DEFINITION OF THE PHYSIOLOGICAL PROPERTIES OF GIP

胃抑制肽(GIP)是由人分泌的一种由42个氨基酸组成的激素。 K细胞，一种特殊的肠道内分泌细胞，因其 抑制酸分泌的能力。虽然有几项研究支持 GIP作为胃酸分泌抑制剂的作用，其他人有 挑战了这一概念，目前精确的生理学 GIP与胃功能的关系尚未得到解决。在……里面 除了据称对胃有抑制作用外，GIP 刺激胰岛细胞释放胰岛素，而且它有 已经提出，多肽在维持身体健康方面起着生理作用 葡萄糖动态平衡。因此，荷尔蒙现在通常被称为 被称为“葡萄糖依赖的促胰岛素肽”，保存了原来的 首字母缩写。然而，它对维护 糖代谢及GIP与类胰高血糖素的精确关系 多肽-1(7-36)(GLP-1)和其他胰腺生理刺激物 胰岛素的释放尚不清楚。大部分关于确切的 GIP的生理作用源于未能区分 来自生理的多肽的药理作用。此外, 相关多肽之间的显著结构同源性，如GIP和 GLP-1，经常造成围绕GLP-1归属的歧义 一种或两种多肽的生理特性。这种不确定性已经 在研究新的候选肽时是一个传统的问题 激素和特异性竞争性受体的可用性 事实证明，几种多肽的拮抗剂在促进 他们的调查。这个实验室最近合成了一种 表征了一种将在研究中使用的特定GIP拮抗剂 在这项提案中概述了确定人的确切生理作用 这是一种重要的调节肽。具体地说，这样做的目的是 项目包括： 1)确定GIP在生理调节中的作用 营养刺激胃酸分泌； 2)表征GIP释放在响应中的相对贡献 到含有葡萄糖和脂肪的膳食，刺激胰岛胰岛素 在生理和病理条件下释放。在.期间 在这些研究过程中，GIP与GLP-1的确切关系， 将确定另一名候选人；以及 3)确定生理反馈涉及的机制 抑制GIP，包括GIP可能自我调节 它自身的表达，以及反馈抑制是否也 依赖于循环中的葡萄糖或胰岛素。 拟议的研究应提供一个重要的基础 有助于确定政府间和平协议的确切作用的信息 作为酸分泌和葡萄糖代谢的调节剂 生理和病理条件。此外，由于 GIP与其他胃肠肽的结构和功能关系密切， 这些研究将促进我们对疾病的总体理解 以胃功能和血糖异常为特征的 动态平衡。

Gastric inhibitory peptide (GIP) is a 42-amino acid hormone secreted by the K-cell, a specific intestinal endocrine cell, and was named for its ability to inhibit acid secretion. While several studies have supported the role of GIP as an inhibitor of gastric acid secretion, others have challenged this notion, and currently the precise physiological relationship between GIP and gastric function has not been resolved. In addition to its purported inhibitory effects in the stomach, GIP stimulates insulin release from pancreatic beta-islet cells, and it has been proposed that the peptide plays a physiological role in maintaining glucose homeostasis. Accordingly, the hormone is now often referred to as "glucose-dependent insulinotropic peptide," conserving the original acronym. However, its specific contribution to the maintenance of glucose metabolism and the precise relationship of GIP to glucagonlike peptide-1(7-36) (GLP-1) and other physiological stimulants of pancreatic insulin release is unknown. Much of the uncertainty regarding the exact physiological role of GIP stems from a failure to distinguish physiological from pharmacological effects of the peptide. In addition, significant structural homology among related peptides, such as GIP and GLP-1, often contributes to the ambiguity surrounding the attribution of physiological properties to one or both peptides. Such uncertainty has been a traditional problem when investigating new candidate peptide hormones, and the availability of specific competitive receptor antagonists to several peptides has proven invaluable in facilitating their investigation. This laboratory has recently synthesized and characterized a specific GIP antagonist which will be used in the studies outlined in this proposal to determine the precise physiological role of this important regulatory peptide. Specifically, the aims of this project are: 1) To determine the role of GIP in the physiological regulation of nutrient-stimulated gastric acid secretion; 2) To characterize the relative contribution of GIP release in response to glucose- and lipid-containing meals, in stimulating pancreatic insulin release under physiological and pathological conditions. During the course of these studies, the precise relationship of GIP to GLP-1, another candidate incretin, will be determined; and 3) To determine the mechanisms involved in physiological feedback inhibition of GIP, including the possibility that GIP may autoregulate its own expression, and whether feedback inhibition might also be dependent on circulating glucose or insulin. The proposed studies should provide an important foundation of information to facilitate the determination of the precise role of GIP as a modulator of acid secretion and of glucose metabolism under both physiological and pathological conditions. Moreover, because of the close structural and functional relationship of GIP to other GI peptides, these studies will advance our general understanding of disorders characterized by abnormalities in gastric function and glucose homeostasis.