LEPTIN AND PERIPHERAL GLUCOSE METABOLISM

瘦素是一种由脂肪组织产生的蛋白质， 循环脂肪抑制因子（82）。 我们的初步数据显示， 正常小鼠输注瘦素抑制胰岛素释放 在脂肪细胞中诱导胰岛素抵抗，但是 促进胰岛素刺激的肌肉糖原合成。 受损 对葡萄糖的急性胰岛素释放是 非胰岛素依赖型糖尿病（NIDDM）的发展（25）和增加 胰岛素刺激的肌肉糖原合成是 在胰岛素形成过程中观察到的早期代谢变化 高脂喂养大鼠的抵抗力（48）。 我们假设瘦素 介导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， 改变组织和途径中胰岛素刺激的葡萄糖利用 具体方式。 具体目标1中描述的实验将检查 瘦素输注对大鼠糖脂代谢的影响 瘦小鼠的三个主要胰岛素反应组织， 确定对胰岛素反应性的影响是否由以下因素介导 长型瘦素受体OB-Rb。 具体目标2 将研究瘦素在修饰胰岛素信号中的作用， 确定瘦素是否改变组织胰岛素受体数量、葡萄糖 转运体数目或易位，以及胰岛素受体酪氨酸 激酶活性 这些过程代表了 胰岛素信号级联，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。 描述的研究 将提供所需的信息，以了解如何 瘦素治疗改变外周组织胰岛素反应性 以及实现这一点的机制。有必要 阐明瘦素活性的这一方面，因为它可以解释 葡萄糖耐受不良的风险增加， 肥胖症

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.