Investigating central and pancreatic GIPR signalling; implications for the treatment of metabolic disease

Obesity and type 2 diabetes are global pandemics. While obesity pharmacotherapies have been dominated by glucagon-like peptide-1 receptor (GLP-1R) agonists, there has been a recent surge of interest into how best to target the glucose-dependent insulinotropic polypeptide receptor (GIPR) to treat these two diseases. Paradoxically, it appears both GIPR agonists and antagonists reduce appetite and result in weight loss in preclinical models. The aim of this thesis was to investigate the metabolic benefits of GIPR targeting and provide an in-depth analysis of GIPR signalling. To this end, a new long-acting GIPR agonist, GIP108, was pharmacologically characterised and when compared to previously published GIPR antagonists, both GIPR agonism and GIPR antagonism resulted in weight loss, but only GIPR agonism improved glycaemia. I next investigated GIPR signalling in neuronal and pancreatic tissue with the aim of exploring functional desensitisation in response to sustained GIPR agonism, a proposed mechanism as to why both GIPR agonism and antagonism reduce appetite. While I was unable to detect cAMP responses to GIPR agonism in hypothalamic neurons, pronounced cAMP responses were detected in pancreatic islets. Prolonged exposure to GIPR agonists resulted in profound target receptor homologous desensitisation in mouse islets, a response that was also observed with GLP-1R agonists. When investigating GIPR desensitisation in vivo, GIP108 pre-treatment reduced acute blood glucose lowering, but not anorectic, responses to GIP treatment. Initial investigations as to the cause of GIPR desensitisation showed minimal agonist- induced internalisation or beta-arrestin-2 activation at the mouse GIPR. Characterisation of novel a GiprHalo/Halo mouse model showed this would not be a suitable model to further explore trafficking of the endogenous GIPR. The results of this thesis provide understanding as to the mechanism of GIPR agonist versus antagonist effects, as well as highlighting the benefits of the design of GIPR agonists with a reduced desensitisation tendency.