Dietary Zinc Reduction Pyruvate Supplementation or Zinc Transporter 5 Knockout Attenuates β-Cell Death in Nonobese Diabetic Mice Islets and Insulinoma Cells

摘要

Pancreatic zinc (Zn²⁺) concentrations are linked to diabetes and pancreatic dysfunction, but Zn²⁺ is also required for insulin processing and packaging. Zn²⁺ released with insulin increases β-cell pancreatic death after streptozotocin toxin exposure in vitro and in vivo. Triosephosphate accumulation, caused by NAD⁺ loss and glycolytic enzyme dysfunction, occur in type-1 diabetics (T1DM) and animal models. We previously showed these mechanisms are also involved in Zn²⁺ neurotoxicity and are attenuated by nicotinamide- or pyruvate-induced restoration of NAD⁺ concentrations, Zn²⁺ restriction, or inhibition of Sir2 proteins. We tested the hypothesis that similar Zn²⁺- and NAD⁺-mediated mechanisms are involved in β-cell toxicity in models of ongoing T1DM using mouse insulinoma cells, islets, and nonobese diabetic (NOD) mice. Zn²⁺, streptozotocin, and cytokines caused NAD⁺ loss and death in insulinoma cells and islets, which were attenuated by Zn²⁺ restriction, pyruvate, nicotinamide, NAD⁺, and inhibitors of Sir2 proteins. We measured diabetes incidence and mortality in NOD mice and demonstrated that pyruvate supplementation, or genetic or dietary Zn²⁺ reduction, attenuated these measures. T-lymphocyte infiltration, punctate Zn²⁺ staining, and β-cell loss increased with time in islets of NOD mice. Dietary Zn²⁺ restriction or Zn²⁺ transporter 5 knockout reduced pancreatic Zn²⁺ staining and increased β-cell mass, glucose homeostasis, and survival in NOD mice, whereas Zn²⁺ supplementation had the opposite effects. Pancreatic Zn²⁺ reduction or NAD⁺ restoration (pyruvate or nicotinamide supplementation) are suggested as novel targets for attenuating T1DM.