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 Citations (Scopus)

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

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Inbred NOD Mouse
Poly(ADP-ribose) Polymerases
Type 1 Diabetes Mellitus
Leukocytes
Apoptosis
Niacinamide
NAD
Cytokines
Interferon Type I
DNA Breaks
Graft Survival
Islets of Langerhans
Interferon-alpha
Cell Death
Necrosis
N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride
Transplants
Recurrence
Incidence
Enzymes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Poly (ADP-Ribose) polymerase inhibition prevents spontaneous and recurrent autoimmune diabetes in NOD mice by inducing apoptosis of islet-infiltrating leukocytes. / Suarez-Pinzon, Wilma L.; Mabley, Jon G.; Power, Robert; Szabo, Csaba; Rabinovitch, Alex.

In: Diabetes, Vol. 52, No. 7, 01.07.2003, p. 1683-1688.

Research output: Contribution to journalArticle

Suarez-Pinzon, Wilma L. ; Mabley, Jon G. ; Power, Robert ; Szabo, Csaba ; Rabinovitch, Alex. / Poly (ADP-Ribose) polymerase inhibition prevents spontaneous and recurrent autoimmune diabetes in NOD mice by inducing apoptosis of islet-infiltrating leukocytes. In: Diabetes. 2003 ; Vol. 52, No. 7. pp. 1683-1688.
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