TYPE 2 diabetes risk was more accurately predicted in a large international analysis that integrated circulating metabolites with genetic and lifestyle data, revealing hundreds of biochemical markers linked to future disease onset.
In one of the most comprehensive metabolomic investigations to date, researchers analysed blood samples from up to 23,634 adults who were initially free from diabetes and followed them for as long as 26 years. The study identified a wide metabolic footprint preceding diagnosis, suggesting that subtle biochemical changes may appear decades before clinical disease develops.
How Circulating Metabolites Shaped Type 2 Diabetes Risk
Type 2 diabetes is a chronic metabolic disorder characterised by insulin resistance and impaired glucose regulation, and it continues to rise globally, placing major strain on healthcare systems. Early identification of individuals at high type 2 diabetes risk is therefore a public health priority.
Among 469 circulating metabolites assessed, 235 were significantly associated with incident disease. Notably, 67 of these associations had not been previously reported and spanned diverse biological pathways, including bile acid metabolism, lipid handling, carnitine transport, the urea cycle, and amino acid pathways involving arginine, glycine, and histidine. Genetic analyses linked these metabolites to core mechanisms underlying type 2 diabetes risk, such as insulin resistance, hepatic function, ectopic fat deposition, and energy and lipid regulation.
Lifestyle factors explained a substantial proportion of variation in diabetes-associated metabolites. Physical activity, obesity, and dietary patterns were more strongly related to metabolites linked to disease than to those unrelated to diabetes, suggesting that behavioural factors may modify risk through specific metabolic pathways.
Improving Prediction of Type 2 Diabetes Risk
A key advance was the identification of a 44-metabolite signature that improved prediction of type 2 diabetes risk beyond conventional clinical factors. This finding supports the potential role of metabolomics in precision prevention, complementing established measures such as body mass index and fasting glucose.
The authors acknowledged several limitations. These included platform-specific differences in metabolite coverage, constraints in inferring causality from observational analyses, and the predominance of non-Hispanic White participants, underscoring the need for randomised trials and validation in more diverse populations. Nonetheless, the long follow-up period and multi-cohort design strengthened confidence in the findings.
These results provide a framework for understanding the early biological processes driving type 2 diabetes risk and may inform targeted lifestyle or pharmacological interventions.
Reference
Li J et al. Circulating metabolites, genetics and lifestyle factors in relation to future risk of type 2 diabetes. Nat Med. 2026; DOI:10.1038/s41591-025-04105-8.
