A decades-long study shows how patterns in circulating metabolites, shaped by genes and lifestyle, can identify people at high risk of type 2 diabetes well before symptoms emerge.
Study: Circulating metabolites, genetics and lifestyle factors in relation to future risk of type 2 diabetes. Image Credit: Halfpoint / Shutterstock
Researchers from Mass General Brigham and Albert Einstein College of Medicine have discovered circulating blood metabolites associated with future T2D risk and subsequently developed a multi-metabolite risk signature that improves prediction beyond conventional risk factors. They have published the findings in the journal Nature Medicine.
Global Burden and Biological Basis of Type 2 Diabetes
Diabetes is a chronic metabolic disease characterized by persistently high blood glucose levels. Its prevalence is exponentially increasing worldwide, making it a major public health crisis. About 589 million adults are currently living with diabetes globally, and this number is predicted to increase to more than 853 million by 2050.
T2D accounts for more than 90% of all diabetes cases. This particular subtype is characterized by insulin resistance, pancreatic beta-cell dysfunction, and subsequent hyperglycemia (high blood glucose).
Role of Blood Metabolites in Diabetes Risk
Previous studies have identified more than 100 metabolites, small molecules produced through metabolism, in the blood that are associated with T2D risk. Recent evidence suggests that blood metabolite profiles can be influenced by genetic, health, and lifestyle factors, including diet and physical activity.
Despite this growing body of evidence, metabolites associated with T2D risk and their genetic and lifestyle determinants remain insufficiently characterized. To fill this gap in the literature, researchers from Mass General Brigham and Albert Einstein College of Medicine comprehensively analyzed blood metabolomic data from up to 23,634 initially diabetes-free individuals to identify metabolites associated with the risk of developing T2D over a follow-up period of up to 26 years.
They also analyzed genomic and lifestyle data from these participants to identify genetic and lifestyle determinants of these metabolites.
Identification of Diabetes-Associated Metabolites
The researchers analyzed 469 circulating metabolites measured across two large-scale mass spectrometry platforms in blood samples collected from 23,634 individuals with diverse racial and ethnic backgrounds, including White, Hispanic, and Black participants. They identified 235 metabolites, including 67 newly identified in this study, that were associated with the risk of developing T2D during the follow-up period.
Notably, the observed associations between these metabolites and T2D risk remained statistically significant even after adjusting for conventional risk factors, including obesity, blood lipids, blood pressure, lifestyle factors such as physical activity and diet quality, and kidney function.
Genetic and Lifestyle Determinants of Metabolic Risk
The researchers further observed that many of the identified metabolites are genetically linked to signaling pathways and clinical traits closely related to T2D pathophysiology, including insulin resistance, glucose and insulin responses, ectopic fat deposition, energy and lipid regulation, and liver function.
They also found that lifestyle factors, particularly physical activity, obesity, and diet, explained a greater proportion of variability in diabetes-associated metabolites than in metabolites not associated with the disease. Further analyses suggested that specific metabolites may act as potential mediators, statistically linking these lifestyle factors with future T2D risk.
By examining these mediating pathways, the researchers found that metabolites mediating the inverse association between physical activity and diabetes risk were mainly involved in ectopic fat deposition-related insulin resistance and liver function impairment. In contrast, metabolites mediating the association between coffee or tea consumption and diabetes risk were linked to polyphenol metabolism, glucose response, insulin resistance, ectopic fat deposition, and liver function, with some metabolites showing protective associations and others showing positive associations with risk.
Taken together with the genetic analyses, these findings support biologically plausible pathways that may underlie T2D development and generate hypotheses for future mechanistic investigation, rather than establishing causality.
Development of a Multi-Metabolite Risk Signature
In the final phase of the study, researchers developed a research-derived signature of 44 metabolites that significantly improved risk prediction beyond conventional clinical risk factors, including age, sex, BMI, and blood glucose. This metabolomic signature was internally validated across multiple cohorts and was able to identify individuals at substantially elevated long-term risk of developing T2D before clinical diagnosis, with strong risk gradients observed across prediction score categories.
In other words, this metabolomic signature captures complex patterns of circulating metabolites associated with future T2D risk. In the future, this set of metabolites could potentially be implemented in clinical and research settings as risk-stratification tools to identify high-risk individuals for timely prevention, or as monitoring biomarkers to evaluate the metabolic effects of dietary and lifestyle interventions.
Implications, Limitations, and Future Directions
Overall, the study findings provide a foundation for a more detailed understanding of T2D pathophysiology, which may facilitate the development of precision prevention strategies targeting specific metabolic pathways.
Because of the observational study design, the researchers could not determine whether the observed associations are causal. However, the study incorporated genetic analyses to strengthen causal inference for selected metabolites, including analyses suggesting limited evidence of reverse causation. Future randomized controlled trials are needed to directly test how diet, physical activity, or other lifestyle interventions influence diabetes-associated metabolites and disease risk.
Although the study included participants from multiple racial and ethnic backgrounds and the observed associations were generally consistent across groups, approximately 77% of the study population was non-Hispanic White. This limitation highlights the need for future studies involving more diverse populations.
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