Targeting GLP-1 receptor trafficking to improve agonist efficacy.
Jones B., Buenaventura T., Kanda N., Chabosseau P., Owen BM., Scott R., Goldin R., Angkathunyakul N., Corrêa IR., Bosco D., Johnson PR., Piemonti L., Marchetti P., Shapiro AMJ., Cochran BJ., Hanyaloglu AC., Inoue A., Tan T., Rutter GA., Tomas A., Bloom SR.
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). 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. Here, we investigate a series of biased GLP-1R agonists with variable propensities for GLP-1R internalization and recycling. 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. Such molecules elicit glycemic benefits in mice without concomitant increases in signs of nausea, a common side effect of GLP-1 therapies. Our study identifies a set of agents with specific GLP-1R trafficking profiles and the potential for greater efficacy and tolerability as T2D treatments.