Department of Ophthalmology and the Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
J Nutr. 2012 Dec;142(12):2119-27. doi: 10.3945/jn.112.167031. Epub 2012 Oct 24.
Pancreatic zinc (Zn(2+)) concentrations are linked to diabetes and pancreatic dysfunction, but Zn(2+) is also required for insulin processing and packaging. Zn(2+) 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 Zn(2+) neurotoxicity and are attenuated by nicotinamide- or pyruvate-induced restoration of NAD(+) concentrations, Zn(2+) restriction, or inhibition of Sir2 proteins. We tested the hypothesis that similar Zn(2+)- 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. Zn(2+), streptozotocin, and cytokines caused NAD(+) loss and death in insulinoma cells and islets, which were attenuated by Zn(2+) 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 Zn(2+) reduction, attenuated these measures. T-lymphocyte infiltration, punctate Zn(2+) staining, and β-cell loss increased with time in islets of NOD mice. Dietary Zn(2+) restriction or Zn(2+) transporter 5 knockout reduced pancreatic Zn(2+) staining and increased β-cell mass, glucose homeostasis, and survival in NOD mice, whereas Zn(2+) supplementation had the opposite effects. Pancreatic Zn(2+) reduction or NAD(+) restoration (pyruvate or nicotinamide supplementation) are suggested as novel targets for attenuating T1DM.
胰腺锌（Zn(2+)）浓度与糖尿病和胰腺功能障碍有关，但 Zn(2+) 也是胰岛素加工和包装所必需的。胰岛素释放的 Zn(2+) 在体外和体内增加了链脲佐菌素毒素暴露后β细胞的胰腺死亡。三磷酸甘油醛（Triosephosphate）的积累是由于 NAD(+)的损失和糖酵解酶功能障碍引起的，这种情况发生在 1 型糖尿病（T1DM）患者和动物模型中。我们之前的研究表明，这些机制也与 Zn(2+)的神经毒性有关，并且可以通过烟酰胺或丙酮酸诱导的 NAD(+)浓度恢复、Zn(2+)限制或抑制 Sir2 蛋白来减轻。我们测试了以下假设：在使用小鼠胰岛素瘤细胞、胰岛和非肥胖型糖尿病（NOD）小鼠的 T1DM 进行的研究中，类似的 Zn(2+)和 NAD(+)介导的机制可能涉及β细胞毒性。Zn(2+)、链脲佐菌素和细胞因子导致胰岛素瘤细胞和胰岛中的 NAD(+)损失和死亡，这些可以通过 Zn(2+)限制、丙酮酸、烟酰胺、NAD(+)和 Sir2 蛋白抑制剂来减轻。我们测量了 NOD 小鼠的糖尿病发病率和死亡率，并证明了丙酮酸补充、或基因或饮食 Zn(2+)减少，可减轻这些指标。随着时间的推移，NOD 小鼠胰岛中的 T 淋巴细胞浸润、点状 Zn(2+)染色和β细胞丢失增加。饮食 Zn(2+)限制或 Zn(2+)转运蛋白 5 敲除减少了 NOD 小鼠的胰腺 Zn(2+)染色，并增加了β细胞的质量、葡萄糖稳态和存活率，而 Zn(2+)补充则产生了相反的效果。胰腺 Zn(2+)减少或 NAD(+)恢复（丙酮酸或烟酰胺补充）被认为是减轻 T1DM 的新靶点。
