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Diabetes. 2010 March; 59(3): e1.
PMCID: PMC2828669

Comment on: Song et al. (2009) Effect of Homocysteine-Lowering Treatment With Folic Acid and B Vitamins on Risk of Type 2 Diabetes in Women

A Randomized, Controlled Trial. Diabetes 58:1921–1928

The Diabetes article by Song et al. (1) presents the results of the first randomized, controlled trial to analyze the long-term effects of folic acid and vitamin B supplementation on the risk of developing type 2 diabetes in women at high risk for cardiovascular disease. Daily supplements significantly lowered homocysteine levels but did not reduce the risk of developing type 2 diabetes. Their results do not support previous findings indicating increased homocysteine levels as a significant predictor of the development of diabetes (2).

These conflicting data must be viewed in light of the increasing evidence gained from clinical trials, which suggests no beneficial effects of homocysteine-lowering strategies on cardiovascular events (3). Given the controversy, it has been suggested that S-adenosylhomocysteine (SAH), the cytotoxic precursor of homocysteine, may be a more sensitive indicator of cardiovascular disease than is homocysteine (4). We have recently studied the mechanisms by which homocysteine and SAH cause endothelial cell damage (5). In our study, human coronary artery endothelial cells were unaffected by exposure to homocysteine, even at supraphysiologic concentrations (500 μmol/l); however, low concentrations (25 μmol/l) of homocysteine induced cytotoxic changes in endothelial cells under culture conditions that increased the intracellular level of SAH (5). We believe our findings show that in the absence of SAH, the vascular effects of homocysteine may be negligible.

These findings may help explain the lack of health benefits observed in several nutritional intervention trials, including that of Song et al. (1). Vitamin supplements that successfully lower homocysteine levels may not affect SAH levels. It would be of interest to see a large-scale, prospective study of SAH, rather than homocysteine, as an indicator of the development of diabetes.


This study was supported in part by research grant 1-04-RA-13 from the American Diabetes Association; grants NSC 91-2320-B-002-185, 93-2314-B-002-125, 94-2320-B-002-121, 95-2320-B-002-116, and 98-2628-B-002-088-MY3 from the National Science Council, Taiwan; and grants NTUH92A14, 93A02, 95S342, and 96S643 from the National Taiwan University Hospital, Taiwan.

No potential conflicts of interest relevant to this article were reported.

The authors thank Rebecca Bartow, PhD, of the Texas Heart Institute at St. Luke's Episcopal Hospital for editorial assistance.


1. Song Y, Cook NR, Albert CM, Van Denburgh M, Manson JE.: Effect of homocysteine-lowering treatment with folic acid and B vitamins on risk of type 2 diabetes in women: a randomized, controlled trial. Diabetes 2009; 58: 1921– 1928 [PMC free article] [PubMed]
2. Cho NH, Lim S, Jang HC, Park HK, Metzger BE.: Elevated homocysteine as a risk factor for the development of diabetes in women with a previous history of gestational diabetes mellitus: a 4-year prospective study. Diabetes Care 2005; 28: 2750– 2755 [PubMed]
3. Lonn E.: Homocysteine-lowering B vitamin therapy in cardiovascular prevention—wrong again? JAMA 2008; 299: 2086– 2087 [PubMed]
4. Wagner C, Koury MJ.: S-Adenosylhomocysteine: a better indicator of vascular disease than homocysteine? Am J Clin Nutr 2007; 86: 1581– 1585 [PubMed]
5. Chang PY, Lu SC, Lee CM, Chen YJ, Dugan TA, Huang WH, Chang SF, Liao WS, Chen CH, Lee YT.: Homocysteine inhibits arterial endothelial cell growth through transcriptional downregulation of fibroblast growth factor-2 involving G protein and DNA methylation. Circ Res 2008; 102: 933– 941 [PubMed]

Articles from Diabetes are provided here courtesy of American Diabetes Association