Targeting GLP-1 receptor trafficking to improve agonist efficacy

B Jones, T Buenaventura, N Kanda, P Chabosseau, BM Owen, R Scott, R Goldin, N Angkathunyakul, IR Corrêa, Domenico Bosco, PR Johnson, L Piemonti, P Marchetti, AMJ Shapiro, BJ Cochran, AC Hanyaloglu, A Inoue, T Tan, GA Rutter, A TomasSR Bloom

Research output: Contribution to journalArticlepeer-review

Abstract

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. © 2018 The Author(s).
Original languageEnglish
Article number1602
JournalNature Communications
Volume9
Issue number11
DOIs
Publication statusPublished - 2018

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