Betaine and Trimethylamine-N-Oxide as Predictors of Cardiovascular Outcomes Show Different Patterns in Diabetes Mellitus: An Observational Study

Abstract

BackgroundBetaine is a major osmolyte, also important in methyl group metabolism. Concentrations of betaine, its metabolite dimethylglycine and analog trimethylamine-N-oxide (TMAO) in blood are cardiovascular risk markers. Diabetes disturbs betaine: does diabetes alter associations between betaine-related measures and cardiovascular risk?MethodsPlasma samples were collected from 475 subjects four months after discharge following an acute coronary admission. Death (n = 81), secondary acute MI (n = 87), admission for heart failure (n = 85), unstable angina (n = 72) and all cardiovascular events (n = 283) were recorded (median follow-up: 1804 days).ResultsHigh and low metabolite concentrations were defined as top or bottom quintile of the total cohort. In subjects with diabetes (n = 79), high plasma betaine was associated with increased frequencies of events; significantly for heart failure, hazard ratio 3.1 (1.2–8.2) and all cardiovascular events, HR 2.8 (1.4–5.5). In subjects without diabetes (n = 396), low plasma betaine was associated with events; significantly for secondary myocardial infarction, HR 2.1 (1.2–3.6), unstable angina, HR 2.3 (1.3–4.0), and all cardiovascular events, HR 1.4 (1.0–1.9). In diabetes, high TMAO was a marker of all outcomes, HR 2.7 (1.1–7.1) for death, 4.0 (1.6–9.8) for myocardial infarction, 4.6 (2.0–10.7) for heart failure, 9.1 (2.8–29.7) for unstable angina and 2.0 (1.1–3.6) for all cardiovascular events. In subjects without diabetes TMAO was only significant for death, HR 2.7 (1.6–4.8) and heart failure, HR 1.9 (1.1–3.4). Adding the estimated glomerular filtration rate to Cox regression models tended to increase the apparent risks associated with low betaine.ConclusionsElevated plasma betaine concentration is a marker of cardiovascular risk in diabetes; conversely low plasma betaine concentrations indicate increased risk in the absence of diabetes. We speculate that the difference reflects control of osmolyte retention in tissues. Elevated plasma TMAO is a strong risk marker in diabetes.

Prospective Associations of Systemic and Urinary Choline Metabolites with Incident Type 2 Diabetes

“…Among patients randomized to placebo or treatment with vitamin B 6 alone, these metabolites also showed good within-person reproducibility. For plasma betaine, this confirms recent results obtained from data in the Nurses' Health Study (39 ), and high reproducibility is imperative when considering novel clinical biomarkers, as biomarker status can be obtained from a single measurement.…”

“…In short, 4164 patients were evaluated for suspected stable angina pectoris at 2 Norwegian university hospitals from 2000 to 2004. About two-thirds were included in the Western Norway B-Vitamin Intervention Trial (WENBIT) and randomized to receive folic acid ϩ vitamin B 12 ϩ vitamin B 6 , folic acid ϩ vitamin B 12 , vitamin B 6 alone, or placebo (13 ).…”

“…Lower circulating betaine concentrations have been reported among patients with T2D than among those without established T2D (5,6 ), and a recent report proposed a relationship between low plasma dimethylglycine and incident diabetes (7 ). Moreover, the intestinal microflora take part in turning dietary choline into trimethylamine N-oxide (TMAO) (8 ), and higher plasma TMAO concentrations have been observed among patients with T2D than among those without T2D (9 ).…”

High mass accuracy assay for trimethylamine N-oxide using stable-isotope dilution with liquid chromatography coupled to orthogonal acceleration time of flight mass spectrometry with multiple reaction monitoring

“…It is also being investigated in other diseases where the aetiology is thought to be related to a perturbance of the gut microbiome, including colorectal cancer [4], diabetes [5] and renal disease [6] as well as being a putative central mediator in cholesterol balance [7]. Described methods for detecting TMAO are centred on the use of liquid chromatographytandem mass spectrometry with multiple reaction monitoring (LC-MS/MS-MRM), often utilising a stable isotopically labelled standard for quantitation [e.g.…”

Trimethylamine Oxide (TMAO): A New Toxic Kid on the Block

“…An observational clinical study reveals elevated levels of plasma TMAO were a strong risk marker for diabetes. Diabetic patients with high plasma TMAO levels was a marker of adverse cardiovascular outcomes, such as death (HR 2.7), myocardial infarction (HR 4.0), heart failure (HR 4.6), unstable angina (HR 9.1) and other cardiovascular complications (HR 2.0) [14]. Though the mechanisms behind the risk are undefined, TMAO could be a valuable marker to predict the risk of diabetes and its complications.…”