Exp Clin Endocrinol Diabetes 2016; 124(04): 251-256
DOI: 10.1055/s-0035-1569330
Article
© Georg Thieme Verlag KG Stuttgart · New York

Diabetes is Associated with Higher Trimethylamine N-oxide Plasma Levels

M. Dambrova
1   Latvian Institute of Organic Synthesis, Riga, Latvia
2   Riga Stradins University, Riga, Latvia
,
G. Latkovskis
3   Paul Stradins Clinical University Hospital, Riga, Latvia
4   University of Latvia, Riga, Latvia
5   Latvian Research Institute of Cardiology, Riga, Latvia
,
J. Kuka
1   Latvian Institute of Organic Synthesis, Riga, Latvia
,
I. Strele
2   Riga Stradins University, Riga, Latvia
,
I. Konrade
2   Riga Stradins University, Riga, Latvia
,
S. Grinberga
1   Latvian Institute of Organic Synthesis, Riga, Latvia
,
D. Hartmane
1   Latvian Institute of Organic Synthesis, Riga, Latvia
,
O Pugovics
1   Latvian Institute of Organic Synthesis, Riga, Latvia
,
A. Erglis
3   Paul Stradins Clinical University Hospital, Riga, Latvia
4   University of Latvia, Riga, Latvia
5   Latvian Research Institute of Cardiology, Riga, Latvia
,
E. Liepinsh
1   Latvian Institute of Organic Synthesis, Riga, Latvia
› Author Affiliations
Further Information

Publication History

received 16 November 2015
first decision 16 November 2015

accepted 18 November 2015

Publication Date:
28 April 2016 (online)

Abstract

Recent studies have revealed strong associations between systemic trimethylamine N-oxide (TMAO) levels, atherosclerosis and cardiovascular risk. In addition, plasma L-carnitine levels in patients with high TMAO concentrations predicted an increased risk for cardiovascular disease and incident major adverse cardiac events. The aim of the present study was to investigate the relation between TMAO and L-carnitine plasma levels and diabetes. Blood plasma samples were collected from 12 and 20 weeks old db/db mice and patients undergoing percutaneous coronary intervention. Diabetic compared to non-diabetic db/L mice presented 10-fold higher TMAO, but lower L-carnitine plasma concentrations at 12 weeks of age. After 8 weeks of observation, diabetic db/db mice had significantly increased body weight, insulin resistance and TMAO concentration in comparison to non-diabetic control. In 191 patients undergoing percutaneous coronary intervention the median (interquartile range) plasma concentration of TMAO was 1.8 (1.2–2.6) µmol/L. Analysis of the samples showed a bivariate association of TMAO level with age, total cholesterol and L-carnitine. The multivariate linear regression analysis revealed that, in addition to L-carnitine as the strongest predictor of log transformed TMAO (p<0.001), the parameters of age, diabetes status and body mass index (BMI) were independently associated with increased log transformed TMAO levels (p<0.01).

Our data provide evidence that age, diabetes and BMI are associated with higher TMAO levels independently of L-carnitine. These data support the hypothesis of TMAO as a cardiovascular risk marker and warrant further investigation of TMAO for diabetes research applications.

Supplementary Material

 
  • References

  • 1 Wang Z, Klipfell E, Bennett BJ et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011; 472: 57-63
  • 2 Ussher JR, Lopaschuk GD, Arduini A. Gut microbiota metabolism of L-carnitine and cardiovascular risk. Atherosclerosis 2013; 231: 456-461
  • 3 Lever M, George PM, Slow S et al. Betaine and Trimethylamine-N-Oxide as Predictors of Cardiovascular Outcomes Show Different Patterns in Diabetes Mellitus: An Observational Study. PLoS One 2014; 9: e114969
  • 4 Koeth RA, Wang Z, Levison BS et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 2013; 19: 576-585
  • 5 Wang Z, Levison BS, Hazen JE et al. Measurement of trimethylamine-N-oxide by stable isotope dilution liquid chromatography tandem mass spectrometry. Anal Biochem 2014; 455: 35-40
  • 6 Bain MA, Fornasini G, Evans AM. Trimethylamine: metabolic, pharmacokinetic and safety aspects. Curr Drug Metab 2005; 6: 227-240
  • 7 Bain MA, Milne RW, Evans AM. Disposition and metabolite kinetics of oral L-carnitine in humans. J Clin Pharmacol 2006; 46: 1163-1170
  • 8 Rebouche CJ. Kinetics, pharmacokinetics, and regulation of L-carnitine and acetyl-L-carnitine metabolism. Ann N Y Acad Sci 2004; 1033: 30-41
  • 9 Tang WH, Wang Z, Levison BS et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med 2013; 368: 1575-1584
  • 10 Bennett BJ, de Aguiar Vallim TQ, Wang Z et al. Trimethylamine-N-oxide, a metaboliteassociated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab 2013; 17: 49-60
  • 11 Dambrova M, Skapare-Makarova E, Konrade I et al. Meldonium decreases the diet-increased plasma levels of trimethylamine N-oxide, a metabolite associated with atherosclerosis. J Clin Pharmacol 2013; 53: 1095-1098
  • 12 Ramsay RR, Gandour RD, van der Leij FR. Molecular enzymology of carnitine transfer and transport. Biochim Biophys Acta 2001; 1546: 21-43
  • 13 Hartiala J, Bennett BJ, Tang WH et al. Comparative genome-wide association studies in mice and humans for trimethylamine N-oxide, a proatherogenic metabolite of choline and L-carnitine. Arterioscler Thromb Vasc Biol 2014; 34: 1307-1313
  • 14 Vidal-Casariego A, Burgos-Pelaez R, Martinez-Faedo C et al. Metabolic effects of L-carnitine on type 2 diabetes mellitus: systematic review and meta-analysis. Exp Clin Endocrinol Diabetes 2013; 121: 234-238
  • 15 Dambrova M, Liepinsh E. Risks and benefits of carnitine supplementation in diabetes. Exp Clin Endocrinol Diabetes 2015; 123: 95-100
  • 16 Liepinsh E, Skapare E, Vavers E et al. High L-carnitine concentrations do not prevent late diabetic complications in type 1 and 2 diabetic patients. Nutr Res 2012; 32: 320-327
  • 17 Morrish NJ, Wang SL, Stevens LK et al. Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes. Diabetologia 2001; 44 (Suppl. 02) S14-S21
  • 18 Matteucci E, Giampietro O. Epidemiology of cardiovascular disease in patients with type 1 diabetes: European perspective. Exp Clin Endocrinol Diabetes 2014; 122: 208-214
  • 19 Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998; 15: 539-553
  • 20 Tabak AG, Herder C, Rathmann W et al. Prediabetes: a high-risk state for diabetes development. Lancet 2012; 379: 2279-2290
  • 21 Grinberga S, Dambrova M, Latkovskis G et al. Determination of trimethylamine-N-oxide in combination with l-carnitine and γ-butyrobetaine in human plasma by UPLC/MS/MS. Biomed Chromatogr 2015; 29: 1670-1674
  • 22 Li X, Chen Y, Liu J et al. Serum metabolic variables associated with impaired glucose tolerance induced by high-fat-high-cholesterol diet in Macaca mulatta. Exp Biol Med (Maywood) 2012; 237: 1310-1321
  • 23 Gao X, Liu X, Xu J et al. Dietary trimethylamine N-oxide exacerbates impaired glucose tolerance in mice fed a high fat diet. J Biosci Bioeng 2014; 118: 476-481
  • 24 Lupachyk S, Watcho P, Stavniichuk R et al. Endoplasmic reticulum stress plays a key role in the pathogenesis of diabetic peripheral neuropathy. Diabetes 2013; 62: 944-952
  • 25 McEntyre CJ, Lever M, Chambers ST 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. Ann Clin Biochem 2015; 52: 352-360
  • 26 Wang Z, Tang WH, Buffa JA et al. Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide. Eur Heart J 2014; 35: 904-910
  • 27 Power SE, O'Toole PW, Stanton C et al. Intestinal microbiota, diet and health. Br J Nutr 2014; 111: 387-402
  • 28 Health behavior among Latvian adult population. FINBALT Health Monitoring 2012;
  • 29 Ufnal M, Zadlo A, Ostaszewski R. TMAO: A small molecule of great expectations. Nutrition 2015; 31: 1317-1323
  • 30 Lloyd AJ, Fave G, Beckmann M et al. Use of mass spectrometry fingerprinting to identify urinary metabolites after consumption of specific foods. Am J Clin Nutr 2011; 94: 981-991
  • 31 Miller CA, Corbin KD, da Costa KA et al. Effect of egg ingestion on trimethylamine-N-oxide production in humans: a randomized, controlled, dose-response study. Am J Clin Nutr 2014; 100: 778-786