Ben JonesTeresa BuenaventuraNisha KandaPauline ChabosseauBryn M. OwenRebecca ScottRobert GoldinNapat AngkathunyakulIvan R. CorrêaDomenico BoscoPaul R. JohnsonLorenzo PiemontiPiero MarchettiA. M.James ShapiroBlake J. CochranAylin C. HanyalogluAsuka InoueTricia TanGuy A. RutterAlejandra TomasStephen R. BloomIRCCS San Raffaele Scientific InstituteUniversity of AlbertaUniversità di PisaNew England BiolabsUniversity of New South Wales (UNSW) AustraliaUniversity of OxfordFaculty of Medicine, Ramathibodi Hospital, Mahidol UniversityImperial College LondonUniversità Vita-Salute San RaffaeleTohoku UniversityUniversité de Genève2019-08-232019-08-232018-12-01Nature Communications. Vol.9, No.1 (2018)204117232-s2.0-85046005577https://repository.li.mahidol.ac.th/handle/123456789/44986© 2018 The Author(s). 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.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyChemistryPhysics and AstronomyArticleSCOPUS10.1038/s41467-018-03941-2