Glucagon is best known for opposing the actions of insulin, to increase blood glucose levels through glycogenolysis and gluconeogenesis in response to hypoglycaemia. However, glucagon also increases energy expenditure and suppresses appetite. These pleiotropic effects of glucagon have been harnessed to develop novel agents to treat diabetes and obesity. Drugs which contain a glucagon receptor agonist element have been counterintuitively shown to improve glucose homeostasis. It remains poorly understood how glucagon acts at the level of the pancreatic islet to modulate insulin secretion.
This work aims to investigate the weight-loss-independent actions of a long acting glucagon analogue, G778, on islet insulin secretory function. Utilising a novel imaging platform, longitudinally visualising pancreatic islets implanted in the anterior chamber of the murine eye, I have demonstrated that chronic treatment of diet-induced obese and diabetic mice with a glucagon analogue induced superior improvement in islet secretory function compared with the equivalent weight loss achieved through dietary restriction alone.
To further investigate the effects of glucagon action in the islet, I developed a mouse model with deletion of the glucagon receptor (GCGR) restricted to pancreatic β-cells. The phenotype of this mouse reveals a defective insulin secretory phenotype, which was confirmed to be a functional deficit and not related to changes in islet development. As part of this thesis I have also developed the novel technique of hyperglycaemic clamps in freely moving mice and the final section of this thesis is dedicated to the method development of this technical challenge.
In summary, this thesis provides evidence for the role of glucagon signalling in the enhancement of insulin secretory function and adds to evidence for the use of glucagonergic agents to treat Type 2 diabetes.