LEPTIN AND PERIPHERAL GLUCOSE METABOLISM

瘦素和外周葡萄糖代谢

• 批准号: 6164563
• 负责人: Ruth B Harris
• 金额: $ 2.16万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6164563
• 关键词: SDS polyacrylamide gel electrophoresis; adipocytes; dietary lipid; fatty acid metabolism; glucose metabolism; glucose tolerance; growth factor receptors; hormone receptor; hormone regulation /control mechanism; insulin dependent diabetes mellitus; insulin sensitivity /resistance; laboratory mouse; leptin; liver metabolism; nutrition related tag; obesity; pancreatic islet function; protein structure; protein tyrosine kinase; receptor expression; western blottings

Leptin is a protein produced by adipose tissue and hypothesized to be a circulating lipostatic factor (82). Our preliminary data shows that leptin infusion into normal mice inhibits insulin release in response to a glucose challenge, induces insulin resistance in adipocytes, but promotes insulin-stimulated glycogen synthesis in muscle. An impaired acute insulin release in response to glucose is a risk factor for development of non-insulin dependent diabetes (NIDDM) (25) and increased insulin-stimulated glycogen synthesis in muscle is characteristic of the early metabolic changes observed during the development of insulin resistance in high-fat fed rats (48). We hypothesize that leptin mediates development of an impaired glucose tolerance that precedes early NIDDM by suppressing glucose stimulated insulin release and modifying insulin-stimulated glucose utilization in a tissue and pathway specific manner. Experiments described in Specific Aim 1 will examine the effects of leptin infusion on glucose and fatty acid metabolism of the three major insulin-responsive tissues in lean mice and will determine whether the effects on insulin responsiveness are mediated by the long-form leptin receptor, OB-Rb. Experiments in Specific Aim 2 will investigate the role of leptin in modifying insulin signaling to determine whether leptin changes tissue insulin receptor number, glucose transporter number or translocation, and insulin receptor tyrosine kinase activity. These processes represent the first stage of the insulin signaling cascade and the results of these experiments will determine how leptin modifies the initial stages of insulin signaling to change peripheral tissue glucose utilization. The studies described in this proposal will provide the information required to understand how leptin treatment modifies insulin responsiveness in peripheral tissues and the mechanisms by which this is achieved. It is essential to elucidate this aspect of leptin activity as it may account for the increased risk of development of glucose intolerance that is associated with obesity.

瘦素是由脂肪组织产生的蛋白质，并被认为是 循环的抑制抑制因子（82）。 我们的初步数据表明 瘦素输注正常小鼠会抑制胰岛素释放的反应 面对葡萄糖挑战，会诱导脂肪细胞中的胰岛素耐药性，但 促进胰岛素刺激的糖原合成。 受损 响应葡萄糖的急性胰岛素释放是一个危险因素 非胰岛素依赖性糖尿病（NIDDM）（25）的发展并增加 胰岛素刺激的糖原合成在肌肉中的特征是 胰岛素发展过程中观察到的早期代谢变化 高脂喂养大鼠的抗性（48）。 我们假设瘦素 介导之前的葡萄糖耐量受损的发展 通过抑制葡萄糖刺激的胰岛素释放和 修改组织和途径中胰岛素刺激的葡萄糖利用 具体方式。 特定目标1中描述的实验将检查 瘦素输注对葡萄糖和脂肪酸代谢的影响 瘦小鼠中的三个主要胰岛素反应组织，将 确定对胰岛素反应的影响是否由 长形的瘦素受体OB-RB。 特定目标2中的实验 将研究瘦素在修改胰岛素信号转导中的作用 确定瘦素是否改变组织胰岛素受体数量，葡萄糖 转运蛋白或易位，胰岛素受体酪氨酸 激酶活性。 这些过程代表了 胰岛素信号级联和这些实验的结果将 确定瘦素如何修饰胰岛素信号的初始阶段 改变周围组织葡萄糖的利用。 描述的研究 在此提案中，将提供了解如何了解的信息 瘦素治疗可修饰外周组织中的胰岛素反应性 以及实现这一目标的机制。至关重要 阐明瘦素活性的这一方面 增加葡萄糖不耐症的风险增加 肥胖。