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Molecules in diabetic patients could help personalise treatments

IMI project RHAPSODY has identified biomarkers associated with diabetes development and progression, findings that could lead the way to personalised treatments.

21 November 2023
In the foreground of the picture is a woman with diabetes checking her glucose levels by scanning a glucose monitor attached to her upper arm. She is wearing sports clothes and in the background, out of focus, is some exercise equipment. Image by via Shutterstock
A woman with diabetes checking her glucose levels. Image by via Shutterstock

According to the World Health Organisation, around 60 million people in Europe over the age of 25 have diabetes – roughly 10 % of the continent’s population. Rates of the disease are also expected to rise among every age group in the years to come.

To help treat or even prevent these diabetes cases, researchers are searching for molecular indications of diabetes within the body. These ‘biomarkers’ can provide a deeper understanding of how diabetes progresses in the body.

“These [biomarkers] are vital to understand in which patients the need for intervention is greatest,” said Professor Guy Rutter of Imperial College London, who specialises in cell biology and functional genomics. “Even the few biomarkers that already exist are not always sought by physicians,” he said.

He is the co-author of a recent study in Nature Communications that has identified new links to molecules that could act as biomarkers for type 2 diabetes progression. The study is part of the Innovative Medicines Initiative (IMI) project RHAPSODY. The project, which ended in 2021, aimed to better understand the factors that lead to diabetes from pre-diabetes, and how the condition may deteriorate in people with diabetes.

Hunting for clues to diabetes progression

“Our research had two overall goals,” said Prof. Rutter. “Firstly to identify new biomarkers with potential prognostic value, and second to provide molecular insights into the disease process at the level of the individual patient, potentially allowing personalised treatments.“

Since there has been so little research done in this area, the team behind the paper used several analytical techniques to study data from bodily proteins (proteomics), lipids (lipidomics), and small charged molecules (metabolomics).

This ‘multi-omics’ approach used blood samples from 3 000 individuals from patient groups across the UK, Switzerland, France, the Netherlands, Sweden and elsewhere. They also worked with pharmaceutical companies from across Europe and north America who have been working with large cohorts of patients with type 2 diabetes.

The researchers then selected different samples for ‘-omics’ tests; for example 1 267 were selected for metabolomics tests, 900 for lipidomics, and 600 for proteomics. In total around 1 300 proteins were examined, of which 23 molecular biomarkers were determined to be associated with diabetes development and progression. Three of these biomarkers belong to the metabolites group, nine to lipids and 11 to proteins.

Understanding the role of the markers

Two biomarkers stood out from the rest. The protein MIC-1/GDF15 was associated with the highest risk of diabetes progression, confirming several previous research results on this protein. Another protein called NogoR had the next-largest correlation with disease progression, leading the researchers to try to better understand its method of action.  

Prof. Rutter and his team first injected NogoR into mice fed a high fat/high sugar diet. This improved their glucose tolerance. In contrast, in mice with type 2 diabetes, injecting NogoR worsened their insulin sensitivity; in other words damaging their ability to regulate blood sugar levels.

This result, says the paper, shows that the effects of NogoR glucose metabolism in animals are complex, and depend on the state of diabetes. In the future, medication might be able to inhibit this protein, thereby preventing it from killing the pancreatic cells responsible for secreting insulin.

A surprising result

A final result from their analysis showed that that the biomarkers identified for diabetes progression are the same as those related to diabetes risk, which suggests that the same biological process happens in both cases.

This, says Prof. Rutter, was the most surprising result. “I think it’s telling us that many of the same mechanisms (deficiencies in insulin secretion or signalling, for example) underlie disease onset and progression,” he said.

Finding such diverse type 2 diabetes biomarkers could contribute to a more accurate reading of diabetes progression in the future, he says. “Current studies involving machine learning are examining the interaction between these different molecular classes to determine whether we can tease out information on sub-groups of patients with the disease,” he said.

Continuing collaboration

Although the RHAPSODY project ended in 2021, the academic labs and industry partners of the project continue to collaborate. Prof. Rutter says that some of the research they are currently working on includes developing ways to bring measurements of these biomarkers towards routine clinical use, though this will require a change in how clinicians can measure multiple markers of different classes.

“We will then need to find ways to analyse the data meaningfully – and rapidly – perhaps using AI [artificial intelligence] and allied technologies, before feeding it back to the relevant healthcare professionals and patients,” he said.

RHAPSODY is supported by the Innovative Medicines Initiative (IMI) programme, a partnership between the European Union and the European pharmaceutical industry.