Mice lacking the poly(ADP-ribose) polymerase gene are resistant to pancreatic beta-cell destruction and diabetes development induced by streptozocin

Human type 1 diabetes results from the selective destruction of insulin-pro ducing pancreatic beta cells during islet inflammation. Cytokines and react ive radicals released during this process con tribute to beta-cell death. H ere we show that mice with a disrupted gene coding for poly (ADP-ribose) po lymerase (PARP(-/-) mice) are completely resistant to the development of di abetes induced by the beta-cell toxin streptozocin. The mice remained normo glycemic and maintained normal levels of total pancreatic insulin content a nd normal islet ultrastructure. Cultivated PARP(-/-) islet cells resisted s treptozocin-induced lysis and maintained intracellular NAD(+) levels. Our r esults identify NAD(+) depletion caused by PARP activation as the dominant metabolic event in islet-cell destruction, and provide information for the development of strategies to prevent the progression or manifestation of th e disease in individuals at risk of developing type 1 diabetes.