Imperial College London
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Dr Alejandra Tomas

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Senior Lecturer
 
 
 
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Contact

 

+44 (0)20 7594 3364a.tomas-catala Website CV

 
 
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Location

 

329ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Bitsi:2022:10.1101/2022.04.21.489075,
author = {Bitsi, S and Manchanda, Y and ElEid, L and Mohamed, N and Hansen, B and Suba, K and Rutter, GA and Salem, V and Jones, B and Tomas, A},
doi = {10.1101/2022.04.21.489075},
title = {Divergent acute <i>versus</i> prolonged pharmacological GLP-1R responses in adult beta cell-selective β-arrestin 2 knockout mice},
url = {http://dx.doi.org/10.1101/2022.04.21.489075},
year = {2022}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - <jats:title>Abstract</jats:title><jats:p>The glucagon-like peptide-1 receptor (GLP-1R) is a major therapeutic target in type 2 diabetes (T2D) and obesity. Following activation, GLP-1Rs are rapidly desensitised by β-arrestins, scaffolding proteins that terminate G protein interactions but also act as independent signalling mediators. While GLP-1R interacts with β-arrestins 1 and 2, expression of the latter is greatly enhanced in beta cells, making this the most relevant isoform. Here, we have assessed <jats:italic>in vivo</jats:italic> glycaemic responses to the pharmacological GLP-1R agonist exendin-4 in adult beta cell-selective β-arrestin 2 knockout (KO) mice. Lean female and high-fat, high-sucrose-fed KO mice of both sexes displayed worse acute responses <jats:italic>versus</jats:italic> control littermates, an effect that was inverted 6 hours post-agonist injection, resulting in prolonged <jats:italic>in vivo</jats:italic> cell-cell connectivity in KO islets implanted in mouse eyes. Similar effects were observed for the clinically relevant semaglutide and tirzepatide but not with exendin-phe1, an agonist biased away from β-arrestin recruitment. <jats:italic>Ex vivo</jats:italic> acute cAMP was impaired, but overnight desensitisation was reduced in KO islets. The acute signalling defect was attributed to enhanced β-arrestin 1 and phosphodiesterase (PDE) 4 activity in the absence of β-arrestin 2, while the reduced desensitisation correlated with altered GLP-1R trafficking, involving impaired recycling and lysosomal targeting and increased trans-Golgi network (TGN) localisation and signalling, as well as reduced GLP-1R ubiquitination by the E3 ubiquitin ligase NEDD4. This study has unveiled fundamental aspects of the role of β-arrestin 2 in regulating pharmacological GLP-1R responses with direct application to the rational design of improved GLP-1R-targeting therape
AU  - Bitsi,S
AU  - Manchanda,Y
AU  - ElEid,L
AU  - Mohamed,N
AU  - Hansen,B
AU  - Suba,K
AU  - Rutter,GA
AU  - Salem,V
AU  - Jones,B
AU  - Tomas,A
DO  - 10.1101/2022.04.21.489075
PY  - 2022///
TI  - Divergent acute <i>versus</i> prolonged pharmacological GLP-1R responses in adult beta cell-selective β-arrestin 2 knockout mice
UR  - http://dx.doi.org/10.1101/2022.04.21.489075
ER  -
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