Type 2 diabetes affects millions of people in the UK and is one of the fastest-growing global health challenges. Many of the most promising treatments work by acting on a large family of membrane proteins called G protein-coupled receptors (GPCRs), which help the body control blood sugar. Some of these drugs, such as Ozempic, have been hugely successful, but many similar drugs fail in clinical trials or work inconsistently from one person to the next, and scientists do not fully understand why.

Researchers at the University of Bath are investigating an overlooked possibility: that chemical oxidative damage building up inside cells during diabetes may be irreversibly changing how these important drug targets behave and respond to their drugs.

Our approach

In type 2 diabetes, the body experiences increased "oxidative stress", which damages the fatty membranes surrounding our cells in a process called lipid peroxidation. This produces reactive molecules that attach permanently to nearby proteins. The damage occurs in cell membranes - exactly where many of the most important diabetes drug targets sit.

This project focuses on the glucagon receptor, an important target for controlling blood sugar. Early experiments at Bath suggest that these reactive molecules can noticeably change how the glucagon receptor works. The team will now examine this link in detail, asking whether this hidden factor could help explain why some diabetes drugs fail or behave unpredictably from patient to patient.

Aims and objectives

The project aims to:

determine how oxidative damage changes the activity of the glucagon receptor, a key blood-sugar-control target
map the wider network of proteins that the receptor interacts with, and how damage alters those interactions
pinpoint the precise locations on the receptor where this chemical damage occurs
lay the groundwork for 'smarter' medicines, that could work even on damaged drug targets, and for treatments tailored to an individual’s level of cell damage

Methods

The team combines cell biology, microscopy and cutting-edge proteomics and bioinformatics. Using laboratory cell models, the researchers measure how the glucagon receptor responds to drugs when exposed to the reactive molecules produced by oxidative damage.

To map the receptor interactions, they use a technique called proximity proteomics, which works like a molecular snapshot, capturing which proteins are interacting with the receptor at a given moment and how this changes when damage occurs. A complementary chemical approach called chemoproteomics uses a specially designed probe to reveal the exact points on the receptor that become damaged.

This work draws on state-of-the-art mass spectrometry at the Bristol Proteomics Facility and a network of expert collaborators in diabetes biology, redox chemistry and chemical biology. In the longer term, the findings could open a new field of research into how cell oxidative damage shapes GPCR drug responses - not only in diabetes, but potentially in other conditions where oxidative stress plays a role, such as neurodegeneration.