Christopher Papandreou1,2, Mònica Bulló1,2, Yan Zheng3, Miguel Ruiz-Canela2,4, Edward Yu3, Marta Guasch-Ferré1,2,3, Estefanía Toledo2,4, Clary Clish5, Dolores Corella2,6, Ramon Estruch2,7,8, Emilio Ros2,9, Montserrat Fitó2,10, Fernando Arós2,11, Miquel Fiol2,12, José Lapetra2,13, Lluís Serra-Majem2,14, Enrique Gómez-Gracia15, Liming Liang16, Georgios A Fragkiadakis17, Cristina Razquin2,4, Frank B Hu3,16,18, Jordi Salas-Salvadó1,2. 1. Human Nutrition Unit, Faculty of Medicine and Health Sciences, Institut d'Investigació Sanitària Pere Virgili, Rovira i Virgili University, Reus, Spain. 2. CIBER Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III, Madrid, Spain. 3. Departments of Nutrition and Epidemiology and Biostatistics, Harvard TH Chan School of Public Health, Boston, MA. 4. Department of Preventive Medicine and Public Health, University of Navarra, IdiSNA, Pamplona, Spain. 5. Broad Institute of MIT and Harvard University, Cambridge, MA. 6. Department of Preventive Medicine, University of Valencia, Valencia, Spain. 7. Departments of Internal Medicine and Endocrinology and Nutrition and Lipid Clinic, Department of Endocrinology and Nutrition, Institut d'Investigacions Biomediques August Pi Sunyer (IDIBARS), Hospital Clinic, University of Barcelona, Barcelona, Spain. 8. Departments of Endocrinology and Nutrition and Lipid Clinic, Department of Endocrinology and Nutrition, Institut d'Investigacions Biomediques August Pi Sunyer (IDIBARS), Hospital Clinic, University of Barcelona, Barcelona, Spain. 9. Departments of Lipid Clinic, Department of Endocrinology and Nutrition, Institut d'Investigacions Biomediques August Pi Sunyer (IDIBARS), Hospital Clinic, University of Barcelona, Barcelona, Spain. 10. Cardiovascular Risk and Nutrition Research Group, Institut de Recerca Hospital del Mar, Barcelona, Spain. 11. Department of Cardiology, University Hospital of Alava, Vitoria, Spain. 12. Institute of Health Sciences IUNICS, University of Balearic Islands and Hospital Son Espases, Palma de Mallorca, Spain. 13. Department of Family Medicine, Primary Care Division of Sevilla, San Pablo Health Center, Seville, Spain. 14. Department of Clinical Sciences, University of Las Palmas de Gran Canaria, Las Palmas, Spain. 15. Department of Preventive Medicine, University of Málaga, Malaga, Spain. 16. Departments of Epidemiology and Biostatistics, Harvard TH Chan School of Public Health, Boston, MA. 17. Department of Nutrition and Dietetics, Technological Education Institute of Crete, Siteia, Crete, Greece. 18. Channing Division for Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
Abstract
Background: The role of trimethylamine-N-oxide (TMAO) in type 2 diabetes (T2D) is currently partially understood and controversial. Objective: The aim of this study was to investigate associations between TMAO and related metabolites with T2D risk in subjects at high risk of cardiovascular disease. Design: This is a case-cohort design study within the Prevención con Dieta Mediterránea (PREDIMED) study, with 251 incident T2D cases and a random sample of 694 participants (641 noncases and 53 overlapping cases) without T2D at baseline (median follow-up: 3.8 y). We used liquid chromatography-tandem mass spectrometry to measure plasma TMAO, l-carnitine, betaine, lyso-phosphatidylcholine (LPC) and lyso-phosphatidylethanolamine (LPE) species, phosphocholine, α-glycerophosphocholine, and choline at baseline and after 1 y. We examined associations with the use of weighted Cox proportional hazard models, accounting for the weighted case-cohort design by the Barlow method. Results: After adjustment for recognized T2D risk factors and multiple testing, individuals in the highest quartile of baseline TMAO and α-glycerophosphocholine had a lower risk of T2D [HR (95% CI): 0.52 (0.29, 0.89) and 0.46 (0.24, 0.89), respectively]. The HR (95% CI) comparing the extreme quartiles of betaine was 0.41 (0.23, 0.74). Similar trends were observed for C16:0 LPC, C18:1 LPC, C18:0 LPC, C20:4 LPC, C22:6 LPC, C18:1 LPC plasmalogen, and C16:0 LPE. After correcting for multiple comparisons, participants in the highest quartile of 1-y changes in oleic acid LPC plasmalogen concentrations had a lower T2D risk than the reference quartile. Conclusion: Whether the associations between plasma TMAO and certain metabolite concentrations with T2D risk reflect its pathophysiology or represent an epiphenomenon needs to be elucidated. This trial is registered at http://www.controlled-trials.com as ISRCTN35739639.
Background: The role of trimethylamine-N-oxide (TMAO) in type 2 diabetes (T2D) is currently partially understood and controversial. Objective: The aim of this study was to investigate associations between TMAO and related metabolites with T2D risk in subjects at high risk of cardiovascular disease. Design: This is a case-cohort design study within the Prevención con Dieta Mediterránea (PREDIMED) study, with 251 incident T2D cases and a random sample of 694 participants (641 noncases and 53 overlapping cases) without T2D at baseline (median follow-up: 3.8 y). We used liquid chromatography-tandem mass spectrometry to measure plasma TMAO, l-carnitine, betaine, lyso-phosphatidylcholine (LPC) and lyso-phosphatidylethanolamine (LPE) species, phosphocholine, α-glycerophosphocholine, and choline at baseline and after 1 y. We examined associations with the use of weighted Cox proportional hazard models, accounting for the weighted case-cohort design by the Barlow method. Results: After adjustment for recognized T2D risk factors and multiple testing, individuals in the highest quartile of baseline TMAO and α-glycerophosphocholine had a lower risk of T2D [HR (95% CI): 0.52 (0.29, 0.89) and 0.46 (0.24, 0.89), respectively]. The HR (95% CI) comparing the extreme quartiles of betaine was 0.41 (0.23, 0.74). Similar trends were observed for C16:0 LPC, C18:1 LPC, C18:0 LPC, C20:4 LPC, C22:6 LPC, C18:1 LPC plasmalogen, and C16:0 LPE. After correcting for multiple comparisons, participants in the highest quartile of 1-y changes in oleic acidLPC plasmalogen concentrations had a lower T2D risk than the reference quartile. Conclusion: Whether the associations between plasma TMAO and certain metabolite concentrations with T2D risk reflect its pathophysiology or represent an epiphenomenon needs to be elucidated. This trial is registered at http://www.controlled-trials.com as ISRCTN35739639.
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