Endocrine Abstracts

Background: There is renewed interest in the therapeutic targeting of the glucose-dependent insulinotropic polypeptide receptor (GIPR) following the market-leading metabolic improvement induced by glucagon-like peptide-1 receptor (GLP-1R)/ GIPR co-agonist tirzepatide. We have previously shown using ex vivo and in vivo models that chronic exposure to the investigational GIPR agonist GIP108 resulted in significant desensitisation of the mouse pancreatic GIPR, a process that likely minimises its therapeutic effect. As there are recognised differences between mouse and human GIPR trafficking processes involved in desensitisation, we assessed whether the human GIPR is also prone to agonist induced receptor desensitisation in pancreatic beta cells. We also studied desensitisation of the mouse and human GIPR in response to chronic exposure to tirzepatide, shown to signal predominantly through the GIPR in human islets. Desensitisation of the human beta cell GLP-1R with liraglutide was also studied for comparison.

Methods: Mouse GIPR desensitisation was studied in dispersed pancreatic islets from wild-type C57BL/6J mice and Glp1r^-/- mice. Human beta cell GIPR and GLP-1R desensitisation was studied using validated human beta cell model EndoC-βH5® cells. Cells were transduced with fluorescence-based cADDis cAMP biosensor enabling cAMP responses to be measured using live cell imaging.

Results: 24-hour pre-treatment with tirzepatide resulted in significant mouse GIPR desensitisation in islets from wild-type and Glp1r^-/- mice. Following identification of suitable pre-treatment and re-challenge doses of peptides based on target engagement and stability studies, we observed significant human GIPR desensitisation following 24-hour GIP108 and tirzepatide pre-treatment, and significant human GLP-1R desensitisation following 24-hour liraglutide pre-treatment.

Conclusion: Chronic GIPR agonism resulted in human beta cell GIPR desensitisation, highlighting the need to develop GIPR agonists with reduced desensitisation tendency. This is an important step towards the design of metabolic pharmacotherapies of the highest possible efficacy for the treatment of obesity and type 2 diabetes.