BIFUNCTIONAL MODULATION OF INSULIN ACTION BY AMINO ACIDS

描述（摘自申请人摘要） 以前的人类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 合成和抑制蛋白水解，而且还降低全身和前臂 葡萄糖处理。 本提案中提供的数据表明， 酸作为新的信号元件在胰岛素靶组织，无论是在体内 （1）氨基酸激活在细胞内重要的中间体， 蛋白质合成的起始，包括p70 S6激酶和PHAS-1， 与胰岛素协同作用。 (2)同时，氨基酸抑制了 胰岛素对葡萄糖转运和利用的关键作用，包括 胰岛素受体底物的酪氨酸磷酸化和 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 对维持蛋白质质量至关重要的特异性阳性信号， 在多个水平上抑制胰岛素的作用。 这种双功能 胰岛素作用的调节表明激素和 营养信号和一种新的机制， 导致胰岛素抵抗。 这项提案的主要目标是了解细胞机制， 氨基酸调节胰岛素信号传导的机制，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： 所述氨基酸刺激p70 S6激酶和PHAS-1磷酸化，（2） 确定氨基酸降低胰岛素刺激的 PI 3-激酶的激活和葡萄糖转运，（3）确定作用 氨基酸在正常人胰岛素抵抗发展中的作用 氨基酸在啮齿类动物中的作用 遗传性胰岛素抵抗的模型。 我在临床内分泌学/代谢学和基础 信号转导研究为我提供了一个独特视角， 探索代谢和经典激素之间令人兴奋的界面 信号系统。 C博士的持续指导和支持。罗纳德 卡恩，在乔斯林糖尿病中心和朗伍德的环境中， 医学领域，为我提供了一个极好的机会，继续我的 调查和进一步发展我的技能，以实现我的目标， 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.