FACTORS THAT MODIFY INSULIN ACTION

胰岛素抵抗与许多病理情况有关。 包括肥胖、胰岛素依赖型糖尿病、蛋白质分解代谢状态 (创伤和败血症)；这是最常见的 人类糖尿病的形式(II型)。主要的缺陷在于后遗症- 胰岛素受体结合。1)观察胰岛素受体(IR) 肌肉和肝脏在结构和功能上的异质性， 糖尿病时IR酪氨酸激酶(TK)活性受损。这个 IR-TK激活在调节胰岛素反应Will中的作用 在正常大鼠(肌肉和肝脏)和动物模型中进行研究 胰岛素抵抗(胰岛素依赖型糖尿病和饮食诱导)。这个 IR TK活性受损的分子基础将被研究 以及它与明显的结构修改的关系 研究了IR亚基。新陈代谢变化的假说 环境可能导致IR遗嘱的加工(糖基化)改变 B测试。改变的IR TK活性的功能相关性将是 通过胰岛素刺激的磷酸化的研究进行评估 完整细胞中的内源性IR TK底物。2)大鼠肌肉 去神经后不久出现严重的胰岛素抵抗 完整的结合和IR TK激活。对其作用机制的研究 受体后胰岛素抵抗将在该模型中继续存在。 葡萄糖转运体数量、亲和力、亚细胞分布和 将研究胰岛素诱导的易位并使其成为可能 内源性IR-TK底物磷酸化的变化 在失神经支配后对肌肉进行评估。3)在任何情况下 研究表明，加速的肌肉蛋白质分解代谢与 通过加速支链氨基酸(BCAA)的氧化 肌肉。我们已经开发出在体内测量的方法 大鼠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体(BCKAD)， 并发现服用糖皮质激素、细菌内毒素 活化的巨噬细胞分泌产物迅速激活肌肉 BCKAD。重组单因子、肿瘤坏死因子、白介素1和-干扰素的作用 干扰素BCKAD活性将在#年在大鼠肌肉中进行研究 在活体和组织培养模型中，培养L-6心肌细胞。这项规定 单因子、激素对支链氨基酸代谢和蛋白质周转的影响 (糖皮质激素和胰岛素)和支链氨基酸将在L-6中进行研究 细胞。表观关联的机制 加速支链氨基酸分解代谢和肌肉蛋白质降解将是 调查过了。了解这些机制是很重要的， 自从支链氨基酸补充剂被提倡作为治疗方法以来， 分解代谢状态。

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.