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Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are an effective drug class used in the treatment of type 2 diabetes mellitus (T2DM) and have recently been licensed for obesity independently of diabetes. Their beneficial effects include the potentiation of glucose-stimulated insulin secretion, enhancement of pancreatic β-cell function, and promotion of weight loss. However, they are associated with gastrointestinal side effects, of which nausea is the most common. Published data from the early stage clinical development of approved GLP-1RAs repeatedly demonstrate that doses in excess of those subsequently licensed have greater glycaemic efficacy but unacceptable tolerability. This suggests that the maximum therapeutic potential of GLP-1R agonism has not yet been reached, offering scope for its optimisation. Recent work suggests that biased agonism – the ability of receptor ligands to selectively activate particular intracellular pathways – can be leveraged to therapeutically optimise GLP-1RAs. Exendin-4-based GLP-1RAs biased towards G-protein signalling over β-arrestin recruitment exhibited enhanced anti-hyperglycaemic effects with reduced signs of nausea. Intriguingly, the superior glycaemic efficacy of G-protein-biased agonists did not translate into commensurate increases in anorectic efficacy, suggesting a divergence between the effects of biased GLP-1RAs upon glucoregulation versus appetite suppression. This project first confirmed the existence of a physiological divergence between the glycaemic and anorectic effects of exendin-4, G-protein-biased exendin-phe1, and β-arrestin-biased exendin-asp3, and demonstrated the impact of this on the “therapeutic window” of these ligands. Two testable hypotheses were then offered for the observed physiological divergence: differences in the access of the biased GLP-1RAs to CNS-located appetite regulatory centres due to their differential endocytic profiles, or the existence of tissue-specific signalling between GLP-1R-expressing neurons versus pancreatic β-cells. Ligand access to the brain and pancreas was directly assessed using fluorescently-tagged forms of the biased GLP-1RAs and was found to be similar between the agonists, thereby excluding the first of the two possibilities. In addition, these experiments suggested the brain uptake of exendin-4-based ligands to be independent of GLP-1R endocytosis at the blood-brain and blood-CSF barriers, challenging a recently proposed hypothesis in the literature. Subsequent investigations comparing responses to the biased GLP-1RAs in neuronal and pancreatic β-cell lines revealed a different rank order of signalling efficacy between the two cell types, and pointed towards differences in the level of GLP-1R expression as an underlying cause. Thus, these data suggest the existence of tissue-specific signalling between the brain and the pancreas, and that this accounts for the divergent glycaemic and anorectic effects of exendin-4-based biased GLP-1RAs. Finally, the in vitro and in vivo properties of pharmacokinetically optimised, acylated forms of the same biased GLP-1RAs were characterised. Interestingly, these studies demonstrated the glycaemic and anorectic efficacy of the biased GLP-1RAs to differ between lean mice and a mouse model of T2DM and obesity. Thus, in addition to tissue-specific signalling, pathophysiological changes in the diabetic, obese state appear to impact biased agonism at the GLP-1R. Open Access |
