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DNA-Damage and NAD+-Depletion are Initial Events in Oxygen Radical Induced Islet Cell Death

  • B. Heller
  • A. Bürkle
  • J. Radons
  • E. Fengler
  • M. Müller
  • V. Burkart
  • H. Kolb
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 426)

Abstract

Previous studies in vitro and in animal models indicate that reactive oxygen intermediates (ROI) contribute to the destruction of pancreatic islet cells in the pathogenesis of insulin dependent diabetes (Mendola et al., 1989; Rabinovitch et al., 1992). During islet inflammation endothelial cells and infiltrating macrophages are thought to release cyto-toxic amounts ROI (Zweier et al., 1988; Brenner et al., 1993). In addition it was shown, that islet cells are highly susceptible to ROI since they possess only low levels of oxygen radical defense systems (Grankvist et al., 1981; Malaisse et al., 1982). We recently have described an in vitro model of oxygen-radical induced islet cell death where ROI are generated by xanthine oxidase in the presence of hypoxanthine (Burkart et al., 1992). In the present study we investigated the initial events of ROI-induced pancreatic islet cell destruction. We observed that DNA strand breaks and the activation of poly(ADP-ribose) polymerase in islet cell nuclei are prominent early consequences of ROI action. The subsequent islet cell death occured several hours after ROI treatment, which appeared to result from depletion of cellular NAD+ pools. Inhibition of poly(ADP-ribose) polymerase by nicotinamide resulted in the preservation of the NAD+ pool and in islet cell survival.

Keywords

Islet Cell Xanthine Oxidase Pancreatic Islet Cell Reactive Oxygen Intermediate PARP Activation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • B. Heller
    • 1
  • A. Bürkle
    • 2
  • J. Radons
    • 1
  • E. Fengler
    • 1
  • M. Müller
    • 2
  • V. Burkart
    • 1
  • H. Kolb
    • 1
  1. 1.Diabetes-ForschungsinstitutHeinrich-Heine Universität DüsseldorfDüsseldorfGermany
  2. 2.Deutsches KrebsforschungszentrumHeidelbergGermany

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