Abstract
The glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of glucose homeostasis and has been successfully targeted for the treatment of type 2 diabetes. Recently described biased GLP-1R agonists with selective reductions in β-arrestin versus G protein coupling show improved metabolic actions in vivo. However, two prototypical G protein-favouring GLP-1R agonists, P5 and exendin-F1, are reported to show divergent effects on insulin secretion. In this study we aimed to resolve this discrepancy by performing a side-by-side characterisation of these two ligands across a variety of in vitro and in vivo assays. Exendin-F1 showed reduced acute efficacy versus P5 for several readouts, including recruitment of mini-G proteins, G protein-coupled receptor kinases (GRKs) and β-arrestin-2. Maximal responses were also lower for both GLP-1R internalisation and the presence of active GLP-1R-mini-Gs complexes in early endosomes with exendin-F1 treatment. In contrast, prolonged insulin secretion in vitro and sustained anti-hyperglycaemic efficacy in mice were both greater with exendin-F1 than with P5. We conclude that the particularly low acute efficacy of exendin-F1 and associated reductions in GLP-1R downregulation appear to be more important than preservation of endosomal signalling to allow sustained insulin secretion responses. This has implications for the ongoing development of affinity- versus efficacy-driven biased GLP-1R agonists as treatments for metabolic disease.
Highlights
With the increasing worldwide prevalence of type 2 diabetes (T2D) [1], there is an urgent need for more effective drugs to treat this con dition
We investigated the relative propensity for each ligand to recruit G protein-coupled receptor kinases (GRKs) to the glucagon-like peptide-1 receptor (GLP-1R), an interme diate step that typically precedes recruitment of β-arrestins to GPCRs, including GLP-1R [42,43]
We developed a time-resolved FRET (TR-FRET) assay to monitor translocation of lanthanide-labelled SNAP-GLP-1R to the late endoly sosomal compartment, which was labelled using the chemical endoly somotropic dye LysoTracker DND99
Summary
With the increasing worldwide prevalence of type 2 diabetes (T2D) [1], there is an urgent need for more effective drugs to treat this con dition. GLP-1R activation aug ments glucose-stimulated insulin secretion, improves beta cell survival and suppresses appetite, with the latter resulting in weight loss and improvements in insulin sensitivity [4]. Optimised GLP-1R agonists based on the amino acid sequence of either the cognate agonist GLP-1(7–36)NH2 or its homologue exendin-4 [5] are approved for the treatment of T2D. These agents improve glycaemic control and induce weight loss and reduce cardiovascular [6] and all-cause mortality [7] in people with T2D
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