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Targeting GLP-1 receptor trafficking to improve agonist efficacy.

  • Jones B Section of Investigative Medicine, Imperial College London, London, W12 0NN, UK.
  • Buenaventura T Section of Cell Biology and Functional Genomics, Imperial College London, London, W12 0NN, UK.
  • Kanda N Section of Cell Biology and Functional Genomics, Imperial College London, London, W12 0NN, UK.
  • Chabosseau P Section of Cell Biology and Functional Genomics, Imperial College London, London, W12 0NN, UK.
  • Owen BM Section of Investigative Medicine, Imperial College London, London, W12 0NN, UK.
  • Scott R Section of Investigative Medicine, Imperial College London, London, W12 0NN, UK.
  • Goldin R Centre for Pathology, Imperial College London, London, W2 1NY, UK.
  • Angkathunyakul N Centre for Pathology, Imperial College London, London, W2 1NY, UK.
  • Corrêa IR New England Biolabs, Inc., Ipswich, 01938, MA, USA.
  • Bosco D Department of Surgery, University of Geneva, Geneva, CH-1211, Switzerland.
  • Johnson PR Nuffield Department of Surgical Sciences, University of Oxford, Oxford, OX3 9DU, UK.
  • Piemonti L Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, Milan, 20132, Italy.
  • Marchetti P Department of Clinical and Experimental Medicine, Islet Cell Laboratory, University of Pisa, Pisa, 56124, Italy.
  • Shapiro AMJ Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, T6G 2C8, AB, Canada.
  • Cochran BJ Section of Renal and Vascular Inflammation, Imperial College London, London, W12 0NN, UK.
  • Hanyaloglu AC Department of Surgery and Cancer, Imperial College London, London, W12 0NN, UK.
  • Inoue A Tohoku University, Sendai, 980-8574, Japan.
  • Tan T Section of Investigative Medicine, Imperial College London, London, W12 0NN, UK.
  • Rutter GA Section of Cell Biology and Functional Genomics, Imperial College London, London, W12 0NN, UK. g.rutter@imperial.ac.uk.
  • Tomas A Section of Cell Biology and Functional Genomics, Imperial College London, London, W12 0NN, UK. a.tomas-catala@imperial.ac.uk.
  • Bloom SR Section of Investigative Medicine, Imperial College London, London, W12 0NN, UK.
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  • 2018-04-25
Published in:
  • Nature communications. - 2018
Animals
Blood Glucose
CHO Cells
Cell Membrane
Cricetulus
Diabetes Mellitus, Experimental
Diabetes Mellitus, Type 2
Endocytosis
Glucagon-Like Peptide 1
Glucagon-Like Peptide-1 Receptor
HEK293 Cells
Humans
Hypoglycemic Agents
Insulin
Insulin-Secreting Cells
Male
Mice
Mice, Inbred C57BL
Nausea
Primary Cell Culture
Protein Transport
RNA, Small Interfering
Treatment Outcome
English 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.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/138432
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