MUSCLE GLUCOSE TRANSPORTER GENE REGULATION

主要的胰岛素反应组织主要负责 维持正常葡萄糖稳态的是骨骼肌。 这 组织表达称为GLUT 4的特定葡萄糖转运蛋白同种型 其在胰岛素缺乏型糖尿病中显著降低。 此外，本发明还 一些研究已经证明，显著的胰岛素抵抗是 与几种类型的糖尿病有关，可能是糖尿病的起始事件， 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发病风险增加 梗塞 对病人的研究表明， 糖尿病心脏中的摄取可能是缺乏组织的关键特征 在缺血发作期间的存活率。 由于心肌GLUT 4 mRNA和 糖尿病患者的蛋白质水平也会降低， 缺血期间葡萄糖摄取可能与缺血性脑血管病患者脑组织中葡萄糖的减少直接相关。 GLUT 4 mRNA的表达。 基于肌肉GLUT 4表达的中心作用， 与糖尿病相关的病理生理学，我们提出了一系列 针对肌肉特异性和激素/代谢依赖性 这个基因的调控。 葡萄糖中的基本分子事件 转运蛋白基因调控显然是核心问题， 对于我们理解肌肉特异性基因调控 以及控制葡萄糖稳态、代谢和能量 生产 为了实现这些目标，我们计划检查 肌肉GLUT 4转录激素/代谢调节 鉴定负责控制GLUT 4的顺式DNA元件 表情 此外，我们建议识别和表征 肌肉特异性DNA结合因子介导正常的 该基因的生理调节。 在这些研究中，我们将使用核连续分析来确定 内源性GLUT 4基因的转录速率。 瞬时转染 使用DNA直接注射到 后躯肌肉将被用于鉴定负责的顺式DNA元件 用于组织特异性和激素/代谢依赖性调节 GLUT 4表达。 在一个赞美的方法，几个记者 将构建体整合到转基因小鼠中，并测定 GLUT 4表达的正常程序。 通过这种方式，我们希望发展 了解肌肉GLUT 4表达的复杂调节， 外周组织抵抗胰岛素作用的分子基础 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.