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Inflammation and prediction of death in type 2 diabetes. Evidence of an intertwined link with tryptophan metabolism.
J. Clin. Endocrinol. Metab.:dgae593 (2024)
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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Ip-10 ; Death Risk ; Inflammation Risk Score ; Prediction Models ; Tryptophan Pathway; Individual Participant Data; Risk Equations; Mortality; Complications; Validation; Disease; Curve
ISSN (print) / ISBN
0021-972X
e-ISSN
1945-7197
Quellenangaben
Article Number: dgae593
Publisher
Endocrine Society
Publishing Place
Bethesda, Md.
Non-patent literature
Publications
Reviewing status
Peer reviewed
Grants
EFPIA
European Union
Innovative Medicines Initiative 2 Joint Undertaking (JU)
European Health Data & Evidence Network (EHDEN) project
Ministero della Salute
Ministero dell' Universita PNRR M4C2I1.3 Heal Italia project
Ministero dell' Istruzione dell'Universita (PRIN)
European Union
Innovative Medicines Initiative 2 Joint Undertaking (JU)
European Health Data & Evidence Network (EHDEN) project
Ministero della Salute
Ministero dell' Universita PNRR M4C2I1.3 Heal Italia project
Ministero dell' Istruzione dell'Universita (PRIN)