MTHFR, B12 and Diabetes

MTHFR, B12 and Diabetes

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Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Kari Asadorian - BSN, RN

Medical Reviewer:

Kari Asadorian - BSN, RN
Dr. Nare Simonyan - PhD Pharmaceutical Science

Edited By:

Dr. Nare Simonyan - PhD Pharmaceutical Science
Last updated:

What is diabetes?

Diabetes mellitus is a chronic condition that occurs when the body either cannot produce sufficient insulin or cannot use insulin effectively. Insulin is a hormone produced by the pancreas that allows glucose in the bloodstream to enter the body’s cells, where it is used for energy or stored for later use.

When insulin is not available or cannot be used properly, blood glucose levels remain elevated (hyperglycemia), which can eventually cause serious damage to various organ systems if untreated.

There are two types of diabetes:

  • Type 1 diabetes (T1DM) is a non-preventable condition that can occur at any age but is most common in children. It is an autoimmune condition in which the body’s immune system attacks the beta cells of the pancreas, resulting in insulin deficiency.
    Those affected require daily insulin injections.
    In the US, around 1.4 million adults and 187,000 children (younger than 20) have type 1 diabetes.1
  • Type 2 diabetes (T2DM) is the most common form of diabetes in adults worldwide. Of the 38 million Americans with diabetes, about 90-95% have type 2. Type 2 diabetes has been linked to many lifestyle factors, which makes it largely preventable, but genetic factors have also been identified.2

Causes of diabetes, prevalence and risk factors

Causes of type 1 diabetes

Genetic factors

The human leukocyte antigen (HLA) region genes are the strongest link to genetic risk for type 1 diabetes, especially class II HLA‑DR and HLA‑DQ alleles/haplotypes.3 In people of European descent, ~90-95 % of T1D patients carry either DR3 or DR4 haplotypes on at least one chromosome. 

In addition to HLA genes, several other genes including INS, CTLA, and PTPN22, have also been associated with an increased risk of Type 1 diabetes, but on a smaller scale.4


Environmental 

Several viruses including enteroviruses (Coxsackie), rotavirus, mumps, rubella and SARS-CoV-2 can infect and damage beta cells or trigger inflammation that results in autoimmune destruction of beta cells, which then develops into T1DM.5

Causes of type 2 diabetes

Obesity and adiposity

People with obesity are estimated to be at least six times more likely to develop T2D than those of normal weight, while being overweight doubles the risk.6 The risk increases when combined with high genetic risk and poor lifestyle. High blood pressure, high triglycerides and low HDL-cholesterol each significantly increase risk of prediabetes progressing to T2D.7


Genetics

Many genetic variants are known to affect insulin secretion and glucose metabolism, which increases susceptibility to T2D. Family history also increases risk.


Unhealthy lifestyle

Poor diet and lack of exercise are significant contributors to weight gain and insulin resistance. 

Regular consumption of high-fat, high-sugar foods is shown to promote lipid accumulation that blocks insulin signalling as well as increasing pro-inflammatory responses in the body.8 Higher levels of circulating lipids and free fatty acids can then impair insulin activity.

Lack of regular physical activity reduces glucose uptake by muscles and worsens insulin sensitivity.9

The relationship between MTHFR, folate levels and diabetes

Some research suggests that people with low folate intake are more likely to develop T2DM. Folate is a methyl group donor in the synthesis of intracellular methylation reactions and DNA. Low folate levels - whether due to inadequate intake or impaired folate metabolism associated with MTHFR - may affect DNA synthesis and methylation.10


It is also suggested that the MTHFR C677T mutation may increase risk of T2DM, especially in Asian populations.11 MTHFR can lead to elevated homocysteine which then increases the risk of microvascular damage, thrombosis, heart disease and other inflammatory conditions.


A 2019 meta‑analysis of over 68 studies found that MTHFR C677T and its TT/CT genotypes were associated with a higher risk of T2DM.12 This is likely due to its effects on folate levels and homocysteine metabolism, which then impair downstream metabolic processes. However, these effects vary by ethnicity and other risk factors, such as diet and lifestyle.13

Diabetes and supplements

Folic acid and folate

A 2024 systematic analysis found that folic acid supplementation reduced homocysteine levels in patients with T2DM, with 10 mg folic acid resulting in a greater reduction than 5 mg.14

Folate is required for the availability of one-carbon units, which assist the remethylation of homocysteine to methionine, which in turn reduces homocysteine.15 The researchers concluded that folic acid supplementation appears to be effective at lowering homocysteine in people with T2DM, which could then reduce risk of cardiovascular disease. However, folic acid supplementation is not consistently found to improve blood glucose or HbA1c (glycosylated haemoglobin). 

Because individuals with T2DM have a higher prevalence of the MTHFR C677T variant - which can reduce conversion efficiency of folic acid to its biologically active form (5-MTHF) - supplementation with L-methylfolate (5-methyltetrahydrofolate) may be a more direct and potentially better-utilized form of folate in this population. Unlike folic acid, L-methylfolate does not require MTHFR-dependent activation and may provide more consistent support for homocysteine metabolism in individuals with reduced enzymatic activity.

A medical food formulated for diabetic neuropathy, Metanx, contains L-methylfolate along with Vitamin B12 (methylcobalamin) Vitamin B6 and pyridoxal-5′-phosphate. It is specifically designed to address nutritional requirements associated with endothelial dysfunction and peripheral neuropathy in diabetes.

B12

Metformin inhibits absorption of vitamin B12, and there is increasing evidence of vitamin B12 deficiency in diabetes patients treated with metformin.16 It is thought that metformin interferes with calcium (required for B12 to bind with intrinsic factor), which reduces B12 absorption in the gut. Metformin may also reduce intrinsic factor production and slow intestinal motility, causing bacterial overgrowth that also affects B12 availability.17

Metformin is the most common anti-diabetic drug, with more than 150 million diabetic patients taking it worldwide.18

B12 deficiency in diabetic patients is serious, as it is a major cause of neuropathy, which is also one of the main complications in T2DM. Many recent studies show that long-term use of metformin could be a cause for the increasing prevalence of peripheral neuropathy among T2DM patients. Other consequences of B12 deficiency include cognitive disorders, depression and anemia - all of which are also common in diabetic patients.19

Many clinicians recommend regular monitoring of vitamin B12 status in patients taking metformin, with supplementation where deficiency or symptoms are present.

A 2020 study found that metformin patients who took methylcobalamin for 12 months showed improved plasma B12 levels and improvement in all neurophysiological symptoms.20 Methylcobalamin is the active form of B12 that, unlike cyanocobalamin, is immediately available for use in the body and requires no further conversion.

The main findings of the CARDIA study

The Coronary Artery Risk Development in Young Adults Study (CARDIA) is designed to identify cardiovascular risk factors that begin in young adulthood.

CARDIA has examined genetic variants that affect homocysteine metabolism (including MTHFR) in relation to homocysteine levels, but as yet there is no clear link between MTHFR and diabetes. However, MTHFR C677T has been implicated in other studies as a factor in cardiovascular disease, as well as in various complications associated with T2DM.

Homocysteine and diabetes

High homocysteine levels are associated with an increased risk of stroke and other cardiovascular conditions. Homocysteine is a harmful amino acid that causes microdamage to the inner lining cells of the vascular system.

Several studies have shown that individuals with diabetes have higher homocysteine levels than people without diabetes. A 2024 study of Chinese diabetic patients found that people with homocysteine levels of ≥20 μmol/L had about double the risk of developing diabetes compared to those with <15 μmol/L.21

A 2025 study found that high homocysteine was a significant risk factor for the development of all microvascular complications in diabetic patients, as well as diabetic nephropathy, retinopathy and neuropathy. Homocysteine levels were significantly higher in diabetic patients with neuropathy.22

Deficiency in Vitamin B12 and folate is known to lead to high homocysteine levels in diabetes patients. It is also shown that diabetes patients have lower vitamin B12 and folate levels than people without diabetes.23 B12 and folate are required for metabolism of homocysteine in the body.

Reducing the risk of diabetes through diet and lifestyle

Diet

Recommendations emphasize the importance of consuming non‐starchy vegetables, whole foods instead of highly processed foods, and minimizing intake of added sugars and refined grains.24 Diet plans that are found to be effective for those with T2DM include the Mediterranean diet, low‐carbohydrate diet, high-fiber diet, intermittent very‐low‐calorie diet and a plant‐based diet. Some of these eating patterns have also been associated with a lower risk of developing T2DM in healthy individuals.25

Reducing alcohol intake is also recommended, as alcohol increases the risk of hypoglycemia and can also cause fluctuations in blood glucose levels.26


Exercise

Regular aerobic exercise training is shown to improve glycemic management in those with T2DM, resulting in significantly less time in hyperglycemia and 0.5-0.7 percentage-point reductions in HbA1c reductions in overall glycemia (as measured by A1C).

High-intensity resistance exercise is found to be more effective than low-to-moderate-intensity resistance training for managing glucose and insulin levels. It is also found that exercising after major meals is most effective in reducing glucose levels, regardless of the type of exercise or intensity.27


Stress management

Stress triggers glucose release via the nervous system, increasing glucose production. In non-diabetic people, glucose is utilized or stored once the stressful situation passes. In those with insulin resistance, glucose remains in the bloodstream, which may worsen T2DM.28

Stress management techniques such as mindfulness meditation are effective in improving glycemic control in people with T2DM.29

MTHFR, B12 and Diabetes

Key takeaways

  • Icon Type 1 diabetes is an autoimmune condition while type 2 diabetes is linked to both genetics and lifestyle
  • Icon MTHFR variants and low folate or B12 levels are linked to higher homocysteine, which is associated with cardiovascular and microvascular complications in diabetes
  • Icon Diet, exercise, stress management and targeted supplementation (especially B12) is essential for maintaining wellbeing

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  • Bioactive L-Methylfolate 3 Mg & Methylated B12
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Frequently Asked Questions about diabetes and MTHFR

How much vitamin B12 should a diabetic take?

The B12 dosage for a person with diabetes depends on their current B12 levels and symptoms (assessed by a health professional) as well as their diet, whether they are taking medication (such as Metformin) and any other health conditions they may have. Some studies have shown that diabetic patients taking Metformin were successfully treated with 1mg methylcobalamin every day for 12 months. Metanx contains 2 mg of methylcobalamin per capsule, a dose consistent with therapeutic use in this population.

Can vitamin B12 affect blood sugar?

Vitamin B12 is not directly involved in glucose breakdown but supports metabolic pathways and nerve function that can in turn affect insulin sensitivity and glucose regulation.30 B12 deficiency has been associated with increased risk of hyperglycemia and gestational diabetes.31 Studies have also reported B12 supplementation with vitamin B12 can improve glycemic control and insulin resistance in T2DM patients.32

Does folic acid affect blood sugar?

Folate is a B vitamin that works with other B vitamins in metabolizing glucose. Studies involving folic acid supplementation in diabetic patients have been mixed, with some showing folic acid may improve glycemic profile by decreasing fasting blood glucose and fasting insulin, while others do not.33 A 2018 meta-analysis found that folate decreased fasting glucose, insulin resistance and insulin but had no clear effect on diabetes or HbA1c.34

Does B6 lower blood sugar?

Yes, B6 is associated with better blood glucose control. Research shows that people with T2DM and gestational diabetes often have lower B6 levels. Supplementation with B6 (pyridoxine) has been shown to lower blood glucose, reduce HbA1c in T2DM, improve glucose tolerance in gestational diabetes and reduce post-meal glucose spikes. This may be because B6 is involved in insulin secretion and action, and deficiency may impair insulin and glucagon release.

Is MTHFR linked to diabetes?

Some studies suggest that the MTHFR C677T mutation may increase risk of T2DM, especially in Asian populations.35
A 2019 meta‑analysis found that MTHFR C677T was associated with a higher risk of T2DM.36 This is likely due to its effects on folate levels and homocysteine metabolism, which then impair downstream metabolic processes. However, these effects vary by ethnicity and other risk factors, such as diet and lifestyle.37 Because MTHFR C677T can reduce the conversion of folic acid to its active form, L-methylfolate has been incorporated into certain diabetes-related medical nutrition formulations, including Metanx, which is designed for the management of diabetic neuropathy.

References

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    https://pubmed.ncbi.nlm.nih.gov/38908773/

  12. Yanzi Meng, Xiaoling Liu, Kai Ma, Lili Zhang, Mao Lu, Minsu Zhao, Min-Xin Guan, Guijun Qin; "Association of MTHFR C677T polymorphism and type 2 diabetes mellitus (T2DM) susceptibility"; Molecular genetics & genomic medicine; 2019 Dec

    https://pubmed.ncbi.nlm.nih.gov/31663297/

  13. Unai Galicia-Garcia, Asier Benito-Vicente, Shifa Jebari, Asier Larrea-Sebal, Haziq Siddiqi, Kepa B Uribe, Helena Ostolaza, César Martín; "Pathophysiology of Type 2 Diabetes Mellitus"; International journal of molecular sciences; 2020 Aug

    https://pmc.ncbi.nlm.nih.gov/articles/PMC7503727/

  14. Kabelo Mokgalaboni, Given. R. Mashaba, Wendy N. Phoswa, Sogolo. L. Lebelo; "Folic acid supplementation on inflammation and homocysteine in type 2 diabetes mellitus: systematic review and meta-analysis of randomized controlled trials"; Nutrition & Diabetes; 2024

    https://www.nature.com/articles/s41387-024-00282-6

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

    https://pubmed.ncbi.nlm.nih.gov/19491213/

  16. Jwaher Haji Alhaji; "Vitamin B12 Deficiency in Patients with Diabetes on Metformin: Arab Countries"; Nutrients; 2022 May

    https://pubmed.ncbi.nlm.nih.gov/35631186/

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    https://pmc.ncbi.nlm.nih.gov/articles/PMC10236989/

  18. Marc Foretz, Bruno Guigas, Benoit Viollet; "Metformin: update on mechanisms of action and repurposing potential"; Nature reviews. Endocrinology; 2023 May

    https://pmc.ncbi.nlm.nih.gov/articles/PMC10153049

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    https://pmc.ncbi.nlm.nih.gov/articles/PMC10236989/

  20. Logan Chappell, Stephen A Brown, Terri M Wensel; "Evaluation of Vitamin B12 Monitoring in Patients on Concomitant Metformin and Proton Pump Inhibitors"; Innovations in pharmacy; 2020 Oct

    https://pubmed.ncbi.nlm.nih.gov/34007643/

  21. Dejian Fu, Wanbao Gong, Xiaomin Bao, Bo Yang, Feng Wang, Yubing Qiao, Yuanjiang Wu, Guangzhen Chen, Weixun Sun, Qiongzhi Xiao, Wenbo Zou, Ning Fang; "Homocysteine levels are associated with diabetes mellitus in Chinese with H-type hypertension"; Nutrition research and practice; 2024 May

    https://pmc.ncbi.nlm.nih.gov/articles/PMC11300120/

  22. Shali S, Gopalakrishna Pillai, Namitha Salim, Sheejamol VS; "Hyperhomocysteinemia: A Predictor of Microvascular Complications in Type 2 Diabetes Mellitus"; Amrita Vishwa Vidyapeetham Healthcare; 2025 Aug

    https://www.cureus.com/articles/358410-hyperhomocysteinemia-a-predictor-of-microvascular-complications-in-type-2-diabetes-mellitus

  23. Dejian Fu, Wanbao Gong, Xiaomin Bao, Bo Yang, Feng Wang, Yubing Qiao, Yuanjiang Wu, Guangzhen Chen, Weixun Sun, Qiongzhi Xiao, Wenbo Zou, Ning Fang; "Homocysteine levels are associated with diabetes mellitus in Chinese with H-type hypertension"; Nutrition research and practice; 2024 May

    https://pmc.ncbi.nlm.nih.gov/articles/PMC11300120/

  24. Zhiwei Li, Hongjia Yan, Liying Chen, Yixing Wang, Jingjing Liang, Xin Feng, Suocheng Hui, Kai Wang; "Effects of whole grain intake on glycemic control: A meta-analysis of randomized controlled trials"; Journal of diabetes investigation; 2022 Nov

    https://pubmed.ncbi.nlm.nih.gov/35678196/

  25. Yun Kai Yeh, Fu‐Shun Yen, Chii‐Min Hwu; "Diet and exercise are a fundamental part of comprehensive care for type 2 diabetes"; Journal of diabetes investigation; 2023 Jun

    https://pmc.ncbi.nlm.nih.gov/articles/PMC10360374/

  26. Brand-Miller Jennie C, Fatima Kaniz, Middlemiss Christopher, Bare Marian, Liu Vicki, Atkinson Fiona, Petocz Peter; "Effect of alcoholic beverages on postprandial glycemia and insulinemia in lean, young, healthy adults"; The American Journal of Clinical Nutrition; 2007 Jun

    https://www.sciencedirect.com/science/article/pii/S0002916523281101

  27. Jill A. Kanaley, Sheri R. Colberg, Matthew H. Corcoran, Steven K. Malin, Nancy R. Rodriguez, Carlos J. Crespo, John P. Kirwan, Juleen R. Zierath; "Exercise/Physical Activity in Individuals with Type 2 Diabetes: A Consensus Statement from the American College of Sports Medicine"; Medicine & Science in Sports & Exercise; 2022 Feb

    https://journals.lww.com/acsm-msse/fulltext/2022/02000/exercise_physical_activity_in_individuals_with.18.aspx

  28. Esther Schrems, Judith R. Gruber, Carmen Schiweck, Alea Ruf, Andreas Reif, Rejane Goldbach, Sharmili Edwin Thanarajah, Silke Matura; "Daily life stress is linked to increased glucose levels in individuals with insulin resistance: a real-world assessment"; Diabetologia; 2025 Oct

    https://link.springer.com/article/10.1007/s00125-025-06552-x

  29. Hidetaka Hamasaki; "The Effects of Mindfulness on Glycemic Control in People with Diabetes: An Overview of Systematic Reviews and Meta-Analyses"; Medicines (Basel); 2023 Sep

    https://pmc.ncbi.nlm.nih.gov/articles/PMC10534311/

  30. Yu Zhang, Ling Chu, Xi’an Zhou, Tingxia Xu, Qingwu Shen, Tao Li, Yanyang Wu; "Vitamin B12-Induced Autophagy Alleviates High Glucose-Mediated Apoptosis of Islet β Cells"; Int. J. Mol. Sci.; 2023,

    https://www.mdpi.com/1422-0067/24/20/15217

  31. Eleni Kouroglou, Panagiotis Anagnostis, Alexandros Daponte, Alexandra Bargiota; "Vitamin B12 insufficiency is associated with increased risk of gestational diabetes mellitus: a systematic review and meta-analysis"; Endocrine; 2019 Nov

    https://pubmed.ncbi.nlm.nih.gov/31463884/

  32. Swayamjeet Satapathy, Debapriya Bandyopadhyay, Binod Kumar Patro, Shahnawaz Khan, Sanjukta Naik; "Folic acid and vitamin B12 supplementation in subjects with type 2 diabetes mellitus: A multi-arm randomized controlled clinical trial"; Complementary therapies in medicine; 2020 Sep

    https://pubmed.ncbi.nlm.nih.gov/33066869/

  33. Omid Asbaghi, Damoon Ashtary-Larky, Reza Bagheri, Seyedeh Parisa Moosavian, Hadi Pourmirzaei Olyaei, Behzad Nazarian, Mahnaz Rezaei Kelishadi, Alexei Wong, Darren G Candow, Frédéric Dutheil, Katsuhiko Suzuki, Amirmansour Alavi Naeini; "Folic Acid Supplementation Improves Glycemic Control for Diabetes Prevention and Management: A Systematic Review and Dose-Response Meta-Analysis of Randomized Controlled Trials"; Nutrients; 2021 Jul

    https://pmc.ncbi.nlm.nih.gov/articles/PMC8308657/

  34. Jie V Zhao, C Mary Schooling, Jia Xi Zhao; "The effects of folate supplementation on glucose metabolism and risk of type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials"; Annals of epidemiology; 2018 Apr

    https://pubmed.ncbi.nlm.nih.gov/29501221/

  35. Yaqin Cai, Bin Liu, Yingping Zhang, Yuqiu Zhou; "MTHFR gene polymorphisms in diabetes mellitus"; International journal of clinical chemistry; 2024 Jul

    https://pubmed.ncbi.nlm.nih.gov/38908773/

  36. Yanzi Meng, Xiaoling Liu, Kai Ma, Lili Zhang, Mao Lu, Minsu Zhao, Min-Xin Guan, Guijun Qin; "Association of MTHFR C677T polymorphism and type 2 diabetes mellitus (T2DM) susceptibility"; Molecular genetics & genomic medicine; 2019 Dec

    https://pubmed.ncbi.nlm.nih.gov/31663297/

  37. Divya Pathak, Dharmsheel Shrivastav, Amit K Verma, Abdulrahman A Alsayegh, Prasant Yadav, Nawaid Hussain Khan, Alhanouf I Al-Harbi, Mohammad Idreesh Khan, Kapil Bihade, Desh Deepak Singh, Mirza Masroor Ali Beg; "Role of metabolizing MTHFR gene polymorphism (rs1801133) and its mRNA expression among Type 2 Diabetes"; Journal of diabetes and metabolic disorders; 2022 Feb

    https://pubmed.ncbi.nlm.nih.gov/35673506/

Katie Stone - Naturopath

About the Author

Katie is a qualified Naturopath (BNatMed) and freelance writer from New Zealand. She specializes in all things health and wellness, particularly dietary supplements and nutrition. Katie is also a dedicated runner and has completed more half-marathons than she can count!

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