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Circulating Metabolites Associate with and Improve the Prediction of All-Cause Mortality in Type 2 Diabetes

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posted on 31.03.2022, 21:35 by Maria Giovanna Scarale, Mario Mastroianno, Cornelia Prehn, Massimiliano Copetti, Lucia Salvemini, Jerzy Adamski, Salvatore De Cosmo, Vincenzo Trischitta, Claudia Menzaghi
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 and RECODe, 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 (HRs, [95%CIs] 1.60, [1.43-1.80]; 1.53, [1.37-1.71]; 0.71, [0.62-0.80] per 1SD). The kynurenine/tryptophan ratio (KTR-a proxy of indoleamine-2,3-dioxygenase which degrades tryptophan to kynurenine and contribute to a pro-inflammatory status) mediated 42% of the significant association between the anti-atherogenic 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.

Funding

M.G.S. was supported by Fondazione Umberto Veronesi. This study was supported by Ministero dell’Istruzione dell’Università e della Ricerca “Progetti di Ricerca di Interesse Nazionale” (PRIN) 2015 grant (to V.T.) and by Ministero della Salute grant RF-2013-02356459 and EFSD/Sanofi Grant 2017 (to C.M.).

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