Novel metabolic actions of GIP

GIP 的新代谢作用

• 批准号: 10413163
• 负责人: Jonathan E Campbell
• 金额: $ 43.5万
• 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/10413163
• 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; Persons; 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; antagonist; 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.

工作总结 肠促胰岛素、葡萄糖依赖性促胰岛素多肽 (GIP) 和胰高血糖素样肽 1 (GLP-1) 是 肠促胰岛素系统占调节餐后代谢的肠道来源激素。 健康个体餐后胰岛素分泌量的 70%，2 型患者则减少至约 30% 了解调节肠促胰素控制胰岛素分泌的机制以及其作用机制。 代谢应激导致功能失调，这是理解 T2D 病理生理学的核心。 最近发现，α 细胞的胰高血糖素原产物对于正常 β 细胞功能至关重要 - 具体来说，我们发现β细胞内的音调是决定性的。 由胰高血糖素原肽输入产生的 cAMP 水平损害α-β细胞通讯。 大大减少胰岛素分泌并导致代谢应激背景下的葡萄糖耐受不良。 受体 (GIPR) 和 GLP-1 受体 (GLP-1R) 在 β 细胞上表达并增强葡萄糖刺激 另一方面，α 细胞只表达 GIPR，而不表达 GLP-1R。 刺激胰高血糖素分泌，而 GLP-1R 则减少胰高血糖素分泌。该项目的目标是了解其重要性。 α 细胞中 GIPR 活性的研究及其对健康和患病代谢调节的潜在贡献 我们最近发现，α 细胞产生的胰高血糖素对于营养刺激的胰岛素是必需的。 分泌，支持α细胞中的GIPR活性增强α-β细胞通讯的假设。 这一假设的推论是，α 细胞中的 GIPR 活性对肠促胰素的作用有有意义的贡献。 此外，通过限制 α 中 GIPR 活性的干预措施来改善餐后情况。 细胞预计会减少胰岛素分泌并损害葡萄糖耐量。 有可能将我们的肠促胰素效应概念扩展到β细胞活性之外，将α细胞纳入其中 此外，阐明 α 细胞中的 GIPR 活性可以提供对新功能的深入了解。 结合 GIPR 活性的抗糖尿病药物的产生，可能解释了 这些化合物所达到的功效超出了 GLP-1R 单激动作用。