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Mice lacking the poly(ADP-ribose) polymerase gene are resistant to pancreatic beta-cell destruction and diabetes development induced by streptozocin

Abstract

Human type 1 diabetes results from the selective destruction of insulin-producing pancreatic beta cells during islet inflammation. Cytokines and reactive radicals released during this process contribute to beta-cell death. Here we show that mice with a disrupted gene coding for poly (ADP-ribose) polymerase (PARP–/– mice) are completely resistant to the development of diabetes induced by the beta-cell toxin streptozocin. The mice remained normoglycemic and maintained normal levels of total pancreatic insulin content and normal islet ultrastructure. Cultivated PARP–/– islet cells resisted streptozocin-induced lysis and maintained intracellular NAD+ levels. Our results identify NAD+ depletion caused by PARP activation as the dominant metabolic event in islet-cell destruction, and provide information for the development of strategies to prevent the progression or manifestation of the disease in individuals at risk of developing type 1 diabetes.

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Figure 1: Analysis of blood glucose levels after the administration of SZ in PARP+/+ (a), PARP–/– (b) and PARP+/– (c) mice.
Figure 2: Insulin levels in the pancreata of SZ-treated PARP+/+, PARP–/– and PARP+/– mice.
Figure 3: Effect of SZ on the death of PARP+/+,PARP–/– and PARP+/– islet cells in vitro.
Figure 4: Expression of GLUT-2 mRNA in PARP+/+ and PARP–/– islets.
Figure 5: SZ-induced DNA fragmentation in PARP+/+ and PARP–/– cells.
Figure 6: Western blot analysis of PARP protein expression in PARP+/+, PARP+/– and PARP–/– islets with a polyclonal antiserum.

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Acknowledgements

We thank W. Fingberg for technical assistance, H. Jahr for support in determining pancreatic insulin contents, W. Waldhäusl and S. Baumgartner-Parzer for conducting blood glucose measurements, J. Friemann for support in the morphometrical studies and W.L. Gai for analysis of GLUT-2 mRNA expression. This work was supported by the Deutsche Forschungsgemeinschaft, the Bundesminister für Gesundheit and by the Minister für Wissenschaft und Forschung des Landes Nordrhein-Westfalen. L.S. and E.F.W. were partially supported by the Austrian Industrial Research Promotion Fund. Z.H. is in receipt of a Special Training Award from the International Agency for Research on Cancer (IARC).

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Correspondence to Volker Burkart.

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Burkart, V., Wang, ZQ., Radons, J. et al. Mice lacking the poly(ADP-ribose) polymerase gene are resistant to pancreatic beta-cell destruction and diabetes development induced by streptozocin. Nat Med 5, 314–319 (1999). https://doi.org/10.1038/6535

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