Novel metabolic actions of GIP

GIP 的新代谢作用

基本信息

批准号：
10624312
负责人：
Jonathan E Campbell
金额：
$ 44.18万
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/10624312
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 Compensation 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 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 glucagon-like peptide 1 glucose production glucose tolerance human data impaired glucose tolerance in vivo insight insulin secretion islet novel nutrient metabolism pharmacologic preclinical study prevent primary endpoint proglucagon receptor response synergism

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。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The role of GIP in α-cells and glucagon secretion.

DOI：
10.1016/j.peptides.2019.170213
发表时间：
2020-03
期刊：
Peptides
影响因子：
3
作者：
El K;Campbell JE
通讯作者：
Campbell JE

Targeting the GIPR for obesity: To agonize or antagonize? Potential mechanisms.

DOI：
10.1016/j.molmet.2020.101139
发表时间：
2021-04
期刊：
Molecular metabolism
影响因子：
8.1
作者：
Campbell JE
通讯作者：
Campbell JE

GIPR Is Predominantly Localized to Nonadipocyte Cell Types Within White Adipose Tissue.

DOI：
10.2337/db21-1166
发表时间：
2022-05-01
期刊：
Diabetes
影响因子：
7.7
作者：
Campbell JE;Beaudry JL;Svendsen B;Baggio LL;Gordon AN;Ussher JR;Wong CK;Gribble FM;D'Alessio DA;Reimann F;Drucker DJ
通讯作者：
Drucker DJ

Repositioning the Alpha Cell in Postprandial Metabolism.

DOI：
10.1210/endocr/bqaa169
发表时间：
2020-11-01
期刊：
Endocrinology
影响因子：
4.8
作者：
El K;Capozzi ME;Campbell JE
通讯作者：
Campbell JE

GIP mediates the incretin effect and glucose tolerance by dual actions on α cells and β cells.

DOI：
10.1126/sciadv.abf1948
发表时间：
2021-03
期刊：
Science advances
影响因子：
13.6
作者：
El K;Gray SM;Capozzi ME;Knuth ER;Jin E;Svendsen B;Clifford A;Brown JL;Encisco SE;Chazotte BM;Sloop KW;Nunez DJ;Merrins MJ;D'Alessio DA;Campbell JE
通讯作者：
Campbell JE