TY - JOUR
T1 - Targeting GLP-1 receptor trafficking to improve agonist efficacy
AU - Jones, Ben
AU - Buenaventura, Teresa
AU - Kanda, Nisha
AU - Chabosseau, Pauline
AU - Owen, Bryn M.
AU - Scott, Rebecca
AU - Goldin, Robert
AU - Angkathunyakul, Napat
AU - Corrêa, Ivan R.
AU - Bosco, Domenico
AU - Johnson, Paul R.
AU - Piemonti, Lorenzo
AU - Marchetti, Piero
AU - Shapiro, A. M.James
AU - Cochran, Blake J.
AU - Hanyaloglu, Aylin C.
AU - Inoue, Asuka
AU - Tan, Tricia
AU - Rutter, Guy A.
AU - Tomas, Alejandra
AU - Bloom, Stephen R.
N1 - Funding Information:
The Section of Endocrinology and Investigative Medicine is funded by grants from the MRC, BBSRC, NIHR, an Integrative Mammalian Biology (IMB) Capacity Building Award, an FP7-HEALTH-2009-241592 EuroCHIP grant and is supported by the NIHR Biomedical Research Center Funding Scheme; B.J. was funded by an MRC Clinical Research Training Fellowship; B.M.O. was funded by a Sir Henry Dale Fellowship (105545/Z/14/Z) jointly funded by the Wellcome Trust and the Royal Society; R.S. was supported by a Wellcome Trust Clinical Research Training Fellowship; A.I. was funded by the Japan Science and Technology (JST), PRESTO (JPMJPR1331), the Japan Society for the Promotion of Science (JSPS), KAKENHI (17K08264), and the PRIME from the Japan Agency for Medical Research and Development (AMED); B.J. C. was supported by an International Atherosclerosis Society Fellowship; G.A.R. was supported by a Wellcome Trust Senior Investigator Award (WT098424AIA), MRC Program grants (MR/J0003042/1, MR/L020149/1) and Experimental Challenge Grant (DIVA, MR/L02036X/1), BBSRC (BB/J015873/1), MRC (MR/N00275X/1), Diabetes UK (BDA/11/0004210, BDA/15/0005275, BDA 16/0005485) and Imperial Confidence in Concept (ICiC) grants, and a Royal Society Wolfson Research Merit Award; A.T. was funded by an MRC New Investigator Research Grant (MR/M012646/1) and a Diabetes UK Early Career Small Grant (16/0005441). The views expressed are those of the authors and not necessarily those of the funders, the NHS, the NIHR or the Department of Health. MIN6B1 cells were kindly provided by Prof. Philippe Halban (University of Geneva, Switzerland) with permission from Prof. Jun-ichi Miyazaki (University of Osaka, Japan) who produced the maternal MIN6 cell line. INS-1 832/3 cells were kindly provided by Prof. Christopher Newgard (Duke University, USA). Human islets from Milan and Geneva were provided through the European Consortium for Islet Transplantation (ECIT), sponsored by JDRF (1-RSC-2014-90-I-X and 1-RSC-2014-100-I-X, respectively). Human islets from Edmonton were provided by the Clinical Islet Transplant Program and by the Alberta Diabetes Institute Islet Core at the University of Alberta with the assistance of the Human Organ Procurement and Exchange (HOPE) program, Trillium Gift of Life Network (TGLN) and other Canadian organ procurement organizations. Human islets from Oxford were isolated within the Diabetes Research and Wellness Foundation (DRWF) Human Islet Isolation Facility. This was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Center (BRC) and by a grant from the Juvenile Diabetes Research Foundation (JDRF). We thank Gala Farooq for assistance with glucose tolerance tests, Zainab Malik, Laura-Jane Ball, and Natarin Caengprasath for technical assistance, Dr. Emlyn Corrin for assistance with trafficking calculations, Dr. James Minnion for helpful discussions, and Prof. Arthur Christopoulos for advice on biased agonism.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-018-03941-2
DO - 10.1038/s41467-018-03941-2
M3 - Article
C2 - 29686402
AN - SCOPUS:85046005577
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1602
ER -
