Effect of Homocysteine-lowering Treatment with Folic Acid and B Vitamins on Risk of Type 2 Diabetes in Women: A Randomized, Controlled Trial

Yiqing Song; Nancy R. Cook; Christine M. Albert; Martin Van Denburgh; JoAnn E. Manson


Diabetes. 2009;58(8):1921-1928. 

In This Article

Abstract and Introduction


Objective Homocysteinemia may play an etiologic role in the pathogenesis of type 2 diabetes by promoting oxidative stress, systemic inflammation, and endothelial dysfunction. We investigated whether homocysteine-lowering treatment by B vitamin supplementation prevents the risk of type 2 diabetes.
Research design and methods The Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS), a randomized, double-blind, placebo-controlled trial of 5,442 female health professionals aged ≥40 years with a history of cardiovascular disease (CVD) or three or more CVD risk factors, included 4,252 women free of diabetes at baseline. Participants were randomly assigned to either an active treatment group (daily intake of a combination pill of 2.5 mg folic acid, 50 mg vitamin B6, and 1 mg vitamin B12) or to the placebo group.
Results During a median follow-up of 7.3 years, 504 women had an incident diagnosis of type 2 diabetes. Overall, there was no significant difference between the active treatment group and the placebo group in diabetes risk (relative risk 0.94 [95% CI 0.79–1.11]; P = 0.46), despite significant lowering of homocysteine levels. Also, there was no evidence for effect modifications by baseline intakes of dietary folate, vitamin B6, and vitamin B12. In a sensitivity analysis, the null result remained for women compliant with their study pills (0.92 [0.76–1.10]; P = 0.36).
Conclusions Lowering homocysteine levels by daily supplementation with folic acid and vitamins B6 and B12 did not reduce the risk of developing type 2 diabetes among women at high risk for CVD.


Homocysteinemia may promote insulin resistance and β-cell dysfunction through its adverse metabolic effects, ultimately contributing to the pathogenesis of type 2 diabetes and associated complications.[1–3] Several lines of evidence from both in vitro and in vivo studies support this hypothesis. First, homocysteinemia directly elicits oxidative stress by increasing reactive oxygen species production and diminishing intracellular antioxidant defense.[2] Experimental studies have suggested that oxidative stress interferes with insulin signaling and impairs pancreatic β-cell insulin secretion,[4,5] thereby accelerating the progression from insulin resistance to overt type 2 diabetes. Second, elevated levels of homocysteine promote systemic inflammation via the activation of a cascade of inflammatory pathways including interleukin-6, tumor necrosis factor-α, and adhesion molecules.[3] Low-grade chronic inflammation, as reflected by elevated circulating levels of inflammatory cytokines, may promote insulin resistance in liver, skeletal muscle, and vascular endothelium.[6,7] Last, homocysteine can exert its damaging effects on the endothelium through mechanisms involving impaired nitric oxide (NO)-dependent vasodilation, endothelial toxicity and injury, oxidative stress, and systemic inflammation.[2,8] The resultant endothelial dysfunction, especially in the capillary and arteriolar endothelium, can reduce insulin delivery to insulin-sensitive peripheral tissues, which in turn impairs insulin-mediated glucose metabolism.[9–11] Collectively, we speculate that elevated homocysteine levels may play an etiologic role in the development of insulin resistance and type 2 diabetes primarily by promoting oxidative stress, systemic inflammation, and endothelial dysfunction.

Homocysteinemia has been recognized as a vascular risk factor for diabetic angiopathy,[12] whereas few human data are currently available on the relation between homocysteine levels and risk of developing type 2 diabetes. In observational studies, homocysteine levels in nondiabetic individuals have been positively correlated with several biomarkers of insulin resistance and/or glucose intolerance in some[13–15] but not all[16–18] studies. In a 4-year prospective cohort study, elevated levels of homocysteine were independently associated with a 3.6-fold increased risk of type 2 diabetes among 170 women with a history of gestational diabetes mellitus.[19] These observations not only provided suggestive evidence linking elevated levels of homocysteine to the development of type 2 diabetes but also led to the suggestion that lowering homocysteine levels may prevent or reduce risk of type 2 diabetes.

Dietary folic acid and vitamins B6 and B12 are the most important modifiable determinants of homocysteine levels, and adequate intake of B vitamins may be potentially beneficial for prevention of type 2 diabetes in the general population. However, no previous prospective cohort studies have specifically examined intakes of individual B vitamins and diabetes risk. Some small and short-term randomized trials for secondary prevention of diabetes complications have been conducted but yielded inconsistent results; some reported that folic acid supplementation (5–10 mg/day) reduced oxidative stress and improved endothelial function in diabetic patients during a period of 2–12 weeks.[20–23] To the best of our knowledge, there are no previous randomized clinical trials assessing the efficacy of B vitamin supplements for primary prevention of type 2 diabetes. In a large cardiovascular disease (CVD) prevention trial, the Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS), we specifically examined the homocysteine-lowering effect by daily supplementation with folic acid, vitamin B6, and vitamin B12 on the risk of type 2 diabetes in women at high risk for CVD.


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