Folate is the natural form of a B vitamin—the synthetic version is known as folic acid. Folate functions in the type of reactions known as “One Carbon Units” where folates assist in the transfer of one-carbon units in nucleic acid and amino acid metabolism. Because of this, folates are critical for DNA, RNA and protein synthesis. Folates are also closely related to the metabolism of homocysteine, a biomarker for heart health.
Natural folate has some important differences in structure as compared to the synthetic folic acid. Folates are found in food in reduced forms and several amino acids attached where folic acid has only one amino acid attached and is in the oxidized form. While folic acid is better absorbed, the differences are sufficient so that in the US and a few other countries, the amount of folic acid recommended is expressed as Dietary Folate Equivalents (DFEs), to take into account that the body has to convert the folic acid into a folate. Folic acid is converted into folate in the body, with one (so far) very important exception. (See below)
Sources of Folate in Foods
Folate can be found in fruits and vegetables, particularly in leafy green vegetables, asparagus, Brussel sprouts, avocados, oranges, papayas and bananas. The highest level of folates is found in beef liver. Since a lack of folate/folic acid has been associated with a birth defect, spina bifida, a form of a neural tube defect, folate/folic acid has been added as a supplement to many foods.
Folate Deficiency and Your Genetics
Folate deficiency results in a form of anemia called megaloblastic anemia. This form of anemia can also be caused by a deficiency of another vitamin, B12. This form of anemia occurs because the body needs both folate and Vitamin B12 to make DNA. Red blood cells only have a lifespan of about 120 days, so the inability to make DNA shows up in the red blood cells. Symptoms of folate deficiency include fatigue, weakness, and shortness of breath. Other symptoms can include sores in the mouth and tongue, changes in the skin or hair and a discoloration of the fingernails. Folate supplementation (taken orally) should always done along with Vitamin B12 supplementation because many of the same symptoms and more can also be caused by B12 deficiency.
Folic acid taken along with Vitamin B12 has not been shown to decrease the rates of heart or blood vessel disease in people with diabetes, though these supplements DID lower the levels of homocysteine AND did lower the risk of stroke. Different types of studies known as observational studies HAVE shown a decrease in heart disease. Observational studies do not have the same high and rigorous standards that placebo-controlled trials have, so that could explain the different results. However, there is a potentially important other reason for the differences in these studies. Most of these studies did not take into account a common gene defect that could affect these results.
MTHFR or the methylenetetrahydrofolate reductase gene.
There is a common genetic change—a polymorphism called C677C>T—that causes people who have this change to be unable to use folates or folic acid efficiently. This genetic mutation or change can occur in up to 40% of the population. The change alters (mutates) an enzyme (Abbreviated MTHFR) that converts homocysteine (the biomarker for heart health) to methionine. People with this polymorphism generally need another form of folate—tetramethylhydrofolate (often just called methylfolate), to overcome the inefficiency of the mutated enzyme. It is also recommended that people with this mutation avoid folic acid supplements.
It is believed that this mutation may be a risk factor for heart disease, stroke, high blood pressure, glaucoma, mood disorders and cancer. The MTHFR-C677C>T mutation has also been associated with high homocysteine levels and diabetic neuropathy and retinopathy , though this association has not always been seen. One potential reason for this discrepancy is that metformin reduces the amount of Vitamin B12 and folate which can then cause an increase in homocysteine—in the study where the association between the presence of the MTHFR-C677T mutation and either diabetic neuropathy or retinopathy was not seen, all the patients were on metformin—this may have masked or potentially affected the results. A more recent study looked at homocysteine levels and MTHFR-C>T before the administration of metformin and found that those with the mutation had significantly higher levels of homocysteine.
A more recent study looked at individualized folate supplementation to take into account the MTHFR-C677C>T mutation and found that rates of gestational diabetes were decreased. Another study looked at the effect of folic acid supplementation on the health of blood vessels in T2D and found that folic acid/folate supplementation could improve the function of blood vessels in T2D.
The Current State of the Science
Science is not for the faint-hearted. It can be messy and all too often, there is no definite answer…until there is.
What do we know—and what don’t we know?
- We know that folate deficiency, along with Vitamin B12 deficiency can have a number of effects. We know that a deficiency in either can cause an anemia called megaloblastic anemia. This is why, as a rule, folate or folic acid is given along with Vitamin B12.
- We know that folate deficiency can increase the levels of homocysteine, used as a biomarker for heart health
- A biomarker is just that—it “marks” that there is an increased risk, in this case, of heart and blood vessel disease. A biomarker is not, however, a diagnostic marker—in other words high homocysteine levels does not diagnose heart disease—it is associated with a higher risk of heart disease.
- We know that metformin can reduce Vitamin B12 levels (as can drugs used to reduce stomach acid and lower cholesterol). Metformin also reduces serum folate levels. Also, anti-seizure drugs, oral birth control and cholesterol lowering medications can reduce folate levels
- We know that a pretty significant part of any population may carry a genetic mutation that makes it difficult to utilize folates and may need to supplement with methylfolate
- We know that at least some studies have shown a positive relationship in diabetes between folate/folic acid supplementation and reducing the rates of heart disease, blood vessel disease and stroke in patients with diabetes and that more recent studies have shown a relationship between the MTHFR-C677C>T mutation – the number of women with gestational diabetes decreased and blood vessel health was improved.
- We know that in at least some studies, high homocysteine and low folate levels was associated with diabetic neuropathy and retinopathy.
- We know that at least in one study, the Diabetic Intervention with Vitamins to Improve Nephropathy (DIVINe) study, high doses of a combination of Vitamin B12, Vitamin B6 and folic acid was associated with worsening diabetic nephropathy and a higher risk of blood vessel disease.
On the other hand:
- We don’t know that supplementing with folate/folic acid OR methylfolate can really decrease the risk of heart disease or stroke in patients with diabetes—there have not been enough studies to be certain. These B vitamins may only be reducing the level of the biomarker homocysteine and not truly affecting the underlying cause.
- We don’t know if the results of the DIVINe study is due to the significantly high doses of B vitamins used, or because the patients already had diabetic renal disease and blood vessel disease.
- We don’t really know if testing for the MTHFR-C66C>T mutation can identify diabetes patients who should supplement with methylfolate.
So, what to do?
The first step is, as always, talk to your physician. You can ask for a blood test to determine what if any MTHFR mutation you may have—there are a number of them. Then, discuss supplementation. If you are positive for the mutation, the methylfolate supplementation should be discussed and you should also take additional Vitamin B12. If you have evidence of kidney disease, limit the supplements. If you are free of kidney disease, consider taking the supplements—but only at recommended daily levels by following manufacturer’s instructions or your physician’s advice. Don’t overdo it!
Overall, folate supplementation may benefit and may help prevent diabetic neuropathy and diabetic retinopathy, particularly if started early in the course of your diabetes. The science is still out, but there are a number of ongoing clinical trials, and as Trinity told Neo (The Matrix) “The answer is out there…”
- Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, et al. (2006). Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 354(15): 1567-1577.
- Yang, Sheng, et al. “MTHFR 677T variant contributes to diabetic nephropathy risk in Caucasian individuals with type 2 diabetes: a meta-analysis.” Metabolism 62.4 (2013): 586-594.
- Russo, G. T., et al. “Diabetic neuropathy is not associated with homocysteine, folate, vitamin B12 levels, and MTHFR C677T mutation in type 2 diabetic outpatients taking metformin.” Journal of endocrinological investigation 39.3 (2016): 305-314.