UCP2 regulates the glucagon response to fasting and starvation.
UCP2 regulates the glucagon response to fasting and starvation.
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DOI：
10.2337/db12-0981
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发表时间：
2013-05
期刊：
影响因子：
7.7
通讯作者：
Wheeler MB
中科院分区：
文献类型：
--
作者：
Allister EM;Robson-Doucette CA;Prentice KJ;Hardy AB;Sultan S;Gaisano HY;Kong D;Gilon P;Herrera PL;Lowell BB;Wheeler MB
在禁食/饥饿期间，高血糖素对维持正常血糖很重要，而高血糖素分泌异常与1型和2型糖尿病有关；然而，低血糖诱导高血糖素分泌的机制尚不清楚。我们先前证明，线粒体解偶联蛋白2(UCP2−/−)在小鼠体内的整体缺失会损害分离的胰岛分泌胰高血糖素。因此，UCP2可能参与了低血糖诱导的胰升糖素分泌的调节，这一点得到了我们目前发现的UCP2在营养缺乏的小鼠和人类胰岛中表达增加的支持。在此基础上，我们建立了α细胞特异性UCP2基因敲除小鼠(UCP2AKO)，我们用它来证明低血糖反应中的血糖恢复是由于胰高血糖素分泌减弱所致。由于线粒体偶联增强，UCP2缺失的α-细胞具有更高水平的细胞内活性氧(ROS)，这转化为刺激/分泌偶联的缺陷。UCP2基因缺失的影响被UCP2抑制剂genipin模拟在小鼠和人的胰岛上，也被外源ROS应用，证实氧化状态和电活动的变化直接减少了胰高血糖素的分泌。因此，α细胞UCP2的缺失扰乱了空腹/降血糖的胰升糖素反应，并表明UCP2对于正常的α细胞葡萄糖感知和维持正常血糖是必需的。
Glucagon is important for maintaining euglycemia during fasting/starvation, and abnormal glucagon secretion is associated with type 1 and type 2 diabetes; however, the mechanisms of hypoglycemia-induced glucagon secretion are poorly understood. We previously demonstrated that global deletion of mitochondrial uncoupling protein 2 (UCP2−/−) in mice impaired glucagon secretion from isolated islets. Therefore, UCP2 may contribute to the regulation of hypoglycemia-induced glucagon secretion, which is supported by our current finding that UCP2 expression is increased in nutrient-deprived murine and human islets. Further to this, we created α-cell–specific UCP2 knockout (UCP2AKO) mice, which we used to demonstrate that blood glucose recovery in response to hypoglycemia is impaired owing to attenuated glucagon secretion. UCP2-deleted α-cells have higher levels of intracellular reactive oxygen species (ROS) due to enhanced mitochondrial coupling, which translated into defective stimulus/secretion coupling. The effects of UCP2 deletion were mimicked by the UCP2 inhibitor genipin on both murine and human islets and also by application of exogenous ROS, confirming that changes in oxidative status and electrical activity directly reduce glucagon secretion. Therefore, α-cell UCP2 deletion perturbs the fasting/hypoglycemic glucagon response and shows that UCP2 is necessary for normal α-cell glucose sensing and the maintenance of euglycemia.
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影响因子：
4.8
作者：
Le Marchand, Sylvain J.;Piston, David W.
通讯作者：
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DOI：
10.1073/pnas.0710434105
发表时间：
2008-08-19
影响因子：
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作者：
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影响因子：
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作者：
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DOI：
10.1210/me.2009-0152
发表时间：
2010-03-01
期刊：
Molecular endocrinology (Baltimore, Md.)
影响因子：
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作者：
Li, Lei O;Hu, Yun-Fu;Coleman, Rosalind A
通讯作者：
Coleman, Rosalind A
影响因子：
7.2
作者：
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通讯作者：
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