• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

靶向 GLP-1 受体转运以提高激动剂疗效。

Targeting GLP-1 receptor trafficking to improve agonist efficacy.

机构信息

Section of Investigative Medicine, Imperial College London, London, W12 0NN, UK.

Section of Cell Biology and Functional Genomics, Imperial College London, London, W12 0NN, UK.

出版信息

Nat Commun. 2018 Apr 23;9(1):1602. doi: 10.1038/s41467-018-03941-2.

DOI:10.1038/s41467-018-03941-2
PMID:29686402
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5913239/
Abstract

Glucagon-like peptide-1 receptor (GLP-1R) activation promotes insulin secretion from pancreatic beta cells, causes weight loss, and is an important pharmacological target in type 2 diabetes (T2D). Like other G protein-coupled receptors, the GLP-1R undergoes agonist-mediated endocytosis, but the functional and therapeutic consequences of modulating GLP-1R endocytic trafficking have not been clearly defined. Here, we investigate a series of biased GLP-1R agonists with variable propensities for GLP-1R internalization and recycling. Compared to a panel of FDA-approved GLP-1 mimetics, compounds that retain GLP-1R at the plasma membrane produce greater long-term insulin release, which is dependent on a reduction in β-arrestin recruitment and faster agonist dissociation rates. Such molecules elicit glycemic benefits in mice without concomitant increases in signs of nausea, a common side effect of GLP-1 therapies. Our study identifies a set of agents with specific GLP-1R trafficking profiles and the potential for greater efficacy and tolerability as T2D treatments.

摘要

胰高血糖素样肽-1 受体 (GLP-1R) 的激活可促进胰岛β细胞分泌胰岛素，减轻体重，是 2 型糖尿病 (T2D) 的重要药物靶点。与其他 G 蛋白偶联受体一样，GLP-1R 会发生激动剂介导的内吞作用，但调节 GLP-1R 内吞作用的功能和治疗后果尚未明确界定。在这里，我们研究了一系列具有不同 GLP-1R 内化和回收倾向的偏向性 GLP-1R 激动剂。与一系列 FDA 批准的 GLP-1 类似物相比，保留在质膜上的 GLP-1R 的化合物会产生更大的长期胰岛素释放，这依赖于β-arrestin 募集的减少和更快的激动剂解离速率。此类分子可在不增加恶心迹象（GLP-1 治疗的常见副作用）的情况下，在小鼠中产生降血糖作用。我们的研究确定了一组具有特定 GLP-1R 转运特征的药物，它们具有作为 T2D 治疗方法的更大疗效和更好耐受性的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1199/5913239/d863545c3e30/41467_2018_3941_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1199/5913239/fdc08a9dd2b5/41467_2018_3941_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1199/5913239/1df60bf82b6f/41467_2018_3941_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1199/5913239/926678d29df7/41467_2018_3941_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1199/5913239/ea1422d3aea1/41467_2018_3941_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1199/5913239/44ab0d3ca004/41467_2018_3941_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1199/5913239/507b3446c0b8/41467_2018_3941_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1199/5913239/3c5d9fcd7fc3/41467_2018_3941_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1199/5913239/8bb3978f8fa6/41467_2018_3941_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1199/5913239/d863545c3e30/41467_2018_3941_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1199/5913239/fdc08a9dd2b5/41467_2018_3941_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1199/5913239/1df60bf82b6f/41467_2018_3941_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1199/5913239/926678d29df7/41467_2018_3941_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1199/5913239/ea1422d3aea1/41467_2018_3941_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1199/5913239/44ab0d3ca004/41467_2018_3941_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1199/5913239/507b3446c0b8/41467_2018_3941_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1199/5913239/3c5d9fcd7fc3/41467_2018_3941_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1199/5913239/8bb3978f8fa6/41467_2018_3941_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1199/5913239/d863545c3e30/41467_2018_3941_Fig9_HTML.jpg

相似文献

1
Targeting GLP-1 receptor trafficking to improve agonist efficacy.靶向 GLP-1 受体转运以提高激动剂疗效。
Nat Commun. 2018 Apr 23;9(1):1602. doi: 10.1038/s41467-018-03941-2.
2
Agonist-induced membrane nanodomain clustering drives GLP-1 receptor responses in pancreatic beta cells.激动剂诱导的膜纳米域聚类驱动胰腺β细胞中的 GLP-1 受体反应。
PLoS Biol. 2019 Aug 20;17(8):e3000097. doi: 10.1371/journal.pbio.3000097. eCollection 2019 Aug.
3
Partial agonism improves the anti-hyperglycaemic efficacy of an oxyntomodulin-derived GLP-1R/GCGR co-agonist.部分激动作用提高了源自胰高血糖素样肽-1 受体/胰高血糖素受体的共激动剂 oxyntomodulin 的抗高血糖疗效。
Mol Metab. 2021 Sep;51:101242. doi: 10.1016/j.molmet.2021.101242. Epub 2021 Apr 30.
4
A Targeted RNAi Screen Identifies Endocytic Trafficking Factors That Control GLP-1 Receptor Signaling in Pancreatic β-Cells.靶向 RNAi 筛选鉴定控制胰腺 β 细胞中 GLP-1 受体信号的内吞运输因子。
Diabetes. 2018 Mar;67(3):385-399. doi: 10.2337/db17-0639. Epub 2017 Dec 28.
5
Incretin therapies: highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors.肠促胰岛素疗法：强调胰高血糖素样肽-1受体激动剂和二肽基肽酶-4抑制剂作用模式的共同特征与差异
Diabetes Obes Metab. 2016 Mar;18(3):203-16. doi: 10.1111/dom.12591. Epub 2016 Jan 5.
6
Immunohistochemical assessment of glucagon-like peptide 1 receptor (GLP-1R) expression in the pancreas of patients with type 2 diabetes.2型糖尿病患者胰腺中胰高血糖素样肽1受体（GLP-1R）表达的免疫组织化学评估
Diabetes Obes Metab. 2017 May;19(5):705-712. doi: 10.1111/dom.12879. Epub 2017 Mar 10.
7
GLP-1R mediates idebenone-reduced blood glucose in mice.GLP-1R 介导艾地苯醌降低小鼠血糖。
Biomed Pharmacother. 2024 Sep;178:117202. doi: 10.1016/j.biopha.2024.117202. Epub 2024 Jul 24.
8
Acylation of the Incretin Peptide Exendin-4 Directly Impacts Glucagon-Like Peptide-1 Receptor Signaling and Trafficking.肠降血糖素肽 Exendin-4 的酰化直接影响胰高血糖素样肽-1 受体信号转导和转运。
Mol Pharmacol. 2021 Oct;100(4):319-334. doi: 10.1124/molpharm.121.000270. Epub 2021 Jul 27.
9
Reduced incretin receptor trafficking upon activation enhances glycemic control and reverses obesity in diet-induced obese mice.激活时减少肠促胰岛素受体转运可增强血糖控制并逆转饮食诱导肥胖小鼠的肥胖。
Am J Physiol Cell Physiol. 2024 Jul 1;327(1):C74-C96. doi: 10.1152/ajpcell.00474.2023. Epub 2024 May 13.
10
The GIP receptor displays higher basal activity than the GLP-1 receptor but does not recruit GRK2 or arrestin3 effectively.GIP受体比GLP-1受体表现出更高的基础活性，但不能有效地募集GRK2或β-arrestin 3。
PLoS One. 2014 Sep 5;9(9):e106890. doi: 10.1371/journal.pone.0106890. eCollection 2014.

引用本文的文献

1
Efficacy and safety of incretin co-agonists: Transformative advances in cardiometabolic healthcare.肠促胰岛素共激动剂的疗效与安全性：心血管代谢医疗保健领域的变革性进展。
World J Cardiol. 2025 Aug 26;17(8):107991. doi: 10.4330/wjc.v17.i8.107991.
2
Receptor Activity-Modifying Protein 3 enhances GLP-1-mediated Insulin Secretion.受体活性修饰蛋白3增强胰高血糖素样肽-1介导的胰岛素分泌。
bioRxiv. 2025 Aug 13:2025.01.24.634724. doi: 10.1101/2025.01.24.634724.
3
Binding kinetics, bias, receptor internalization and effects on insulin secretion in vitro and in vivo of a novel GLP-1R/GIPR dual agonist, HISHS-2001.

本文引用的文献

1
Potent Prearranged Positive Allosteric Modulators of the Glucagon-like Peptide-1 Receptor.胰高血糖素样肽-1受体的强效预构正变构调节剂
ChemistryOpen. 2017 Jun 5;6(4):501-505. doi: 10.1002/open.201700062. eCollection 2017 Aug.
2
Genetic evidence that β-arrestins are dispensable for the initiation of β-adrenergic receptor signaling to ERK.β-抑制蛋白对于β-肾上腺素能受体向细胞外调节蛋白激酶（ERK）的信号传导起始并非必需的遗传证据。
Sci Signal. 2017 Jun 20;10(484):eaal3395. doi: 10.1126/scisignal.aal3395.
3
Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein.
新型GLP-1R/GIPR双重激动剂HISHS-2001的结合动力学、偏向性、受体内化及其对体外和体内胰岛素分泌的影响
Diabetes Obes Metab. 2025 Oct;27(10):5938-5949. doi: 10.1111/dom.16652. Epub 2025 Aug 20.
4
The dual GLP-1 and GIP receptor agonist tirzapetide provides an unintended interaction with the β-adrenoceptors and plays a role in glucose metabolism in hyperglycemic or senescent cardiac cells.双重GLP-1和GIP受体激动剂替尔泊肽与β-肾上腺素能受体产生意外相互作用，并在高血糖或衰老心肌细胞的葡萄糖代谢中发挥作用。
Cardiovasc Diabetol. 2025 Aug 18;24(1):338. doi: 10.1186/s12933-025-02828-z.
5
Exploring Conformational Transitions in Biased and Balanced Ligand Binding of GLP-1R.探索胰高血糖素样肽-1受体（GLP-1R）偏向性和平衡性配体结合中的构象转变。
Molecules. 2025 Jul 31;30(15):3216. doi: 10.3390/molecules30153216.
6
GLP-1R associates with VAPB and SPHKAP at ERMCSs to regulate β-cell mitochondrial remodelling and function.胰高血糖素样肽-1受体（GLP-1R）在内质网-线粒体接触位点（ERMCSs）与VAPB和SPHKAP结合，以调节β细胞线粒体重塑和功能。
bioRxiv. 2025 Jul 20:2024.04.28.591531. doi: 10.1101/2024.04.28.591531.
7
Estimation of Dopamine D Receptor Agonist Binding Kinetics Using Time-Resolved Functional Assays: Relation to Agonist-Induced Receptor Internalization by Investigational Antiparkinsonian Therapeutics.使用时间分辨功能测定法估算多巴胺 D 受体激动剂结合动力学：与研究性抗帕金森病治疗药物诱导的受体内化的关系。
ACS Chem Neurosci. 2025 Jul 2;16(13):2502-2512. doi: 10.1021/acschemneuro.5c00270. Epub 2025 Jun 19.
8
GIP Receptor Antagonists in the Pharmacotherapy of Obesity: Physiologic, Genetic, and Clinical Rationale.GIP受体拮抗剂在肥胖症药物治疗中的应用：生理学、遗传学及临床依据
Diabetes. 2025 Aug 1;74(8):1334-1338. doi: 10.2337/dbi24-0027.
9
The Premise of the Paradox: Examining the Evidence That Motivated GIPR Agonist and Antagonist Drug Development Programs.悖论的前提：审视推动GIPR激动剂和拮抗剂药物研发项目的证据。
J Clin Med. 2025 May 29;14(11):3812. doi: 10.3390/jcm14113812.
10
Differential Role of Phosphorylation in Glucagon Family Receptor Signaling Revealed by Mass Spectrometry.质谱法揭示磷酸化在胰高血糖素家族受体信号传导中的差异作用
J Proteome Res. 2025 Jul 4;24(7):3367-3378. doi: 10.1021/acs.jproteome.5c00079. Epub 2025 Jun 12.
与G蛋白复合物结合的活化胰高血糖素样肽-1受体的冷冻电镜结构
Nature. 2017 Jun 8;546(7657):248-253. doi: 10.1038/nature22394. Epub 2017 May 24.
4
Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators.人 GLP-1 受体跨膜结构域与别构调节剂复合物的结构。
Nature. 2017 Jun 8;546(7657):312-315. doi: 10.1038/nature22378. Epub 2017 May 17.
5
β-arrestin-2 is an essential regulator of pancreatic β-cell function under physiological and pathophysiological conditions.β-arrestin-2 是生理和病理条件下胰腺 β 细胞功能的重要调节剂。
Nat Commun. 2017 Feb 1;8:14295. doi: 10.1038/ncomms14295.
6
Occurrence of nausea, vomiting and diarrhoea reported as adverse events in clinical trials studying glucagon-like peptide-1 receptor agonists: A systematic analysis of published clinical trials.在研究胰高血糖素样肽-1受体激动剂的临床试验中报告为不良事件的恶心、呕吐和腹泻的发生情况：已发表临床试验的系统分析
Diabetes Obes Metab. 2017 Mar;19(3):336-347. doi: 10.1111/dom.12824. Epub 2016 Dec 19.
7
A Pluridimensional View of Biased Agonism.偏向性激动作用的多维度视角
Mol Pharmacol. 2016 Nov;90(5):587-595. doi: 10.1124/mol.116.105940. Epub 2016 Sep 16.
8
Glucagon-Like Peptide-1 and Its Class B G Protein-Coupled Receptors: A Long March to Therapeutic Successes.胰高血糖素样肽-1及其B类G蛋白偶联受体：通往治疗成功的漫长征程。
Pharmacol Rev. 2016 Oct;68(4):954-1013. doi: 10.1124/pr.115.011395.
9
Structure-based discovery of opioid analgesics with reduced side effects.基于结构的副作用减少的阿片类镇痛药的发现。
Nature. 2016 Sep 8;537(7619):185-190. doi: 10.1038/nature19112. Epub 2016 Aug 17.
10
The Extracellular Surface of the GLP-1 Receptor Is a Molecular Trigger for Biased Agonism.胰高血糖素样肽-1受体的细胞外表面是偏向激动作用的分子触发因素。
Cell. 2016 Jun 16;165(7):1632-1643. doi: 10.1016/j.cell.2016.05.023.