Glucagon analogue therapy for obesity and metabolic disease; implications of amino acid metabolism
File(s)
Author(s)
Hope, David
Type
Thesis
Abstract
Obesity and its related comorbidities pose a significant challenge to the individual and
global healthcare systems. Bariatric surgery has provided a benchmark for weight loss
outcomes however is limited by supply of resources, side effects and patient preference.
Over the last two decades, significant progress has been made in the development of
pharmacotherapies for the treatment of obesity and metabolic disease. GLP-1-based
analogues have emerged as a safe and effective anti-obesity medicines (AOM), for
example, Semaglutide (Novo Nordisk) and Tirzepetide (Eli Lilly).
‘Multi-agonists’ targeting multiple hormone receptors are actively being developed and
have the potential to achieve substantial weight loss. A key component of many of these
is glucagon receptor activity, which leverages metabolic benefits of glucagon including
enhanced energy expenditure and improved lipid metabolism. However, glucagon
enhances hepatic amino acid catabolism and can lead to hypoaminoacidemia in excess.
Emerging evidence also suggests that hypoaminoacidemia leads to a divergent activation
of energy expenditure, which raises the possibility that glucagon-mediated EE may be a
response to low plasma amino acid availability. This thesis aims to determine whether a
long-acting analogue active at the glucagon receptor results in chronic suppression of
amino acids and the implications of this on whole-body physiology.
In this thesis, a long-acting glucagon analogue, G108, is used to explore the effect on
amino acid metabolism. In an obese mouse model, a high protein diet ‘rescues’ plasma
amino acids and mitigates against functional muscle loss in G108-treated mice. Glucagon mediated energy expenditure and body weight loss are also linked to its action on hepatic
amino acid catabolism. This was confirmed with mechanistic studies in obese mice.
Despite a high protein diet, key benefits of glucagon receptor signalling remained in
G018-treated mice, including improved hepatic lipid metabolism and blood glucose
control. A phase 1 study was carried out using a potent GLP-1R/GCGR co-agonist, G3215,
which led to a broad reduction in plasma amino acids and highlighting the importance of
screening for changes in protein metabolism in further development. Finally, strategies
are suggested to optimise glucagon-receptor targeted multi-agonists for the treatment of
obesity and metabolic disease.
global healthcare systems. Bariatric surgery has provided a benchmark for weight loss
outcomes however is limited by supply of resources, side effects and patient preference.
Over the last two decades, significant progress has been made in the development of
pharmacotherapies for the treatment of obesity and metabolic disease. GLP-1-based
analogues have emerged as a safe and effective anti-obesity medicines (AOM), for
example, Semaglutide (Novo Nordisk) and Tirzepetide (Eli Lilly).
‘Multi-agonists’ targeting multiple hormone receptors are actively being developed and
have the potential to achieve substantial weight loss. A key component of many of these
is glucagon receptor activity, which leverages metabolic benefits of glucagon including
enhanced energy expenditure and improved lipid metabolism. However, glucagon
enhances hepatic amino acid catabolism and can lead to hypoaminoacidemia in excess.
Emerging evidence also suggests that hypoaminoacidemia leads to a divergent activation
of energy expenditure, which raises the possibility that glucagon-mediated EE may be a
response to low plasma amino acid availability. This thesis aims to determine whether a
long-acting analogue active at the glucagon receptor results in chronic suppression of
amino acids and the implications of this on whole-body physiology.
In this thesis, a long-acting glucagon analogue, G108, is used to explore the effect on
amino acid metabolism. In an obese mouse model, a high protein diet ‘rescues’ plasma
amino acids and mitigates against functional muscle loss in G108-treated mice. Glucagon mediated energy expenditure and body weight loss are also linked to its action on hepatic
amino acid catabolism. This was confirmed with mechanistic studies in obese mice.
Despite a high protein diet, key benefits of glucagon receptor signalling remained in
G018-treated mice, including improved hepatic lipid metabolism and blood glucose
control. A phase 1 study was carried out using a potent GLP-1R/GCGR co-agonist, G3215,
which led to a broad reduction in plasma amino acids and highlighting the importance of
screening for changes in protein metabolism in further development. Finally, strategies
are suggested to optimise glucagon-receptor targeted multi-agonists for the treatment of
obesity and metabolic disease.
Version
Open Access
Date Issued
2023-01
Date Awarded
2023-03
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Tan, Tricia
Bloom, Stephen
Owen, Bryn
Sponsor
Medical Research Council (Great Britain)
Grant Number
MR/S02171X/1
Publisher Department
Department of Metabolism, Digestion and Reproduction
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)