Edward Yu1,2, Christopher Papandreou3,4, Miguel Ruiz-Canela4,5,6, Marta Guasch-Ferre1,3,4, Clary B Clish7, Courtney Dennis7, Liming Liang8, Dolores Corella4,9, Montserrat Fitó4,10, Cristina Razquin4,5,6, José Lapetra4,11, Ramón Estruch4,12, Emilio Ros4,13, Montserrat Cofán4,13, Fernando Arós4,14, Estefania Toledo4,5,6, Lluis Serra-Majem4,15, José V Sorlí4,9, Frank B Hu1,2,16, Miguel A Martinez-Gonzalez1,4,5,6, Jordi Salas-Salvado17,4. 1. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA. 2. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA. 3. Human Nutrition Unit, Faculty of Medicine and Health Sciences, Institut d'Investigació Sanitària Pere Virgili, Rovira i Virgili University, Reus, Spain. 4. CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. 5. Department of Preventive Medicine and Public Health, University of Navarra, Pamplona, Spain. 6. IdiSNA (Instituto de Investigación Sanitària de Navarra), Navarra, Spain. 7. Broad Institute of MIT and Harvard University, Cambridge, MA. 8. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA. 9. Department of Preventive Medicine, University of Valencia, Valencia, Spain. 10. Cardiovascular and Nutrition Research Group, Institut de Recerca Hospital del Mar, Barcelona, Spain. 11. Department of Family Medicine, Unit Research, Distrito Sanitario Atención Primaria Sevilla, Sevilla, Spain. 12. Department of Internal Medicine Institut d'Investigacions Biomèdiques August Pi Sunyer (IDI- BAPS), Hospital Clinic, University of Barcelona, Barcelona, Spain. 13. Lipid Clinic, Department of Endocrinology and Nutrition (IDIBAPS), Hospital Clinic, University of Barcelona, Barcelona, Spain. 14. Department of Cardiology, University Hospital of Álava, Vitoria, Spain. 15. Research Institute of Biomedical and Health Sciences, University of Las Palmas de Gran Canaria, Las Palmas, Spain. 16. Channing Division for Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, MA. 17. Human Nutrition Unit, Faculty of Medicine and Health Sciences, Institut d'Investigació Sanitària Pere Virgili, Rovira i Virgili University, Reus, Spain; jordi.salas@urv.cat.
Abstract
BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: Baseline tryptophanand 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.
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