REGULATION OF GLUCOSE TRANSPORTER GENE EXPRESSION

GLUT 4葡萄糖转运蛋白是在肌肉中表达的主要同种型， 脂肪组织，这两种组织类型主要负责 维持全身葡萄糖稳态。GLUT 4亚型发挥着 在这一过程中的关键作用，通过促进葡萄糖的吸收，在这些 组织对胰岛素刺激的反应。GLUT 4葡萄糖的调节 转运蛋白的功能发生在多个层次，其中几个是 与胰岛素抵抗和糖尿病有关。例如多个 研究证明，GLUT 4表达在以下状态下降低： 胰岛素缺乏型糖尿病和禁食。进一步的患者研究表明， 提示脂肪组织GLUT 4表达与NIDDM相关。 最近，组织特异性模式以及 GLUT 4表达激素/代谢调节已经显示发生 在转录水平上。 基于GLUT 4基因在病理生理学中的中心作用， 与糖尿病相关，我们提出了一系列研究，以解决 该基因的组织特异性和激素/代谢调节。的 参与GLUT 4基因调控的基本分子事件清楚地 重要的问题，这是必要的，我们了解脂肪和 肌肉特异性基因调控以及葡萄糖的控制 体内平衡、新陈代谢和能量产生。因此，我们计划 继续我们的研究描绘分子机制负责 胰岛素的激素/代谢和组织特异性调节， GLUT 4基因。这将通过详细分析 GLUT 4启动子功能及顺式DNA调控元件的鉴定 使用几种互补的方法。这些研究将使 组织特异性DNA结合因子的分离与鉴定 负责激素/代谢（胰岛素缺乏型糖尿病和 禁食/再喂养状态）和组织特异性（白色脂肪，棕色 脂肪、心脏和骨骼肌）调节该基因。

The GLUT4 glucose transporter is the major isoform expressed in muscle and adipose tissue, the two tissue types primarily responsible for the maintenance of whole body glucose homeostasis. The GLUT4 isoform plays a key role in this process by facilitating the uptake of glucose in these tissues in response to insulin stimulation. Regulation of GLUT4 glucose transporter functions occurs at multiple levels, several of which are associated with insulin resistance and diabetes. For example, multiple studies have documented that GLUT4 expression is decreased in states of insulin-deficient diabetes and fasting. Further patient studies have suggested a correlation in adipose tissue expression of GLUT4 with NIDDM. More recently, both the tissue-specific pattern as well as the hormonal/metabolic regulation of GLUT4 expression have been shown to occur at the transcriptional level. Based upon the central role of the GLUT4 gene in the pathophysiology associated with diabetes, we have proposed a series of studies to address the tissue-specific and hormonal/metabolic regulation of this gene. The basic molecular events involved in GLUT4 gene regulation are clearly important issues which are necessary for our understanding of adipose and muscle-specific gene regulation as well as for the control of glucose homeostasis, metabolism and energy production. We therefore plan to continue our studies delineating the molecular mechanisms responsible for the hormonal/metabolic and tissue-specific regulation of the insulin- responsive GLUT4 gene. This will be accomplished by detailed analysis of GLUT4 promoter function and identification of cis-DNA regulatory elements using several complementary approaches. These studies will then allow for the characterization and isolation of tissue-specific DNA binding factors responsible for the hormonal/metabolic (insulin-deficient diabetes and fasting/refeeding states) and tissue-specific (white adipose, brown adipose, cardiac and skeletal muscle) regulation of this gene.