Differential metabolite accumulation may be the cause of strain differences in sensitivity to streptozotocin-induced β cell death in inbred mice
Differential metabolite accumulation may be the cause of strain differences in sensitivity to streptozotocin-induced β cell death in inbred mice
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DOI：
10.1210/en.139.6.2885
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发表时间：
1998-06-01
期刊：
影响因子：
4.8
通讯作者：
Cameron, DP
中科院分区：
文献类型：
--
作者：
Cardinal, JW;Allan, DJ;Cameron, DP
近交系小鼠对链脲佐菌素（STZ）致糖尿病效应的敏感性各不相同。为了研究这种品系差异的基础，我们暴露了来自两种对药物敏感性不同的小鼠品系的胰岛细胞。我们对它们进行形态学检查，并测量胰岛NAD + NADH含量、链脲佐菌素代谢产物积累、葡萄糖转运能力、Glut 2水平和培养基亚硝酸盐积累。C57 b1/6 J小鼠对STZ比Balb/c小鼠更敏感，这是通过体内和体外胰腺胰岛素消耗和β细胞死亡的程度来判断的。细胞死亡方式为坏死。在体外暴露于药物30分钟后，更敏感的C57 bl/6 J胰岛比更耐药的Balb/c胰岛含有更高水平的链脲佐菌素代谢物和更少的NAD + NADH。在3-O-甲基葡萄糖转运、Glut 2水平和培养基亚硝酸盐积累方面没有任何菌株差异，表明STZ转运和一氧化氮代谢不是STZ敏感性和代谢物积累差异的原因，因此STZ敏感性的菌株差异似乎是由于在STZ转运后和NAD + NADH耗尽前β细胞内发生的细胞内事件。STZ代谢物的积累似乎与STZ敏感性有关。进一步的研究是必要的，以确定是否差异STZ代谢物积累是负责STZ敏感性。
Inbred strains of mice vary in their sensitivity to the diabetogenic effects of streptozotocin (STZ). To investigate the basis for this strain difference we exposed islet cells from two strains of mice that differ in sensitivity to the drug. We examined them morphologically and measured islet NAD + NADH content, streptozotocin metabolite accumulation, glucose transport capacity, Glut2 levels and medium nitrite accumulation. C57b1/6J mice were more sensitive to STZ than Balb/c mice as judged by the extent of pancreatic insulin depletion and beta cell death, in vivo and in vitro. The mode of cell death was necrosis. After a 30-min in vitro exposure to the drug the more sensitive C57bl/6J islets contained higher levels of streptozotocin metabolites and less NAD + NADH than the more resistant Balb/c islets. The lack of any strain differences in 3-O-methyl glucose transport, Glut2 levels and medium nitrite accumulation suggested that STZ transport and nitric oxide metabolism were not responsible for differences in STZ sensitivity and metabolite accumulation.Thus the strain differences in STZ sensitivity appears to be due to intracellular events within the beta cell occurring after STZ transport and before NAD + NADH depletion. STZ metabolite accumulation appears to be associated with STZ sensitivity. Further studies are warranted to determine if differential STZ metabolite accumulation is responsible for STZ sensitivity.