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Comparative Analysis of Orthosteric and Allosteric GLP-1R Agonists’ Effects on Insulin Secretion from Healthy, Diabetic, and Recovered INS-1E Pancreatic Beta Cells

Joshua Reed, Victoria Higginbotham, Steve Bain Orcid Logo, Venkat Kanamarlapudi Orcid Logo

International Journal of Molecular Sciences, Volume: 25, Issue: 12, Start page: 6331

Swansea University Authors: Victoria Higginbotham, Steve Bain Orcid Logo, Venkat Kanamarlapudi Orcid Logo

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DOI (Published version): 10.3390/ijms25126331

Abstract

Despite the availability of different treatments for type 2 diabetes (T2D), post-diagnosis complications remain prevalent; therefore, more effective treatments are desired. Glucagon-like peptide (GLP)-1-based drugs are currently used for T2D treatment. They act as orthosteric agonists for the GLP-1...

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Published in: International Journal of Molecular Sciences
ISSN: 1422-0067
Published: MDPI AG 2024
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URI: https://cronfa.swan.ac.uk/Record/cronfa66723
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spelling v2 66723 2024-06-13 Comparative Analysis of Orthosteric and Allosteric GLP-1R Agonists’ Effects on Insulin Secretion from Healthy, Diabetic, and Recovered INS-1E Pancreatic Beta Cells 29dd07a8a73cf872888e406e01ee766f Victoria Higginbotham Victoria Higginbotham true false 5399f4c6e6a70f3608a084ddb938511a 0000-0001-8519-4964 Steve Bain Steve Bain true false 63741801137148abfa4c00cd547dcdfa 0000-0002-8739-1483 Venkat Kanamarlapudi Venkat Kanamarlapudi true false 2024-06-13 MEDS Despite the availability of different treatments for type 2 diabetes (T2D), post-diagnosis complications remain prevalent; therefore, more effective treatments are desired. Glucagon-like peptide (GLP)-1-based drugs are currently used for T2D treatment. They act as orthosteric agonists for the GLP-1 receptor (GLP-1R). In this study, we analyzed in vitro how the GLP-1R orthosteric and allosteric agonists augment glucose-stimulated insulin secretion (GSIS) and intracellular cAMP production (GSICP) in INS-1E pancreatic beta cells under healthy, diabetic, and recovered states. The findings from this study suggest that allosteric agonists have a longer duration of action than orthosteric agonists. They also suggest that the GLP-1R agonists do not deplete intracellular insulin, indicating they can be a sustainable and safe treatment option for T2D. Importantly, this study demonstrates that the GLP-1R agonists variably augment GSIS through GSICP in healthy, diabetic, and recovered INS-1E cells. Furthermore, we find that INS-1E cells respond differentially to the GLP-1R agonists depending on both glucose concentration during and before treatment and/or whether the cells have been previously exposed to these drugs. In conclusion, the findings described in this manuscript will be useful in determining in vitro how pancreatic beta cells respond to T2D drug treatments in healthy, diabetic, and recovered states. Journal Article International Journal of Molecular Sciences 25 12 6331 MDPI AG 1422-0067 diabetes; INS-1E cells; glucose; GLP-1R; allosteric agonists; orthosteric agonists; GSIS; GSICP; insulin 7 6 2024 2024-06-07 10.3390/ijms25126331 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University This research received no external funding. 2024-07-23T14:47:09.3848917 2024-06-13T16:26:57.1345677 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Joshua Reed 1 Victoria Higginbotham 2 Steve Bain 0000-0001-8519-4964 3 Venkat Kanamarlapudi 0000-0002-8739-1483 4 66723__30951__f0cd2439828248f8aaedf9062c61b6cb.pdf 66723.VoR.pdf 2024-07-23T14:45:42.5772197 Output 3257414 application/pdf Version of Record true © 2024 by the authors.This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY) license. true eng https://creativecommons.org/licenses/by/4.0/
title Comparative Analysis of Orthosteric and Allosteric GLP-1R Agonists’ Effects on Insulin Secretion from Healthy, Diabetic, and Recovered INS-1E Pancreatic Beta Cells
spellingShingle Comparative Analysis of Orthosteric and Allosteric GLP-1R Agonists’ Effects on Insulin Secretion from Healthy, Diabetic, and Recovered INS-1E Pancreatic Beta Cells
Victoria Higginbotham
Steve Bain
Venkat Kanamarlapudi
title_short Comparative Analysis of Orthosteric and Allosteric GLP-1R Agonists’ Effects on Insulin Secretion from Healthy, Diabetic, and Recovered INS-1E Pancreatic Beta Cells
title_full Comparative Analysis of Orthosteric and Allosteric GLP-1R Agonists’ Effects on Insulin Secretion from Healthy, Diabetic, and Recovered INS-1E Pancreatic Beta Cells
title_fullStr Comparative Analysis of Orthosteric and Allosteric GLP-1R Agonists’ Effects on Insulin Secretion from Healthy, Diabetic, and Recovered INS-1E Pancreatic Beta Cells
title_full_unstemmed Comparative Analysis of Orthosteric and Allosteric GLP-1R Agonists’ Effects on Insulin Secretion from Healthy, Diabetic, and Recovered INS-1E Pancreatic Beta Cells
title_sort Comparative Analysis of Orthosteric and Allosteric GLP-1R Agonists’ Effects on Insulin Secretion from Healthy, Diabetic, and Recovered INS-1E Pancreatic Beta Cells
author_id_str_mv 29dd07a8a73cf872888e406e01ee766f
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author_id_fullname_str_mv 29dd07a8a73cf872888e406e01ee766f_***_Victoria Higginbotham
5399f4c6e6a70f3608a084ddb938511a_***_Steve Bain
63741801137148abfa4c00cd547dcdfa_***_Venkat Kanamarlapudi
author Victoria Higginbotham
Steve Bain
Venkat Kanamarlapudi
author2 Joshua Reed
Victoria Higginbotham
Steve Bain
Venkat Kanamarlapudi
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container_title International Journal of Molecular Sciences
container_volume 25
container_issue 12
container_start_page 6331
publishDate 2024
institution Swansea University
issn 1422-0067
doi_str_mv 10.3390/ijms25126331
publisher MDPI AG
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
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description Despite the availability of different treatments for type 2 diabetes (T2D), post-diagnosis complications remain prevalent; therefore, more effective treatments are desired. Glucagon-like peptide (GLP)-1-based drugs are currently used for T2D treatment. They act as orthosteric agonists for the GLP-1 receptor (GLP-1R). In this study, we analyzed in vitro how the GLP-1R orthosteric and allosteric agonists augment glucose-stimulated insulin secretion (GSIS) and intracellular cAMP production (GSICP) in INS-1E pancreatic beta cells under healthy, diabetic, and recovered states. The findings from this study suggest that allosteric agonists have a longer duration of action than orthosteric agonists. They also suggest that the GLP-1R agonists do not deplete intracellular insulin, indicating they can be a sustainable and safe treatment option for T2D. Importantly, this study demonstrates that the GLP-1R agonists variably augment GSIS through GSICP in healthy, diabetic, and recovered INS-1E cells. Furthermore, we find that INS-1E cells respond differentially to the GLP-1R agonists depending on both glucose concentration during and before treatment and/or whether the cells have been previously exposed to these drugs. In conclusion, the findings described in this manuscript will be useful in determining in vitro how pancreatic beta cells respond to T2D drug treatments in healthy, diabetic, and recovered states.
published_date 2024-06-07T14:47:07Z
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