Targeting GLP-1 receptor trafficking to improve agonist efficacy

B Jones; T Buenaventura; N Kanda; P Chabosseau; BM Owen; R Scott; R Goldin; N Angkathunyakul; IR Corrêa; Domenico Bosco; PR Johnson; L Piemonti; P Marchetti; AMJ Shapiro; BJ Cochran; AC Hanyaloglu; A Inoue; T Tan; GA Rutter; A Tomas; SR Bloom

doi:10.1038/s41467-018-03941-2

Targeting GLP-1 receptor trafficking to improve agonist efficacy

B Jones, T Buenaventura, N Kanda, P Chabosseau, BM Owen, R Scott, R Goldin, N Angkathunyakul, IR Corrêa, Domenico Bosco, PR Johnson, L Piemonti, P Marchetti, AMJ Shapiro, BJ Cochran, AC Hanyaloglu, A Inoue, T Tan, GA Rutter, A TomasSR Bloom

IRCCS Ospedale San Raffaele

Research output: Contribution to journal › Article › peer-review

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. © 2018 The Author(s).

Original language	English
Article number	1602
Journal	Nature Communications
Volume	9
Issue number	11
DOIs	https://doi.org/10.1038/s41467-018-03941-2
Publication status	Published - 2018

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Jones, B., Buenaventura, T., Kanda, N., Chabosseau, P., Owen, BM., Scott, R., Goldin, R., Angkathunyakul, N., Corrêa, IR., Bosco, D., Johnson, PR., Piemonti, L., Marchetti, P., Shapiro, AMJ., Cochran, BJ., Hanyaloglu, AC., Inoue, A., Tan, T., Rutter, GA., ... Bloom, SR. (2018). Targeting GLP-1 receptor trafficking to improve agonist efficacy. Nature Communications, 9(11), [1602]. https://doi.org/10.1038/s41467-018-03941-2

Targeting GLP-1 receptor trafficking to improve agonist efficacy. / Jones, B; Buenaventura, T; Kanda, N; Chabosseau, P; Owen, BM; Scott, R; Goldin, R; Angkathunyakul, N; Corrêa, IR; Bosco, Domenico; Johnson, PR; Piemonti, L; Marchetti, P; Shapiro, AMJ; Cochran, BJ; Hanyaloglu, AC; Inoue, A; Tan, T; Rutter, GA; Tomas, A; Bloom, SR.

In: Nature Communications, Vol. 9, No. 11, 1602, 2018.

Research output: Contribution to journal › Article › peer-review

Jones, B, Buenaventura, T, Kanda, N, Chabosseau, P, Owen, BM, Scott, R, Goldin, R, Angkathunyakul, N, Corrêa, IR, Bosco, D, Johnson, PR, Piemonti, L, Marchetti, P, Shapiro, AMJ, Cochran, BJ, Hanyaloglu, AC, Inoue, A, Tan, T, Rutter, GA, Tomas, A & Bloom, SR 2018, 'Targeting GLP-1 receptor trafficking to improve agonist efficacy', Nature Communications, vol. 9, no. 11, 1602. https://doi.org/10.1038/s41467-018-03941-2

Jones, B ; Buenaventura, T ; Kanda, N ; Chabosseau, P ; Owen, BM ; Scott, R ; Goldin, R ; Angkathunyakul, N ; Corrêa, IR ; Bosco, Domenico ; Johnson, PR ; Piemonti, L ; Marchetti, P ; Shapiro, AMJ ; Cochran, BJ ; Hanyaloglu, AC ; Inoue, A ; Tan, T ; Rutter, GA ; Tomas, A ; Bloom, SR. / Targeting GLP-1 receptor trafficking to improve agonist efficacy. In: Nature Communications. 2018 ; Vol. 9, No. 11.

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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. {\textcopyright} 2018 The Author(s).",

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AU - Buenaventura, T

AU - Kanda, N

AU - Chabosseau, P

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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

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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).

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