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 TomasStephen R. Bloom

Research output: Contribution to journalArticlepeer-review

41 Citations (Scopus)

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.

Original languageEnglish
Article number1602
JournalNature communications
Volume9
Issue number1
DOIs
Publication statusPublished - 2018 Dec 1

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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