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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月14日

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

摘要

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.