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Nat Commun. 2018 Apr 23;9(1):1602. doi: 10.1038/s41467-018-03941-2.

Targeting GLP-1 receptor trafficking to improve agonist efficacy.

Author information

1
Section of Investigative Medicine, Imperial College London, London, W12 0NN, UK.
2
Section of Cell Biology and Functional Genomics, Imperial College London, London, W12 0NN, UK.
3
Centre for Pathology, Imperial College London, London, W2 1NY, UK.
4
Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand.
5
New England Biolabs, Inc., Ipswich, 01938, MA, USA.
6
Department of Surgery, University of Geneva, Geneva, CH-1211, Switzerland.
7
Nuffield Department of Surgical Sciences, University of Oxford, Oxford, OX3 9DU, UK.
8
Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, Milan, 20132, Italy.
9
Vita-Salute San Raffaele University, Milan, 20132, Italy.
10
Department of Clinical and Experimental Medicine, Islet Cell Laboratory, University of Pisa, Pisa, 56124, Italy.
11
Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, T6G 2C8, AB, Canada.
12
Section of Renal and Vascular Inflammation, Imperial College London, London, W12 0NN, UK.
13
School of Medical Sciences, UNSW Sydney, Sydney, 2052, NSW, Australia.
14
Department of Surgery and Cancer, Imperial College London, London, W12 0NN, UK.
15
Tohoku University, Sendai, 980-8574, Japan.
16
Section of Cell Biology and Functional Genomics, Imperial College London, London, W12 0NN, UK. g.rutter@imperial.ac.uk.
17
Section of Cell Biology and Functional Genomics, Imperial College London, London, W12 0NN, UK. a.tomas-catala@imperial.ac.uk.

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.

PMID:
29686402
PMCID:
PMC5913239
DOI:
10.1038/s41467-018-03941-2
[Indexed for MEDLINE]
Free PMC Article

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