The glucagon‐like peptide 1 (GLP‐1) receptor performs an important role in glycaemic control, stimulating the release of insulin. It is an attractive target for treating type 2 diabetes. Recently, several reports of adverse side effects following prolonged use of GLP‐1 receptor therapies have emerged: most likely due to an incomplete understanding of signalling complexities.

We describe the expression of the GLP‐1 receptor in a panel of modified yeast strains that couple receptor activation to cell growth via single Gα/yeast chimeras. This assay enables the study of individual ligand–receptor G protein coupling preferences and the quantification of the effect of GLP‐1 receptor ligands on G protein selectivity.

The GLP‐1 receptor functionally coupled to the chimeras representing the human Gαs, Gαi and Gαq subunits. Calculation of the dissociation constant for a receptor antagonist, exendin‐3 revealed no significant difference between the two systems. We obtained previously unobserved differences in G protein signalling bias for clinically relevant therapeutic agents, liraglutide and exenatide; the latter displaying significant bias for the Gαi pathway. We extended the use of the system to investigate small‐molecule allosteric compounds and the closely related glucagon receptor.

These results provide a better understanding of the molecular events involved in GLP‐1 receptor pleiotropic signalling and establish the yeast platform as a robust tool to screen for more selective, efficacious compounds acting at this important class of receptors in the future.