Dietary haem iron intake is linked to an increased risk of type 2 diabetes (T2D), but the underlying plasma biomarkers are not well understood. We analysed data from 204,615 participants (79% females) in three large US cohorts over up to 36 years, examining the associations between iron intake and T2D risk. We also assessed plasma metabolic biomarkers and metabolomic profiles in subsets of 37,544 (82% females) and 9,024 (84% females) participants, respectively. Here we show that haem iron intake but not non-haem iron is associated with a higher T2D risk, with a multivariable-adjusted hazard ratio of 1.26 (95% confidence interval 1.20–1.33; P for trend <0.001) comparing the highest to the lowest quintiles. Haem iron accounts for significant proportions of the T2D risk linked to unprocessed red meat and specific dietary patterns. Increased haem iron intake correlates with unfavourable plasma profiles of insulinaemia, lipids, inflammation and T2D-linked metabolites. We also identify metabolites, including l-valine and uric acid, potentially mediating the haem iron–T2D relationship, highlighting their pivotal role in T2D pathogenesis.

膳食血红素摄入量与 2 型糖尿病 (T2D) 风险增加有关，但其潜在的血浆生物标志物尚不清楚。我们分析了美国三个大型队列的 204,615 名参与者（79% 为女性）长达 36 年的数据，研究了铁摄入量与 T2D 风险之间的关联。我们还分别评估了 37,544 名（82% 女性）和 9,024 名（84% 女性）参与者的血浆代谢生物标志物和代谢组学概况。在这里，我们表明，血红素铁摄入量而非非血红素铁摄入量与较高的 T2D 风险相关，与最高风险比相比，多变量调整后的风险比为 1.26（95% 置信区间 1.20–1.33；趋势P <0.001）到最低的五分位数。血红素铁在与未加工红肉和特定饮食模式相关的 T2D 风险中占很大比例。血红素铁摄入量增加与胰岛素血症、血脂、炎症和 T2D 相关代谢物的不良血浆特征相关。我们还鉴定了代谢物，包括L-缬氨酸和尿酸，可能介导血红素铁与 T2D 关系，强调它们在 T2D 发病机制中的关键作用。