Regulation of insulin secretion by uncoupling protein
Regulation of insulin secretion by uncoupling protein
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DOI：
10.1042/bst0340802
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发表时间：
2006-11-01
影响因子：
3.9
通讯作者：
Kashemsant, N.
中科院分区：
文献类型：
--
作者：
Chan, C. B.;Kashemsant, N.
解偶联蛋白（UCPs）通过解偶联氧化磷酸化来调节细胞ATP的产生。UCP 2在胰岛β细胞中表达，其诱导减少葡萄糖刺激的胰岛素分泌。在生理条件下，作为呼吸副产物形成的超氧化物激活UCP 2。这导致ATP产生减少，从而损害ATP依赖性K+通道的关闭以阻止胰岛素分泌。提示UCP 2的生理作用是通过反馈回路防止过量超氧化物的产生。UCP 2诱导也可以通过改变NAD/NADH或通过促进脂肪酸阴离子的循环来改变脂肪酸代谢。最近，UCP 2已被提出在饥饿期间保持低胰岛素分泌，这是在转录辅阻遏物surtuin-1的控制下的功能，surtuin-1已被证明与UCP 2启动子结合。病理性UCP 2表达或激活可能抑制葡萄糖刺激的胰岛素分泌，从而加速糖尿病发作。在ob/ob小鼠中，在5周龄时UCP 2的诱导先于胰岛素分泌缺陷和高脂血症的发展。激活蛋白激酶A依赖性途径可以使UCP 2过表达胰岛的胰岛素分泌正常化。相反，降低UCP 2表达可能促进胰岛素分泌增加。UCP 2基因敲除小鼠受到保护，不受高脂饮食的致糖尿病影响，其胰岛对葡萄糖的敏感性增加，ATP/ADP升高。这些结果支持UCP 2作为一个基因在2型糖尿病发病机制中的作用。
UCPs (uncoupling proteins) can regulate cellular ATP production by uncoupling oxidative phosphorylation. UCP2 is expressed in islet beta-cells and its induction reduces glucose-stimulated insulin secretion. Under physiological conditions, superoxide, formed as a by-product of respiration, activates UCP2. This leads to reduced ATP production, which impairs closure of the ATP-depenclent K+ channels to prevent insulin secretion. it is suggested that the physiological role of UCP2 is to prevent excessive superoxide generation through a feedback loop. UCP2 induction may also alter fatty acid metabolism by altering NAD/NADH or by facilitating cycling of fatty acid anions. Recently, UCP2 has been proposed to keep insulin secretion low during starvation, a function under the control of the transcription co-repressor, surtuin-1, which has been shown to bind to the UCP2 promoter. Pathological UCP2 expression or activation may suppress glucose-stimulated insulin secretion to the extent that diabetes onset is hastened. in ob/ob mice, induction of UCP2 at age 5 weeks precedes development of insulin secretion defects and hyperglycaemia. Activating protein kinase A-dependent pathways can normalize insulin secretion in UCP2-overexpressing islets. Conversely, lowering UCP2 expression may promote increased insulin secretion. UCP2 knockout mice were protected from the diabetogenic effects of a high-fat diet and their islets exhibited increased sensitivity to glucose and elevated ATP/ADP. These results support a role for UCP2 as a gene contributing to the pathogenesis of Type 2 diabetes.