BIFUNCTIONAL MODULATION OF INSULIN ACTION BY AMINO ACIDS

描述(摘自申请人的摘要) 以前的人体研究已经证明了氨基酸的重要作用。 在蛋白质和葡萄糖代谢中：氨基酸刺激蛋白质 抑制蛋白质的合成和分解，但也会减少全身和前臂 葡萄糖处理。本提案中提供的数据表明，氨基 酸在体内胰岛素靶组织中作为新的信号元件 在体外：(1)氨基酸激活中间体，这些中间体在 启动蛋白质合成，包括p70S6激酶和PHAS-1，在 与胰岛素有协同作用。(2)同时，氨基酸抑制步入 胰岛素对葡萄糖的转运和利用至关重要，包括 胰岛素受体底物的酪氨酸磷酸化及其激活 磷脂酰肌醇3-激酶(PI-3-Kinase)。综合来看，这些数据 支持氨基酸及其代谢物作为 特定的正信号对蛋白质质量的维持至关重要，但也 从多个层面抑制胰岛素的作用。这种双功能 胰岛素作用的调节提示荷尔蒙和 营养信号与营养因子的一种新机制 会导致胰岛素抵抗。 这个提案的主要目标是了解细胞机制。 通过哪些氨基酸调节胰岛素信号并研究其作用 氨基酸在胰岛素抵抗的病理生理学中的作用。我们的研究 将针对四个具体目标：(1)通过以下方式确定机制 哪些氨基酸刺激p70 S6激酶和PHAS-1的磷酸化，(2) 确定氨基酸减少胰岛素刺激的机制 PI3-激酶的激活与葡萄糖转运，(3)确定作用 氨基酸在正常人群胰岛素抵抗发生中的作用 (4)评价氨基酸在啮齿动物体内的作用。 遗传性胰岛素抵抗的模型。 我在临床内分泌学/新陈代谢和基础知识方面的培训和技能 信号转导研究为我提供了一个独特的视角 探索新陈代谢和经典荷尔蒙之间令人兴奋的界面 信号系统。C.Ronald博士的持续指导和支持 在乔斯林糖尿病中心和朗伍德的环境中 医疗领域，为我提供了一个继续我的 并进一步发展我的技能，以实现我作为一名 独立调查员。

DESCRIPTION (taken from the applicant's abstract) Previous human studies have demonstrated an important role for amino acids in both protein and glucose metabolism: amino acids stimulate protein synthesis and inhibit proteolysis, but also decrease whole-body and forearm glucose disposal. Data presented in this proposal demonstrate that amino acids act as novel signaling elements in insulin target tissues both in vivo and in vitro: (1) Amino acids activate intermediates important in the initiation of protein synthesis, including p70 S6 kinase and PHAS-1, in synergy with insulin. (2) Concurrently, amino acids inhibit steps in insulin action critical for glucose transport and utilization, including tyrosine phosphorylation of insulin receptor substrates and activation of phosphatidylinositol 3-kinase (PI 3-kinase). Taken together, these data support the hypothesis that amino acids and their metabolites act as specific positive signals critical for maintenance of protein mass, yet also inhibit the action of insulin at multiple levels. This bifunctional modulation of insulin action suggests crosstalk between hormonal and nutritional signals and a novel mechanism by which nutritional factors contribute to insulin resistance. The broad goals of this proposal are to understand the cellular mechanisms by which amino acids modulate insulin signaling and to investigate the role of amino acids in the pathophysiology of insulin resistance. Our studies will be directed at four specific aims: (1) to identify the mechanisms by which amino acids stimulate p70 S6 kinase and PHAS-1 phosphorylation, (2) to identify the mechanisms by which amino acids decrease insulin-stimulated activation of PI 3-kinase and glucose transport, (3) to determine the role of amino acids in the development of insulin resistance in normal physiology, and (4) to evaluate the contribution of amino acids in rodent models of genetic insulin resistance. My training and skills in both clinical endocrinology/metabolism and basic signal transduction investigation provide me with a unique perspective to explore the exciting interface between metabolic and classical hormonal signaling systems. The continuing mentoring and support of Dr. C. Ronald Kahn, within the environment of the Joslin Diabetes Center and Longwood Medical Area, provide me with an excellent opportunity to continue my investigation and to further develop my skills to attain my goal as an independent investigator.