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Folate, vitamin B6, and vitamin B12 in relation to diabetes

Folate, vitamin B6, and vitamin B12 in relation to diabetes


To say that diabetes is a problem would be a huge understatement. Researchers believe that type 2 diabetes - aka ‘diabesity’ - is a global public health concern currently approaching epidemic proportions.

In the US alone, the prevalence of diabetes has increased significantly over the past few decades. In 2018, 34.2 million Americans were diagnosed: that’s 10.5% of the population.

The percentage of adults with diabetes is increasing with age, reaching 26.8% among those aged 65 years and over.  

A 30-year study on adult men and women has suggested that three very important nutrients may play a major role in the development of diabetes: folate, vitamin B6, and vitamin B12. 

The Coronary Artery Risk Development in Young Adults (CARDIA) study

The CARDIA study involved a total of 4,704 non-diabetic American adults aged 18–30 years. The adults were enrolled between 1985–1986 and monitored until 2015–2016. A dietary assessment was conducted at the beginning of the study and again in 1992–1993, and in 2005–2006. 

In this large prospective cohort study, folate intake (including both dietary and supplemental resources) was inversely associated with the incidence of diabetes among American adults

during a 30-year follow-up.

The researchers wanted to understand whether a link existed between the adults’ intakes of folate, vitamin B6, and vitamin B12 and the incidence of diabetes. 


Over the 30-year follow-up, a total of 655 cases of diabetes occurred among the adults. Analysis of the results showed that these cases were most prevalent among those with a low intake of folate. Adults who took supplements were also found to have higher levels of folate and lower levels of serum C-reactive protein. 

Another significant finding was that higher folate intake was also associated with lower plasma homocysteine: a major factor in the onset of diabetes.  

The researchers concluded that a low intake of folate in young adulthood could predispose adults to develop diabetes later in life. They also suggested that this finding may be partly related to homocysteine level, insulin sensitivity, and systemic inflammation.

To understand these findings, it’s important to first understand the role that these factors play in diabetes.  

Diabetes: prevalence and risk factors

Most of us are aware of the causes of type 2 diabetes. A sedentary lifestyle and being overweight or obese are two of the most common factors, accounting for about 90% to 95% of diabetes cases in the United States.

It’s estimated that more than 1.7 billion adults worldwide are overweight, and 312 million of them are obese. Around 155 million children worldwide are also overweight or obese .

Every year, over 18 million people die from cardiovascular disease, for which diabetes and hypertension are major predisposing factors.

However, other factors are at play.

Another major player in the development of diabetes is hyperhomocysteinemia, a condition caused by abnormally high levels of homocysteine in the blood (above 15 µmol/L). Homocysteine is an amino acid that the body produces through breaking down protein. Elevated homocysteine levels can lead to serious diseases as well as arterial damage and blood clots in your blood vessels.

Previous studies have indicated that high homocysteine levels are often due to a deficiency in vitamin B-12 or folate . Hyperhomocysteinemia has also been linked to insulin resistance . 

Elevated homocysteine can occur for a variety of reasons, including genetic defects and renal dysfunction. However, low intake of specific nutrients also play a major role - particularly folate, vitamin B6, and B12. 

These B vitamins are crucial for the breakdown and clearance of homocysteine. Folate acts as a prerequisite substrate donor, while vitamins B6 and B12 are essential coenzymes. In addition, these B vitamins are important components of one-carbon metabolism that contributes to DNA methylation, which is also involved in the pathogenesis of diabetes.

Previous clinical trials have shown that folate supplementation can improve insulin resistance and reduce levels of inflammatory mediators . This is a significant benefit in reducing the risk of type 2 diabetes.  

Prior to the present study, there was only limited research into the link between long-term consumptions of folate, vitamin B6, or vitamin B12 to incident diabetes. One study found an inverse association between dietary intake of folate in relation to diabetes risk among Korean women aged 40 years and over . A similar study in Japanese women aged 40–79 years showed the same association. However, the diabetes cases in these studies were self-reported and were not validated with medical records.

Researchers wanted to understand just how much of an impact these B vitamins could have on insulin resistance and systemic inflammation.

The CARDIA study findings

  • Participants with higher folate intake were more likely to have higher total energy intake, have better overall dietary quality, be older and males, have a higher education level (in whites), be never smokers (in whites), consume more alcohol, exercise more, have lower BMI, have higher HDL–to–LDL ratio (in whites), and higher TG in blacks, but lower TG in whites.
    Additionally, they were less likely to have a family history of diabetes (in blacks) and more likely to use folic acid supplements. 
  • During 30 years of follow-up, 655 incident cases of diabetes occurred. Folate intake was inversely associated with the incidence of diabetes.  
  • Regarding the association between intake of vitamin B6 or vitamin B12 and the incidence of diabetes, a significant inverse association was observed only for vitamin B6.  
  • The associations between B vitamin intakes and diabetes incidence were not significantly modified by age at baseline, sex, race (black vs. white), or fasting glucose at baseline.  
  • Interestingly, the inverse association between folate intake and diabetes incidence seemed to be more pronounced among older participants and whites. This is possibly because these people consumed more folate in their diet and in supplements.  
  • When examining the link between folate intake and serum homocysteine, biomarkers of insulin resistance, and systemic inflammation, researchers again found that folate intake was significantly inversely associated with the levels of homocysteine.  
  • Folate intake was also inversely associated with CRP concentrations among supplement users. C-reactive protein (CRP) is a protein made by the liver. CRP levels in the blood increase when there is a condition causing inflammation somewhere in the body. 

Nutritional status and the risk of diabetes

This study revealed two very important factors:

  • A low intake of folate is associated with an increased risk of developing type 2 diabetes
  • A high intake of folate is associated with a reduced risk of developing type 2 diabetes
  • Folate intake was significantly associated with lower levels of Hcy, insulin, and CRP.

American young adults with higher folate intake are less likely to develop diabetes later in life, presumably due to the role of folate in reducing homocysteine levels, insulin resistance, and systemic inflammation.

Vitamin B6 and B12 in relation to diabetes

Vitamin B12 is crucial for reducing homocysteine. It also plays a major role as a cofactor in the methylation process of L-methylfolate, and is then required for the conversion of homocysteine to methionine. The conversion of homocysteine to cysteine also requires active B6 (also known as pyridoxal-5-phosphate). 

However, a lack of any particular nutrient can lead to dangerously high homocysteine levels. In addition, the essential components that your body requires in order to function properly may be reduced.

Although vitamin B12 is present in many animal products such as organ meats and dairy, many people (the eldery, vegans, vegetarians) may not obtain it through their diet. This means supplementation is necessary. Fortunately, the right B12 supplements are generally very effective. One study showed that when individuals took 500 µg/day of vitamin B12 for 2 months, their homocysteine levels were reduced to less than 5 µmol/.  

Although the CARDIA study appeared to show that intakes of vitamin B6 and B12 had no impact on the development of diabetes, researchers hypothesized that nutrient supplementation may only benefit individuals with insufficient dietary intakes.

Unlike folate, the vast majority of the participants in the study were not lacking in vitamin B6 and B12. This could mean that the benefits of these two B vitamins on diabetes risk may not be as significant as folate. 

Instead, the positive benefits of folate in terms of reducing the risk of diabetes was more likely due to folate’s ability to reduce homocysteine. 

Homocysteine and diabetes

The link between elevated homocysteine and a higher risk of diabetes has been demonstrated in a number of clinical studies.

Various researchers have reported a higher level of homocysteine in patients with type 1 or type 2 diabetes than in normal subjects . In addition, a European study reported an independent association between homocysteine level and the utilization of glucose in the body.

A 2018 study involving mice showed that chronic folate deficiency led to obesity after just six weeks, while glucose intolerance and insulin resistance developed after 16 weeks. In addition, folate deficiency reduced insulin signaling and increased serum triglyceride levels.
After 24 weeks without folate, the mice displayed anxiety and impaired spatial learning and memory performance. The authors of the study concluded that folate deficiency could induce obesity, glucose and lipid metabolic disorders, which in turn led to cognitive dysfunction .

Further studies have noted a positive correlation between homocysteine levels and fasting insulin concentration in people with insulin-resistant diabetes and also in those with impaired glucose tolerance. 

Homocysteine has been found to inhibit insulin secretion. Elevated plasma homocysteine levels have been reported in hyperinsulinaemic obese individiuals and also in those with type 2 diabetes. 

By inhibiting insulin secretion, homocysteine can impair the insulin secretory response to low and high glucose concentrations. This effect is believed to explain the possible role of hyperhomocysteinemia in the development of type 2 diabetes.

Studies in rats have found that insulin is directly involved in regulating the metabolism of homocysteine. This appears to be linked to hepatic cystathionine β-synthase, a transmethylation enzyme involved in the conversion of homocysteine to cystathionine. When researchers examined insulin-deficient rats, they found that this enzyme was elevated and plasma homocysteine was reduced by insulin administration. 

The importance of folate

The authors of the CARDIA study noted that folate deficiency had previously been shown to severely hamper biosynthesis and secretion of insulin in pancreatic b-cells . Other studies have reported that low folate can impair glucose tolerance in spontaneously hypertensive rats.

Folate supplementation, on the other hand, has been shown to:

  • Decrease hyperglycemia caused by a gestational high-fat and high-sucrose diet in rats
  • Reduce insulin resistance in rats with metabolic syndrome
  • Significantly decrease circulating insulin and CRP levels in humans
  • Reduce oxidative stress, ameliorate endothelial dysfunction, and modulate DNA methylation of genes associated with insulin signaling which may influence the risk of diabetes .

Folate is the natural active form of vitamin B9 in food. Folate is vital at every age and stage of life. It’s required for many different functions within the human body, particularly the production of red blood cells. 

Deficiency or low levels of folate can be caused by genetics, certain diseases, or medications. Although folate occurs naturally in many foods such as legumes and leafy greens, many people either don’t eat the right foods or are unable to obtain folate from their food. 

The link between folate intake and homocysteine levels

As mentioned above, high levels of homocysteine have been linked to a number of negative health effects. Along with a higher risk of developing diabetes, elevated homocysteine may lead to vascular damage caused by toxic accumulation in endothelial cells and the generation of free radicals.

Elevated homocysteine is strongly linked to low levels of plasma folate. There are also links between blood levels of vitamin B12 and pyridoxal-5-phosphate (the active form of B6).
Unsurprisingly, varying degrees of hyperhomocysteinemia have been found in all inflammatory diseases. Hyperhomocysteinemia is also considered as a risk factor for inflammatory
diseases including life-threatening cardiovascular disease, stroke, renal failure and cancer.

It has also been shown that hyperhomocysteinemia not only is produced from inflammation, but the oxidative stress generated from hyperhomocysteinemia will again promote inflammation. As a result, elevated homocysteine and inflammation markers are often detected at the same time, even if they are not correlated .

Numerous studies have indicated that correct doses of vitamins such as folic acid, vitamin B6, vitamin B12, and betaine (or TMG) may control or alleviate the risk of elevated homocysteine .  

For this reason, taking bioactive folate 5-MTHF directly has been shown to significantly increase blood serum folate levels compared with folic acid supplementation. 

One of folate’s most crucial roles is in ridding the body of excess homocysteine. However, ordinary folic acid supplements will not provide the full spectrum of effects if an individual is unable to convert folate to its biologically active form called 5-methyltetrahydrofolate (5-MTHF) or L-Methylfolate.

Because a large percentage of the population has the genetic enzyme deficiency that prevents the proper conversion of folate to 5-MTHF, many people are vulnerable to low blood folate levels and subsequently, higher than desired homocysteine (even if they take a folic acid supplement daily). 

For this reason, taking bioactive folate 5-MTHF directly has been shown to significantly increase blood serum folate levels compared to folic acid supplementation. 

Key point: This form of folate is vital for people who have a genetic enzyme deficiency because it requires no conversion to become metabolically active. 

Reducing the risk of diabetes through diet and supplements

Type 2 diabetes is largely preventable. Reducing one’s risk of developing this disease begins with dietary intervention and the inclusion of specific nutrients. 

Four simple changes to the diet can have a massive impact. 

  1. Swapping refined grains and other processed starches for whole grains
  2. Reducing or avoiding foods and beverages that contain high amounts of sugar (soda, alcohol, juices, sports drinks). These can be replaced with water, coffee, or tea.
  3. Increasing intake of healthy omega-3 fats (oily fish, avocado, nuts)
  4. Limiting intake of red meat and avoiding all processed meats. Replace with lean protein: nuts, beans, whole grains, poultry, or fish.
  5. Reducing alcohol intake overall. A lower alcohol consumption (up to a drink a day for women, up to two drinks a day for men) increases the efficiency of insulin at getting glucose inside cells.
  6. Get active. Walking briskly for a half hour every day reduces the risk of developing type 2 diabetes by 30%.

The right supplements

If the CARDIA study proved nothing else, it’s that supplementation with folate is essential for reducing the risk of diabetes.

And, as highlighted in the research above, this must be obtained with quality methylfolate - not folic acid. It should also be taken alongside vitamin B6 and vitamin B12.

Some of the most highly-recommended methylfolate supplements are in the Methyl-Life™ product range, including B-Methylated II and Methylfolate 7.5+. 

Methyl-Life’s™ B-Methylated II product contains a moderate dose (3 mg) of internationally-patented Magnafolate® PRO [(6S)-5-methyltetrahydrofolic acid, Calcium salt, Type C Crystalline molecule (L-Methylfolate)] as well as active B12 in the form of methylcobalamin at a healthy dose of 3.75 mg. This best-selling product is formulated specially for people with a heightened need for bioavailable folate due to genetic (MTHFR) defects, dietary deficiencies or drug-induced need (i.e. taking warfarin, coumadin, metformin, etc.). B-Methylated II has the same amount of active L-Methylfolate as Metanx, a prescription ‘medical food’ designed particularly for those with diabetes to improve their condition with these key nutrients (highlighted in the studies above). 

Methyl-Life’s™ unique and internationally-patented L-5-Methylfolate ingredient is crystalline calcium salt-based for superior stability and absorption. And a recent study has revealed that this proprietary form of methylfolate offers much greater purity than any other L-Methylfolate competing in the market today (approximately 3x more pure to be exact). Methylfolate is often known or labeled as L-MTHF, L-5-Methylfolate, L-5-MTHF, and (6S)-5-Methylfolate.

The Methylfolate 7.5+ product was designed especially for those dealing with diabetic symptoms as well as encountering low mood challenges. This particular product contains 7.5 mg of L-Methylfolate which has been shown to increase neurotransmitter levels, like serotonin. It also contains the active forms of B12 (hydroxocobalamin and adenosylcobalamin). This is especially helpful for those who are dealing with mental health and/or dementia/Alzheimer’s challenges in addition to diabetes or cardiovascular symptoms.

Not all methylfolate supplements are the same, so do you research before choosing the product you depend on to improve your health.
    Written By,
    - Jamie Hope
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