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Novel metabolic actions of GIP

GIP 的新代谢作用

基本信息

批准号：
10207625
负责人：
Jonathan E Campbell
金额：
$ 48.45万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10207625
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

项目摘要

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