Imperial College London
Alternate

ProfessorGuyRutter

Faculty of Medicine, Department of Medicine

Visiting Professor
 
 
 
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Contact

 

+44 (0)20 7594 3340g.rutter Website

 
 
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Location

 

ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Tomas:2023,
author = {Tomas, Catala A and Bitsi, S and Manchanda, Y and El, Eid L and Oqua, A and Mohamed, N and Hansen, B and Suba, K and Rutter, G and Jones, B and Salem, V},
journal = {Science Advances},
pages = {1--23},
title = {Divergent acute versus prolonged pharmacological GLP-1R responses in adult beta cell-specific β-arrestin 2 knockout mice},
url = {https://www.science.org/doi/10.1126/sciadv.adf7737},
volume = {9},
year = {2023}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Tomas,Catala A
AU  - Bitsi,S
AU  - Manchanda,Y
AU  - El,Eid L
AU  - Oqua,A
AU  - Mohamed,N
AU  - Hansen,B
AU  - Suba,K
AU  - Rutter,G
AU  - Jones,B
AU  - Salem,V
EP  - 23
PY  - 2023///
SN  - 2375-2548
SP  - 1
TI  - Divergent acute versus prolonged pharmacological GLP-1R responses in adult beta cell-specific β-arrestin 2 knockout mice
T2  - Science Advances
UR  - https://www.science.org/doi/10.1126/sciadv.adf7737
UR  - http://hdl.handle.net/10044/1/103578
VL  - 9
ER  -
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