Targeting GLP-1 receptor trafficking to improve agonist efficacy

Ben Jones, Teresa Buenaventura, Nisha Kanda, Pauline Chabosseau, Bryn M. Owen, Rebecca Scott, Robert Goldin, Napat Angkathunyakul, Ivan R. Corrêa, Domenico Bosco, Paul R. Johnson, Lorenzo Piemonti, Piero Marchetti, A. M. James Shapiro, Blake J. Cochran, Aylin C. Hanyaloglu, Asuka Inoue, Tricia Tan, Guy A. Rutter (), Alejandra Tomas () and Stephen R. Bloom
Additional contact information
Ben Jones: Imperial College London
Teresa Buenaventura: Imperial College London
Nisha Kanda: Imperial College London
Pauline Chabosseau: Imperial College London
Bryn M. Owen: Imperial College London
Rebecca Scott: Imperial College London
Robert Goldin: Imperial College London
Napat Angkathunyakul: Imperial College London
Ivan R. Corrêa: New England Biolabs, Inc.
Domenico Bosco: University of Geneva
Paul R. Johnson: University of Oxford
Lorenzo Piemonti: San Raffaele Scientific Institute
Piero Marchetti: University of Pisa
A. M. James Shapiro: University of Alberta
Blake J. Cochran: Imperial College London
Aylin C. Hanyaloglu: Imperial College London
Asuka Inoue: Tohoku University
Tricia Tan: Imperial College London
Guy A. Rutter: Imperial College London
Alejandra Tomas: Imperial College London
Stephen R. Bloom: Imperial College London

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: 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.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03941-2

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DOI: 10.1038/s41467-018-03941-2

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