Plasma trimethylamine-N-oxide and related metabolites are associated with type 2 diabetes risk in the Prevención con Dieta Mediterránea (PREDIMED) trial.

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.

[1]  F. Hu,et al.  Association between microbiota-dependent metabolite trimethylamine-N-oxide and type 2 diabetes. , 2017, The American journal of clinical nutrition.

[2]  C. Cho,et al.  Trimethylamine-N-Oxide: Friend, Foe, or Simply Caught in the Cross-Fire? , 2017, Trends in Endocrinology & Metabolism.

[3]  Jian Yan,et al.  Trimethylamine‐N‐oxide (TMAO) response to animal source foods varies among healthy young men and is influenced by their gut microbiota composition: A randomized controlled trial , 2017, Molecular nutrition & food research.

[4]  I. Phillips,et al.  Trimethylamine and Trimethylamine N-Oxide, a Flavin-Containing Monooxygenase 3 (FMO3)-Mediated Host-Microbiome Metabolic Axis Implicated in Health and Disease , 2016, Drug Metabolism and Disposition.

[5]  D. Raj,et al.  Trimethylamine N-Oxide: The Good, the Bad and the Unknown , 2016, Toxins.

[6]  A. Svardal,et al.  Major Increase in Microbiota-Dependent Proatherogenic Metabolite TMAO One Year After Bariatric Surgery , 2016, Metabolic syndrome and related disorders.

[7]  G. Latkovskis,et al.  Diabetes is Associated with Higher Trimethylamine N-oxide Plasma Levels , 2016, Experimental and Clinical Endocrinology & Diabetes (Barth).

[8]  R. Obeid,et al.  Plasma trimethylamine N-oxide concentration is associated with choline, phospholipids, and methyl metabolism. , 2016, The American journal of clinical nutrition.

[9]  F. Villarroya,et al.  Dietary Betaine Supplementation Increases Fgf21 Levels to Improve Glucose Homeostasis and Reduce Hepatic Lipid Accumulation in Mice , 2016, Diabetes.

[10]  A. von Eckardstein,et al.  Plasma Concentrations of Trimethylamine-N-oxide Are Directly Associated with Dairy Food Consumption and Low-Grade Inflammation in a German Adult Population. , 2016, The Journal of nutrition.

[11]  P. Clifton,et al.  A review of potential metabolic etiologies of the observed association between red meat consumption and development of type 2 diabetes mellitus. , 2015, Metabolism: clinical and experimental.

[12]  M. Lever,et al.  Variation of betaine, N,N-dimethylglycine, choline, glycerophosphorylcholine, taurine and trimethylamine-N-oxide in the plasma and urine of overweight people with type 2 diabetes over a two-year period , 2015, Annals of clinical biochemistry.

[13]  C. Cardwell,et al.  A posteriori dietary patterns are related to risk of type 2 diabetes: findings from a systematic review and meta-analysis. , 2014, Journal of the Academy of Nutrition and Dietetics.

[14]  M. Garg,et al.  The association between dietary patterns and type 2 diabetes: a systematic review and meta-analysis of cohort studies. , 2014, Journal of human nutrition and dietetics : the official journal of the British Dietetic Association.

[15]  E. Gibney,et al.  Relationship between the lipidome, inflammatory markers and insulin resistance. , 2014, Molecular bioSystems.

[16]  H. Hara,et al.  Serum choline plasmalogens, particularly those with oleic acid in sn-2, are associated with proatherogenic state[S] , 2014, Journal of Lipid Research.

[17]  S. Hazen,et al.  Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide. , 2014, European heart journal.

[18]  D. Corella,et al.  Prevention of Diabetes With Mediterranean Diets , 2014, Annals of Internal Medicine.

[19]  Jinyan Huang,et al.  Association of homocysteine with type 2 diabetes: a meta-analysis implementing Mendelian randomization approach , 2013, BMC Genomics.

[20]  F. Hu,et al.  Systems Epidemiology: A New Direction in Nutrition and Metabolic Disease Research , 2013, Current Nutrition Reports.

[21]  S. Hazen,et al.  Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. , 2013, The New England journal of medicine.

[22]  Dolores Corella,et al.  Primary prevention of cardiovascular disease with a Mediterranean diet. , 2013, The New England journal of medicine.

[23]  A. Peters,et al.  Identification of Serum Metabolites Associated With Risk of Type 2 Diabetes Using a Targeted Metabolomic Approach , 2013, Diabetes.

[24]  Brian J. Bennett,et al.  Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. , 2013, Cell metabolism.

[25]  Dolores Corella,et al.  Cohort profile: design and methods of the PREDIMED study. , 2012, International journal of epidemiology.

[26]  P. O S I T I O N S T A T E M E N T.  Diagnosis and Classification of Diabetes Mellitus , 2011, Diabetes Care.

[27]  C. Anania,et al.  Pediatric nonalcoholic fatty liver disease, metabolic syndrome and cardiovascular risk. , 2011, World journal of gastroenterology.

[28]  Dolores Corella,et al.  A short screener is valid for assessing Mediterranean diet adherence among older Spanish men and women. , 2011, The Journal of nutrition.

[29]  S. Carr,et al.  Lipid profiling identifies a triacylglycerol signature of insulin resistance and improves diabetes prediction in humans. , 2011, The Journal of clinical investigation.

[30]  V. Mootha,et al.  Metabolite profiles and the risk of developing diabetes , 2011, Nature Medicine.

[31]  Brian J. Bennett,et al.  Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease , 2011, Nature.

[32]  V. Basevi.  Diagnosis and Classification of Diabetes Mellitus , 2011, Diabetes Care.

[33]  B. A. Evans,et al.  The M3-muscarinic acetylcholine receptor stimulates glucose uptake in L6 skeletal muscle cells by a CaMKK-AMPK-dependent mechanism. , 2010, Cellular signalling.

[34]  R. Gerszten,et al.  Metabolite profiling identifies markers of uremia. , 2010, Journal of the American Society of Nephrology : JASN.

[35]  S. Carr,et al.  Metabolic Signatures of Exercise in Human Plasma , 2010, Science Translational Medicine.

[36]  V. Mootha,et al.  Discovery and therapeutic potential of drugs that shift energy metabolism from mitochondrial respiration to glycolysis , 2010, Nature Biotechnology.

[37]  Orian S. Shirihai,et al.  The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1α , 2010, Cell.

[38]  Arvind Ramanathan,et al.  A plasma signature of human mitochondrial disease revealed through metabolic profiling of spent media from cultured muscle cells , 2010, Proceedings of the National Academy of Sciences.

[39]  Michelle M Wiest,et al.  The plasma lipidomic signature of nonalcoholic steatohepatitis , 2009, Hepatology.

[40]  K. Park,et al.  Lysophosphatidylcholine Activates Adipocyte Glucose Uptake and Lowers Blood Glucose Levels in Murine Models of Diabetes* , 2009, The Journal of Biological Chemistry.

[41]  W. Atkinson,et al.  Plasma and urine betaine and dimethylglycine variation in healthy young male subjects. , 2009, Clinical biochemistry.

[42]  S. Vollset,et al.  Divergent associations of plasma choline and betaine with components of metabolic syndrome in middle age and elderly men and women. , 2008, The Journal of nutrition.

[43]  S. Tayebati,et al.  Pathways of acetylcholine synthesis, transport and release as targets for treatment of adult-onset cognitive dysfunction. , 2008, Current medicinal chemistry.

[44]  G. Rossi,et al.  Diagnosis and Classification of Diabetes Mellitus The information that follows is based largely on the reports of the Expert Committee on the Diagnosis and Classification of Diabetes (Diabetes Care 20:1183–1197, 1997, and Diabetes Care 26:3160–3167, 2003). , 2008, Diabetes Care.

[45]  F. Stephens,et al.  New insights concerning the role of carnitine in the regulation of fuel metabolism in skeletal muscle , 2007, The Journal of physiology.

[46]  M. Uusitupa,et al.  Orally administered betaine has an acute and dose-dependent effect on serum betaine and plasma homocysteine concentrations in healthy humans. , 2006, The Journal of nutrition.

[47]  B. Metzger,et al.  Elevated homocysteine as a risk factor for the development of diabetes in women with a previous history of gestational diabetes mellitus: a 4-year prospective study. , 2005, Diabetes care.

[48]  R. Turner,et al.  Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man , 1985, Diabetologia.

[49]  A. De Gaetano,et al.  L-carnitine improves glucose disposal in type 2 diabetic patients. , 1999, Journal of the American College of Nutrition.

[50]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[51]  R. Elosua,et al.  Validation of the Minnesota Leisure Time Physical Activity Questionnaire in Spanish men. The MARATHOM Investigators. , 1994, American journal of epidemiology.