![]() Sustained signaling by internalized GLP-1Rs has been reported, but without increasing insulin release 10. The GLP-1R is rapidly internalized when activated by its cognate agonist 9, but the effect of internalization and subsequent post-endocytic trafficking on overall GLP-1 responses is not clear. In this study, we have investigated the role of receptor trafficking in glucagon-like peptide-1 receptor (GLP-1R) agonism, an important treatment modality for type 2 diabetes (T2D) which improves pancreatic beta cell function and insulin sensitivity 8. Control of receptor trafficking might therefore be a useful strategy to enable sustained signaling, with significant implications for drug development 7. Surprisingly, this process does not always result in the termination of intracellular signaling, with several receptors known to generate responses from the endosomal compartment 2, 3, 4, 5, 6. ![]() Many G protein-coupled receptors (GPCRs) undergo agonist-mediated endocytosis 1. Our study identifies a set of agents with specific GLP-1R trafficking profiles and the potential for greater efficacy and tolerability as T2D treatments. Such molecules elicit glycemic benefits in mice without concomitant increases in signs of nausea, a common side effect of GLP-1 therapies. Compared to a panel of FDA-approved GLP-1 mimetics, compounds that retain GLP-1R at the plasma membrane produce greater long-term insulin release, which is dependent on a reduction in β-arrestin recruitment and faster agonist dissociation rates. Here, we investigate a series of biased GLP-1R agonists with variable propensities for GLP-1R internalization and recycling. Like other G protein-coupled receptors, the GLP-1R undergoes agonist-mediated endocytosis, but the functional and therapeutic consequences of modulating GLP-1R endocytic trafficking have not been clearly defined. ![]() Glucagon-like peptide-1 receptor (GLP-1R) activation promotes insulin secretion from pancreatic beta cells, causes weight loss, and is an important pharmacological target in type 2 diabetes (T2D). ![]()
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