Poly (ADP-Ribose) polymerase inhibition prevents spontaneous and recurrent autoimmune diabetes in NOD mice by inducing apoptosis of islet-infiltrating leukocytes

Wilma L. Suarez-Pinzon, Jon G. Mabley, Robert Power, Csaba Szabó, Alex Rabinovitch

    Research output: Contribution to journalArticle

    36 Scopus citations

    Abstract

    Poly (ADP-ribose) polymerase (PARP) is a nuclear enzyme that consumes NAD in response to DNA strand breaks. The PARP inhibitor nicotinamide prevents NAD consumption and protects islet β-cells from chemically induced necrosis but not cytokine-induced apoptosis. Therefore, it is unclear how nicotinamide protects NOD mice from autoimmune diabetes in which apoptosis is the mode of β-cell death. To investigate the mechanism of diabetes prevention by PARP inhibition, we studied the effects of a novel, potent PARP inhibitor, PJ34, a phenanthridinone derivative, on diabetes development in NOD mice and on diabetes recurrence in diabetic NOD mice transplanted with syngeneic islets. PJ34 administration from age 5 or 15 weeks significantly decreased insulitis, β-cell destruction and diabetes incidence, and protection from diabetes continued for 12 weeks after PJ34 therapy was stopped. Similarly, syngeneic islet graft survival was prolonged and outlasted therapy in PJ34-treated mice. Immunohistochemical studies revealed significantly fewer leukocytes in islet grafts of PJ34-treated mice, together with increased apoptosis of these cells and decreased expression of the T helper 1-type cytokine interferon (IFN)-γ. These results suggest that PARP inhibition protects against autoimmune β-cell destruction in NOD mice by inducing apoptosis of islet-infiltrating leukocytes and decreasing IFN-γ expression in the islets.

    Original languageEnglish (US)
    Pages (from-to)1683-1688
    Number of pages6
    JournalDiabetes
    Volume52
    Issue number7
    DOIs
    StatePublished - Jul 1 2003

    ASJC Scopus subject areas

    • Internal Medicine
    • Endocrinology, Diabetes and Metabolism

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