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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.

Original publication

DOI

10.1038/s41467-018-03941-2

Type

Journal article

Journal

Nat Commun

Publication Date

23/04/2018

Volume

9

Keywords

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