Incretin Action in Physiology and Diabetes

描述（由申请方提供）：肠促胰岛素效应描述了当摄入营养物质时肠道因子增加胰岛素分泌，主要由葡萄糖依赖性促胰岛素多肽（GIP）和胰高血糖素样肽1（GLP-1）介导。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（T2DM）中存在该系统的特定功能障碍。在最近的研究中，我们已经确定肠促胰岛素效应在人体中是稳定的和可重现的，内源性GLP-1具有重要的肠促胰岛素外效应，并且糖尿病受试者中高血糖症的纠正特异性地恢复肠促胰岛素效应。现在有两类药物可供使用， 基于GLP-1受体的信号传导治疗糖尿病。然而，关于肠促胰岛素系统的功能仍然存在重要的未回答的问题，这些问题对于了解这些新的治疗方向是否需要优化至关重要。本提案将通过解决以下具体目标来解决这些问题：1）确定GLP-1和GIP在非糖尿病受试者中调节胰岛素分泌的相互作用。我们假设对肠促胰岛素的敏感性在非糖尿病受试者中是可重复的，并且将反向变化，使得GIP或GLP-1将是任何给定个体中的主要肠促胰岛素。2)确定GLP-1在非糖尿病受试者中β细胞和非β细胞作用的相对敏感性。我们假设对GLP-1对β细胞功能的影响相对敏感的个体也会对GLP-1对其他组织的影响敏感。3)确定高血糖对肠促胰岛素调节2型糖尿病患者胰岛激素分泌作用的相对影响。我们假设，在血糖控制不良的糖尿病受试者中，胰高血糖素释放的抑制将是GLP-1的主要作用，但随着血糖控制的改善，GLP-1的促胰岛素作用将增加。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肠促胰岛素和GLP-1r激动剂。在本项目结束时，我们将更清楚地了解肠促胰岛素如何调节β细胞功能，以及GIP和GLP-1相互作用的性质，以控制这一过程。此外，本文提出的实验结果将提供用于调节多种GLP-1应答的模型。我们将把健康受试者研究的结果与血糖校正前后T2DM受试者的平行测量结果联系起来。该项目的一个关键方面是关注肠促胰岛素系统工作中的个体间差异。这种方法是关键的第一步，以确定是否有生理性 预测肠促胰岛素治疗的应答者和非应答者的存在的基础;这些知识对于推进个性化医学和治疗学的概念是必要的。总的来说，该项目的成果将提供重要的新信息，促进糖尿病患者的治疗。

DESCRIPTION (provided by applicant): The incretin effect describes the augmentation of insulin secretion by gut factors when nutrients are ingested, and is primarily mediated by glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). 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). In recent studies we have determined that the incretin effect is stable and reproducible in humans, that there are important extra-incretin effects of endogenous GLP-1, and that correction of hyperglycemia in diabetic subjects specifically restores the incretin effect. There are now available two classes of drugs to treat diabetes based on signaling through the GLP-1 receptor. However, there are still important unanswered questions about the function of the incretin system that are essential to know if these new therapeutic directions are to be optimized. This proposal will take up these issues by addressing the following specific aims: 1) Determine the interaction of GLP-1 and GIP to regulate insulin secretion in nondiabetic subjects. We hypothesize that sensitivity to the incretin will be reproducible within nondiabetic subjects and will vary inversely such that either GIP or GLP-1 will be the dominant incretin in any given individual. 2) Determine the relative sensitivitie of β-cell and nonβ-cell actions of GLP-1 in nondiabetic subjects. We hypothesize that individuals who are relatively sensitive to the effects of GLP-1 on β-cell function will also be sensitive to the effects of GLP-1 on other tissues as well. 3) Determine the relative effects of hyperglycemia on the actions of the incretins to regulate islet hormone secretion in persons with T2DM. We hypothesize that in diabetic subjects with poor glycemic control, suppression of glucagon release will be the predominant action of GLP-1, but with improved glucose control insulinotropic effects of GLP-1 will increase. 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 incretins and a GLP-1r agonist in human research. At the conclusion of this project we will have a much clearer picture of how the incretins regulate β-cell function, and the nature of the interactions of GIP and GLP-1 to control this process. In addition, the results of the experiments proposed herein will provide a model for the regulation of the multiple GLP-1 responses. We will connect the findings from studies of healthy subjects with parallel measures in T2DM subjects before and after glycemic correction. A critical aspect of this project is a focus on inter-individual variation in the workings of the incretin system. This approach is a critical first step to establish whether there is a physiologic basis on which to predict the existence of responders and non-responders to incretin therapies; such knowledge is imperative to advance the concept of personalized medicine and therapeutics. Overall, the outcomes of this project will provide important new information that will advance the treatment of persons with diabetes.