UCP-2 and UCP-3 proteins are differentially regulated in pancreatic beta-cells.
UCP-2 and UCP-3 proteins are differentially regulated in pancreatic beta-cells.
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DOI：
10.1371/journal.pone.0001397
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发表时间：
2008-01-02
期刊：
影响因子：
3.7
通讯作者：
Haataja L
中科院分区：
文献类型：
--
作者：
Li Y;Maedler K;Shu L;Haataja L
解偶联蛋白2 （UCP-2）表达增加与胰岛素分泌受损有关，而2型糖尿病患者骨骼肌中UCP-3蛋白水平降低。在目前的研究中，我们假设葡萄糖对胰岛中UCP-2和UCP-3的调节有相反的作用。生成显性阴性UCP-2和野生型UCP-3腺病毒，并测量转导的人胰岛胰岛素释放量。定量PCR检测UCP-2和UCP-3 mRNA水平。研究了不同葡萄糖浓度培养的人胰岛细胞中UCP-2和UCP-3蛋白的表达。利用免疫组织化学方法对人胰腺切片进行UCP-3亚细胞定位分析。与对照组相比，人胰岛UCP-2显性阴性表达增加了胰岛素分泌（p<0.05）。UCP-3 mRNA在人胰岛中有表达，而UCP-2 mRNA的相对丰度是前者的8.1倍（p<0.05）。免疫组织化学分析证实UCP-3蛋白与线粒体在人β细胞中共定位。高糖暴露后，人胰岛中UCP-2蛋白表达增加了~ 2倍，而UCP-3蛋白表达减少了~ 40% （p<0.05）。UCP-3过表达可改善葡萄糖刺激的胰岛素分泌。UCP-2和UCP-3可能在调节β细胞功能中具有不同的作用。慢性高血糖患者UCP-2表达升高和UCP-3表达降低可能导致葡萄糖刺激的胰岛素分泌受损。这些数据表明，抑制UCP-2的机制或增加UCP-3表达和/或功能的机制是抵消2型糖尿病患者胰岛素分泌缺陷的潜在治疗靶点。
Increased uncoupling protein-2 (UCP-2) expression has been associated with impaired insulin secretion, whereas UCP-3 protein levels are decreased in the skeleton muscle of type-2 diabetic subjects. In the present studies we hypothesize an opposing effect of glucose on the regulation of UCP-2 and UCP-3 in pancreatic islets. Dominant negative UCP-2 and wild type UCP-3 adenoviruses were generated, and insulin release by transduced human islets was measured. UCP-2 and UCP-3 mRNA levels were determined using quantitative PCR. UCP-2 and UCP-3 protein expression was investigated in human islets cultured in the presence of different glucose concentrations. Human pancreatic sections were analyzed for subcellular localization of UCP-3 using immunohistochemistry. Dominant negative UCP-2 expression in human islets increased insulin secretion compared to control islets (p<0.05). UCP-3 mRNA is expressed in human islets, but the relative abundance of UCP-2 mRNA was 8.1-fold higher (p<0.05). Immunohistochemical analysis confirmed co-localization of UCP-3 protein with mitochondria in human beta-cells. UCP-2 protein expression in human islets was increased ∼2-fold after high glucose exposure, whereas UCP-3 protein expression was decreased by ∼40% (p<0.05). UCP-3 overexpression improved glucose-stimulated insulin secretion. UCP-2 and UCP-3 may have distinct roles in regulating beta-cell function. Increased expression of UCP-2 and decreased expression of UCP-3 in humans with chronic hyperglycemia may contribute to impaired glucose-stimulated insulin secretion. These data imply that mechanisms that suppress UCP-2 or mechanisms that increase UCP-3 expression and/or function are potential therapeutic targets to offset defects of insulin secretion in humans with type-2 diabetes.
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