NITRIC-OXIDE DONORS DECREASE THE FUNCTION AND SURVIVAL OF HUMAN PANCREATIC-ISLETS

Nitric oxide (NO) has been proposed as a possible mediator of beta-cel l damage in human IDDM. This hypothesis is based on in vitro Studies w ith rodent pancreatic islets. In the present study we examined whether human beta-cells are affected by NO. In view of species differences i n beta-cell sensitivity to damaging agents, rat islets were investigat ed in parallel. isolated islets were exposed for 90 min to different c oncentrations of three chemically unrelated NO donors, SIN-1, GSNO or RES. At the end of this incubation, human insulin release was mostly s imilar in control and NO-treated islets but, 48 h later, islet retriev al, islet DNA and insulin content: and glucose-induced insulin release were markedly lower in islets exposed to NO donors. Rat islets were a lready inhibited during the initial 90 min, 48 h later their loss in b eta-cell function was similar to that in human islets. Nicotinamide or succinic acid monomethyl ester partially protected against SIN-I indu ced islet cell loss, but not against the functional inhibition of huma n pancreatic islets. Exposure of human or rat islets re, RES was assoc iated with significant DNA strand breakage. as judged by the comet ass ay (single cell gel electrophoresis) and by ultrastructural signs of c ell damage. PNA damage was mole severe in rat islet cells exposed to s imilar amounts of RES. It is concluded that NO donors can damage human pancreatic islets, an effect paralleled by induction of nuclear DNA s trand breaks.