Regulation of insulin Secretion by the GLP-1 Receptor

 描述（由申请人提供）： 胰高血糖素样肽1（GLP-1）是过去20年来糖尿病研究和药物开发的主要焦点。肠促胰岛素系统对于正常的葡萄糖稳态是必不可少的，并且最近的证据表明在2型糖尿病（T2 DM）中存在该系统的特定功能障碍。虽然最初提出作为一种激素，从肠内分泌细胞分泌到循环中，但最近的工作提出了关于这是否是内源性GLP-1作用的重要机制的问题。事实上，GLP-1以低水平循环，并通过特定的酶代谢迅速失活。新出现的信息表明，血源性GLP-1可能无法解释其许多作用。我们最近观察到GLP-1受体活性在空腹状态下的重要作用，此时血浆水平非常低且不变。这些在小鼠和人类中的研究表明β细胞GLP-1作为旁分泌因子调节胰岛素分泌的作用。目前这是一个不发达的研究领域，但有可能极大地改变对GLP-1的肠促胰岛素作用和生理学的理解。鉴于已经有了基于GLP-1的坚实的治疗基础，新的机制理解可以迅速转化为临床应用。这项建议会 通过解决以下具体目标来处理禁食/旁分泌GLP-1行动问题：1.确定空腹GLP-1浓度和α细胞分泌对胰岛素释放的作用; 2.确定基础GLP-1作用对胰岛细胞对胰岛素抵抗的反应的作用; 3.确定基础GLP-1对瘦型、肥胖、前驱糖尿病和糖尿病受试者空腹血糖调节的作用。这些目标中的每一个都将在选定的人类受试者组中进行。 本文拟定的研究将使用我们近年来开发或完善的人体研究方法，并利用FDA向我们小组发布的IND，在人体研究中使用合成GLP-1和GLP-1 r激动剂exendin-（9-39）。在本项目结束时，我们将更清楚地了解GLP-1如何调节β细胞功能，以及空腹GLP-1 r信号传导和胰岛旁分泌作用在此过程中的作用。该项目的一个关键方面是检查GLP-1的β-细胞分泌，其在细胞内是重要的。 调节空腹胰岛素分泌。此外，本文提出的实验结果将检验GLP-1在补偿异常葡萄糖代谢中的新作用。我们将把对胰岛素抵抗的健康受试者的研究结果与糖尿病和糖尿病前期受试者的平行测量结果联系起来。这些相关假设是由优化GLP-1系统作为改善代谢控制的手段的目标驱动的。总体而言，该项目的结果将有利于目前在VA系统内部和外部需要更好治疗的广大糖尿病患者。

 DESCRIPTION (provided by applicant): The incretin glucagon-like peptide 1 (GLP-1) has been a major focus of diabetes research and drug development for the past 20 years. The incretin system is essential for normal glucose homeostasis and recent evidence indicates that there is specific dysfunction of this system in type 2 diabetes (T2DM). While initially proposed to act as a hormone, secreted into the circulation from enteroendocrine cells, recent work has raised questions as to whether this is an important mechanism of endogenous GLP-1 action. In fact, GLP-1 circulates at low levels and is rapidly inactivated by specific enzymatic metabolism. Emerging information suggests that blood borne GLP-1 may not account for many of its actions. We have recently observed an important effect of GLP-1 receptor activity in the fasting state when plasma levels are very low and unchanging. These studies, in mice and humans, suggest a role for -cell GLP-1 to regulate insulin secretion as a paracrine factor. This is currently an underdeveloped area of research, but has the potential to dramatically change the understanding of the incretin effect and physiology of GLP-1. Given that there is already a solid base of therapeutics based on GLP-1, new mechanistic understanding could be rapidly translated into clinical application. This proposal will take up the issue of fasting/paracrine GLP-1 action by addressing the following specific aims: 1. Determine the roles of fasting GLP-1 concentrations and alpha-cell secretion on insulin release; 2. Determine the role of basal GLP-1 action on the -cell response to insulin resistance; 3. Determine the role of basal GLP-1 action on fasting glucose regulation in lean, obese, prediabetic, and diabetic subjects. Each of these aims will be conducted in selected groups of human subjects. The studies proposed herein will use methods of human investigation that we have developed or refined in recent years and take advantage of INDs issued to our group by the FDA to use synthetic GLP-1 and a GLP-1r agonist, exendin-(9-39), in human research. At the conclusion of this project we will have a much clearer picture of how GLP-1 regulates β-cell function, and the role of fasting GLP-1r signaling and islet paracrine action in this process. A critical aspect of this project is the examination of -cell secretion of GLP-1 as central in the regulation of fasting insulin secretion. In addition, the results of the experiments proposed herei will examine a novel role for GLP-1 in the compensation for abnormal glucose metabolism. We will connect the findings from studies of healthy subjects made insulin resistant with parallel measures in diabetic and prediabetic subjects. These related hypotheses are driven by the goal of optimizing the GLP-1 system as a means of improving metabolic control. Overall, the outcomes of this project will be beneficial to the broad swath of diabetic patients currently needing better treatment, both inside and outside the VA system.