Glucagon analogue therapy for obesity and metabolic disease; implications of amino acid metabolism

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.