en
Scientific article
Open access
English

Targeting GLP-1 receptor trafficking to improve agonist efficacy

Published inNature Communications, vol. 9, no. 1, 1602
Publication date2018
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
  • Animals
  • Blood Glucose/drug effects
  • CHO Cells
  • Cell Membrane/drug effects/metabolism
  • Cricetulus
  • Diabetes Mellitus
  • Experimental
  • Type 2/blood/drug therapy/pathology
  • Endocytosis/drug effects
  • Glucagon-Like Peptide 1/metabolism
  • Glucagon-Like Peptide-1 Receptor/agonists/metabolism
  • HEK293 Cells
  • Humans
  • Hypoglycemic Agents/pharmacology/therapeutic use
  • Insulin/genetics/metabolism
  • Insulin-Secreting Cells/drug effects/metabolism
  • Male
  • Mice
  • Inbred C57BL
  • Nausea/chemically induced/epidemiology
  • Primary Cell Culture
  • Protein Transport/drug effects
  • RNA
  • Small Interfering/metabolism
  • Treatment Outcome
Funding
  • Autre - MRC, BBSRC, NIHR, an Integrative Mammalian Biology (IMB) Capacity Building Award
  • European Commission - European Obesity Consortium studying the Hypothalamus and its Interaction with Peripheral organs. [241592]
Citation (ISO format)
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
Main files (1)
Article (Published version)
Secondary files (2)
Identifiers
ISSN of the journal2041-1723
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379downloads

Technical informations

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