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Targeting GLP-1 receptor trafficking to improve agonist efficacy

Jones, Ben
Buenaventura, Teresa
Kanda, Nisha
Chabosseau, Pauline
Owen, Bryn M
Scott, Rebecca
Goldin, Robert
Angkathunyakul, Napat
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Published in Nature communications. 2018, vol. 9, no. 1, 1602
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.
Keywords AnimalsBlood Glucose/drug effectsCHO CellsCell Membrane/drug effects/metabolismCricetulusDiabetes MellitusExperimentalType 2/blood/drug therapy/pathologyEndocytosis/drug effectsGlucagon-Like Peptide 1/metabolismGlucagon-Like Peptide-1 Receptor/agonists/metabolismHEK293 CellsHumansHypoglycemic Agents/pharmacology/therapeutic useInsulin/genetics/metabolismInsulin-Secreting Cells/drug effects/metabolismMaleMiceInbred C57BLNausea/chemically induced/epidemiologyPrimary Cell CultureProtein Transport/drug effectsRNASmall Interfering/metabolismTreatment Outcome
PMID: 29686402
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Research group La transplantation d'îlots de Langerhans (623)
Autre: MRC, BBSRC, NIHR, an Integrative Mammalian Biology (IMB) Capacity Building Award
European Commission: EUROCHIP
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JONES, Ben et al. Targeting GLP-1 receptor trafficking to improve agonist efficacy. In: Nature Communications, 2018, vol. 9, n° 1, p. 1602. doi: 10.1038/s41467-018-03941-2 https://archive-ouverte.unige.ch/unige:128571

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Deposited on : 2020-01-09

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