Faculty, Staff and Student Publications

Publication Date

2-1-2026

Journal

Nature Medicine

DOI

10.1038/s41591-025-04105-8

PMID

41535386

PMCID

PMC12920144

PubMedCentral® Posted Date

1-14-2026

PubMedCentral® Full Text Version

Post-print

Abstract

The human metabolome reflects complex metabolic states affected by genetic and environmental factors. However, metabolites associated with type 2 diabetes (T2D) risk and their determinants remain insufficiently characterized. Here we integrated blood metabolomic, genomic and lifestyle data from up to 23,634 initially T2D-free participants from ten cohorts. Of 469 metabolites examined, 235 were associated with incident T2D during up to 26 years of follow-up, including 67 associations not previously reported across bile acid, lipid, carnitine, urea cycle and arginine/proline, glycine and histidine pathways. Further genetic analyses linked these metabolites to signaling pathways and clinical traits central to T2D pathophysiology, including insulin resistance, glucose/insulin response, ectopic fat deposition, energy/lipid regulation and liver function. Lifestyle factors-particularly physical activity, obesity and diet-explained greater variations in T2D-associated versus non-associated metabolites, with specific metabolites revealed as potential mediators. Finally, a 44-metabolite signature improved T2D risk prediction beyond conventional factors. These findings provide a foundation for understanding T2D mechanisms and may inform precision prevention targeting specific metabolic pathways.

Keywords

Humans, Diabetes Mellitus, Type 2, Life Style, Female, Male, Metabolome, Risk Factors, Middle Aged, Adult, Obesity, Insulin Resistance, Metabolomics, Diet

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