Obesity and related diseases of type 2 diabetes mellitus and non-alcoholic fatty liver disease are highly prevalent and responsible for a huge burden of morbidity and mortality. Better understanding of the signalling properties of endogenous metabolic mediators is key to the development of new drugs to treat these conditions. Bile acids and glucagon both regulate post-prandial metabolism, with diverse effects on many tissues and organ systems. Bile acids stimulate gut hormone secretion from the gut and have direct effects on hepatic and peripheral glucose and lipid processing. Glucagon has a particular role in the liver, where it increases endogenous glucose production and decreases lipid storage.
In this thesis I firstly investigated the acute effect of two species of bile acid, ursodeoxycholic acid and chenodeoxycholic acid, on glucose homeostasis and circulating hormone levels after a meal. Both bile acids increased secretion of the anorectic hormones glucagon-like peptide 1 and peptide tyrosine tyrosine. This was associated with an increase in indices of insulin sensitivity. These findings suggest that manipulation of circulating bile acid levels during a meal could be helpful for the treatment of obesity and related diseases.
Secondly, I studied the effect of an allosteric protein, Receptor Activity Modifying Protein 2 (RAMP2) on signalling of the glucagon receptor (GCGR). In human hepatocytes, RAMP2 decreases surface expression of GCGR, and this is associated with an increase in responsiveness to glucagon stimulation. These findings were not translated to differences in glucagon responsiveness in a mouse model of hepatic RAMP2 upregulation. Further experiments in mouse hepatoma cells suggest that this discrepancy may be due to a species difference in activity of the GCGR and RAMP2 orthologs. This body of work improves our understanding of GCGR physiology and is relevant to the development of drugs that target the receptor.