MUSCLE GLUCOSE TRANSPORTER GENE REGULATION

胰岛素反应的主要组织主要负责 维持正常血糖动态平衡的是骨骼肌。这 组织表达一种称为GLUT4的特定葡萄糖转运蛋白亚型 在胰岛素缺乏的糖尿病患者中，这一比例显著降低。此外， 几项研究已经证明，显著的胰岛素抵抗是 与几种形式的糖尿病相关，并可能是启动事件 在NIDDM的发展中。此外，糖尿病患者有一个 与急性心肌梗死相关的冠状动脉并发症风险增加 脑梗塞。患者研究表明，血糖的下降 糖尿病心脏的摄取可能是组织缺乏的一个关键特征 在缺血发作期间的生存能力。由于心肌GLUT4mRNA和GLUT4 糖尿病患者的蛋白质水平也会降低，无法增加 脑缺血时的葡萄糖摄取可能与脑缺血减少直接相关。 GLUT4基因的表达。 基于肌肉中GLUT4表达的中枢作用 与糖尿病相关的病理生理学，我们提出了一系列 解决肌肉特异性和激素/代谢依赖性的研究 对这种基因的调节。与葡萄糖有关的基本分子事件 转运蛋白基因调控显然是核心问题，它们是 对我们理解肌肉特异性基因调控很重要 以及在控制葡萄糖动态平衡、代谢和能量方面 制作。为了实现这些目标，我们计划研究 肌肉GLUT4转录和TO的激素/代谢调节 确定控制GLUT4的顺式DNA元件 表情。此外，我们建议识别和表征 肌特异性DNA结合因子介导的正常 该基因的生理调节。 在这些研究中，我们将使用核运行分析来确定 内源性GLUT4基因的转录速率。瞬时转染法 用DNA直接注射检测报告构建物 后躯肌肉将被用来识别顺式DNA元件 对于组织特异性和激素/代谢依赖的调节 GLUT4表达。在一种称赞的方式中，几名记者 构建物将被整合到转基因小鼠中，并进行检测 GLUT4表达的正常程序。通过这种方式，我们希望能够发展 了解肌肉GLUT4表达和蛋白表达的复杂调控 外周组织对胰岛素抵抗作用的分子基础 糖尿病。

The major insulin-responsive tissue primarily responsible for the maintenance of normal glucose homeostasis is skeletal muscle. This tissue expresses a specific glucose transporter isoform termed GLUT4 which is substantially decreased in insulin-deficient diabetes. Further, several studies have documented that marked insulin resistance is associated with several forms of diabetes and may be the initiating event in the development of NIDDM. In addition, diabetic patients have an increased risk of coronary morbidity associated with acute myocardial infarction. Patient studies have suggested that the decrease in glucose uptake in the diabetic heart may be a key feature for lack of tissue viability during ischemic episodes. Since cardiac muscle GLUT4 mRNA and protein levels are also decreased in diabetes, the inability to increase glucose uptake during ischemia may be directly related to the decreased expression of GLUT4 mRNA. Based upon the central role of muscle GLUT4 expression in the pathophysiology associated with diabetes, we have proposed a series of studies to address the muscle-specific and hormonal/metabolic-dependent regulation of this gene. The basic molecular events involved in glucose transporter gene regulation are clearly central issues which are important for both our understanding of muscle-specific gene regulation as well as in the control of glucose homeostasis, metabolism and energy production. To accomplish these goals we plan to examine the hormonal/metabolic regulation of muscle GLUT4 transcription and to identify the cis-DNA elements responsible for the control of GLUT4 expression. In addition, we propose to identify and characterize muscle-specific DNA binding factors which mediate the normal physiological regulation of this gene. In these studies we will use nuclear run-on analysis to determine the transcription rate of the endogenous GLUT4 gene. Transient transfection assays of reporter constructs using direct injection of DNA into hindquarter muscle will be used to identify cis-DNA elements responsible for the tissue-specific and hormonal/metabolic dependent regulation of GLUT4 expression. In a complimentary approach, several reporter constructs will be integrated into transgenic mice and assayed for the normal program of GLUT4 expression. In this manner, we hope to develop an understanding of the complex regulation of muscle GLUT4 expression and a molecular basis for peripheral tissue resistance to insulin action in diabetes.