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Title: Glucagon-like peptide-1 receptor biased agonism and its functional consequences in type 2 diabetes
Author: Jones, Benjamin
ISNI:       0000 0004 7657 5564
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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Glucagon-like peptide-1 (GLP-1) is released by the intestine in response to food ingestion, and plays a key role in postprandial metabolism. Furthermore, pharmacological GLP-1 receptor agonists are an effective treatment for type 2 diabetes, as they stimulate pancreatic beta cells to secrete insulin, and increase insulin sensitivity via weight loss. GLP-1R activation is coupled to insulin secretion via cyclic AMP generation. However, recent evidence suggests an important additional role of non-canonical pathways such as recruitment of β-arrestins, which can act as protein scaffolds to coordinate activation of other signalling proteins. Paradoxically, arrestin recruitment may negatively modulate signalling by inducing receptor desensitisation and sequestration from the plasma membrane, although this has not yet been demonstrated for the GLP- 1R. Biased agonism is a new concept in pharmacology, defined by differential activation of divergent signalling pathways from the same receptor by different agonists. In this project, peptide agonists based on GLP-1 and its homologue exendin-4, but with a variety of substitutions close to the peptide N-terminal region, were designed and tested for biased signalling between cAMP generation and β- arrestin recruitment. To determine the downstream consequences of bias, selected agonists were tested for insulin secretion in vitro using INS-1 832/3 cells and human islets. Despite an important role for β-arrestin recruitment in insulin secretion suggested by the literature, agonists with minimal β- arrestin recruitment were considerably more insulinotropic than those with robust arrestin responses. This was due to reduced GLP-1R desensitisation. When tested in high-fat, high-sucrose fed mice, a rodent model of type 2 diabetes, agonists with minimal arrestin recruitment were more effective than exendin-4 at preventing hyperglycaemia. Surprisingly, appetite suppression with biased peptides was unaltered, suggesting that these compounds might achieve glycaemic improvements without concomitant increases in nausea. As such, biased agonists targeting the GLP-1R may represent a therapeutic advance in type 2 diabetes treatment.
Supervisor: Bloom, Steve ; Rutter, Guy ; Tan, Tricia Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral