Plasma Betaine Levels Research Articles

Supplementing dietary betaine during late gestation increases plasma betaine and methionine concentrations in pregnant Merino ewes but not neonatal lambs

Supplementing dietary betaine during pregnancy has improved vigour and post-natal survival rates to day seven in twin lambs, potentially due to improvements in the circulating metabolite profile of these animals. This study determined whether maternal betaine supplementation during late gestation would increase circulating levels of betaine, creatinine and other amino acids in ewes and their newborn lambs, leading to subsequent improvements in lamb viability and growth. Twenty-five single-bearing Merino ewes received dietary betaine at either 0 (Control, CTL), 2 (Low Betaine, LB) or 4 g/day (High Betaine, HB) from day 125 of gestation (dG 125) until parturition (150.7 ± 0.6 days). Blood samples were collected from the ewes prior to feeding (0 h), and at 2, 4, 6, 8 and 24 h post-feeding on dG 125 and dG 140 prior to feeding and from the lamb within 2 h after birth. Lamb viability measures were taken at 2, 24 and 72 h and day 7 post-partum, marking (⁓30 days of age) and weaning (⁓104 days of age). Betaine supplementation at LB and HB increased plasma betaine levels at 6, 8 and 24 h post-feeding on dG 125 (P < 0.05) and tended to increase plasma betaine on dG 140 (P = 0.085). Plasma methionine levels increased at 2 and 4 h post-feeding on dG 125 relative to baseline levels (0 h) in LB ewes, yet remained unchanged in HB ewes. On dG 125, creatinine levels were higher in CTL ewes compared with betaine-supplemented ewes at 4 and 8 h post-feeding (both P < 0.05). While plasma betaine and methionine levels were unchanged in neonatal lambs, plasma concentrations of glutamine and lysine were higher (P < 0.05) in HB lambs compared to CTL and LB lambs. HB lambs tended to be heavier at marking (P = 0.057) and were heavier at weaning compared to CTL and LB lambs (P < 0.05). This study indicated that betaine supplementation increased plasma betaine and methionine levels in ewes, but not in neonatal lambs. Further research is warranted to determine whether higher levels of betaine supplementation increase neonatal concentrations.

Commercial Extruded Plant-Based Diet Lowers Circulating Levels of Trimethylamine N-Oxide (TMAO) Precursors in Healthy Dogs: A Pilot Study.

Elevations in circulating trimethylamine N-oxide (TMAO) and its precursors are observed in humans and dogs with heart failure and are associated with adverse outcomes in people. Dietary intervention that reduces or excludes animal ingredients results in rapid reduction of plasma TMAO and TMAO precursors in people, but the impact of diet in dogs has not been studied. The objective of the current study was to determine the effect of diet on plasma TMAO and 2 of its precursors (choline and betaine) in dogs fed a commercial extruded plant-based diet (PBD) or a commercial extruded traditional diet (TD) containing animal and plant ingredients. Sixteen healthy adult mixed breed dogs from a university colony were enrolled in a randomized, 2-treatment, 2-period crossover weight-maintenance study. Mean (SD) age and body weight of the dogs were 2.9 years (± 1.7) and 14.5 kg (± 4.0), respectively. Eight dogs were female (3 intact, 5 spayed) and 8 dogs were male (4 intact, 4 castrated). Plasma choline, betaine and TMAO were quantified by LC-SID-MRM/MS at baseline, and after 4 weeks on each diet. Choline and betaine were also quantified in the diets. Plasma choline levels were significantly lower (P = 0.002) in dogs consuming a PBD (Mean ± SD, 6.8 μM ± 1.2 μM) compared to a TD (Mean ± SD, 7.8 μM ± 1.6 μM). Plasma betaine levels were also significantly lower (P = 0.03) in dogs consuming a PBD (Mean ± SD, 109.1 μM ± 25.3 μM) compared to a TD (Mean ± SD, 132.4 μM ± 32.5 μM). No difference (P = 0.71) in plasma TMAO was detected in dogs consuming a PBD (Median, IQR, 2.4 μM, 2.1 μM) compared to a TD (Median, IQR, 2.3 μM, 1.1 μM). Betaine content was lower in the PBD than in the TD while choline content was similar in the diets. Our findings indicate consumption of a commercial extruded PBD for 4 weeks reduces circulating levels of the TMAO precursors choline and betaine, but not TMAO, in healthy adult dogs.

Associations of Circulating Levels of Trimethylamine N-oxide, Choline, Carnitine, and Betaine with Inflammatory Markers Among Breast Cancer Survivors

ObjectivesWe examined the associations of circulating levels of trimethylamine N-oxide (TMAO) and its precursors (choline, carnitine, and betaine) with inflammatory markers in breast cancer survivors in Korea.MethodsA total of 431 women (285 premenopausal breast cancer) aged 30–78 years were included. Least-squares mean (LS-mean)s and 95% confidence interval (CI)s were estimated for plasma levels of high-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6, IL-8, tumor necrosis factor-α (TNF-α), and adiponectin according to plasma levels of TMAO, choline, carnitine, and betaine, using the generalized linear models.ResultsAmong premenopausal breast cancer survivors, increasing circulating levels of choline were associated with increasing levels of IL-6, IL-8, and TNF-α; LS-means (95% CIs) of the lowest and the highest quartiles were 0.75 (0.56–0.96) and 1.01 (0.80–1.24) pg/mL (p for trend = 0.019) for IL-6, 11.49 (8.19–15.97) and 17.73 (12.96–24.13) pg/mL (p for trend = 0.005) for IL-8, and 9.45 (7.47–11.88) and 11.99 (9.63–14.88) pg/mL (p for trend = 0.021) for TNF-α, respectively. Increasing plasma betaine levels were associated with increasing levels of adiponectin but decreasing levels of hs-CRP and IL-6; LS-means (95% CIs) of the lowest and the highest quartiles were 7.25 (5.65–9.23) and 9.05 (7.10–11.47) μg/mL (p for trend = 0.044) for adiponectin, 0.68 (0.45–0.96) and 0.35 (0.16–0.57) mg/L (p for trend 0.017) for hs-CRP, and 0.98 (0.77–1.21) and 0.75 (0.57–0.97) pg/mL (p for trend = 0.013) for IL-6, respectively. However, plasma levels of TMAO and its precursors were not significantly associated with inflammatory markers in postmenopausal breast cancer survivors.ConclusionsIn this cross-sectional study of breast cancer survivors, increasing plasma levels of choline were associated with increasing levels of inflammatory markers, but plasma levels of betaine were inversely associated with these markers among premenopausal breast cancer survivors.Funding SourcesThis work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea Government (Ministry of Science and ICT) (No. 2014R1A2A2A01007794, 2019R1F1A1061017, and 2021R1F1A1062476).

High Betaine and Dynamic Increase of Betaine Levels Are Both Associated With Poor Prognosis of Patients With Pulmonary Hypertension.

Background and ObjectiveThe association between plasma betaine levels and cardiovascular diseases (CVDs) has been revealed except for pulmonary hypertension (PH). In this study, we aimed to explore the role of betaine in patients with PH.MethodsInpatients with PH at Fuwai Hospital were enrolled after excluding relative comorbidities. Each patient received at least one follow-up through a clinical visit, and the fasting blood was obtained both at the first and second hospitalization for betaine detection. The primary endpoint was defined as composite outcome events and the mean duration was 14.3 (6.9, 21.3) months. The associations of betaine and changes of betaine (Δbetaine) with disease severity and prognosis were explored.ResultsFinally, a total of 216 patients with PH were included and the medians for betaine plasma levels in the total patients group, low betaine, and high betaine groups were 49.8 (39.0, 68.3) μM, 39.0 (33.5, 44.7) μM, and 68.1 (57.8, 88.7) μM, respectively. High betaine was associated with poor World Health Organization Functional Class (WHO-FC), increased N-terminal pro-brain natriuretic peptide (NT-proBNP), low tricuspid annular plane systolic excursion (TAPSE), and cardiac output index even after adjusting for confounders. Patients with high betaine were over twice the risk to receive the poor prognosis than those with a low level [hazard ratio (HR) = 2.080, (95% CI: 1.033–4.188)]. Moreover, the decrease of betaine level after further treatment was positively correlated to ΔNT-proBNP indicating Δbetaine might be an effector of disease severity, and dynamic increase of betaine was also associated with poor prognosis in PH.ConclusionBetaine was associated with disease severity and might be an effector in PH. Patients with increased levels or with dynamic rise of betaine heralded a poor prognosis.

A wheat aleurone-rich diet improves oxidative stress but does not influence glucose metabolism in overweight/obese individuals: Results from a randomized controlled trial

Background and aimsAleurone is the innermost layer of wheat bran, rich in fiber, minerals, vitamins, phenolic compounds, and betaine. The metabolic effects of aleurone rich foods are still unknown. Our aim was to investigate the effects of consuming a Wheat Aleurone rich diet vs. a Refined Wheat diet for 8 weeks on fasting and postprandial glycemic and lipid metabolism, inflammation, and oxidative stress in overweight/obese individuals. Methods and resultsAccording to a randomized cross-over study design, 23 overweight/obese individuals, age 56 ± 9 years (M±SD), were assigned to two isoenergetic diet – Wheat Aleurone and Refined Wheat diets – for 8 weeks. The diets were similar for macronutrient composition but different for the aleurone content (40–50 g/day in the Wheat Aleurone diet). After each diet, fasting and postprandial plasma metabolic profile, ferulic acid metabolites and 8-isoprostane concentrations in 24-h urine samples were evaluated. Compared with the Refined Wheat Diet, the Wheat Aleurone Diet increased fasting plasma concentrations of betaine by 15% (p = 0.042) and decreased the excretion of 8-isoprostane by 33% (p = 0.035). Conversely, it did not affect the fasting and postprandial glucose, insulin and triglyceride responses, homocysteine, and C-Reactive Protein concentrations, nor excretion of phenolic metabolites. ConclusionAn 8-week Wheat Aleurone Diet improves the oxidative stress and increases plasma betaine levels in overweight/obese individuals with an increased cardiometabolic risk. However, further studies with longer duration and larger sample size are needed to evaluate the benefits of aleurone-rich foods on glucose and lipid metabolism in individuals with more severe metabolic abnormalities. Clinical trial registry numberNCT02150356, (https://clinicaltrials.gov).

Association between plasma betaine levels and dysglycemia in patients with coronary artery disease.

Background: Dietary betaine intake was reported to associate with favorable profile of metabolic disorders. However, the role of circulating betaine in coronary artery disease (CAD) patients with dysglycemia is still unknown. The present study aimed to investigate the potential associations between plasma betaine levels and dysglycemia in CAD patients.Methods: Total 307 subjects were enrolled in the present study with 165 CAD patients (57 with dysglycemia and 108 with normal glycemia) and 142 age- and sex-matched controls (CON). Fasting plasma betaine was detected using liquid chromatography tandem mass spectrometry.Results: Plasma betaine was lower in normal glycemia CAD patients (28.29 (22.38–35.73) μM) compared with healthy controls (29.75 (25.32–39.15) μM), and was further decreased in CAD patients with dysglycemia (24.14 (20.84–30.76) μM, P<0.01). Betaine levels were inversely correlated with fasting glucose, glycated hemoglobin% (HbA1c), diastolic blood pressure (DBP), triglyceride (TG) and alanine aminotransferase (ALT) levels (all, P≤0.05). Subjects in the highest betaine tertile group had lowest frequency of CAD and dysglycemia (all, P<0.01). Increased betaine levels were independently associated with low risk of dysglycemia in CAD after adjustment for multiple traditional risk factors (OR = 0.04, 95% CI: 0–0.37, P=0.01). Furthermore, betaine had good performance at distinguishing CAD with dysglycemia from normal glycemia CAD (AUC = 0.62, P<0.01).Conclusion: Plasma betaine levels are independently and inversely associated with dysglycemia in CAD after adjustment for multiple factors, and may be useful for risk stratification of dysglycemia in CAD.

Dietary Betaine Supplementation Increases Fgf21 Levels to Improve Glucose Homeostasis and Reduce Hepatic Lipid Accumulation in Mice.

Identifying markers of human insulin resistance may permit development of new approaches for treatment and prevention of type 2 diabetes. To this end, we analyzed the fasting plasma metabolome in metabolically characterized human volunteers across a spectrum of insulin resistance. We demonstrate that plasma betaine levels are reduced in insulin-resistant humans and correlate closely with insulin sensitivity. Moreover, betaine administration to mice with diet-induced obesity prevents the development of impaired glucose homeostasis, reduces hepatic lipid accumulation, increases white adipose oxidative capacity, and enhances whole-body energy expenditure. In parallel with these beneficial metabolic effects, betaine supplementation robustly increased hepatic and circulating fibroblast growth factor (Fgf)21 levels. Betaine administration failed to improve glucose homeostasis and liver fat content in Fgf21(-/-) mice, demonstrating that Fgf21 is necessary for betaine's beneficial effects. Together, these data indicate that dietary betaine increases Fgf21 levels to improve metabolic health in mice and suggest that betaine supplementation merits further investigation as a supplement for treatment or prevention of type 2 diabetes in humans.

Genome-wide association study and targeted metabolomics identifies sex-specific association of CPS1 with coronary artery disease.

Metabolites derived from dietary choline and L-carnitine, such as trimethylamine N-oxide and betaine, have recently been identified as novel risk factors for atherosclerosis in mice and humans. We sought to identify genetic factors associated with plasma betaine levels and determine their effect on risk of coronary artery disease (CAD). A two-stage genome-wide association study (GWAS) identified two significantly associated loci on chromosomes 2q34 and 5q14.1. The lead variant on 2q24 (rs715) localizes to carbamoyl-phosphate synthase 1 (CPS1), which encodes a mitochondrial enzyme that catalyses the first committed reaction and rate-limiting step in the urea cycle. Rs715 is also significantly associated with decreased levels of urea cycle metabolites and increased plasma glycine levels. Notably, rs715 yield a strikingly significant and protective association with decreased risk of CAD in only women. These results suggest that glycine metabolism and/or the urea cycle represent potentially novel sex-specific mechanisms for the development of atherosclerosis.

Dietary intake and blood levels of choline in a cohort of Canadian pregnant women and newborn infants (827.9)

The developing fetus has a high demand for choline which must be supplied by the mother. To date, very few studies have examined dietary choline intake during pregnancy and its relationship with biomarkers of choline metabolism. We determined dietary intake of choline in 368 pregnant women using a food frequency questionnaire during early and late pregnancy. We measured plasma free choline and metabolite levels in maternal blood samples at 12‐16 weeks gestation and at delivery and in cord blood. Mean dietary choline intake was 313±135 mg/d and did not change appreciably across gestation. Conversely, mean plasma choline levels significantly increased by 49% (p&lt;0.0001), betaine levels significantly decreased by 22% (p&lt;0.0001) and dimethylglycine levels significantly increased by 16% (p&lt;0.0001) from early to late pregnancy. Mean plasma levels of trimethylamine N‐oxide (TMAO) did not change significantly. Maternal dietary choline intake during early pregnancy was only correlated with maternal blood levels of dimethylglycine (r=0.13; p= 0.02) but not with choline, betaine or TMAO levels. Furthermore, maternal plasma choline levels at delivery were not correlated with cord blood choline levels, whereas maternal plasma betaine levels correlated with cord blood betaine levels (r=0.34; p&lt;0.0001). Our data indicate that plasma choline levels significantly increase during pregnancy despite no appreciable change in dietary choline intake and that dietary choline intake does not predict maternal or cord blood levels of choline.Grant Funding Source: Supported by CIHR MOP #106446

Different metabolic and absorption patterns of betaine in response to dietary intake of whole-wheat grain, wheat aleurone or rye aleurone in catheterized pigs

In the present study, a novel method of measuring the uptake of nutrients by 1H NMR spectroscopy was performed to determine dietary effects. Six pigs catheterized in the portal vein and mesenteric artery were fed breads made from whole-wheat grain (WWG), wheat aleurone flour (WAF; 19 % aleurone of bread) or rye aleurone flour (RAF; 15 % aleurone of bread) in a repeated 3 × 3 crossover design. Three meals were provided daily (at 0, 5 and 10 h), and each period comprised of 1 week. Portal and arterial blood samples were collected at fasting (−30 min) on day 4–7, and on day 7, pooled blood samples were collected at 0–2.5, 2.5–5, 5–7.5 and 7.5–10 h after first (0 h) daily meal. Using the arterial-venous difference and ANOVA–simultaneous component analysis, plasma betaine was found to accumulate during the experimental period. On day 7, plasma betaine concentrations was 20–40 % higher than when feeding the WAF diet compared with RAF and WWG (P = 0.001), whereas the content of betaine in the WAF diet was about twice as high. The arterial-venous difference showed a tendency (P = 0.078) for the diet–time interaction of betaine absorption in the absorption phases but there was no diet effect (P = 0.31), which indicates a steady-state absorption has been reached on day 7. Furthermore, high plasma betaine levels correlated with low plasma creatine of endogenous origin. In conclusion, the explorative method revealed that the plasma concentration and absorption of betaine were differentially modified by the diets.

The effect of dietary betaine on intestinal and plasma levels of betaine in uninfected and coccidia-infected broiler chicks.

Chicks fed betaine supplemented diets and infected with Eimeria acervulina and Eimeria maxima had markedly higher levels of betaine in the duodenum and mid-gut than unsupplemented, infected chicks. Uninfected chicks fed betaine exhibited almost twice the levels of betaine in the gut as infected chicks. Plasma betaine levels were lower in E. maxima-infected chicks than in E. acervulina-or Eimeria tenella-infected chicks. Betaine supplementation reversed the decrease in weight gain in E. maxima- infected chicks but had no effect on the decrease in weight gains in E acervulina- and E. tenella-infected chicks. Coccidia-infected birds on normal diets regularly exhibit increases in plasma NO(2)(+)NO(3). This increase was abolished in E.tenella-infected birds on betaine supplement. Betaine feeding did not alter this effect in E. acervulina- and E. maxima-infected birds. Results indicate that betaine supplementation has a positive effect on gut betaine levels in birds infected with E. acervulina and E. maxima. In all treatment groups, infection lowered the levels of betaine.