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.

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).

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.

Molecular target structures in alloxan-induced diabetes in mice.

Type 1 diabetes results from irreversible damage of insulin-producing beta-cells. In laboratory animals, diabetes can be induced with alloxan (ALX), a 2,4,5,6-tetraoxopyrimidine. ALX is a potent generator of reactive oxygen species (ROS), which can mediate beta-cell toxicity.

Differential regulation of Th1-type and Th2-type cytokine profiles in pancreatic islets of C57BL/6 and BALB/c mice by multiple low doses of streptozotocin.

In the nonobese diabetic (NOD) mouse, the T helper (Th)1-type inflammatory cytokines interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha play a critical role in the development of type 1 diabetes, whereas the Th2-type anti-inflammatory cytokines interleukin (IL)-4 and IL-10 operate counterregulatory. There are no comprehensive analyses on cytokine profiles in the mouse model of diabetes induced with multiple low doses of streptozotocin (MLD-STZ). Therefore, we used islets to study ex vivo effects of MLD-STZ and in vitro effects of STZ on IFN-gamma, TNF-alpha, IL-4, and IL-10 on both levels of protein-producing cells and the mRNA expression, as well as the mRNA expression of the Th3-type cytokine transforming growth factor TGF-beta1.