Circulating metabolites, genetics and lifestyle factors in relation to future risk of type 2 diabetes

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.

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Journal
Nature Medicine
Published
2026-01-14
DOI
https://doi.org/10.1038/s41591-025-04105-8
Citations
1
Primary Topic
Metabolomics and Mass Spectrometry Studies
Type
article
Field-Weighted Citation Impact
22.24
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article

Circulating metabolites, genetics and lifestyle factors in relation to future risk of type 2 diabetes

Jordi Salas‐Salvadó, QIBIN QI, Ching-ti Liu, Eun Hye Moon et al.
1 citations
Nature Medicine
Metabolomics and Mass Spectrometry Studies
22.24
article

Circulating metabolites, genetics and lifestyle factors in relation to future risk of type 2 diabetes

Jordi Salas‐Salvadó, QIBIN QI, Ching-ti Liu, Eun Hye Moon, Guning Liu, Chengyong Jia, Buu Minh Thanh Truong, Anne M. Drolet, Jordi Merino, Zhendong Mei, Jenkinson, Liming Liang, Xikun Han, Nona Sotoodehnia, Casey M. Rebholz, JoAnn E. Manson, Alexis C. Wood, Miguel Angel Martínez-González, Jie Hu, Eric Boerwinkle, Yongmei Liu, Lesley F. Tinker, Taryn Alkis, Xiuqing Guo, Jennifer A. Brody, Frank B. Hu, Shilpa N. Bhupathiraju, Xingyan Wang, Marta Guasch-Ferré, Rozenn N. Lemaitre, Jerome I. Rotter, Jun Li, Bing Yu, Katherine L. Tucker, Simin Liu, Stephen S. Rich, Kai Luo, Robert C. Kaplan, Thomas J. Wang, Su Yon Jung, Elizabeth Selvin, Jie Yao, A. Heather Eliassen, Clary B. Clish, Kathryn M. Rexrode, Kari E. North, Huan Yun, Josée Dupuis, Robert E. Gerszten, Xiyuan Zhang, James B. Meigs
article en
1 citations

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.

Nature MedicineVol. 32(2)
Broad Institute (US), Boston University (US), University of North Carolina at Chapel Hill (US), University of Copenhagen (DK), Brigham and Women's Hospital (US), Albert Einstein College of Medicine (US), Beth Israel Deaconess Medical Center (US), University of Massachusetts Lowell (US), Harvard University (US), Johns Hopkins University (US), University of California, Los Angeles (US), University of Washington (US), University of California, Irvine (US), University of Michigan (US), Novo Nordisk Foundation (DK), Instituto de Salud Carlos III (ES), UCLA Medical Center (US), Massachusetts General Hospital (US), Fred Hutch Cancer Center (US), Institut de Recerca Biomèdica Catalunya Sud (ES), Navarre Institute of Health Research (ES), Navarrabiomed (ES), Duke Medical Center (US), Children's Nutrition Research Center at Baylor College of Medicine (US), The University of Texas Health Science Center (US), Harbor–UCLA Medical Center (US), McGill University (CA), University of Virginia (US), Universitat Rovira i Virgili (ES), Brandeis University (US), Universidad de Navarra (ES), The University of Texas Health Science Center at Houston (US)
Openalex Percentile: Top 3%
Metabolomics and Mass Spectrometry Studies
22.24
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Circulating metabolites, genetics and lifestyle factors in relation to future risk of type 2 diabetes — Jordi Salas‐Salvadó, QIBIN QI, et al. · Nature Medicine (2026) | TGRS Research Map | TGRS