The synthetic form of a B vitamin is called folic acid; the natural form is called folate. Folate participates in “One Carbon Unit” processes, which help transfer one-carbon units in the metabolism of amino acids and nucleic acids. Folates are therefore essential for the production of DNA, RNA, and proteins. Folates have a close relationship with homocysteine metabolism, which is a biomarker for heart health.
When compared to manufactured folic acid, the structure of natural folate differs significantly. Whereas folic acid only has one amino acid connected and is in the oxidized state, folates are found in food in reduced forms with many amino acids attached.
Although folic acid is more readily absorbed, the variations are significant enough that the recommended daily intake of folic acid in the United States and a few other countries is expressed as Dietary Folate Equivalents (DFEs), accounting for the fact that the folic acid must be converted by the body into folate. The body converts folic acid to folate, with one (so far) significant exception. (Refer below.)
Food Sources of Folate
Fruits and vegetables, especially leafy greens, asparagus, Brussel sprouts, avocados, oranges, papayas, and bananas, are good sources of folate. Beef liver has the maximum amount of folates. Folate/folic acid has been added as a supplement to many foods since it has been linked to a birth problem called spina bifida, which is a type of neural tube defect.
Your Genetics and Folate Deficiency
Megaloblastic anemia is a kind of anemia caused by a folate shortage. Another vitamin shortage that can result in this type of anemia is B12. Because the body need both folate and vitamin B12 to create DNA, this type of anemia develops. Given that red blood cells only live for approximately 120 days, their incapacity to produce DNA is evident in them.
A deficit in folate can cause weakness, exhaustion, and dyspnea. Additional signs and symptoms may include tongue and mouth sores, skin or hair abnormalities, and fingernail discolouration. Oral folate supplementation should always be used in conjunction with vitamin B12 administration, as B12 insufficiency can also produce many of the same symptoms as well as additional ones.
While taking folic acid and vitamin B12 together did lower homocysteine levels and reduce the risk of stroke, there has been no evidence that these supplements reduce the rates of heart or blood vessel disease in diabetics. Studies of many kinds, referred to as observational studies, HAVE shown a decline in heart disease.
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The distinct outcomes may be explained by the fact that observational studies are not held to the same strict and exacting criteria as placebo-controlled trials. Still, there may be another, more significant explanation for the variations observed in these research. A common gene abnormality that might have an impact on these results was not considered in the majority of these research.
The gene for methylenetetrahydrofolate reductase is known as MTHFR
People who have the polymorphism a common genetic alteration, are unable to utilise folic acid or folates effectively. Up to 40% of the population may experience this genetic mutation or alteration. An enzyme called MTHFR, which is short for homocysteine (a biomarker for heart health), is altered or mutated as a result of the change.
Tetramethylhydrofolate, also commonly referred to as methylfolate, is typically required by people with this polymorphism in order to compensate for the inefficiency of the mutant enzyme. Additionally, it is advised that those who carry this mutation stay away from folic acid supplements.
This mutation is thought to put people at risk for cancer, heart disease, stroke, high blood pressure, glaucoma, and mood problems. Although this correlation has not always been observed, the MTHFR mutation has also been linked to elevated homocysteine levels, diabetic neuropathy, and retinopathy.
This discrepancy may be due in part to metformin’s reduction of vitamin B12 and folate levels, which can raise homocysteine levels. In the study where there was no correlation found between the presence of the MTHFR mutation and either diabetic neuropathy or retinopathy, all of the patients were taking metformin, which may have obscured or otherwise impacted the findings.
In a more recent investigation, homocysteine levels and MTHFR were examined prior to metformin treatment. The results showed that those with the mutation had considerably higher homocysteine levels.
In a more recent study, incidences of gestational diabetes were found to be reduced when customized folate supplementation was examined in consideration of the MTHFR mutation. Another study examined how folic acid supplementation affected the health of blood vessels in people with type 2 diabetes and discovered that folic acid/folate supplementation may enhance blood vessel function in people with T2D.
The Status of Science Right Now
The study of science is not for the timid. It can be complicated, and unless there is a clear solution, there is frequently none.
What is known to us, and what is unknown to us?
- We are aware that low levels of folate and vitamin B12 can have a variety of consequences. We are aware that megaloblastic anemia can result from a deficit in either. For this reason, vitamin B12 is typically administered alongside folate, also known as folic acid.
- We are aware that a lack in folate can raise homocysteine levels, which are a biomarker for heart health.
- A biomarker is precisely that—it “marks” the presence of an elevated risk, in this case, of blood vessel and heart disease. Despite being linked to an increased risk of heart disease, elevated homocysteine levels are not a diagnostic sign, meaning they do not identify heart disease.
- Metformin, like medications that lower cholesterol and lessen stomach acid, is known to impair vitamin B12 levels. Serum folate levels are also lowered by metformin. Moreover, medications that lower cholesterol, oral contraceptives, and anti-seizure treatments can drop folate levels.
- We are aware that a sizable portion of any population may be genetically mutated, making it harder for them to use folates and maybe requiring methylfolate supplements.
- We are aware that supplementing with folate/folic acid has been shown in some studies to positively correlate with lower rates of heart disease, blood vessel disease, and stroke in patients with diabetes; additionally, more recent research has linked the MTHFR mutation to a decrease in the number of women with gestational diabetes and an improvement in blood vessel health.
- We are aware that diabetic neuropathy and retinopathy have been linked, at least in some studies, to elevated homocysteine and low folate levels.
- We do know that high doses of a combination of vitamin B12, vitamin B6, and folic acid were linked to worsening diabetic nephropathy and an increased risk of blood vessel damage, at least in one trial, the Diabetic Intervention with Vitamins to Improve Nephropathy (DIVINe) study.
Conversely, though
- There have not been enough research to determine whether supplementing with folate/folic acid OR methylfolate can actually lower the risk of heart disease or stroke in persons with diabetes. It’s possible that these B vitamins aren’t actually addressing the root reason, rather lowering the biomarker homocysteine levels.
- We are unsure if the DIVINe study’s findings are the consequence of the patients’ pre-existing blood vessel and diabetic renal diseases or of the noticeably high B vitamin dosages used.
- It’s unclear if diagnosing diabetic patients with the MTHFR mutation can determine whether they need to take methylfolate supplements.
What then should I do?
As usual, the first thing to do is to consult your doctor. To find out if you have any of the several MTHFR mutations, you can request a blood test. Next, talk about supplements. If the mutation is found in you, you should talk to your doctor about taking methylfolate supplements and getting more vitamin B12.
Limit your supplement intake if you have renal disease symptoms. Consider taking the supplements if you do not have renal disease, but only at the daily dosages advised by the manufacturer or on the advice of your doctor. Avoid going overboard!
Overall, if taken early in the course of diabetes, folate supplementation may be beneficial and may help prevent diabetic retinopathy and neuropathy. Although the science is still developing, some clinical trials are now underway, and as Trinity stated to Neo in The Matrix, “The answer is out there.”
DiabetesCouncils Article | Reviewed by Dr. Sergii Vasyliuk MD on June 10, 2020
Citations
- http://lpi.oregonstate.edu/mic/vitamins/folate
- 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.
- https://ghr.nlm.nih.gov/gene/MTHFR#resources
- http://www.molvis.org/molvis/v19/1626/
- 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.
- http://www.tandfonline.com/doi/abs/10.1080/2331205X.2015.1017973
- http://www.karger.com/Article/Abstract/367656
- http://www.tandfonline.com/doi/abs/10.1080/2331205X.2015.1017973
- https://www.researchgate.net/publication/43348402_Effect_of_B-Vitamin_Therapy_on_Progression_of_Diabetic_Nephropathy_A_Randomized_Controlled_Trial
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