Impact of N-terminally substituted glucagon family receptor agonists on signal bias, trafficking and downstream responses

Receptors for the peptide hormones glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon (GCG) are important regulators of insulin secretion and energy metabolism. Here we sought to investigate how signal bias between cyclic AMP and β-arrestin-2 recruitment can modulate the effects of prolonged agonist stimulation at each of these receptors. We generated analogues of GLP-1, GCG and GIP which in some cases showed selective reduction in β-arrestin-2 recruitment cAMP signalling compared to the parent peptide. Despite reduced acute signalling potency and/or efficacy, some biased GLP-1 and GIP analogues increased maximal sustained insulin secretion, although only at high agonist concentrations. Biased GCG analogues did not affect maximal insulin release from beta cells, or glucose output in hepatocytes.