INSULIN ACTION IN NORMAL AND RESISTANT STATES

本建议的主要目的是更好地了解 胰岛素生理作用以及进一步表征如何 某些因素可以直接改变脂肪细胞中的胰岛素作用。 先前 研究表明，生长激素，糖皮质激素和一种因子存在， 在来自慢性肾病患者的血清中， 和/或胰岛素刺激的葡萄糖转运。 磺酰脲类，口服 降血糖剂，增强胰岛素刺激转运。 他们的 将通过测量葡萄糖来进一步探索作用机制 前质膜和低密度微粒体中的“转运蛋白”， 在胰岛素暴露于完整细胞后。 这些研究将调查 这些因素可能通过影响 葡萄糖“转运蛋白”对胰岛素的反应。 的机理 与慢性肾病相关的胰岛素抵抗将是 广泛评价。 有强有力的证据表明这种状态是由 一个循环的因素。 随着生物测定的可用性， 尿毒症因子，预期可以纯化至均一， 通过使用高压液相色谱法完成。 是 还预计将确定氨基酸组成。 如果 这些目标的实现，然后进一步研究的来源， 并对影响因素和作用机制进行探讨。 第三大领域 研究关注的是糖部分的作用， 胰岛素受体在胰岛素结合、受体功能和刺激 受体后事件 虽然这一地区大部分尚未开发，但它是 已知唾液酸残基对于影响胰岛素 反应和末端半乳糖残基的去除导致损失 高亲和力结合。 通过以下方法去除糖部分的效果 适当的糖苷酶消化对受体功能的几个方面 将被评估。 这些包括受体内化， 调节和自身磷酸化。 后者被吹捧为 胰岛素细胞效应的后结合引发剂。 的影响 胰岛素模拟剂、反调节激素和磺酰脲类药物对 还将研究磷酸化或胰岛素受体。 是 预计拟议的研究将有助于我们的基本 了解胰岛素作用的早期步骤（受体和葡萄糖 运输）以及我们对 在某些疾病状态下改变胰岛素反应性。

The major objectives of this proposal are to gain a better understanding of the physiological action of insulin as well as to further characterize how certain factors can directly alter insulin action in fat cells. Previous studies suggest that growth hormone, glucocorticoids and a factor present in serum from patients with chronic renal disease inhibit either basal and/or insulin-stimulated glucose transport. Sulfonylureas, oral hypoglycemic agents, potentiate insulin-stimulated transport. Their mechanism of action will be further explored by measuring glucose "transporters" in plasma membranes and low density microsomes before and after insulin exposure to the intact cell. These studies will investigate the possibility that these factors act by influencing the translocation of glucose "transporters" in response to insulin. The mechanism of the insulin resistance associated with chronic renal disease will be extensively evaluated. There is strong evidence that this state is caused by a circulating factor. With the availability of a bio-assay for this uremic factor, it is anticipated that purification to homogeneity can be accomplished through the use of high-pressure liquid chromatography. It is also anticipated that the amino acid composition will be determined. If these aims are achieved, then further studies concerning the source of the factor and mechanism of action will be explored. The third major area of investigation is concerned with the role of the carbohydrate moiety of the insulin receptor in insulin binding, receptor function and stimulation of post receptor events. Although this area is largely unexplored, it is known that sialic acid residues are important for effecting an insulin response and that removal of terminal galactose residues results in a loss of high affinity binding. The effects of removal of sugar moieties by appropriate glycosidase digestion on several aspects of receptor function will be evaluated. These include receptor internalization, down regulation, and autophosphorylation. The latter has been touted as the post-binding initiator of insulin's cellular effects. The effects of insulin mimickers, counter-regulatory hormones and sulfonylureas on the phosphorylation or the insulin receptor will also be studied. It is anticipated that the proposed studies will contribute to our basic knowledge of the early steps of insulin action (receptor and glucose transport) as well as to our understanding of the pathophysiology of altered insulin responsiveness in certain disease states.