Association of Tryptophan Metabolites with Incident Type 2 Diabetes in the PREDIMED Trial: A Case-Cohort Study

• Published in: Clinical chemistry (Baltimore, Md.) Md.), 2018-08, Vol.64 (8), p.1211-1220
• Main Authors: Yu, Edward, Papandreou, Christopher, Ruiz-Canela, Miguel, Guasch-Ferre, Marta, Clish, Clary B, Dennis, Courtney, Liang, Liming, Corella, Dolores, Fitó, Montserrat, Razquin, Cristina, Lapetra, José, Estruch, Ramón, Ros, Emilio, Cofán, Montserrat, Arós, Fernando, Toledo, Estefania, Serra-Majem, Lluis, Sorlí, José V, Hu, Frank B, Martinez-Gonzalez, Miguel A, Salas-Salvado, Jordi
• Format: Article
• Language: English
• Subjects: Body mass index; Body size; Cardiovascular disease; Cohort analysis; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Health risk assessment; Insulin; Insulin resistance; Kynurenic acid; Metabolites; Quinolinic acid; Risk analysis; Risk factors; Tryptophan
• ISSN: 0009-9147; 1530-8561
• DOI: 10.1373/clinchem.2018.288720

Metabolites of the tryptophan-kynurenine pathway (i.e., tryptophan, kynurenine, kynurenic acid, quinolinic acid, 3-hydroxyanthranilic) may be associated with diabetes development. Using a case-cohort design nested in the Prevención con Dieta Mediterránea (PREDIMED) study, we studied the associations of baseline and 1-year changes of these metabolites with incident type 2 diabetes (T2D). Plasma metabolite concentrations were quantified via LC-MS for n = 641 in a randomly selected subcohort and 251 incident cases diagnosed during 3.8 years of median follow-up. Weighted Cox models adjusted for age, sex, body mass index, and other T2D risk factors were used. Baseline tryptophan was associated with higher risk of incident T2D (hazard ratio = 1.29; 95% CI, 1.04-1.61 per SD). Positive changes in quinolinic acid from baseline to 1 year were associated with a higher risk of T2D (hazard ratio = 1.39; 95% CI, 1.09-1.77 per SD). Baseline tryptophan and kynurenic acid were directly associated with changes in homeostatic model assessment for insulin resistance (HOMA-IR) from baseline to 1 year. Concurrent changes in kynurenine, quinolinic acid, 3-hydroxyanthranilic acid, and kynurenine/tryptophan ratio were associated with baseline-to-1-year changes in HOMA-IR. Baseline tryptophan and 1-year increases in quinolinic acid were positively associated with incident T2D. Baseline and 1-year changes in tryptophan metabolites predicted changes in HOMA-IR. Tryptophan levels may initially increase and then deplete as diabetes progresses in severity.