Inhibition of poly (ADP-ribose) synthetase by gene disruption or inhibition with 5-iodo-6-amino-1,2-benzopyrone protects mice from multiple-low-dose-streptozotocin-induced diabetes

1. Activation of poly(ADP-ribose) synthetase (PARS, also termed polyADP-rib ose polymerase or PARP) has been proposed as a major mechanism contributing to beta -cell destruction in type I diabetes. In the present study, we hav e investigated the role of PARS in mediating the induction of diabetes and beta -cell death in the multiple-low-dose-streptozotocin (MLDS) model of ty pe I diabetes. 2 Mice genetically deficient in PARS were found to be less sensitive to MLD S than wild type mice, with a lower incidence of diabetes and reduced hyper glycemia. 3 A potent inhibitor of PARS, 5-iodo-6-amino-1,2-benzopyrone (INH2BP), was also found to protect mice from MLDS and prevent beta -cell loss, in a dose -dependent manner. Paradoxically, in the PARS deficient mice, the compound increased the onset of diabetes. 4 In vitro the cytokine combination; interleukin-1 beta, tumor necrosis fac tor-alpha and interferon-gamma inhibited glucose-stimulated insulin secreti on from isolated rat islets of Langerhans and decreased RIN-SF cell viabili ty. The PARS inhibitor, INH2BP, protected both the rat islets and the beta -cell line, RIN-SF, from these cytokine-mediated effects. These protective effects were not mediated by inhibition of cytokine-induced nitric oxide fo rmation. 5 Inhibition of PARS by INH2BP was unable to protect rat islet cells from c ytokine-mediated apoptosis. 6 Cytokines, peroxynitrite and streptozotocin were all shown to induce PARS activation in RIN5F cells, an effect suppressed by INH2BP. 7 The present study provides evidence for in vivo PARS activation contribut ing to beta -cell damage and death in the MLDS model of diabetes, and indic ates a role for PARS activation in cytokine-mediated depression of insulin secretion and cell viability in vitro.