Betaine absorbed more rapidly in pigs fed a supplement versus when present in cereal dietary fiber

The net absorption of betaine and choline was determined for 4 h after the first meal of the day in three experiments with porto-arterial catheterized pigs in which betaine was added as a supplement to a low-betaine diet (n = 4 pigs) and compared to the net absorption of betaine and choline from high-fiber breads differing in amount and source of dietary fiber (two experiments, n = 6 pigs each). Plasma betaine peaked after 30 min when betaine was fed as a supplement, whereas it peaked after 120-180 min when high-fiber breads were fed. Plasma betaine showed no diet x time interaction after feeding with high-fiber breads, indicating that the absorption kinetic did not differ between fiber sources. The net absorption of choline was not affected by the experimental diets. In conclusion, betaine in cereal sources has to be liberated from the matrix prior to absorption, causing delayed absorption.

Hedemann, M.S., et al., Distinct Difference in Absorption Pattern in Pigs of Betaine Provided as a Supplement or Present Naturally in Cereal Dietary Fiber. J Agric Food Chem, 2015

Postprandial plasma betaine and other methyl donor-related responses after consumption of minimally processed wheat bran or aleurone

The bran and particularly the aleurone fraction of wheat are high in betaine and other physiological methyl donors, which may exert beneficial physiological effects. We conducted two randomised, controlled, cross-over postprandial studies to assess and compare plasma betaine and other methyl donor-related responses following the consumption of minimally processed bran and aleurone fractions (study A) and aleurone bread (study B). For both studies, standard pharmacokinetic parameters were derived for betaine, choline, folate, dimethylglycine (DMG), total homocysteine and methionine from plasma samples taken at 0, 0.5, 1, 2 and 3 h. In study A (n 14), plasma betaine concentrations were significantly and substantially elevated from 0.5 to 3 h following the consumption of both bran and aleurone compared with the control; however, aleurone gave significantly higher responses than bran. Small, but significant, increases were also observed in DMG measures; however, no significant responses were observed in other analytes. In study B (n 13), plasma betaine concentrations were significantly and substantially higher following consumption of the aleurone bread compared with the control bread; small, but significant, increases were also observed in DMG and folate measures in response to consumption of the aleurone bread; however, no significant responses were observed in other analytes. Peak plasma betaine concentrations, which were 1.7-1.8 times the baseline levels, were attained earlier following the consumption of minimally processed aleurone compared with the aleurone bread (time taken to reach peak concentration 1.2 v. 2.1 h). These results showed that the consumption of minimally processed wheat bran, and particularly the aleurone fraction, yielded substantial postprandial increases in plasma betaine concentrations. Furthermore, these effects appear to be maintained when aleurone was incorporated into bread.

Keaveney, E.M., et al., Postprandial plasma betaine and other methyl donor-related responses after consumption of minimally processed wheat bran or wheat aleurone, or wheat aleurone incorporated into bread. Br J Nutr, 2015: p. 1-9

The metabolic burden of methyl donor deficiency with focus on the betaine homocysteine methyltransferase pathway

Methyl groups are important for numerous cellular functions such as DNA methylation, phosphatidylcholine synthesis, and protein synthesis. The methyl group can directly be delivered by dietary methyl donors, including methionine, folate, betaine, and choline. The liver and the muscles appear to be the major organs for methyl group metabolism. Choline can be synthesized from phosphatidylcholine via the cytidine-diphosphate (CDP) pathway. Low dietary choline loweres methionine formation and causes a marked increase in S-adenosylmethionine utilization in the liver. The link between choline, betaine, and energy metabolism in humans indicates novel functions for these nutrients. This function appears to goes beyond the role of the nutrients in gene methylation and epigenetic control. Studies that simulated methyl-deficient diets reported disturbances in energy metabolism and protein synthesis in the liver, fatty liver, or muscle disorders. Changes in plasma concentrations of total homocysteine (tHcy) reflect one aspect of the metabolic consequences of methyl group deficiency or nutrient supplementations. Folic acid supplementation spares betaine as a methyl donor. Betaine is a significant determinant of plasma tHcy, particularly in case of folate deficiency, methionine load, or alcohol consumption. Betaine supplementation has a lowering effect on post-methionine load tHcy. Hypomethylation and tHcy elevation can be attenuated when choline or betaine is available.

Obeid, R., The metabolic burden of methyl donor deficiency with focus on the betaine homocysteine methyltransferase pathway. Nutrients, 2013. 5(9): p. 3481-95

The nutritional burden of methylation reactions

Purpose of review: Methyl group metabolism is a metabolically demanding process that has significant nutritional implications. Methionine is required not only for protein synthesis but also as the primary source of methyl groups. However, demethylated methionine can be remethylated by methyl groups from methylneogenesis (via folate) and betaine (synthesized from choline). This review discusses the impact of methylation precursors and products on the methionine requirement. Recent findings: Recent evidence has clearly demonstrated that transmethylation reactions can consume a significant proportion of the flux of methionine. In particular, synthesis of creatine and phosphatidylcholine consume most methyl groups and their dietary provision could spare methionine. Importantly, methionine can become limiting for protein and phosphatidylcholine synthesis when creatine synthesis is upregulated. Other research has shown that betaine and choline seem to be more effective than folate at reducing hyperhomocysteinemia and impacting cardiovascular outcomes suggesting they may be limiting. Summary: It appears that methyl groups can become limiting when dietary supply is inadequate or if transmethylation reactions are upregulated. These situations can impact methionine availability for protein synthesis, which can reduce growth. The methionine requirement can likely be spared by methyl donor and methylated product supplementation.

Bertolo, R.F. and L.E. McBreairty, The nutritional burden of methylation reactions. Current Opinion in Clinical Nutrition & Metabolic Care, 2013. 16(1): p. 102-8.

Plasma choline and betaine correlate with serum folate, plasma S-adenosyl-methionine and S-adenosyl-homocysteine in healthy volunteers

Background: Choline is essential for mammalian cell function. It plays a critical role in cell membrane integrity, neurotransmission, cell signaling and lipid metabolism. Moreover, choline is involved in methylation in two ways: a) its synthesis requires methyl groups donated by S-adenosyl-methionine (AdoMet); and b) choline oxidation product betaine methylates homocysteine (Hcy) to methionine (Met) and produces dimethylglycine. This later donates one carbon units to tetrahydrofolate (THF).
Methods: To evaluate the correlations of choline and betaine with folate, AdoMet, S-anenosyl-homocysteine (AdoHcy), total homocysteine (tHcy), and DNA methylation, choline, betaine and dimethylglycine were measured by LC-MS/MS in plasma of 109 healthy volunteers, in whom folate, AdoMet, AdoHcy, tHcy, and DNA methylation have previously been reported.
Results: Using a bivariate model, choline and betaine showed strong positive correlations with folate (r=0.346 and r=0.226), AdoHcy (r=0.468 and r=0.296), and correlated negatively with AdoMet/AdoHcy ratio (r=-0.246 and r=-0.379). Only choline was positively correlated with AdoMet (r=0.453). Using a multivariate linear regression model, choline correlated strongly with folate (beta=17.416), AdoMet (beta=61.272), and AdoHcy (beta=9.215). Betaine correlated positively with folate (beta=0.133) and negatively with tHcy (beta=-0.194) ratio. Choline is an integral part of folate and methylation pathways.
Conclusions: Our data highlight the importance of integrating choline in studies concerning addressing pathological conditions related to folate, homocysteine and methylation metabolism.

Imbard, A., et al., Plasma choline and betaine correlate with serum folate, plasma S-adenosyl-methionine and S-adenosyl-homocysteine in healthy volunteers. Clin Chem Lab Med, 2012.

Improved growth performance

120 female pigs were fed either a control commercial diet or the control diet supplemented with 2, 4 and 6% betaine for 31 days. Pigs fed betaine had:

- lower average daily feed intake (ADFI) (for 2% diet)
- higher average daily gain (ADG)
- lower feed conversion ratio (FCR)
- increased loin CIE a* (redness)
- higher loin shear force value
- decreased total blood cholesterol concentrations
- increased saturated fatty acid and decreased unsaturated fatty acid levels in muscle
- increased betaine concentrations in the loin muscle

It was concluded that dietary betaine supplementation of finishing pigs can improve growth performance, reduce blood cholesterol concentrations, and produce detectable betaine concentrations in the lion muscle.

Yang et al (2009). "Effects of dietary glycine betaine on growth and pork quality of finishing pigs." Asian-Australasion J Animal Sci 22(5): 706.

Moderate changes in dietary choline/betaine intake and blood indicators of status

Healthy premenopausal women (n=45, 18–46 years) with the MTHFR 677CC (n=28) or TT (n=17) genotype consumed a folate-restricted diet for 2 weeks followed by randomization to one of four dietary treatments (n=6–9/group) differing in total choline (344–486 mg/day), betaine (122–349 mg/day) and/or folate (400–800 μg dietary folate equivalents/day) content for 12 weeks.

No significant changes were detected in the measured variables (plasma levels of choline moieties (i.e., betaine, choline, phosphatidylcholine and sphingomyelin) and/or leukocyte global DNA methylation) in response to dietary increases in choline (i.e., 41% increase) or betaine (i.e., 286% increase) intake between pretreatment (Week 2) and posttreatment (Week 14) values. However, the MTHFR C677T genotype, alone or together with a diet, influenced betaine (P=.03) and phosphatidylcholine (P=.03).

These data suggest that choline/betaine status is not a reliable indicator of moderate changes in dietary choline/betaine intake possibly due to the engagement of compensatory mechanisms. In addition, the MTHFR C677T genotype appears to influence the direction and use of choline moieties in this group of women.

Abratte et al (2009). "Choline status is not a reliable indicator of moderate changes in dietary choline consumption in premenopausal women." J Nutr Biochem 20(1): 62-9.

Individuality of plasma and urine betaine and DMG

The individuality (within subject consistency) of plasma and urine betaine and N,N-dimethylglycine (DMG) was compared in two groups of 8 males (ages 19 to 40) either over a single day or over an 8 week period. The study found that plasma betaine and urinary betaine excretions are more individual than DMG, and that plasma and urine betaine are highly individual in the general population.

Lever et al (2009). "Plasma and urine betaine and dimethylglycine variation in healthy young male subjects." Clin Biochem 42: 706-12.

Papers 2004-7

Lever et al (2004). "Short and long-term variation of plasma glycine betaine concentrations in humans." Clin Biochem 37(3): 184-90.

Slow et al (2004). "Betaine analogues alter homocysteine metabolism in rats." Int J Biochem Cell Biol 36(5): 870-80.

Lever et al (2005). "Homocysteine, glycine betaine, and N,N-dimethylglycine in patients attending a lipid clinic." Metabolism - Clinical and Experimental 54(1): 1-14.

Slow et al (2005). "The betaine content of New Zealand foods and estimated intake in the New Zealand diet." J Food Comp Anal 18: 473-85.

Lever et al (2007). "An abnormal urinary excretion of glycine betaine may persist for years." Clin Biochem 40(11): 798-801.

Lever et al (2007). "Inter- and intra-individual variations in normal urinary glycine betaine excretion." Clin Biochem 40(7): 447-53.

Lever et al (2007). "Sex differences in the control of plasma concentrations and urinary excretion of glycine betaine in patients attending a lipid disorders clinic." Clin Biochem 40(16-17): 1225-31.

Atkinson et al (2008). "Dietary and supplementary betaine: acute effects on plasma betaine and homocysteine concentrations under standard and postmethionine load conditions in healthy male subjects." Am J Clin Nutr 87(3): 577-585.

Betaine overcomes perturbations caused by choline deficiency

Rats were fed either a standard (25%) casein or soybean protein diet, however both diets were choline-deprived. The study found that:

- Hyperhomocysteinemia induced by choline deprivation was effectively suppressed by choline, betaine or methionine supplementation.

- Hepatic SAM:SAH ratio was improved.

They concluded that this might be a useful model for investigating the role of betaine in the regulation of plasma homocysteine concentration.

Setoue et al (2008). "Choline deprivation induces hyperhomocysteinemia in rats fed low methionine diets." J Nutr Sci Vitaminol (Tokyo) 54(6): 483-90.

Betaine Metabolism and Distribution

A couple of studies investigating the intake and distribution of betaine in tissues:

Clow et al (2008) "Elevated tissue betaine content in developing rats are due to dietary betaine, not synthesis"

Increase in tissue betaine reflects high dietary betaine and not a change in endogenous betaine synthesis.

Slow et al (2008) "Plasma Dependent and Independent Accumulation of Betaine in Male and Female Rat Tissues"

The authors measured the betaine concentration of plasma and various tissues (brain, heart, lungs, liver, kidney, spleen, intestine, reproductive tissues, skeletal muscle and skin) in male and female rats. Some of the findings were:

- betaine was highest in the liver and kidney
- plasma betaine concentrations were significantly lower than tissue levels except in the brain and skeletal muscle
- there was significant plasma-related accumulation of betaine in the heart, skin and skeletal muscle, while the lung, liver, kidney, spleen, and intestine showed significant plasma-related and plasma-independent accumulations of betaine.