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 Szabo, 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
StatePublished - Jul 1 2003
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this