Role of GLP-1 in Normal and Abnormal Glucose Tolerance

描述（由申请人提供）：2型糖尿病在美国构成了巨大的健康负担，尽管这种疾病的患病率越来越高，但在了解其根本原因方面仍存在重大差距。本提案的总体目标是确定GI激素胰高血糖素样肽1（GLP-1）在非糖尿病患者和2型糖尿病患者中调节葡萄糖耐量的作用。在健康人体中，GLP-1刺激胰岛素分泌，并与膳食吸收期间肠道产生的其他信号一起，占胰岛素分泌的30-60%。在动物和人类中的研究表明，阻断GLP-1的作用会导致葡萄糖耐受不良。在患有2型糖尿病和其他形式的异常葡萄糖耐量的人中，通过来自肠道的刺激（例如GLP-1）增加胰岛素分泌受到严重损害。GLP-1和GLP-1激动剂治疗试验的结果支持目前青睐的GLP-1作为激素发挥作用的模型。然而，我们小组和其他人最近的研究结果表明，GLP-1可能主要通过神经通路发出信号，可能起源于内脏床。基于这些数据，我们提出内源性GLP-1刺激胰岛素分泌的作用是通过起源于门静脉直接分布的神经反射。本项目的具体目的是确定：1）内源性GLP-1刺激人体胰岛素分泌是否由副交感神经信号介导，以及该机制在2型糖尿病患者中是否异常; 2）内源性GLP-1促进胰岛素分泌的神经激活机制和途径;（3）肝门静脉去神经对糖耐量的影响及对GLP-1的反应。确定肠道GLP-1作用的神经系统的作用对于理解餐后胰岛素分泌如何调节以及为什么肠促胰岛素轴在糖尿病患者中受损非常重要。这些研究的结果将增加对GLP-1和肠促胰岛素轴调节葡萄糖代谢的理解，并有助于开发治疗2型糖尿病的新策略。

DESCRIPTION (provided by applicant): Type 2 diabetes constitutes an enormous health burden in the United States, and despite the increasing prevalence of this disease there are still major gaps in understanding the underlying causes. The overall goal of this proposal is to determine the role of the GI hormone glucagon-like peptide 1 (GLP-1) to regulate glucose tolerance in non-diabetic persons and patients with type 2 diabetes. In healthy humans GLP-1 stimulates insulin secretion, and together with other signals arising from the gut during meal absorption, accounts for 30-60% of the insulin secreted. Studies in animals and humans indicate that blocking the action of GLP-1 causes glucose intolerance. In persons with type 2 diabetes, and other forms of abnormal glucose tolerance, the augmentation of insulin secretion by stimuli from the gut, such as GLP-1, is severely impaired. The findings from therapeutic trials of GLP-1 and GLP-1-agonists support the currently favored model that GLP-1 acts as a hormone. However, recent findings by our group and others have shown that GLP-1 may signal primarily through neural pathways, likely originating in the splanchnic bed. Based on this data we propose that the action of endogenous GLP-1 to stimulate insulin secretion is through a neural reflex originating in the immediate distribution of the portal vein. The specific aims of this project will determine: 1) whether the stimulation of insulin secretion by endogenous GLP-1 in humans is mediated by parasympathetic signaling, and whether this mechanism is abnormal in persons with type 2 diabetes; 2) the mechanisms and pathways of neural activation by which endogenous GLP-1 promotes insulin secretion; 3) the effect of hepatic-portal denervation on glucose tolerance and the response to GLP-1. Establishing the role of a neural system by which intestinal GLP-1 acts is important for understanding how post prandial insulin secretion is regulated and why the incretin axis is impaired in diabetic patients. The results of these studies will add to the understanding of the regulation of glucose metabolism by GLP-1 and the incretin axis, and contribute to the development of new strategies to treat type 2 diabetes.