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

Jon G. Mabley, Wilma L. Suarez-Pinzon, György Haskó, Andrew L. Salzman, Alex Rabinovitch, Ernest Kun, Csaba Szabó

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    64 Scopus citations

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)909-919
    Number of pages11
    JournalBritish Journal of Pharmacology
    Volume133
    Issue number6
    DOIs
    StatePublished - Jan 1 2001

    Keywords

    • Diabetes
    • DNA single strand break
    • Inducible nitric oxide synthase
    • Inflammation
    • Islets of Langerhans
    • Nitric oxide
    • Peroxynitrite
    • Poly (ADP-ribose) synthetase
    • Superoxide

    ASJC Scopus subject areas

    • Pharmacology

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