Detecting the undetected: measuring levels of three proteins in the blood can aid detection of undiagnosed prediabetes

Scientists have used a proteomics approach to identify a three-protein signature in the blood that can improve detection of isolated impaired glucose tolerance, a form of prediabetes. The research, led by scientists from the Medical Research Council (MRC) Epidemiology Unit at the University of Cambridge, UK, and Berlin Institute of Health at Charité, Germany, is published today in Nature Medicine.

Medical and behavioural interventions in individuals with prediabetes are effective in delaying or preventing the onset of type 2 diabetes, but a substantial proportion of people with prediabetes are missed by current clinical screening and diagnostic techniques. Individuals with isolated impaired glucose tolerance (isolated IGT), a common subtype of prediabetes, can only be identified through oral glucose tolerance testing as they have normal results with more commonly undertaken tests. Oral glucose tolerance testing is a time-consuming procedure requiring repeated blood draws, and is not routinely performed as part of type 2 diabetes clinical screening strategies.

The authors used a proteomic assay to measure the levels of nearly 5,000 proteins in blood plasma samples from more than 11,000 participants in the Fenland Study, each of whom underwent an oral glucose tolerance test. The authors created a machine learning algorithm that was able to extract a core set of few proteins out of the thousands measured that were most informative in identifying people most likely to have isolated IGT in advance of undertaking an oral glucose tolerance test.  

The authors identified a signature of only three proteins that when combined with standard screening techniques for impaired glucose tolerance improved identification of individuals with isolated IGT in the Fenland study cohort, and subsequently confirmed this finding in the independent Whitehall II study. Their results also indicate that fasting before the blood sample is taken does not significantly change the reliability of the three protein signature for identifying people with impaired glucose tolerance, which would greatly increase the application of the test in clinical practice.

PhD student Julia Carrasco Zanini, first author on the paper, said:

“The Fenland Study is unique for its size in combining genetic data and blood sampling with objective measurements of a range of clinical characteristics that includes oral glucose tolerance testing. By combining this resource with broad-capture proteomics technology we were able to identify protein signatures that substantially improved detection of impaired glucose tolerance.”

The authors suggest that by replacing the two-step screening strategy recommended by current guidelines with a three-step screening strategy that incorporates testing for the three-protein signature, the number of individuals who need to undergo oral glucose tolerance testing to identify an isolated IGT case could be substantially reduced. However, they note that some individuals with isolated IGT would still be missed, an important consideration for clinical implementation.

Senior author Professor Claudia Langenberg said:

“Our strategy has the potential to address an important unmet clinical need: the identification of a meaningful proportion of people with prediabetes who currently remain undetected. Early identification would enable preventive lifestyle and behavioural interventions to improve the health of affected individuals and alleviate the burden to health-care systems caused by their delayed diagnosis.

We would now like to evaluate the three-protein signature in other populations and ethnic groups, and ultimately to test the three step strategy for identifying prediabetes in randomised screening trials.”

The Fenland Study is funded by the Medical Research Council. Proteomic measurements were supported and governed by a collaboration agreement between the University of Cambridge and SomaLogic.

Reference

Carrasco-Zanini J. et al. Proteomic signatures for identification of impaired glucose tolerance; Nature Medicine; 10 Nov 2022; DOI: 10.1038/s41591-022-02055-z

When published this paper will be available at https://www.nature.com/articles/s41591-022-02055-z

Research briefing

Carrasco-Zanini J. and Langenberg C. Broad-capture proteomics and machine learning for early detection of type 2 diabetes risk; Nature Medicine; 10 Nov 2022; DOI: 10.1038/s41591-022-02056-y

When published this research briefing will be available at https://www.nature.com/articles/s41591-022-02056-y

 

ENDS

 

Notes

Julia Carrasco Zanini is a PhD student at the MRC Epidemiology Unit

Professor Claudia Langenberg is Director of Queen Mary University of London’s Precision Healthcare University Research Institute and Professor at the Berlin Institute of Health at Charité, and was an MRC investigator and programme leader at the MRC Epidemiology Unit when this work was done.

About the University of Cambridge

The University of Cambridge is one of the world’s top ten leading universities, with a rich history of radical thinking dating back to 1209. Its mission is to contribute to society through the pursuit of education, learning and research at the highest international levels of excellence.

The University comprises 31 autonomous Colleges and 150 departments, faculties and institutions. Its 24,450 student body includes more than 9,000 international students from 147 countries. In 2020, 70.6% of its new undergraduate students were from state schools and 21.6% from economically disadvantaged areas.

Cambridge research spans almost every discipline, from science, technology, engineering and medicine through to the arts, humanities and social sciences, with multi-disciplinary teams working to address major global challenges. Its researchers provide academic leadership, develop strategic partnerships and collaborate with colleagues worldwide.

The University sits at the heart of the ‘Cambridge cluster’, in which more than 5,300 knowledge-intensive firms employ more than 67,000 people and generate £18 billion in turnover. Cambridge has the highest number of patent applications per 100,000 residents in the UK. www.cam.ac.uk

About the MRC Epidemiology Unit

The MRC Epidemiology Unit is a department at the University of Cambridge. It is working to improve the health of people in the UK and around the world.  Obesity, type 2 diabetes and related metabolic disorders present a major and growing global public health challenge. These disorders result from a complex interplay between genetic, developmental, behavioural and environmental factors that operate throughout life. The mission of the Unit is to investigate the individual and combined effects of these factors and to develop and evaluate strategies to prevent these diseases and their consequences. www.mrc-epid.cam.ac.uk

About the Medical Research Council

The Medical Research Council is at the forefront of scientific discovery to improve human health. Founded in 1913 to tackle tuberculosis, the MRC now invests taxpayers’ money in some of the best medical research in the world across every area of health. Thirty-three MRC-funded researchers have won Nobel prizes in a wide range of disciplines, and MRC scientists have been behind such diverse discoveries as vitamins, the structure of DNA and the link between smoking and cancer, as well as achievements such as pioneering the use of randomised controlled trials, the invention of MRI scanning, and the development of a group of antibodies used in the making of some of the most successful drugs ever developed. Today, MRC-funded scientists tackle some of the greatest health problems facing humanity in the 21st century, from the rising tide of chronic diseases associated with ageing to the threats posed by rapidly mutating micro-organisms. The Medical Research Council is part of UK Research and Innovation. https://mrc.ukri.org/