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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
International Journal of Molecular Sciences, Volume: 25, Issue: 12, Start page: 6331
Swansea University Authors:
Victoria Higginbotham, Steve Bain , Venkat Kanamarlapudi
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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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ISSN: | 1422-0067 |
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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 5399f4c6e6a70f3608a084ddb938511a 63741801137148abfa4c00cd547dcdfa |
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 |
format |
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International Journal of Molecular Sciences |
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25 |
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6331 |
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1422-0067 |
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10.3390/ijms25126331 |
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MDPI AG |
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Faculty of Medicine, Health and Life Sciences |
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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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1805377788015804416 |
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11.024221 |