Death rate is increased in type 2 diabetes. Unraveling biomarkers of novel pathogenic pathways capable to identify high-risk patients is instrumental to tackle this burden. We investigated the association between serum metabolites and all-cause mortality in type 2 diabetes and then whether the associated metabolites mediate the effect of inflammation on mortality risk and improve ENFORCE (EstimatioN oF mORtality risk in type2 diabetic patiEnts) and RECODe (Risk Equation for Complications Of type 2 Diabetes), two well-established all-cause mortality prediction models in diabetes. Two cohorts comprising 856 individuals (279 all-cause deaths) were analyzed. Serum metabolites (n = 188) and pro- and anti-inflammatory cytokines (n = 7) were measured. In the pooled analysis, hexanoylcarnitine, kynurenine, and tryptophan were significantly and independently associated with mortality (hazard ratio [HR] 1.60 [95% CI 1.43–1.80]; 1.53 [1.37–1.71]; and 0.71 [0.62–0.80] per 1 SD). The kynurenine-to-tryptophan ratio (KTR), a proxy of indoleamine-2,3-dioxygenase, which degrades tryptophan to kynurenine and contributes to a proinflammatory status, mediated 42% of the significant association between the antiatherogenic interleukin (IL) 13 and mortality. Adding the three metabolites improved discrimination and reclassification (all P < 0.01) of both mortality prediction models. In type 2 diabetes, hexanoylcarnitine, tryptophan, and kynurenine are associated to and improve the prediction of all-cause mortality. Further studies are needed to investigate whether interventions aimed at reducing KTR also reduce the risk of death, especially in patients with low IL-13.

中文翻译：

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循环代谢物与 2 型糖尿病全因死亡率相关并提高了对全因死亡率的预测

2型糖尿病的死亡率增加。解开能够识别高危患者的新型致病途径的生物标志物有助于解决这一负担。我们研究了血清代谢物与 2 型糖尿病全因死亡率之间的关系，然后研究了相关代谢物是否介导炎症对死亡风险的影响并改善 ENFORCE（2 型糖尿病患者死亡风险的估计）和 RECODE（并发症风险方程） 2 型糖尿病），两种成熟的糖尿病全因死亡率预测模型。分析了包括 856 人（279 人全因死亡）的两个队列。测量了血清代谢物 (n = 188) 和促炎和抗炎细胞因子 (n = 7)。在汇总分析中，己酰肉碱、犬尿氨酸、和色氨酸与死亡率显着且独立相关（风险比 [HR] 1.60 [95% CI 1.43–1.80]；1.53 [1.37–1.71]；和 0.71 [0.62–0.80]/1 SD）。犬尿氨酸与色氨酸的比率 (KTR) 是吲哚胺-2,3-双加氧酶的代表，可将色氨酸降解为犬尿氨酸并导致促炎状态，介导了 42% 的抗动脉粥样硬化白细胞介素 (IL) 13 和死亡。添加这三种代谢物改善了两种死亡率预测模型的区分和重新分类（所有 P < 0.01）。在 2 型糖尿病中，己酰肉碱、色氨酸和犬尿氨酸与全因死亡率的预测相关并改善了预测。需要进一步研究来调查旨在减少 KTR 的干预措施是否也能降低死亡风险，