Targeting GLP-1 receptor trafficking to improve agonist efficacy.

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.

• Authors: Ben Jones, Teresa Buenaventura, Nisha Kanda, Pauline Chabosseau, Bryn M Owen, Rebecca Scott, Robert Goldin, Napat Angkathunyakul, Ivan R Corrêa Jr, Domenico Bosco, Paul R Johnson, Lorenzo Piemonti, Piero Marchetti, A M James Shapiro, Blake J Cochran, Aylin C Hanyaloglu, Asuka Inoue, Tricia Tan, Guy A Rutter, Alejandra Tomas, Stephen R Bloom
• Journal: Nature communications (Nat Commun) Vol. 9 Issue 1 Pg. 1602 (04 23 2018) ISSN: 2041-1723 [Electronic] England
• PMID: 29686402 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Glucagon-Like Peptide-1 Receptor
• Hypoglycemic Agents
• Insulin
• RNA, Small Interfering
• Glucagon-Like Peptide 1

Topics

• Animals
• Blood Glucose (drug effects)
• CHO Cells
• Cell Membrane (drug effects, metabolism)
• Cricetulus
• Diabetes Mellitus, Experimental
• Diabetes Mellitus, 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
• Mice, Inbred C57BL
• Nausea (chemically induced, epidemiology)
• Primary Cell Culture
• Protein Transport (drug effects)
• RNA, Small Interfering (metabolism)
• Treatment Outcome