INSULIN ACTION IN NORMAL AND RESISTANT STATES

这项建议的主要目的是为了更好地了解 胰岛素的生理作用以及如何进一步表征 某些因素可以直接改变脂肪细胞中的胰岛素作用。上一首 研究表明，生长激素、糖皮质激素和一种因子存在 在慢性肾脏疾病患者的血清中抑制 和/或胰岛素刺激的葡萄糖转运。口服磺脲类药物 降血糖药，增强胰岛素刺激的运输。他们的 通过测量血糖将进一步探讨其作用机制 质膜和低密度微粒体内的“转运蛋白” 在胰岛素接触完好的细胞后。这些研究将调查 这些因素通过影响细胞移位而起作用的可能性 葡萄糖“转运体”对胰岛素的反应。其作用机制是 与慢性肾脏疾病相关的胰岛素抵抗 经过广泛评估。有强有力的证据表明，这种状态是由 由一个循环因子决定。随着对此的生物检测的可用性 尿毒症因子，预计纯化到均一可 通过使用高压液相色谱来完成。它是 还预计氨基酸组成将被确定。如果 这些目标的实现，然后进一步研究的来源 将探索其作用因素和作用机制。第三个主要领域 研究关注的是碳水化合物部分的作用 胰岛素受体在胰岛素结合、受体功能和刺激中的作用 受体后事件。虽然这一领域在很大程度上还未被开发，但它是 已知唾液酸残基对胰岛素的作用很重要 反应和去除末端半乳糖残基导致损失 高亲和力结合。脱除糖份的效果 糖苷酶对受体功能的几个方面的适当消化 将会被评估。这些包括受体内化，向下 调节和自动磷酸化。后者被吹捧为 胰岛素细胞效应的结合后启动剂。的影响 胰岛素模拟物、逆调节激素和磺脲类药物 还将研究磷酸化或胰岛素受体。它是 预期拟议的研究将有助于我们的基本 胰岛素作用的早期步骤(受体和葡萄糖)的知识 运输)以及我们对心脏的病理生理学的理解 在某些疾病状态下改变胰岛素的反应性。

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.