Deciphering the interplay between incretin receptors: new directions in Obesity and Diabetes treatments

Summary

Recently several incretin-based drugs originally designed to treat type II diabetes mellitus (T2DM) have obtained FDA approval for weight loss e.g semaglutide. These therapies mimic the action of the hormone glucagon-like peptide 1 (GLP-1) by stimulating the GLP-1 receptor (GLP-1R) which is expressed on tissues including pancreatic beta cells where it enhances insulin release in a glucose dependent manner.

A second incretin-hormone, the gastric inhibitory polypeptide (GIP) shares a similar mechanism of action to GLP-1 on enhancing glucose dependent insulin release, however, its therapeutic use has been less well studied. The role of GIP receptor (GIPR) remains equivocal, with studies of both GIPR agonism and GIPR antagonism combined with GLP-1R agonism proving to be superior to GLP-1R alone for weight loss and glucose control.

Project aims

As the obesity field is moving towards poly-pharmacology, such as the dual GLP-1/GIP receptor agonist Tirzepatide that was recently approved for weight loss, this project aims to understand the interplay between GLP-1R and GIPR.

In collaboration with AstraZeneca, state-of-the-art pharmacological assays, high performance single molecule imaging and molecular glues (which join two biological molecules together) will enable exploration of GIPR and GLP-1R complex formation.

Additionally, the receptor interaction will be further explored by downstream signalling interrogation using mono and dual agonistic/antagonistic therapeutic agents.

The data we generate will provide enhanced knowledge of GIPR/GLP-1R signalling and may lead to improve weight loss therapeutics.

Contact details

Graham Ladds - grl30@cam.ac.uk

Opportunities

This project is open to applicants who want to do a:

• PhD