FACTORS THAT MODIFY INSULIN ACTION

我们建议继续开展三个独立但相关的项目。1)我们 从骨骼肌中部分提纯出耐热、耐酸的成分 非透析性因子，推测是一种抑制蛋白质的多肽 兔网织红细胞裂解物的合成，显然是在 翻译启蒙。此外，大鼠的横隔膜与 仅葡萄糖产生的抑制活性明显高于 在添加胰岛素和氨基酸的培养液中孵育。建议 研究包括：a)确认和扩展这些发现，确认多肽 肌源性翻译抑制物的性质和作用部位 胰岛素和氨基酸在ITS中的启动和各自作用 调节；b)提纯和鉴定肌肉提取物中的多肽(S) 它们抑制翻译启动，并受胰岛素和/或 氨基酸；c)研究该抑制剂的作用方式和机制(S) 胰岛素和/或氨基酸的抑制作用。可行的假设是 该抑制物促进eIF-2α的磷酸化和胰岛素 肌肉治疗降低了抑制物的活性；d)研究生理和 可能调节活动和/或的病理状态 抑制物在体内的可抑制性，例如糖尿病的影响， 荷尔蒙、肌肉工作和去神经；2)运动增强胰岛素 肌肉在制动或短期失神经时的敏感性 会导致胰岛素抵抗。我们研究了分离的比目鱼肌6-24 切断坐骨神经后数小时观察胰岛素下降 结合，降低胰岛素对葡萄糖转运的敏感性，并显著 胰岛素抵抗的糖原合成，指示受体和 受体后缺陷。肌肉活动的分子机制 调节胰岛素受体和受体-功能的偶联 在不同类型的肌肉中进行了研究，并与几种 胰岛素作用参数：如葡萄糖转运糖原合成， 糖酵解、氨基酸转运和蛋白质合成。3)学习 关于支链氨基酸分解代谢的调节 将在两个方面继续：a)支链的反馈调节 酮酸脱氢酶，b)介导加速氧化的机制 糖尿病、禁食和运动时肌肉的支链氨基酸。这些研究 与了解糖尿病和其他疾病的代谢改变有关 与胰岛素抵抗和蛋白质消耗有关的疾病。

We propose to continue work on three separate but related projects. 1) We have partially purified from skeletal muscle a heat and acid stable non-dialysable factor, presumed to be a peptide, which inhibits protein synthesis in rabbit reticulocyte lysates, apparently at the level of translation initiation. Moreover, rat hemidiaphragms incubated with glucose alone yield significantly more inhibitor activity than those incubated in media supplemented with insulin and amino acids. Proposed studies include: a) confirm and extend these findings, confirm peptide nature of the muscle derived translational inhibitor and site of action on initiation and delineate respective role of insulin and amino acids in its regulation; b) purify and characterize peptide(s) in the muscle extract which inhibit translation initiation and are regulated by insulin and/or amino acids; c) study the mode of action of this inhibitor(s) and mechanism of suppression by insulin and/or amino acids. Working hypotheses are that the inhibitor promotes the phosphorylation of eIF-2Alpha and that insulin treatment of muscle reduces inhibitor activity; d) study physiological and pathological conditions which may modulate the activity and/or suppressibility of the inhibitor in vivo e.g. the effects of diabetes, hormones, muscle work and denervation; 2) exercise enhances insulin sensitivity of muscles, while immobilization or short-term denervation causes insulin resistance. We have studied isolated soleus muscles 6-24 hours after cutting the sciatic nerve and observed decreased insulin binding, decreased sensitivity to insulin of glucose transport and marked resistance to insulin of glycogen synthesis, indicating receptor and post-receptor defects. The molecular mechanisms by which muscle activity modulates the insulin receptor and receptor-function coupling will be investigated in different types of muscle, and with respect to several parameters of insulin action: e.g. glucose transport glycogen synthesis, glycolysis, amino acid transport and protein synthesis. 3) Studies concerning the regulation of branched chain amino acid (BCAA) catabolism will be continued in 2 areas: a) feedback regulation of branched chain keto acid dehydrogenase, b) mechanisms mediating accelerated oxidation of BCAA by muscles in diabetes, fasting and during exercise. These studies are relevant to understanding of altered metabolism in diabetes and other diseases associated with insulin resistance and protein wasting.