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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 beta-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 beta-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 beta-cell loss increased with time in islets of NOD mice. Dietary Zn2+ restriction or Zn2+ transporter 5 knockout reduced pancreatic Zn2+ staining and increased beta-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. J. Nutr. 142: 2119-2127, 2012.
- 出版日期2012-12
