Scientific Article
unige:128571 
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Targeting GLP-1 receptor trafficking to improve agonist efficacy |
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| Published in | Nature Communications. 2018, vol. 9, no. 1, p. 1602 | |
| 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 | |
| Identifiers | PMID: 29686402 | |
| Full text |
 Article (Published version) (3.2 MB) -  Free access Supplemental data (42.5 MB) - Free access Appendix (900 Kb) - Free accessOther version: https://www.nature.com/articles/s41467-018-03941-2 Dataset: https://www.nature.com/articles/s41467-018-03941-2#Sec49 |
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| Research group | La transplantation d'îlots de Langerhans (623) | |
| Projects | MRC, BBSRC, NIHR, an Integrative Mammalian Biology (IMB) Capacity Building Award FP7: EUROCHIP | |
| 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 https://archive-ouverte.unige.ch/unige:128571 |
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