The role of GLP-1 in normal and abnormal glucose tolerance

描述（由申请人提供）：2型糖尿病（T2DM）在美国构成了巨大的健康负担，尽管患病率不断上升，但在了解该疾病的发病机制方面仍存在重大差距。本提案的总体目标是确定调节肽胰高血糖素样肽1 （GLP-1）在非糖尿病人和T2DM患者中调节葡萄糖耐量的作用。GLP-1调节胰岛激素分泌，对正常的葡萄糖耐量至关重要。重要的是，GLP-1能有效降低T2DM患者的血糖，两种新型的抗糖尿病药物都是基于GLP-1信号。尽管GLP-1的临床应用前景光明，但其作用机制仍存在主要问题。更好地了解内源性GLP-1系统对于其最佳利用治疗糖尿病至关重要。人们普遍认为，GLP-1通过内分泌机制起作用，肠道是循环中这种肽的唯一来源。然而，越来越多的证据质疑循环肽作为GLP-1作用的主要介质的重要性。此外，由于GLP-1受体通过参与代谢的神经元在脑和周围神经系统的离散区域表达，因此GLP-1的神经介导可能是内分泌作用机制的另一种可行选择。我们最近的实验数据表明中枢和外周神经信号参与GLP-1介导的葡萄糖耐量。在这个应用中，我们建议确定神经机制在调解GLP-1效应中的重要性。该项目的具体目标将确定：1)2细胞和神经GLP-1受体对葡萄糖耐量的相对贡献；2)脑内产生的GLP-1是否调节胰岛素分泌和餐后血糖的控制；3)循环GLP-1介导健康人及糖尿病人血糖调节的作用。研究神经GLP-1信号在胰岛素分泌和全身葡萄糖稳态中的作用将促进对代谢调节的认识，并有可能扩大GLP-1系统在治疗糖尿病中的临床作用。公共卫生相关性：GLP-1是一种胃肠道激素，具有广泛的促进葡萄糖处理的作用。一些新的药物已经被开发出来，通过GLP-1系统来改善糖尿病患者的血糖控制。该项目的目标是了解GLP-1作用的不同机制，从而使该系统能够更精确地应用于糖尿病的治疗。

DESCRIPTION (provided by applicant): Type 2 diabetes (T2DM) constitutes an enormous health burden in the United States, and despite increasing prevalence there are still major gaps in understanding the pathogenesis of this disease. The overall goal of this proposal is to determine the role of the regulatory peptide glucagon-like peptide 1 (GLP-1) to regulate glucose tolerance in nondiabetic persons and patients with T2DM. GLP-1 regulates islet hormone secretion and is essential for normal glucose tolerance. Importantly, GLP-1 is effective at lowering blood glucose in persons with T2DM, and two new classes of antidiabetes drugs are based on GLP-1 signaling. Despite the promise surrounding the clinical application of GLP-1 major questions remain about its mechanism of action. A better understanding of the endogenous GLP-1 system is critical for its optimal utilization to treat diabetes. It has generally been accepted that GLP-1 acts by an endocrine mechanism and that the intestine is the sole source of this peptide in the circulation. However, there is emerging evidence to question the importance of circulating peptide as the primary mediator of GLP-1 actions. Moreover, since the GLP-1 receptor is expressed in discrete regions of the brain and peripheral nervous system by neurons involved in metabolism, neural mediation of GLP-1 is a plausible alternative to an endocrine mechanism of action. We have data from recent experiments that implicate central and peripheral nervous signaling as contributing to GLP-1 mediated glucose tolerance. In this application we propose to determine the importance of neural mechanisms in mediation GLP-1 effects. The specific aims of this project will determine: 1) the relative contributions of 2-cell and neural GLP-1 receptors to glucose tolerance; 2) whether GLP-1 produced in the brain regulates insulin secretion and the control of glucose after meals; 3) the role of circulating GLP-1 to mediate the gluco-regulatory effects of GLP-1 in healthy and diabetic humans. Investigating the role of neural GLP-1 signaling on insulin secretion and whole body glucose homeostasis will advance knowledge of metabolic regulation with the potential to expand the clinical role of the GLP-1 system for treating diabetes. PUBLIC HEALTH RELEVANCE: GLP-1 is a GI hormone that has a broad range of effects to promote glucose disposal. Several new drugs have been developed that improve blood glucose control in diabetic patients by acting through the GLP-1 system. The goal of this project is to understand the different mechanisms by which GLP-1 acts to allow new and more refined applications of this system to the treatment of diabetes.