E-Thesis 130 views
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
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...
|Supervisor:||Kanamarlapudi, Venkateswarlu ; Bain, Steve C.|
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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.
Type 2 diabetes, Glucagon-like peptide 1
Faculty of Medicine, Health and Life Sciences