FACTORS THAT MODIFY INSULIN ACTION

改变胰岛素作用的因素

• 批准号: 3224337
• 负责人: MARIA G BUSE
• 金额: $ 21.8万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-05-01 至 1993-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3224337
• 关键词: aminoacid metabolism; aminoacid transport; artificial endocrine pancreas; autoradiography; branched chain aminoacid; diabetes mellitus; dietary lipid; gel electrophoresis; glucocorticoids; glucose transport; glycosylation; hormone regulation /control mechanism; immunoprecipitation; insulin; insulin receptor; insulin sensitivity /resistance; insulinlike factor; laboratory rat; monokines; muscle metabolism; nutrition related tag; protein biosynthesis; protein metabolism; protein tyrosine kinase; radioimmunoassay; radiotracer; starvation; striated muscles; tissue /cell culture

Insulin resistance is associated with many pathological conditions including obesity, insulinopenic diabetes, protein catabolic states (trauma and sepsis); it is the salient feature of the most common form of diabetes in man (Type II). The major defect resides post- insulin-receptor-binding. 1) We observed insulin receptor (IR) structural and functional heterogeneity between muscle and liver, and impaired IR tyrosine kinase (TK) activation in diabetes. The role of IR TK activation in modulating the insulin response will be studied in normal rats (muscle and liver) and in models of insulin resistance (insulinopenic diabetes and diet induced). The molecular basis of impaired IR TK activation will be investigated and its relationship to apparent structural modifications of the IR - subunit studied. The hypothesis that changes in the metabolic milieu may lead to altered processing (glycosylation) of IR will b tested. Functional relevance of altered IR TK activity will be assessed by studies of insulin stimulated phosphorylation of endogenous IR TK substrates in intact cells. 2) Rat muscles develop profound insulin resistance shortly after denervation with intact binding and IR TK activation. Studies of mechanisms of post-receptor insulin resistance will be continued in this model. Glucose transporter number, affinity, subcellular distribution and insulin induced translocation will be studied and possible alterations in the phosphorylation of endogenous IR TK substrates assessed in muscle after denervation. 3) In all conditions studied, accelerated net muscle protein catabolism is associated with accelerated branched chain amino acid (BCAA) oxidation by muscle. We have developed methods to measure the in vivo activation state of the rate limiting enzyme of BCAA catabolism in muscle, branched chain - keto acid dehydrogenase complex (BCKAD), and found that administration of glucorticoids, bacterial endotoxin and activated macrophage secretion products rapidly activate muscle BCKAD. The effect of recombinant monokines, TNF, IL-1 and - interferon on BCKAD activation will be studied in rat muscle in vivo and in a tissue culture model, L-6 myocytes. The regulation of BCAA metabolism and protein turnover by monokines, hormones (glucocorticoids and insulin) and BCAA will be studied in L-6 cells. The mechanism of the apparent association between accelerated BCAA catabolism and muscle protein degradation will be investigated. Understanding of these mechanisms is important, since BCAA supplementation has been advocated as therapy in the catabolic state.

胰岛素抵抗与许多病理状况有关 包括肥胖、胰岛素缺乏型糖尿病、蛋白质分解代谢状态 （创伤和败血症）；这是最常见的显着特征 人类糖尿病的一种形式（II 型）。 主要缺陷在于后 胰岛素受体结合。 1）我们观察胰岛素受体（IR） 肌肉和肝脏之间的结构和功能异质性， 糖尿病中 IR 酪氨酸激酶 (TK) 激活受损。 这 IR TK 激活在调节胰岛素反应中的作用 在正常大鼠（肌肉和肝脏）和模型中进行研究 胰岛素抵抗（胰岛素缺乏性糖尿病和饮食引起）。 这 将研究 IR TK 激活受损的分子基础 及其与表观结构修饰的关系 IR - 研究的亚基。 新陈代谢发生变化的假说 环境可能会导致 IR 的加工（糖基化）发生改变 b 测试过。 改变的 IR TK 活性的功能相关性将是 通过胰岛素刺激磷酸化的研究评估 完整细胞中的内源 IR TK 底物。 2) 大鼠肌肉 去神经后不久就会出现严重的胰岛素抵抗 完整的结合和 IR TK 激活。 机制研究 受体后胰岛素抵抗将在该模型中继续。 葡萄糖转运蛋白数量、亲和力、亚细胞分布和 将研究胰岛素诱导的易位并可能 内源 IR TK 底物磷酸化的改变 去神经支配后对肌肉进行评估。 3) 在所有条件下 研究表明，加速净肌肉蛋白分解代谢与 加速支链氨基酸 (BCAA) 氧化 肌肉。 我们开发了测量体内 支链氨基酸分解代谢限速酶的激活状态 肌肉，支链-酮酸脱氢酶复合物（BCKAD）， 并发现给予糖皮质激素、细菌内毒素 并激活巨噬细胞分泌产物迅速激活肌肉 BCKAD。 重组单核因子、TNF、IL-1 和 - 的作用 将在大鼠肌肉中研究干扰素对 BCKAD 激活的影响 体内和组织培养模型中，L-6 肌细胞。 法规 单核因子、激素对 BCAA 代谢和蛋白质周转的影响 （糖皮质激素和胰岛素）和 BCAA 将在 L-6 中进行研究 细胞。 之间明显关联的机制 加速 BCAA 分解代谢和肌肉蛋白降解 调查了。 了解这些机制很重要 自从 BCAA 补充剂被提倡作为治疗方法以来 分解代谢状态。