Prevention of Spontaneous and Experimentally Induced Diabetes in Mice with Zinc Sulfate-Enriched Drinking Water is Associated with Activation and Reduction of NF-κB and AP-1 in Islets,Respectively

Abstract

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)-κB 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-κB and AP-1 in islets of NOD and MLD-STZ–injected male C57BL/6 mice. We hypothesized that Zn²⁺ may affect NF-κB, 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-κB 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-κB 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-κB may play a critical role in immune-mediated diabetes. Depending on the mode of β-cell destruction, Zn²⁺ may prevent apoptosis through activation of NF-κB in NOD mice or prevent inflammatory immune destruction through inhibition of NF-κB in MLD-STZ-treated C57BL/6 mice.