Control of human pancreatic beta cell kinome by glucagon-like peptide-1 receptor biased agonism.
GLP-1
beta cell function
exenatide
incretin physiology
insulin analogues
Journal
Diabetes, obesity & metabolism
ISSN: 1463-1326
Titre abrégé: Diabetes Obes Metab
Pays: England
ID NLM: 100883645
Informations de publication
Date de publication:
08 2023
08 2023
Historique:
revised:
03
04
2023
received:
25
02
2023
accepted:
03
04
2023
medline:
4
7
2023
pubmed:
12
4
2023
entrez:
11
4
2023
Statut:
ppublish
Résumé
To determine the kinase activity profiles of human pancreatic beta cells downstream of glucagon-like peptide-1 receptor (GLP-1R) balanced versus biased agonist stimulations. This study analysed the kinomic profiles of human EndoC-βh1 cells following vehicle and GLP-1R stimulation with the pharmacological agonist exendin-4, as well as exendin-4-based biased derivatives exendin-phe1 and exendin-asp3 for acute (10-minute) versus sustained (120-minute) responses, using PamChip protein tyrosine kinase and serine/threonine kinase assays. The raw data were filtered and normalized using BioNavigator. The kinase analyses were conducted with R, mainly including kinase-substrate mapping and Kyoto Encyclopedia of Genes and Genomes pathway analysis. The present analysis reveals that kinomic responses are distinct for acute versus sustained GLP-1R agonist exposure, with individual responses associated with agonists presenting specific bias profiles. According to pathway analysis, several kinases, including JNKs, PKCs, INSR and LKB1, are important GLP-1R signalling mediators, constituting potential targets for further research on biased GLP-1R downstream signalling. The results from this study suggest that differentially biased exendin-phe1 and exendin-asp3 can modulate distinct kinase interaction networks. Further understanding of these mechanisms will have important implications for the selection of appropriate anti-type 2 diabetes therapies with optimized downstream kinomic profiles.
Substances chimiques
Exenatide
9P1872D4OL
Glucagon-Like Peptide-1 Receptor
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2105-2119Subventions
Organisme : Medical Research Council
ID : MR/R010676/1
Pays : United Kingdom
Informations de copyright
© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.
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