1. Inflammation and prediction of death in type 2 diabetes. Evidence of an intertwined link with tryptophan metabolism.
- Author
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Menzaghi C, Marucci A, Mastroianno M, Di Ciaccia G, Armillotta MP, Prehn C, Salvemini L, Mangiacotti D, Adamski J, Fontana A, De Cosmo S, Lamacchia O, Copetti M, and Trischitta V
- Abstract
Objective: To study whether inflammation is associated with and helps predict mortality risk in patients with type 2 diabetes. To explore the intertwined link between inflammation and tryptophan metabolism on death risk., Design: Two prospective cohorts: the aggregate Gargano Mortality Study (1,731 individuals; 872 all-cause deaths) as discovery sample, the Foggia Mortality Study (490 individuals; 256 deaths) as validation sample. Twenty-seven inflammatory markers were measured. Causal mediation analysis and in vitro studies were carried out to explore the link between inflammatory markers and the kynurenine-to-tryptophan ratio (KTR) in shaping mortality risk., Results: Using multivariable stepwise Cox regression analysis, IL-4, IL-6, IL-8, IL-13, RANTES and IP-10, were independently associated with death. An inflammation score (I-score) comprising these six molecules is strongly associated with death in both the discovery and the validation cohorts HR (95%CI) = 2.13 (1.91-2.37) and 2.20 (1.79-2.72), respectively. The I-score improved discrimination and reclassification measures (all P<0.01) of two mortality prediction models based on clinical variables. The causal mediation analysis showed that 28% of the KTR effect on mortality was mediated by IP-10. Studies in cultured endothelial cells showed that 5-Methoxy-tryptophan, an anti-inflammatory metabolite derived from tryptophan, reduces the expression of IP-10, thus providing a functional basis for the observed causal mediation., Conclusions: Adding the I-score to clinical prediction models may help identify individuals who are at greater risk of death. Deeply addressing the intertwined relationship between low-grade inflammation and imbalanced tryptophan metabolism in shaping mortality risk may help discover new therapies targeting patients characterized by these abnormalities., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)
- Published
- 2024
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