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.

工作摘要 肠脉毒素，葡萄糖依赖性胰岛素多肽（GIP）和胰高血糖素样肽1（GLP-1）是 衍生的骑马，可调节餐后代谢。增加系统最多 在健康个体中，餐后胰岛素分泌的70％，2型患者降至约30％ 糖尿病（T2D）。了解调节肠降血糖素控制胰岛素分泌的机制，以及如何 随着代谢胁迫的功能失调，是理解T2D的病理生理学的核心。我们有 最近发现，来自α细胞的Proglucagon产品对于正常β细胞功能至关重要 - A 现象称为α到β细胞通信。具体而言，我们发现指出了内部的音调 由Proglucagon Petides的输入产生的营地水平。障碍α到β细胞通信 在代谢胁迫的背景下，大大减少了胰岛素分泌，并导致葡萄糖耐药。 GIP 受体（GIPR）和GLP-1受体（GLP-1R）在β细胞上表达，潜在的葡萄糖刺激 胰岛素分泌。另一方面，α细胞仅表达GIPR，而不表达GLP-1R。确实，GIP 刺激胰高血糖素的分泌，而GLP-1R降低了它。该项目的目的是了解重要性 Alpha细胞中GIPR活性以及健康和疾病的代谢调节的潜在贡献 国家。我们最近发现的，α细胞产生的谷歌对于营养刺激的胰岛素是必需的 分泌，支持α细胞中GIPR活性增强α-β细胞通信的假设。 这一假设的推论是，α细胞中的GIPR活性有意义地有助于增加 通过增强胰岛素分泌的餐后情况。此外，限制alpha中GIPR活性的干预措施 预计细胞会降低胰岛素的分泌并损害葡萄糖耐受性。检验该假设具有 扩展我们的增加效果概念以外的潜力，以将α细胞纳入为 重要组成部分。此外，澄清α细胞中GIPR活性可以提供对新的洞察力 产生纳入GIPR活性的抗糖尿病药物，有可能解释 这些化合物超过GLP-1R单极管的功效。