Incretin action in physiology and diabetes

肠促胰素在生理学和糖尿病中的作用

• 批准号: 8925072
• 负责人: DAVID A. D'ALESSIO
• 金额: $ 35.38万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-10 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8925072
• 关键词: Address; Affect; Agonist; Area; Beta Cell; Blood Glucose; Caring; Cell physiology; Cells; Chronic; Development; Diabetes Mellitus; Disease; Dose; Eating; Effectiveness; Evolution; Functional disorder; Gastric Emptying; Gastrointestinal tract structure; Glucagon; Glucose; Health; Hormones; Human; Hyperglycemia; Individual; Infusion procedures; Insulin; Intestinal Mucosa; Intestines; Investigation; Knowledge; Measures; Mediating; Mediator of activation protein; Medical; Methods; Modeling; Nature; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Outcome; Patients; Peptides; Persons; Pharmaceutical Preparations; Pharmacology; Physiological; Physiology; Process; Regulation; Relative (related person); Research; Role; Signal Transduction; System; Testing; Therapeutic; Therapeutic Intervention; Tissues; Variant; Work; absorption; base; blood glucose regulation; design; diabetic; gastric inhibitory polypeptide receptor; glucagon-like peptide; glucose tolerance; glycemic control; impaired glucose tolerance; improved; insulin secretion; islet; non-diabetic; novel; novel therapeutics; personalized medicine; personalized therapeutic; proctolin; receptor; research study; response; restoration; trait

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.

描述（由适用提供）：增加效应描述了摄入养分时肠道因子的胰岛素分泌的增强，并且主要是由葡萄糖依赖性胰岛素多肽（GIP）和胰葡萄糖样肽1（GLP-1）介导的。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。在最近的研究中，我们确定在人类中的增加效果是稳定且可重复的，内源性GLP-1的重要外素外影响，并且在糖尿病受试者中对高血糖的纠正措施专门恢复了增加的效果。现在有两类药物可 治疗糖尿病是基于通过GLP-1受体的信号传导。但是，仍然存在有关增长系统功能的重要问题，这对于知道这些新的治疗方向是否要优化至关重要。该提案将通过解决以下特定目的来解决这些问题：1）确定GLP-1和GIP的相互作用以调节非糖尿病受试者中的胰岛素分泌。我们假设对增加的敏感性将为3）确定GLP-1对非糖尿病受试者的β细胞和非β细胞作用的相对灵敏度。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）确定高血糖对增加T2DM患者的胰岛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，胰血糖素释放的抑制作用将是GLP-1的主要作用，但是随着葡萄糖控制的改善，GLP-1的胰岛素胰岛素效应将增加。本文提出的研究将使用近年来我们开发或完善的人类投资方法，并利用FDA向我们的小组发出的IND来使用合成的增加素和在人类研究中使用GLP-1R激动剂。在该项目的结论中，我们将对增加蛋白如何调节β细胞功能以及GIP和GLP-1的相互作用的性质有更清晰的了解。此外，本文提出的实验结果将为调节多个GLP-1响应提供模型。我们将在血糖校正前后的T2DM受试者中与对健康受试者的研究的发现联系。该项目的一个关键方面是专注于增加系统工作的个人间变化。这种方法是确定是否存在生理的关键第一步 预测响应者和非反应者增加疗法的基础；这种知识必须提高个性化医学和治疗的概念。总体而言，该项目的结果将提供重要的新信息，以推动对糖尿病患者的治疗。