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Scarale, M.G.* ; Mastroianno, M.* ; Prehn, C. ; Copetti, M.* ; Salvemini, L.* ; Adamski, J. ; De Cosmo, S.* ; Trischitta, V.* ; Menzaghi, C.*

Circulating metabolites associate with and improve the prediction of all-cause mortality in type 2 diabetes.

Diabetes 71, 1363-1370 (2022)

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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.

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