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.

瘦素是一种由脂肪组织产生的蛋白质，假设为 循环脂肪因子(82)。我们的初步数据显示， 正常小鼠注射瘦素可抑制胰岛素的释放 可诱导脂肪细胞产生胰岛素抵抗，但 促进肌肉中胰岛素刺激的糖原合成。一个受损害的人 葡萄糖引起的急性胰岛素释放是高血压的危险因素 非胰岛素依赖型糖尿病(NIDDM)的发展(25)和增加 肌肉中胰岛素刺激的糖原合成是 胰岛素发育过程中早期代谢变化的观察 高脂饮食大鼠的抵抗力(48)。我们假设瘦素 调节糖耐量受损的发生 早期NIDDM通过抑制葡萄糖刺激的胰岛素释放和 改变组织和途径中胰岛素刺激的葡萄糖利用 具体的方式。在特定目标1中描述的实验将检验 瘦素输注对糖尿病大鼠糖和脂肪酸代谢的影响 瘦小鼠体内三种主要的胰岛素反应组织 确定对胰岛素反应性的影响是否通过 长型瘦素受体，OB-Rb。特定目标实验2 将研究瘦素在修饰胰岛素信号转导中的作用 确定瘦素是否会改变组织的胰岛素受体数量、血糖 转运体数量或易位与胰岛素受体酪氨酸 激活酶活性。这些进程代表了 胰岛素信号级联，这些实验的结果将 确定瘦素如何改变胰岛素信号的初始阶段 来改变外周组织的葡萄糖利用。这些研究描述了 将提供所需信息以了解如何 瘦素治疗改善外周组织的胰岛素反应性 以及实现这一目标的机制。这是至关重要的 阐明瘦素活性的这一方面，因为它可能解释 与此相关的发生糖耐量异常的风险增加 与肥胖有关。