Divergent acute versus prolonged pharmacological GLP-1R responses in adult beta cell-specific β-arrestin 2 knockout mice
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
The glucagon-like peptide-1 receptor (GLP-1R) is a major type 2 diabetes therapeutic target. Stimulated GLP-1Rs are rapidly desensitized by β-arrestins, scaffolding proteins that not only terminate G protein interactions but also act as independent signaling mediators. Here, we have assessed in vivo glycemic responses to the pharmacological GLP-1R agonist exendin-4 in adult β cell–specific β-arrestin 2 knockout (KO) mice. KOs displayed a sex-dimorphic phenotype consisting of weaker acute responses that improved 6 hours after agonist injection. Similar effects were observed for semaglutide and tirzepatide but not with biased agonist exendin-phe1. Acute cyclic adenosine 5′-monophosphate increases were impaired, but desensitization reduced in KO islets. The former defect was attributed to enhanced β-arrestin 1 and phosphodiesterase 4 activities, while reduced desensitization co-occurred with impaired GLP-1R recycling and lysosomal targeting, increased trans-Golgi network signaling, and reduced GLP-1R ubiquitination. This study has unveiled fundamental aspects of GLP-1R response regulation with direct application to the rational design of GLP-1R–targeting therapeutics.
Date Issued
2023-05
Date Acceptance
2023-04-04
Citation
Science Advances, 2023, 9 (18), pp.1-23
ISSN
2375-2548
Publisher
American Association for the Advancement of Science
Start Page
1
End Page
23
Journal / Book Title
Science Advances
Volume
9
Issue
18
Copyright Statement
Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Identifier
https://www.science.org/doi/10.1126/sciadv.adf7737
Publication Status
Published
Article Number
eadf7737
Date Publish Online
2023-05-03