Regulation of insulin Secretion by the GLP-1 Receptor

GLP-1 受体对胰岛素分泌的调节

• 批准号: 9378729
• 负责人: DAVID A. D'ALESSIO
• 金额: --
• 依托单位: DURHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-10-01 至 2020-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9378729
• 关键词: Address; Age; Agonist; Alpha Cell; Amino Acids; Applications Grants; Area; Beta Cell; Blood; Blood Circulation; Blood Glucose; Caring; Cell physiology; Cell secretion; Cells; Cross-Sectional Studies; Diabetes Mellitus; Disease Progression; Effectiveness; Endocrine; Enteroendocrine Cell; Fasting; Financial compensation; Functional disorder; GLP-I receptor; Glucose; Glucose Intolerance; Goals; Health system; Healthcare Systems; Hormones; Human; Incidence; Infusion procedures; Insulin; Insulin Resistance; Intervention; Investigation; Islet Cell; Literature; Measures; Mediating; Metabolic Control; Metabolism; Methods; Modeling; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Physiology; Plasma; Population; Prediabetes syndrome; Prevalence; Process; Production; Publishing; Regulation; Reporting; Research; Rodent; Role; Saline; Signal Transduction; Solid; System; Testing; Therapeutic; Thinness; Tissues; Translating; Work; base; blood glucose regulation; burden of illness; clinical application; diabetes mellitus therapy; diabetic; diabetic patient; drug development; economic cost; experimental study; fasting glucose; glucagon-like peptide; glucagon-like peptide 1; glucose metabolism; glucose tolerance; human subject; improved; inhibitor/antagonist; insulin secretagogues; insulin secretion; islet; mortality; novel; nutrient absorption; paracrine; prevent; public health relevance; research and development; response

 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.

 描述（由申请人提供）： 在过去的20年中，增加胰高血糖素样肽1（GLP-1）一直是糖尿病研究和药物发育的主要重点。增加的系统对于正常的葡萄糖稳态至关重要，最近的证据表明，该系统在2型糖尿病（T2DM）中存在特定的功能障碍。虽然最初建议用作果子，并从肠内分泌细胞中分泌到循环中，但最近的工作提出了有关这是否是内源性GLP-1作用的重要机制的问题。实际上，GLP-1在低水平的圆圈，并被特定的酶促代谢迅速失活。新兴的信息表明，出生的GLP-1可能无法解释其许多行动。最近，当血浆水平非常低且不变时，我们观察到在禁食状态下GLP-1受体活性的重要作用。这些研究在小鼠和人类中，提出了细胞GLP-1的作用，将胰岛素分泌作为旁分泌因子。目前，这是一个欠发达的研究领域，但有可能显着改变对GLP-1的效果和生理的理解。鉴于已经基于GLP-1的理论基础，因此可以将新的机械理解迅速转化为临床应用。该提议将 通过解决以下特定目的来解决禁食/旁分泌GLP-1动作问题：1。确定禁食GLP-1浓度和α细胞分泌在胰岛素释放中的作用； 2。确定基本GLP-1作用对胰岛素抵抗反应的作用； 3。确定基本GLP-1作用在瘦，肥胖，糖尿病前和糖尿病患者中禁食葡萄糖调节的作用。这些目的中的每一个都将在本文提出的选择中进行选择，将使用我们近年来开发或完善的人类投资方法，并利用FDA发给我们组的IND来使用合成GLP-1和GLP-1R激动剂，Exendin-（9-39） - （9-39）。在该项目的结论中，我们将对GLP-1调节β细胞功能以及禁食GLP-1R信号传导和胰岛旁分泌作用在此过程中的作用有更清晰的了解。该项目的一个关键方面是对GLP-1的细胞分泌作为中心的检查 禁食胰岛素分泌的调节。此外，此处提出的实验结果将研究GLP-1在葡萄糖代谢异常的补偿中的新作用。我们将通过对糖尿病和糖尿病前期受试者的平行度量的健康受试者的研究进行研究。这些相关的假设是由优化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，该项目的结果将对目前在VA系统内部和外部需要更好的治疗糖尿病患者的广泛特警有益。