Incretin action in physiology and diabetes

描述(申请人提供)：内分泌素效应描述了当营养物质被摄入时，肠道因素增加胰岛素的分泌，主要由葡萄糖依赖的促胰岛素多肽(GIP)和胰高血糖素样肽1(GLP-1)介导。胰岛素系统是维持正常血糖稳态所必需的，最近的证据表明，在2型糖尿病(T2 DM)中存在该系统的特殊功能障碍。在最近的研究中，我们已经确定在人类中胰岛素效应是稳定的和可重复性的，内源性GLP-1有重要的额外胰岛素效应，纠正糖尿病受试者的高血糖特异性地恢复了胰岛素效应。现在有两类药物可供选择 根据GLP-1受体的信号传递治疗糖尿病。然而，关于胰岛素系统的功能仍然有一些重要的悬而未决的问题，这些问题对于了解这些新的治疗方向是否需要优化是必不可少的。这项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在调节非糖尿病受试者胰岛素分泌方面的相互作用。我们假设，对胰岛素的敏感性在非糖尿病受试者中是可重复的，并且将相反地变化，使得GIP或GLP-1将是任何给定个体的主要胰岛素。2)测定非糖尿病受试者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将对GLP-1对其他组织的影响敏感。3)确定高血糖对胰岛素调节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患者中，GLP-1的主要作用是抑制胰高血糖素的释放，但随着血糖控制的改善，GLP-1的胰岛素调节作用将增强。本文提出的研究将使用我们近年来开发或改进的人类研究方法，并利用FDA向我们小组发布的INDS在人类研究中使用合成的生长素和GLP-1R激动剂。在本项目结束时，我们将对胰岛素如何调节β细胞的功能，以及GIP和GLP-1相互作用控制这一过程的性质有一个更清晰的了解。此外，本文提出的实验结果将为调节多种GLP-1反应提供一个模型。我们将把健康受试者的研究结果与T2 DM受试者血糖纠正前后的平行测量联系起来。这个项目的一个关键方面是关注胰岛素系统的工作机制中的个体间差异。这一方法是确定是否存在生理学上的 在此基础上预测对胰岛素治疗有反应者和无应答者的存在；这种知识对于推进个性化药物和治疗的概念是必不可少的。总体而言，该项目的成果将提供重要的新信息，推动糖尿病患者的治疗。

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.