Nicotinamide nucleotide transhydrogenase: A key role in insulin secretion (Retracted article. See vol. 19, pg. 344, 2014)
Nicotinamide nucleotide transhydrogenase: A key role in insulin secretion (Retracted article. See vol. 19, pg. 344, 2014)
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DOI：
10.1016/j.cmet.2005.10.008
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发表时间：
2006-01-01
期刊：
影响因子：
29
通讯作者：
Ashcroft, FM
中科院分区：
文献类型：
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作者：
Freeman, H;Shimomura, K;Ashcroft, FM
C57BL/6J 小鼠表现出葡萄糖不耐受和胰岛素分泌减少。 QTL 作图确定了烟酰胺核苷酸转氢酶 (Nnt) 作为候选基因，这是一种核编码的线粒体蛋白，被认为参与自由基解毒。为了研究其功能作用，我们使用 siRNA 敲低胰岛素分泌 MIN6 细胞中的 Nnt。这导致胰岛素分泌显着减少，并且由葡萄糖引起的 [Ca2+](i) 升高，但不是甲苯磺丁脲。我们在 Nnt 中发现了两个 ENU 诱导的点突变（N68K、G745D）。 Nnt突变小鼠是葡萄糖不耐受的，并且在葡萄糖耐量测试期间分泌较少的胰岛素。孤立的胰岛显示出对葡萄糖的反应受损的胰岛素分泌，但对甲苯磺丁脲没有反应，并且葡萄糖不能提高 ATP 水平。 Nnt 0 细胞中葡萄糖的利用和活性氧的产生增加。我们假设 Nnt 突变/缺失使 p 细胞线粒体代谢脱节，导致 ATP 产生减少，K-ATP 通道活性增强，从而损害胰岛素分泌。
The C57BL/6J mouse displays glucose intolerance and reduced insulin secretion. QTL mapping identified Nicotinamide Nucleotide Transhydrogenase (Nnt), a nuclear-encoded mitochondrial protein thought to be involved in free radical detoxification, as a candidate gene. To investigate its functional role, we used siRNA to knockdown Nnt in insulin-secreting MIN6 cells. This produced a dramatic reduction in insulin secretion and the rise in [Ca2+](i) evoked by glucose, but not tolbutamide. We identified two ENU-induced point mutations in Nnt (N68K, G745D). Nnt mutant mice were glucose intolerant and secreted less insulin during a glucose tolerance test. Isolated islets showed impaired insulin secretion in response to glucose, but not to tolbutamide, and glucose failed to enhance ATP levels. Glucose utilization and production of reactive oxygen species were increased in Nnt 0 cells. We hypothesize that Nnt mutations/deletion uncouple p cell mitochondrial metabolism leading to less ATP production, enhanced K-ATP channel activity, and consequently impaired insulin secretion.