The clinical significance of betaine, an osmolyte with a key role in methyl group metabolism

doi:10.1016/j.clinbiochem.2010.03.009

Clinical Biochemistry

Volume 43, Issue 9, June 2010, Pages 732-744

https://doi.org/10.1016/j.clinbiochem.2010.03.009 Get rights and content

Abstract

Betaine is an essential osmolyte and source of methyl groups and comes from either the diet or by the oxidation of choline. Its metabolism methylates homocysteine to methionine, also producing N,N-dimethylglycine. Betaine insufficiency is associated with the metabolic syndrome, lipid disorders and diabetes, and may have a role in vascular and other diseases. Betaine is important in development, from the pre-implantation embryo to infancy. Betaine supplementation improves animal and poultry health, but the effect of long-term supplementation on humans is not known, though reports that it improves athletic performance will stimulate further studies. Subsets of the population that may benefit from betaine supplementation could be identified by the laboratory, in particular those who excessively lose betaine through the urine.

Plasma betaine is highly individual, in women typically 20–60 μmol/L and in men 25–75 μmol/L. Plasma dimethylglycine is typically < 10 μmol/L. Urine betaine excretion is minimal, even following a large betaine dose. It is constant, highly individual and normally < 35 mmol/mole creatinine. The preferred method of betaine measurement is by LC-MS/MS, which is rapid and capable of automation. Slower HPLC methods give comparable results. Proton NMR spectrometry is another option but caution is needed to avoid confusion with trimethylamine-N-oxide.

Section snippets

Introducing betaine

In the 1860s, a German chemist, Scheibler, isolated a new organic base from sugar beet (Beta vulgaris). He called it “betaine” [1], [2] and showed that it was N,N,N-trimethylglycine (Fig. 1). Beet is still the main source of betaine, and commercially available betaine is obtained as a natural by-product of the sugar beet industry. Other natural products have been isolated which are chemically related to betaine, and these are generically called “betaines”; the more common examples are shown in

Roles of betaine

Mammals use betaine for two key functions: it is one of the major osmolytes that are accumulated in most tissues to assist cell volume regulation [7], [8], [9], and it is a methyl donor for the remethylation of homocysteine to methionine. The osmolyte role means that tissue betaine concentrations are higher than plasma concentrations, which has been well documented in the rat [10] where almost all tissues have higher concentrations than the blood. The osmoregulated betaine transporter BGT-1 was

Betaine in health and disease

The importance of betaine in normal physiology suggests that a betaine insufficiency would have adverse consequences, and because the enzyme BHMT has been highly conserved in chordate evolution with no known metabolic abnormalities associated with low or absent BHMT, it seems to play an essential role. However, there are only partial answers as to what that role might be.

Control of plasma and urine betaine and dimethylglycine

Plasma betaine concentrations are lower than most tissue concentrations [10], but despite its role as an osmolyte, plasma betaine concentrations are only slightly affected by osmotic stress, and appear to remain stable for years [47]. They are higher in men than in women [96], [191], and this sex difference is also observed in rats [10]. Plasma betaine is probably mainly controlled by liver betaine concentrations, which in turn are controlled by the activity of BHMT [10], and since the control

Summary

Betaine is essential as a tissue osmolyte and as a source of methyl groups, and the supply of betaine clearly affects lipid metabolism. This supply may be inadequate in some patients with diabetes mellitus or with the metabolic syndrome, and these patients typically have elevated plasma homocysteine and dyslipidemia. Therefore, betaine deficiency may contribute to the health problems of this increasing section of the population. This subgroup could benefit from a modest level of betaine

Acknowledgments

We are grateful for support from the Heart Foundation of New Zealand, the Neurological Foundation of New Zealand and the Paykel Trust. Comment from Professor Per Ueland has been especially appreciated. Other valuable suggestions have been made by Dr. Stuart Craig and by Professors Steve Chambers and Peter George.