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Experimental Biology and Medicine 229:1177-1185 (2004)
© 2004 Society for Experimental Biology and Medicine

ORIGINAL RESEARCH ARTICLE

Prevention of Spontaneous and Experimentally Induced Diabetes in Mice With Zinc Sulfate-Enriched Drinking Water Is Associated with Activation and Reduction of NF-{kappa}B and AP-1 in Islets, Respectively

Patricia Schott-Ohly*, Abdelhakim Lgssiar*, Hans-Joachim Partke*, Mohamed Hassan{dagger}, Nadira Friesen* and Helga Gleichmann*,1

* German Diabetes Center, German Diabetes Research Institute, and {dagger} Institute of Pathology, Heinrich-Heine-University of Düsseldorf, D-40225 Düsseldorf, Germany

To whom requests for reprints should be addressed at 1 Deutsches Diabetes-Forschung-sinstitut, Auf’m Hennekamp 65, D-40225 Düsseldorf, Germany. E-mail: gleich{at}ddfi.uni-duesseldorf.de

Recently, we reported that zinc sulfate-enriched (25 mM) drinking water (Zn2+) protected male C57BL/6 mice from diabetes induced by multiple low doses of streptozotocin (MLD-STZ) and that MLD-STZ activates the transcription factors nuclear factor (NF)-{kappa}B and activator protein (AP)-1 in islets of these mice. Therefore, we studied the effect of Zn2+ on spontaneous diabetes in female nonobese diabetic (NOD) mice and on the activity of NF-{kappa}B and AP-1 in islets of NOD and MLD-STZ–injected male C57BL/6 mice. We hypothesized that Zn2+ may affect NF-{kappa}B, which may play a key role in immune-mediated diabetogenesis. Here we continuously administered Zn2+ to NOD mice, to both parents and their F1 offspring, and treated C57BL/6 male mice with MLD-STZ either alone or in addition to Zn2+ . We assessed effects of Zn2+ on insulitis and peri-insulitis in 8-week-old NOD mice and analyzed NF-{kappa}B and AP-1 activities in islets. Zn2+ significantly prevented diabetes in female F1 offspring and significantly reduced insulitis and peri-insulitis. Zn2+ significantly stimulated NF-{kappa}B and AP-1 activation in NOD mice, in contrast, in C57BL/6 mice, Zn2+ significantly reduced their activation by MLD-STZ. These data demonstrate that NF-{kappa}B may play a critical role in immune-mediated diabetes. Depending on the mode of ß-cell destruction, Zn2+ may prevent apoptosis through activation of NF-{kappa}B in NOD mice or prevent inflammatory immune destruction through inhibition of NF-{kappa}B in MLD-STZ–treated C57BL/6 mice.

Key Words: activator protein (AP)-1 • MLD-STZ diabetes • NOD mice • nuclear factor (NF)- {kappa}B • zinc sulfate




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