Abstract
Aim To determine the kinase activity profiles of human pancreatic beta cells downstream of GLP-1R balanced versus biased agonist stimulations.
Materials and methods This study analysed the kinomic profiles of human EndoC-βh1 cells following vehicle and glucagon-like peptide-1 receptor (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 (PTK) and serine/threonine kinase (STK) assays. The raw data were filtered and normalised using BioNavigator. The kinase analyses were conducted with R, mainly including kinase-substrate mapping and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis.
Results The present analysis reveals that kinomic responses are distinct for acute versus sustained GLP-1R agonist (GLP-1RA) 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.
Conclusion 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-T2D therapies with optimised downstream kinomic profiles.
Competing Interest Statement
GAR has received funding from Sun Pharmaceuticals AT and BJ have received funding from Eli Lilly