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.

Recently, we reported that zinc sulfate-enriched (25 mM) drinking water (Zn(2+)) 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 Zn(2+) 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 Zn(2+) may affect NF-kappa B, which may play a key role in immune-mediated diabetogenesis. Here we continuously administered Zn(2+) to NOD mice, to both parents and their F(1) offspring, and treated C57BL/6 male mice with MLD-STZ either alone or in addition to Zn(2+) . We assessed effects of Zn(2+) on insulitis and peri-insulitis in 8-week-old NOD mice and analyzed NF-kappa B and AP-1 activities in islets. Zn(2+) significantly prevented diabetes in female F(1) offspring and significantly reduced insulitis and peri-insulitis. Zn(2+) significantly stimulated NF-kappa B and AP-1 activation in NOD mice, in contrast, in C57BL/6 mice, Zn(2+) 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 beta-cell destruction, Zn(2+) 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.

Interleukin-11 inhibits NF-kappaB and AP-1 activation in islets and prevents diabetes induced with streptozotocin in mice.

This laboratory has reported that multiple low doses of streptozotocin (MLD-STZ) similarly upregulate the T helper (Th)1-type proinflammatory cytokines tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma in islets of both the diabetes-susceptible male and the diabetes-resistant female C57BL/6 mice and that MLD-STZ downregulates the anti-inflammatory Th2-type cytokines interleukin (IL)-4 and IL-10, as well as the anti-inflammatory Th3-type cytokine-transforming growth factor (TGF)-ss1 in islets of male, but not female, mice. Thus, diabetes is associated with a relative preponderance of local proinflammatory cytokines. Here, we investigated the effects of MLD-STZ on the anti-inflammatory cytokine IL-11 and the transcription factors nuclear factor (NF)-kappaB and activator protein (AP)-1, which are involved in gene activation of proinflammatory cytokines, and on the cytosolic kinase (IKK-alpha) of NF-kappaB inhibitor (IkappaB). Furthermore, the effect of recombinant human (rh)IL-11 on MLD-STZ diabetes, insulitis, cytokines, IKK-alpha, NF-kappaB, and AP-1 was analyzed in islets. Interleukin-11 prevented diabetes without affecting insulitis; attenuated TNF-alpha and IFN-gamma response; and stimulated IL-4 production and inhibited activation of IKK-alpha, NF-kappaB, and AP-1. The results demonstrated the potential of rhIL-11 in preventing MLD-STZ diabetes through enhancement of anti-inflammatory responses in islets. In this process, the transcription factors NF-kappaB and AP-1 might play a key role.

Generation of hydroxyl radicals mediated by streptozotocin in pancreatic islets of mice in vitro.

Type I diabetes is considered a multifactorial autoimmune process initiated by an environmental factor. There is evidence that reactive oxygen species are involved in destructing insulin-producing beta-cells. In mice, reactive oxygen species and nitric monoxide contribute to beta-cell damage in the non-obese diabetic strain developing spontaneously diabetes and in diabetes induced with multiple low doses of streptozotocin. Previously, we found that zinc sulfate induced metallothionein in pancreatic islets, protected beta-cells against streptozotocin toxicity in vitro, and prevented diabetes induced with multiple low doses of streptozotocin. Since metallothionein is known to scavenge hydroxyl radicals in cell-free systems, we hypothesize that the protective effect of zinc sulfate results from metallothionein induction scavenging hydroxyl radicals generated by multiple low doses of streptozotocin. Therefore, we studied whether levels of hydroxyl radicals are increased by streptozotocin in isolated islets in vitro. Here, we demonstrate basal and streptozotocin-stimulated hydroxyl radicals by electron spin resonance spectroscopy in combination with hydroxyl radical-specific spin trapping in islet homogenates. Furthermore, in islet cultures, streptozotocin augmented generation of reactive oxygen species as determined by fluorescence. Of the group of reactive oxygen species, the streptozotocin-augmented generation of hydrogen peroxide was also specifically determined. We conclude that streptozotocin-mediated hydroxyl radicals and generation of reactive oxygen species may be crucial effectors in beta-cell damage.