Control of human pancreatic beta cell kinome by glucagon‐like peptide‐1 receptor biased agonism

Abstract

AbstractAimTo determine the kinase activity profiles of human pancreatic beta cells downstream of glucagon‐like peptide‐1 receptor (GLP‐1R) balanced versus biased agonist stimulations.Materials and MethodsThis 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.ResultsThe 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.ConclusionThe 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.