Dual agonists acting at both the glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) are a novel recent class of drugs which have been shown to simultaneously correct hyperglycaemia and cause sustained weight loss, making them a major drug class to treat the obese diabetic patient population. It is known that selectively activating certain intracellular pathways associated with a particular G protein-coupled receptor (GPCR), termed biased agonism, can simultaneously increase therapeutic efficacy and reduce associated side effects which can limit dosage of GPCR-targeting drugs. This approach has not been investigated in dual GLP-1R/GCGR agonists, yet it could improve the therapeutic efficacy of this drug class.

A GLP-1R/GCGR agonist peptide, “SRB103Gln3”, was discovered that displays significant reductions in β-arrestin recruitment at both receptors versus a comparator, “SRB103His3”, with both peptides maintaining full cAMP signalling. In hepatoma cells, SRB103Gln3 displayed more prolonged signalling than SRB103His3 after overnight stimulation, suggesting SRB103Gln3 could prolong signalling at the GCGR by reducing β-arrestin-mediated receptor desensitisation.

In lean and obese mice, SRB103Gln3 displayed greater anti-hyperglycaemic effects at prolonged timepoints compared to SRB103His3 with little reduction in acute food intake. Studies using Gcgr-/- mice were performed in an attempt to identify the contribution of GCGR to the observed effects. When administered chronically, SRB103Gln3 maintains its optimal anti-hyperglycaemic effects compared to SRB103His3, and both dual agonists displayed a trajectory suggesting greater weight loss compared to the GLP-1R mono-agonist liraglutide. In rats, SRB103Gln3 had profound effects on reducing food intake and weight loss compared to SRB103His3.

These findings highlight the benefit of selectively reducing β-arrestin recruitment associated with dual GLP-1R/GCGR agonist signalling, and could improve the therapeutic utility of this class of compounds.