DNA repair enzyme po ly(adenosine diphosphoribose) [poly(ADP-ribose)] polymerase (PARP) is activated to form ADP-ribose polymers from nicotinamide adenine dinucl eotide (NAD+), thereby depleting the intracellular NAD+ pool to lethal levels. These findings give rise to the development of strategies aim ing at the protection of islet cells from NO toxicity in diabetes-susc eptible individuals. However, general suppression of NO formation has only limited effects and acute systemic adverse effects cannot be excl uded. At present the most promising approach seems to be the reduction of islet PARP activity by well-tolerated inhibitory agents.