FACTORS THAT MODIFY INSULIN ACTION

胰岛素抵抗与许多病理条件有关 包括肥胖、胰岛素缺乏性糖尿病、蛋白质分解代谢状态 （创伤和脓毒症）;这是最常见的 2型糖尿病（Type II） 最大的缺陷在于后- 胰岛素受体结合。 1)观察胰岛素受体（IR） 肌肉和肝脏之间的结构和功能异质性， 和糖尿病中IR酪氨酸激酶（TK）活化受损。 的 IR TK激活在调节胰岛素反应中的作用将 在正常大鼠（肌肉和肝脏）和 胰岛素抵抗（胰岛素缺乏性糖尿病和饮食诱导）。 的 将研究IR TK活化受损的分子基础 及其与表观结构修饰的关系 IR -亚基研究。 假设新陈代谢的变化 环境可能导致IR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研究评估， 完整细胞中的内源性IR TK底物。 2)大鼠肌肉 在去神经支配后不久出现严重的胰岛素抵抗， 完整结合和IR TK活化。 研究的机制 受体后胰岛素抗性将在该模型中继续。 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， 内源性IR TK底物磷酸化的改变 在去神经支配后的肌肉中评估。 3)在所有条件下 研究表明，加速净肌肉蛋白催化剂与 支链氨基酸（BCAA）的氧化， 肌肉. 我们已经开发了测量体内 支链氨基酸催化剂限速酶的活化状态 肌肉，支链-酮酸脱氢酶复合物（BCKAD）， 发现使用糖皮质激素、细菌内毒素 并且激活的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- 干扰素对BCKAD激活作用将在大鼠肌肉中进行研究， 体内和组织培养模型中，L-6肌细胞。 调控 BCAA代谢和蛋白质周转的单核因子，激素 （糖皮质激素和胰岛素）和支链氨基酸将在L-6研究 细胞 之间的明显关联的机制 加速BCAA催化剂和肌肉蛋白质降解将是 研究了 了解这些机制是重要的， 由于BCAA补充剂已被提倡作为治疗， 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.