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-ribose polymerase or PARP) has been proposed as a major mechanism contributing to β-cell destruction in type I diabetes. In the present study, we have investigated the role of PARS in mediating the induction of diabetes and β-cell death in the multiple-low-dose-streptozotocin (MLDS) model of type I diabetes. 2 Mice genetically deficient in PARS were found to be less sensitive to MLDS than wild type mice, with a lower incidence of diabetes and reduced hyperglycemia. 3 A potent inhibitor of PARS, 5-iodo-6-amino-1,2-benzopyrone (INH ₂BP), was also found to protect mice from MLDS and prevent β-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-1β, tumor necrosis factor-α and interferon-γ inhibited glucose-stimulated insulin secretion from isolated rat islets of Langerhans and decreased RIN-5F cell viability. The PARS inhibitor, INH ₂BP, protected both the rat islets and the β-cell line, RIN-5F, from these cytokine-mediated effects. These protective effects were not mediated by inhibition of cytokine-induced nitric oxide formation. 5 Inhibition of PARS by INH ₂BP was unable to protect rat islet cells from cytokine-mediated apoptosis. 6 Cytokines, peroxynitrite and streptozotocin were all shown to induce PARS activation in RIN-5F cells, an effect suppressed by INH ₂BP. 7 The present study provides evidence for in vivo PARS activation contributing to β-cell damage and death in the MLDS model of diabetes, and indicates a role for PARS activation in cytokine-mediated depression of insulin secretion and cell viability in vitro.