TY - JOUR
T1 - Targeting GLP-1 receptor trafficking to improve agonist efficacy
AU - Jones, B
AU - Buenaventura, T
AU - Kanda, N
AU - Chabosseau, P
AU - Owen, BM
AU - Scott, R
AU - Goldin, R
AU - Angkathunyakul, N
AU - Corrêa, IR
AU - Bosco, Domenico
AU - Johnson, PR
AU - Piemonti, L
AU - Marchetti, P
AU - Shapiro, AMJ
AU - Cochran, BJ
AU - Hanyaloglu, AC
AU - Inoue, A
AU - Tan, T
AU - Rutter, GA
AU - Tomas, A
AU - Bloom, SR
PY - 2018
Y1 - 2018
N2 - 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. © 2018 The Author(s).
AB - 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. © 2018 The Author(s).
U2 - 10.1038/s41467-018-03941-2
DO - 10.1038/s41467-018-03941-2
M3 - Article
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 11
M1 - 1602
ER -