CELLULAR MECHANISM FOR INSULIN RESISTANCE

胰岛素抵抗的细胞机制

• 批准号: 2136390
• 负责人: Kathryn Anne DeFea
• 金额: $ 2.37万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-01-15 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2136390
• 关键词: CELLULAR; MECHANISM; INSULIN; RESISTANCE

The ultimate purpose of this research proposal is to determine the role of feedback inhibition of Insulin Receptor Substrate (IRS-1) in insulin resistance. Differentiated 3T3-L1 adipocytes, treated with the phosphatase inhibitor okadate acid (OKA), have been shown to exhibit insulin resistance, accompanied by decreased insulin stimulated tyrosine phosphorylation of IRS-1 and an increase serine/threonine kinase activity capable of phosphorylating IRS-1. We are attempting to identify the serine threonine kinase activity, first by examining the role of two likely candidate proteins, MAP kinase and Protein Kinase C, and by attempting to purify a novel kinase. We will attempt to establish the biological relevance of this kinase activity by examining the effect of expressing IRS-1 mutants, lacking one or more of the potential ser/thr phosphorylation sites, on the OKA induced insulin resistance. We hope to establish a direct correlation between ser/thr phosphorylation of IRS-1 and a decrease in its tyrosine phosphorylation by insulin stimulated IR, decreased PI-3 kinase binding and decreased glucose uptake.

本研究提案的最终目的是确定 胰岛素受体底物（IRS-1）的反馈抑制 阻力 分化的3 T3-L1脂肪细胞，用 磷酸酶抑制剂冈田酸（OKA）已被证明表现出 胰岛素抵抗，伴有胰岛素刺激酪氨酸减少 IRS-1磷酸化和丝氨酸/苏氨酸激酶活性增加 能够磷酸化IRS-1。 我们正试图找出 丝氨酸苏氨酸激酶活性，首先通过检查两个 可能的候选蛋白质，MAP激酶和蛋白激酶C， 试图纯化一种新的激酶 我们将尝试建立 通过检查以下因素的影响， 表达IRS-1突变体，缺乏一个或多个潜在的ser/thr 磷酸化位点，对OKA诱导的胰岛素抵抗。 我们希望 为了建立丝氨酸/苏氨酸磷酸化与 IRS-1及其酪氨酸磷酸化被胰岛素降低 刺激IR，降低PI-3激酶结合和降低葡萄糖 摄取。