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The influence of GLP-1R agonists on glucose-stimulated insulin secretion and the receptor internalisation in normal, diabetic and recovered pancreatic beta-cells / JOSHUA REED

Swansea University Author: JOSHUA REED

  • E-Thesis – open access under embargo until: 10th February 2027

DOI (Published version): 10.23889/SUthesis.59405

Abstract

Type 2 diabetes (T2D), which has become a global pandemic in recent decades, is a metabolic disease largely characterised by impaired insulin secretion and action in patients. Glucagon-like peptide (GLP)-1 is an incretin hormone responsible for augmenting insulin secretion from pancreatic beta-cells...

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Published: Swansea 2022
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
Supervisor: Kanamarlapudi, Venkateswarlu ; Bain, Steve C.
URI: https://cronfa.swan.ac.uk/Record/cronfa59405
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first_indexed 2022-02-15T18:38:59Z
last_indexed 2022-02-16T04:27:13Z
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spelling 2022-02-15T19:00:45.4014732 v2 59405 2022-02-15 The influence of GLP-1R agonists on glucose-stimulated insulin secretion and the receptor internalisation in normal, diabetic and recovered pancreatic beta-cells 53c9aa130ec3d2b8e6f38e08c4716be4 JOSHUA REED JOSHUA REED true false 2022-02-15 Type 2 diabetes (T2D), which has become a global pandemic in recent decades, is a metabolic disease largely characterised by impaired insulin secretion and action in patients. Glucagon-like peptide (GLP)-1 is an incretin hormone responsible for augmenting insulin secretion from pancreatic beta-cells during the postprandial period. Given that native GLP-1 has a very short half-life, GLP-1 mimetics have been developed, which have a much greater duration of action, and are currently an effective treatment option for T2D by prolonging insulin secretion in patients. Additionally, there is continuing emerging evidence that these therapies alleviate the post-diagnosis complications of T2D to a greater extent than other treatments. Current GLP-1 based therapies all act as orthosteric agonists for the GLP-1 receptor (GLP-1R). Interestingly, it has emerged that GLP-1R also has allosteric binding sites and agonists have been developed for these sites. The objective of this study was to determine if allosteric agonists had superior effects on insulin secretion compared to orthosteric, and could therefore be a more effective treatment for T2D. Rat pancreatic beta-cell lines (INS-1E and INS-1 832/3) have been shown to mimic native islet beta-cell behaviour, and therefore in vitro experiments carried out with these cell lines in this study have clinical relevance. This study demonstrated how INS-1E and INS-1 832/3 cells responded to varying treatments with both types of GLP-1R agonists and the differential mechanisms by which these agonists mediated their actions. Additionally, how cells responded to treatments depending on whether they are in healthy, diabetic or recovered states was assessed to demonstrate how islet beta-cells’ response can be altered depending on the conditions they have been chronically exposed to pre-treatment. Overall, findings from this study demonstrate that allosteric agonists have a superior duration of action and the mechanisms by which both types of agonist exert their actions are distinct. E-Thesis Swansea Type 2 diabetes, Glucagon-like peptide 1 15 2 2022 2022-02-15 10.23889/SUthesis.59405 COLLEGE NANME COLLEGE CODE Swansea University Kanamarlapudi, Venkateswarlu ; Bain, Steve C. Doctoral Ph.D KESS/Simbec 2022-02-15T19:00:45.4014732 2022-02-15T18:34:22.8435231 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine JOSHUA REED 1 Under embargo Under embargo 2022-02-15T18:44:53.1195267 Output 21715176 application/pdf E-Thesis – open access true 2027-02-10T00:00:00.0000000 Copyright: The author, Joshua Reed, 2022. true eng
title The influence of GLP-1R agonists on glucose-stimulated insulin secretion and the receptor internalisation in normal, diabetic and recovered pancreatic beta-cells
spellingShingle The influence of GLP-1R agonists on glucose-stimulated insulin secretion and the receptor internalisation in normal, diabetic and recovered pancreatic beta-cells
JOSHUA REED
title_short The influence of GLP-1R agonists on glucose-stimulated insulin secretion and the receptor internalisation in normal, diabetic and recovered pancreatic beta-cells
title_full The influence of GLP-1R agonists on glucose-stimulated insulin secretion and the receptor internalisation in normal, diabetic and recovered pancreatic beta-cells
title_fullStr The influence of GLP-1R agonists on glucose-stimulated insulin secretion and the receptor internalisation in normal, diabetic and recovered pancreatic beta-cells
title_full_unstemmed The influence of GLP-1R agonists on glucose-stimulated insulin secretion and the receptor internalisation in normal, diabetic and recovered pancreatic beta-cells
title_sort The influence of GLP-1R agonists on glucose-stimulated insulin secretion and the receptor internalisation in normal, diabetic and recovered pancreatic beta-cells
author_id_str_mv 53c9aa130ec3d2b8e6f38e08c4716be4
author_id_fullname_str_mv 53c9aa130ec3d2b8e6f38e08c4716be4_***_JOSHUA REED
author JOSHUA REED
author2 JOSHUA REED
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publishDate 2022
institution Swansea University
doi_str_mv 10.23889/SUthesis.59405
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 - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
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description Type 2 diabetes (T2D), which has become a global pandemic in recent decades, is a metabolic disease largely characterised by impaired insulin secretion and action in patients. Glucagon-like peptide (GLP)-1 is an incretin hormone responsible for augmenting insulin secretion from pancreatic beta-cells during the postprandial period. Given that native GLP-1 has a very short half-life, GLP-1 mimetics have been developed, which have a much greater duration of action, and are currently an effective treatment option for T2D by prolonging insulin secretion in patients. Additionally, there is continuing emerging evidence that these therapies alleviate the post-diagnosis complications of T2D to a greater extent than other treatments. Current GLP-1 based therapies all act as orthosteric agonists for the GLP-1 receptor (GLP-1R). Interestingly, it has emerged that GLP-1R also has allosteric binding sites and agonists have been developed for these sites. The objective of this study was to determine if allosteric agonists had superior effects on insulin secretion compared to orthosteric, and could therefore be a more effective treatment for T2D. Rat pancreatic beta-cell lines (INS-1E and INS-1 832/3) have been shown to mimic native islet beta-cell behaviour, and therefore in vitro experiments carried out with these cell lines in this study have clinical relevance. This study demonstrated how INS-1E and INS-1 832/3 cells responded to varying treatments with both types of GLP-1R agonists and the differential mechanisms by which these agonists mediated their actions. Additionally, how cells responded to treatments depending on whether they are in healthy, diabetic or recovered states was assessed to demonstrate how islet beta-cells’ response can be altered depending on the conditions they have been chronically exposed to pre-treatment. Overall, findings from this study demonstrate that allosteric agonists have a superior duration of action and the mechanisms by which both types of agonist exert their actions are distinct.
published_date 2022-02-15T04:16:41Z
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