Divergent acute versus prolonged pharmacological GLP-1R responses in adult β cell-specific β-arrestin 2 knockout mice
The glucagon-like peptide-1 receptor (GLP-1R) is a major type 2 diabetes therapeutic target. Stimulated GLP-1Rs are rapidly desensitized by β-arrestins, scaffolding proteins that not only terminate G protein interactions but also act as independent signaling mediators. Here, we have assessed in vivo...
| Main Authors: | , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2023
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| Online Access: | https://hdl.handle.net/10356/169850 |
| _version_ | 1824455549985488896 |
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| author | Bitsi, Stavroula El Eid, Liliane Manchanda, Yusman Oqua, Affiong I. Mohamed, Nimco Hansen, Ben Suba, Kinga Rutter, Guy A. Salem, Victoria Jones, Ben Tomas, Alejandra |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Bitsi, Stavroula El Eid, Liliane Manchanda, Yusman Oqua, Affiong I. Mohamed, Nimco Hansen, Ben Suba, Kinga Rutter, Guy A. Salem, Victoria Jones, Ben Tomas, Alejandra |
| author_sort | Bitsi, Stavroula |
| collection | NTU |
| description | The glucagon-like peptide-1 receptor (GLP-1R) is a major type 2 diabetes therapeutic target. Stimulated GLP-1Rs are rapidly desensitized by β-arrestins, scaffolding proteins that not only terminate G protein interactions but also act as independent signaling mediators. Here, we have assessed in vivo glycemic responses to the pharmacological GLP-1R agonist exendin-4 in adult β cell-specific β-arrestin 2 knockout (KO) mice. KOs displayed a sex-dimorphic phenotype consisting of weaker acute responses that improved 6 hours after agonist injection. Similar effects were observed for semaglutide and tirzepatide but not with biased agonist exendin-phe1. Acute cyclic adenosine 5'-monophosphate increases were impaired, but desensitization reduced in KO islets. The former defect was attributed to enhanced β-arrestin 1 and phosphodiesterase 4 activities, while reduced desensitization co-occurred with impaired GLP-1R recycling and lysosomal targeting, increased trans-Golgi network signaling, and reduced GLP-1R ubiquitination. This study has unveiled fundamental aspects of GLP-1R response regulation with direct application to the rational design of GLP-1R-targeting therapeutics. |
| first_indexed | 2025-02-19T03:39:59Z |
| format | Journal Article |
| id | ntu-10356/169850 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2025-02-19T03:39:59Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | ntu-10356/1698502023-08-13T15:37:13Z Divergent acute versus prolonged pharmacological GLP-1R responses in adult β cell-specific β-arrestin 2 knockout mice Bitsi, Stavroula El Eid, Liliane Manchanda, Yusman Oqua, Affiong I. Mohamed, Nimco Hansen, Ben Suba, Kinga Rutter, Guy A. Salem, Victoria Jones, Ben Tomas, Alejandra Lee Kong Chian School of Medicine (LKCMedicine) Science::Medicine Beta Arrestin 2 Knockout Mouse The glucagon-like peptide-1 receptor (GLP-1R) is a major type 2 diabetes therapeutic target. Stimulated GLP-1Rs are rapidly desensitized by β-arrestins, scaffolding proteins that not only terminate G protein interactions but also act as independent signaling mediators. Here, we have assessed in vivo glycemic responses to the pharmacological GLP-1R agonist exendin-4 in adult β cell-specific β-arrestin 2 knockout (KO) mice. KOs displayed a sex-dimorphic phenotype consisting of weaker acute responses that improved 6 hours after agonist injection. Similar effects were observed for semaglutide and tirzepatide but not with biased agonist exendin-phe1. Acute cyclic adenosine 5'-monophosphate increases were impaired, but desensitization reduced in KO islets. The former defect was attributed to enhanced β-arrestin 1 and phosphodiesterase 4 activities, while reduced desensitization co-occurred with impaired GLP-1R recycling and lysosomal targeting, increased trans-Golgi network signaling, and reduced GLP-1R ubiquitination. This study has unveiled fundamental aspects of GLP-1R response regulation with direct application to the rational design of GLP-1R-targeting therapeutics. Published version This work was supported by MRC grant MR/R010676/1 (to A.T., B.J., and G.A.R.), UKRI COVID-19 Grant Extension Allocation (coA) (to AT.), and Society for Endocrinology Early Career Grant (to S.B.). 2023-08-08T01:37:09Z 2023-08-08T01:37:09Z 2023 Journal Article Bitsi, S., El Eid, L., Manchanda, Y., Oqua, A. I., Mohamed, N., Hansen, B., Suba, K., Rutter, G. A., Salem, V., Jones, B. & Tomas, A. (2023). Divergent acute versus prolonged pharmacological GLP-1R responses in adult β cell-specific β-arrestin 2 knockout mice. Science Advances, 9(18), eadf7737-. https://dx.doi.org/10.1126/sciadv.adf7737 2375-2548 https://hdl.handle.net/10356/169850 10.1126/sciadv.adf7737 9 2-s2.0-85159548050 18 9 eadf7737 en Science Advances © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). application/pdf |
| spellingShingle | Science::Medicine Beta Arrestin 2 Knockout Mouse Bitsi, Stavroula El Eid, Liliane Manchanda, Yusman Oqua, Affiong I. Mohamed, Nimco Hansen, Ben Suba, Kinga Rutter, Guy A. Salem, Victoria Jones, Ben Tomas, Alejandra Divergent acute versus prolonged pharmacological GLP-1R responses in adult β cell-specific β-arrestin 2 knockout mice |
| title | Divergent acute versus prolonged pharmacological GLP-1R responses in adult β cell-specific β-arrestin 2 knockout mice |
| title_full | Divergent acute versus prolonged pharmacological GLP-1R responses in adult β cell-specific β-arrestin 2 knockout mice |
| title_fullStr | Divergent acute versus prolonged pharmacological GLP-1R responses in adult β cell-specific β-arrestin 2 knockout mice |
| title_full_unstemmed | Divergent acute versus prolonged pharmacological GLP-1R responses in adult β cell-specific β-arrestin 2 knockout mice |
| title_short | Divergent acute versus prolonged pharmacological GLP-1R responses in adult β cell-specific β-arrestin 2 knockout mice |
| title_sort | divergent acute versus prolonged pharmacological glp 1r responses in adult β cell specific β arrestin 2 knockout mice |
| topic | Science::Medicine Beta Arrestin 2 Knockout Mouse |
| url | https://hdl.handle.net/10356/169850 |
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