Obesity is a growing global epidemic and current medical therapies have proven inadequate. Endogenous satiety hormones provide an attractive target for the development of drugs which aim to cause effective weight loss with minimal side effects. Two related peptide hormones, glucagon and glucagon-like peptide 1 (GLP-1), are the subject of this thesis. Both have been found to reduce appetite and cause weight loss. Additionally, glucagon increases energy expenditure. GLP-1 also improves glucose homeostasis, whereas glucagon causes undesirable hyperglycaemia. It is proposed that co-administration of both peptides will have an additive effect on appetite reduction, while GLP-1 will protect against the hyperglycaemic effect of glucagon.
In this thesis, I have investigated the effects of co-administration of glucagon and GLP-1 on energy balance. Co-infusion of glucagon and GLP-1 in humans reduces food intake, increases energy expenditure and improves glucose homeostasis. This supports the notion that dual agonism at the glucagon and GLP-1 receptors is a rational approach to the development of a new therapy for obesity and diabetes.
To further understand the cellular mechanisms by which glucagon activates the glucagon receptor, I have investigated the interaction of the glucagon receptor with RAMP2, a member of the family of Receptor Activity Modifying Proteins. This work suggests that RAMP2 interacts with the glucagon receptor modifying the agonist activity of glucagon, GLP-1 and related peptides. This work improves our fundamental understanding of the glucagon receptor’s physiological function and how this is modified by RAMP2. It could potentially suggest new therapeutic avenues for obesity and diabetes. For example, it may inform the construction of new peptide analogues with selective agonist activities, incorporating therapeutically desirable properties such as appetite suppression and increase in energy expenditure, without undesired properties such as increasing hepatic glucose output and provoking hyperglycaemia.