Novel metabolic actions of GIP

GIP 的新代谢作用

• 批准号: 10029069
• 负责人: Jonathan E Campbell
• 金额: $ 39.28万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10029069
• 关键词: Agonist; Alanine; Alpha Cell; Amino Acids; Anabolism; Antidiabetic Drugs; Area; Automobile Driving; B-Lymphocytes; Beta Cell; Binding; Cell Communication; Cell physiology; Cell secretion; Cells; Communication; Coupled; Cyclic AMP; Data; Diet; Disease; Eating; Equilibrium; Fatty Acids; Fatty acid glycerol esters; Functional disorder; GLP-I receptor; Gases; Gastric Inhibitory Polypeptide; Generations; Glucagon; Glucose; Glucose Intolerance; Goals; Homeostasis; Hormones; Human; Hyperglycemia; Hypoglycemia; Impairment; Individual; Insulin; Intervention; Intestines; Knock-out; Knockout Mice; Link; Macronutrients Nutrition; Measures; Mediating; Medicine; Metabolic; Metabolic stress; Metabolism; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Patients; Peptides; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Physiology; Plasma; Play; Positioning Attribute; Postabsorptive Hypoglycemia; Production; Receptor Signaling; Regulation; Rodent; Role; Signal Transduction; Specificity; Stimulus; System; Testing; Thinking; Time; Work; analog; blood glucose regulation; diabetic; feeding; gastric inhibitory polypeptide receptor; glucagon-like peptide 1; glucose production; glucose tolerance; human data; impaired glucose tolerance; in vivo; insight; insulin secretion; islet; novel; nutrient metabolism; preclinical study; prevent; primary endpoint; proglucagon; receptor; response

Summary of Work Incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), are intestinally derived hormones that regulate postprandial metabolism. The incretin system accounts for up to 70% of postprandial insulin secretion in healthy individuals and diminishes to ~30% in people with type 2 diabetes (T2D). Understanding the mechanisms that regulate incretin control of insulin secretion, and how this becomes dysfunctional with metabolic stress, is central to understanding the pathophysiology of T2D. We have recently discovered that proglucagon products from alpha-cells are essential for normal beta-cell function – a phenomenon termed alpha-to-beta cell communication. Specifically, we found that intra--cell tone is dictated by the level of cAMP generated by input from proglucagon peptides. Impairing alpha-to-beta cell communication greatly diminishes insulin secretion and results in glucose intolerance in the context of metabolic stress. The GIP receptor (GIPR) and GLP-1 receptor (GLP-1R) are expressed on beta-cells and potentiate glucose-stimulated insulin secretion. On the other hand, alpha cells only express the GIPR and not the GLP-1R. Indeed, GIP stimulates glucagon secretion, while GLP-1R decreases it. The goal of this project is to understand the importance of GIPR activity in alpha cells and the potential contribution to metabolic regulation in both healthy and diseased states. Our recent discovery that glucagon production from alpha cells is necessary for nutrient stimulated insulin secretion, support the hypothesis that GIPR activity in alpha cells enhances alpha-to-beta cell communication. A corollary to this hypothesis is that GIPR activity in alpha cells contribute meaningfully to the incretin effect in a postprandial situation by enhancing insulin secretion. Moreover, interventions that limit GIPR activity in alpha cells would be expected to decrease insulin secretion and impair glucose tolerance. Testing this hypothesis has the potential to extend our concept of the incretin effect beyond beta cell activity to incorporate the alpha cell as a vital component. Furthermore, clarification of GIPR activity in alpha cells can provide insight into the new generation of anti-diabetic medications that incorporate GIPR activity, potentially explaining the increased efficacy achieved by these compounds above and beyond GLP-1R monoagonism.

工作概要 肠降血糖素，葡萄糖依赖性促胰岛素多肽（GIP）和胰高血糖素样肽1（GLP-1）， 调节餐后代谢的母体激素。肠促胰岛素系统占 健康个体餐后胰岛素分泌的70%，2型糖尿病患者减少至约30% 糖尿病（T2 D）。了解调节肠促胰岛素控制胰岛素分泌的机制，以及这是如何发生的。 在代谢应激下变得功能障碍，是理解T2 D病理生理学的核心。我们有 最近发现，来自α细胞的胰高血糖素原产物对于正常β细胞功能是必需的， 这种现象被称为α-细胞与β-细胞的通讯。具体来说，我们发现脑细胞内的音调 由胰高血糖素原肽输入产生的cAMP水平。破坏α-细胞与β-细胞之间的交流 大大减少胰岛素分泌并导致代谢应激情况下的葡萄糖耐受不良。所述GIP 受体（GIPR）和GLP-1受体（GLP-1 R）在β细胞上表达，并增强葡萄糖刺激的 胰岛素分泌另一方面，α细胞仅表达GIPR而不表达GLP-1 R。事实上，GIP 刺激胰高血糖素分泌，而GLP-1 R则降低胰高血糖素分泌。本项目的目标是了解 α细胞中的GIPR活性以及对健康和患病的代谢调节的潜在贡献 states.我们最近发现α细胞产生胰高血糖素是营养刺激胰岛素所必需的 分泌，支持α细胞中的GIPR活性增强α至β细胞通讯的假设。 这一假设的一个推论是，α细胞中的GIPR活性对肠促胰岛素的作用有意义， 通过增强胰岛素分泌来改善餐后情况。此外，限制GIPR α活性的干预措施 预期细胞会减少胰岛素分泌并损害葡萄糖耐量。测试这个假设 将肠促胰岛素效应的概念扩展到β细胞活性之外以将α细胞作为 一个重要的组成部分。此外，澄清α细胞中的GIPR活性可以提供对新的 产生包含GIPR活性的抗糖尿病药物，可能解释了增加的 这些化合物所实现的功效超过GLP-1 R单激动作用。