A massive long-term study has uncovered a blood-based metabolite signature that predicts who is more likely to develop type 2 diabetes, beyond standard risk factors. The work also links diet, lifestyle and genetics to these tiny molecules, pointing toward more personalized prevention.
Type 2 diabetes often develops silently over many years, but a new study suggests that tiny molecules circulating in the blood could offer an early warning — and eventually help tailor prevention to each person.
Researchers from Mass General Brigham and Albert Einstein College of Medicine have identified hundreds of blood metabolites, or small molecules produced as the body breaks down food and carries out daily functions, that are linked to the future risk of type 2 diabetes. They also created a metabolomic “signature” that predicted who would go on to develop the disease better than traditional risk factors alone.
The work, published in Nature Medicine, draws on data from 23,634 people of diverse ethnic backgrounds across 10 long-term cohort studies, followed for up to 26 years. None had type 2 diabetes at the start.
By analyzing 469 different metabolites in blood samples, along with detailed genetic, diet and lifestyle information, the team found that 235 metabolites were associated with either higher or lower risk of developing type 2 diabetes. Sixty-seven of those links had not been reported before.
The researchers then combined the most informative metabolites into a 44-molecule signature that improved prediction of future diabetes risk beyond standard measures such as body mass index, blood sugar and cholesterol.
First and co-corresponding author Jun Li, an assistant professor of medicine and associate epidemiologist in the Mass General Brigham Department of Medicine, noted that the study highlights how everyday choices may shape the body’s internal chemistry in ways that affect diabetes risk.
“Interestingly, we found that diet and lifestyle factors may have a stronger influence on metabolites linked to type 2 diabetes than on metabolites not associated with the disease,” Li, who is also an assistant professor in the Department of Nutrition at Harvard T.H. Chan School of Public Health, said in a news release.
She explained that this influence was especially clear for well-known risk and protective factors.
“This is especially true for obesity, physical activity, and intake of certain foods and beverages such as red meat, vegetables, sugary drinks, and coffee or tea. Increasing evidence suggests that these dietary and lifestyle factors are associated with greater or lower risk of type 2 diabetes. Our study revealed that specific metabolites may act as potential mediators, linking these factors with type 2 diabetes risk,” Li added.
In other words, the metabolites may be part of the biological chain that connects what people eat and how active they are to whether they eventually develop type 2 diabetes. Understanding those links could help researchers pinpoint which pathways matter most — and which might be targeted by new drugs or lifestyle interventions.
The study also examined how genetics intersect with metabolism and diabetes risk. The metabolites tied to type 2 diabetes were found to be genetically linked to clinical traits and tissue types that are relevant to the disease, suggesting that inherited factors and lifestyle may converge on common biological pathways.
Senior and co-corresponding author Qibin Qi, a professor in the Department of Epidemiology & Population Health and associate director of that department’s Center for Population Cohorts at Albert Einstein College of Medicine, emphasized that the scale and design of the project set it apart.
“Our study is the largest and most comprehensive investigation of blood metabolic profiles associated with the risk of type 2 diabetes that integrates genomic and diet and lifestyle data from a wide range of people, and lays important groundwork for future studies,” Qi said in the news release.
Type 2 diabetes is the most common form of diabetes worldwide, accounting for more than 90% of cases. It occurs when the body becomes resistant to insulin or does not make enough of it, leading to high blood sugar that can damage blood vessels and organs over time. Because it often progresses quietly, many people are diagnosed only after complications have begun.
Today, clinicians estimate diabetes risk using factors such as age, weight, family history, blood pressure, cholesterol and blood sugar levels. Metabolomic signatures, like the one developed in this study, could one day help identify high-risk individuals earlier and more precisely, potentially years before standard tests would flag a problem.
That could open the door to more personalized prevention. For example, two people with similar body weight and blood sugar might have very different metabolite profiles, reflecting different underlying biology. In the future, those profiles might guide tailored advice on diet, exercise or medications.
The researchers caution, however, that their findings are an early step. Observational studies like this one can reveal associations but cannot prove that specific metabolites cause diabetes.
“While these new findings offer important insights, additional experimental studies and clinical trials are needed to confirm the causality of these associations and clarify how these metabolic pathways contribute to the development of type 2 diabetes,” Qi added.
The collaborative team plans to keep probing why people develop diabetes through different biological routes, with the goal of informing more targeted prevention strategies for those at highest risk.
Li pointed out that mapping the biology of disease is key to better care.
“A better understanding of the biological pathways behind disease can help drive the development of new treatments,” she added. “Our findings lay the groundwork for a deeper understanding of type 2 diabetes and may help inform the development of precision preventive strategies targeting specific metabolic pathways.”
For now, the study reinforces what many public health experts already advise: maintaining a healthy weight, staying physically active and paying attention to diet — including limiting sugary drinks and processed meats and eating more vegetables — are important steps to reduce the risk of type 2 diabetes.
What is new is the promise that, in the coming years, a simple blood test measuring dozens of metabolites could help reveal who needs those preventive steps most urgently, and which strategies might work best for them.
Source: Mass General Brigham