Bettina Newman, RDN
James McGuire, DPM, PT
Patricia M. O’Connell
Is nutrition at the top of your mind when you are initially faced with a patient with a diabetic foot ulcer (DFU)? Right away, you may wonder what their blood sugars and A1C are; you review their medical record, take their history, and establish a care plan. Will that care plan address diabetic peripheral neuropathy (DPN), one of the main causes of DFU? In addition to lifestyle modifications that you may include in your plan, supplemental nutrients may have positive direct and indirect impacts on this root cause of the ulceration, and recommending or prescribing particular nutrients may pay great dividends in the form of favorable DFU outcomes.
According to the National Institute of Diabetes and Digestive and Kidney Diseases, up to 50% of diabetic individuals have diabetic peripheral neuropathy.1 Furthermore, it is estimated that 90% of DFUs are associated with diabetic neuropathy.2 The health of nerve structure and function is dependent upon the presence of adequate oxygen and nutrients. Decreased blood flow deprives the tissues of these vital factors. Endothelial health is therefore of utmost importance. Hyperhomocysteinemia, reduced nitric oxide (NO), and increased oxidative stress compromise the health of blood vessels. Insufficient delivery of oxygen and nutrients can also negatively impact skin integrity as well as immune health, further setting the stage for ulceration.
Early detection of DPN is important as is observing or testing for pre-existing nutritional deficiencies, especially since an ulcer places exaggerated calorie and nutrient demands on the patient. A recent study (N=131) found that vitamin D was the most prevalent deficiency affecting 55.7% of DFU patients; 73% of the patients studied displayed suboptimal vitamin C levels.3 If a patient has had genetic testing done, consideration of these results may also be relevant to nutrient considerations.
Among the nutrients that have been associated with wound healing are vitamins A, C, D, and E; the minerals zinc and copper; a combination of magnesium and vitamin E; the amino acids arginine and glutamine and a leucine metabolite. Generally speaking, these nutrients aid in combatting oxidative stress, inflammation, and infection; supporting mitochondrial function; and providing building blocks for new tissue formation.
The gut microbiome has been a topic of great interest in recent years, and dysbiosis has been found to contribute to insulin resistance in type 2 diabetes mellitus (T2DM).4 A 2017 longitudinal study found that the greatest difference between the skin microbiome of individuals with T2DM compared to non-diabetics was diversity.5 In a review of 39 studies, oral or topical use of various probiotic strains appeared to reduce wound infections, especially when used in conjunction with antibiotics.6
As beneficial as the aforementioned nutrients and probiotics may be in supporting the body’s natural wound-healing capabilities, they do not necessarily address the underlying DPN. For this purpose, the clinician may consider prescribing a trio of B vitamins B6, B9, and B12 accompanied by an antioxidant. These nutrients have roles in glucose metabolism and endothelial and nerve health via activities related to homocysteine metabolism, NO synthesis, and reduction of oxidative stress. Let’s look at vitamin B9 (folate).
Folate may be ingested as food folate, as folic acid used in food fortification and many dietary supplements, or as one of several synthetic forms, not all of which have the same bioactive benefits. (6S)-5-methyltetrahydrofolic acid ([6S]-5-MTHF) is the primary biologically active isomer of folate; food folate and folic acid require further metabolism to become (6S)-5-MTHF. This metabolism requires the activity of several enzymes, perhaps the most crucial being methylenetetrahydrofolate reductase (MTHFR). Deciding which form of folate to recommend to a patient can be challenging. A patient may have gene variants (polymorphisms) that inhibit the efficiency with which MTHFR converts what was originally food folate or folic acid into the bioactive (6S)-5-MTHF. Polymorphisms in the MTHFR gene are common genetic causes for elevated homocysteine levels.7 Furthermore, the MTHFR SNPs (single-nucleotide polymorphisms) have been associated with vasculopathy, which has been linked to DPN.8
A pharmacokinetic study demonstrated that the peak concentration (bioavailability) following the administration of (6S)-5-MTHF is almost seven times higher compared to folic acid, irrespective of the patient’s genotype.9 Clinical studies have shown that direct supplementation with (6S)-5-MTHF reduces homocysteine levels and increases plasma folate levels more effectively than folic acid.10-12
(6S)-5-MTHF also increases endothelial NO synthase coupling and NO production and directly scavenges superoxide radicals. Better NO bioavailability means increased vasodilation to enhance blood flow.13,14 With respect to DFU, researchers have suggested that “nitric oxide synthesis is critical to wound collagen accumulation and acquisition of mechanical strength.”15
We can find evidence in mice that folic acid accelerated granulation tissue formation, proliferation of fibroblasts, and tissue regeneration and reduced the healing time that diabetes typically delays. Supplementation alleviated diabetes-induced impaired collagen deposition in wounds and significantly lessened lipid peroxidation, protein nitrotyrosination, and glutathione depletion.16 Also, in a retrospective cohort study of the medical records of 29 veterans with T2DM and early stage DFU, high-dose folic acid supplementation brought significant improvement (P=<.05) in wound closure and re-epithelialization.17
When deciding on which form of folate to recommend for optimal safety and efficacy, it is helpful to consider the patient’s known or potential genetic polymorphisms and to be aware that unmetabolized folic acid (UMFA) accumulation may carry its own health implications. Concerns have been raised about correlations between UMFA and cognitive decline and anemia, and an association with a decline in the immune system capacity to kill off malignant or pre-malignant cells was confirmed. Having given consideration to the potential harmful effects of excess folic acid, some countries have avoided establishing a folic acid food fortification program.18-22
To alleviate concerns about MTHFR polymorphisms and about UMFA accumulation, clinicians might prefer to recommend a “finished folate.” (6S)-5-MTHF is well-absorbed regardless of gastrointestinal pH. This form is typically available as a glucosamine salt or a calcium salt. There is a patented (6S)-5-MTHF glucosamine salt form that shows good stability, and it is 100 times more water soluble and has 10% greater bioavailability compared to the calcium salt form.23
Another bonus of supplementation with the (6S)-5-MTHF glucosamine salt form is that its risk of masking vitamin B12 deficiency is low. Nevertheless, it is still a good idea to consider including vitamin B12 in a DPN care plan because lower levels of vitamin B12 are common among the diabetic population.
The metabolically active form of vitamin B12 is methylcobalamin. Among this vitamin’s many functions are the formation and maintenance of the myelin sheath and its participation in the homocysteine metabolic pathway. In a meta-analysis of studies comprising a total of 1114 subjects, vitamin B12 (mean 0.5 mg daily) added to folic acid supplementation produced an additional 7% (3% to 10%) reduction in blood homocysteine. Besides it neuroprotective benefits, vitamin B12 may directly aid in healing DFUs by participating in protein synthesis and functioning as a growth factor.24
A third B vitamin to consider with respect to DPN and DFU is pyridoxal 5’-phosphate (P5’P), the metabolically active coenzyme form of vitamin B6. P5’P-dependent enzymes are involved in many biochemical reactions, including the transsulfuration of homocysteine. P5’P also helps to combat free radicals and inhibit the formation of advanced glycation end products (AGEs). These activities contribute to vascular endothelial health, a critical requisite for diabetic wound healing and for the maintenance of skin health as previously described. Especially with aging, diabetic individuals may tend toward low plasma and skin P5’P concentrations.
We’ve seen that B vitamins have some antioxidant potential. However, since elevated blood sugar stimulates generation of free radicals and free radicals damage vascular and microvascular endothelium, it may be helpful to also consider an antioxidant, especially one with multiple actions. Alpha-lipoic acid, a water- and fat-soluble antioxidant, has therapeutic potential in the management of T2DM, a 50-plus-year track record for treatment of peripheral neuropathy, and a significantly improved wound healing time in mice (P<0.05) and in patients undergoing hyperbaric oxygen treatments, inhibited oxidative damage, and accelerated healing of chronic wounds.25-28
In summary, we have discussed the roles of vitamins B6, B12, and B9 ([6S]-5-MTHF) as well as the powerful antioxidant alpha-lipoic acid. We have presented a rationale for their consideration in the care of a patient who is at risk for DFU or perhaps already needs treatment for the condition. Observations shared by podiatrists who have been prescribing a medical food to help patients meet their distinct nutrient requirements related to DPN reveal the difference a prescription can make in DPN symptoms and the propensity for ulcer formation. Will nutrition now be the top of your mind when you are initially faced with a patient with a diabetic foot ulcer (DFU)?
- What Is Diabetic Neuropathy? National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. https://www.niddk.nih.gov/health-information/diabetes/overview/preventing-problems/nerve-damage-diabetic-neuropathies/what-is-diabetic-neuropathy#common. Accessed July 15, 2020.
- Alexiadou K, Doupis J. Management of diabetic foot ulcers. Diabetes Ther. 2012;3(1):4. doi:10.1007/s13300-012-0004-9.
- Pena G, Kuang B, Cowled P, Howell S, Dawson J, Philpot R, et al. Micronutrient status in diabetic patients with foot ulcers. Adv Wound Care (New Rochelle). 2020;9(1):9-15. doi:10.1089/wound.2019.0973.
- Sharma S, Tripathi P. Gut microbiome and type 2 diabetes: where we are and where to go? J Nutr Biochem. 2019 Jan;63:101-108. doi:10.1016/j.jnutbio.2018.10.003.
- Gardiner M, Vicaretti M, Sparks J, et al. A longitudinal study of the diabetic skin and wound microbiome. PeerJ. 2017;5:e3543. doi:10.7717/peerj.3543.
- Fijan S, Frauwallner A, Langerholc T, Krebs B, Ter Haar Née Younes JA, et al. Efficacy of using probiotics with antagonistic activity against pathogens of wound infections: an integrative review of literature. Biomed Res Int. 2019 Dec 12;2019:7585486. doi:10.1155/2019/7585486.
- Moll S, Varga EA. Homocysteine and MTHFR mutations. Circulation. 2015;132(1):e6-e9. doi:10.1161/CIRCULATIONAHA.114.013311.
- Yigit S, Karakus N, Inanir A. Association of MTHFR gene C677T mutation with diabetic peripheral neuropathy and diabetic retinopathy. Mol Vis. 2013;19:1626-1630.
- Willems FF, Boers GH, Blom HJ, Aengevaeren WR, Verheugt FW. Pharmacokinetic study on the utilisation of 5-methyltetrahydrofolate and folic acid in patients with coronary artery disease. Br J Pharmacol. 2004 Mar;141(5):825-30. doi: 10.1038/sj.bjp.0705446.
- Antoniades C, Shirodaria C, Warrick N, et al. 5-methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels: effects on vascular tetrahydrobiopterin availability and endothelial nitric oxide synthase coupling. Circulation. 2006;114(11):1193‐1201. doi:10.1161/CIRCULATIONAHA.106.612325.
- Yuyun MF, Ng LL, Ng GA. Endothelial dysfunction, endothelial nitric oxide bioavailability, tetrahydrobiopterin, and 5-methyltetrahydrofolate in cardiovascular disease. Where are we with therapy? Microvasc Res. 2018;119:7‐12. doi:10.1016/j.mvr.2018.03.012.
- Smith DE, Hornstra JM, Kok RM, Blom HJ, Smulders YM. Folic acid supplementation does not reduce intracellular homocysteine, and may disturb intracellular one-carbon metabolism. Clin Chem Lab Med. 2013;51(8):1643-1650. doi:10.1515/cclm-2012-0694.
- Stanhewicz AE, Kenney WL. Role of folic acid in nitric oxide bioavailability and vascular endothelial function. Nutr Rev. 2017;75(1):61‐70. doi:10.1093/nutrit/nuw053.
- Joshi R, Adhikari S, Patro BS, Chattopadhyay S, Mukherjee T. Free radical scavenging behavior of folic acid: evidence for possible antioxidant activity. Free Radic Biol Med. 2001;30(12):1390-1399. doi:10.1016/s0891-5849(01)00543-3.
- Frank S, Kämpfer H, Wetzler C, Pfeilschifter J. Nitric oxide drives skin repair: novel functions of an established mediator. Kidney Int. 2002 Mar;61(3):882-888. doi:10.1046/j.1523-1755.2002.00237.x.
- Zhao M, Zhou J, Chen YH, Yuan L, Yuan MM, Zhang XQ, et al. Folic acid promotes wound healing in diabetic mice by suppression of oxidative stress. J Nutr Sci Vitaminol (Tokyo). 2018;64(1):26‐33. doi:10.3177/jnsv.64.26.
- Boykin JV Jr, Hoke GD, Driscoll CR, Dharmaraj BS. High-dose folic acid and its effect on early stage diabetic foot ulcer wound healing. Wound Repair Regen. 2020;28(4):517-525. doi:10.1111/wrr.12804.
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- Sahasrabudhe MR, Lakshminarayan Rao MV. Effect of vitamin B12 on the synthesis of protein and nucleic acids in the liver. Nature. 1951 Oct 6;168(4275):605-606. doi:10.1038/168605b0.
- Gomes MB, Negrato CA. Alpha-lipoic acid as a pleiotropic compound with potential therapeutic use in diabetes and other chronic diseases. Diabetol Metab Syndr. 2014;6(1):80. doi:10.1186/1758-5996-6-80.
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- Alleva R, Nasole E, Di Donato F, Borghi B, Neuzil J, Tomasetti M. Alpha-lipoic acid supplementation inhibits oxidative damage, accelerating chronic wound healing in patients undergoing hyperbaric oxygen therapy. Biochem Biophys Res Commun. 2005 Jul 29;333(2):404-10. doi:10.1016/j.bbrc.2005.05.119.
Bettina Newman, RDN
Bettina Newman, RDN (Registered Dietitian Nutritionist), is writer and technical support for PharmaceutiX®, a manufacturer and provider of trusted medical foods for patients with conditions associated with metabolic nutritional impairments. After running her own practice for 20 years, Bettina joined XYMOGEN®, a leading professional-channel nutraceutical company and the parent company of PharmaceutiX. For 17 years at XYMOGEN, Bettina enjoyed her position as project writer and field consultants’ technical support. Her career began in 1973 with nutrition research, teaching, and in-patient nutrition care. Dr. Robert Atkins, Bettina’s mentor from 1974 until his untimely death in 2003, hired Bettina as Chief Nutritionist for his Diet Revolution Centers. She also assisted him with his books and cookbooks as well as planning programs for the Atkins Center. Bettina co-authored Lose Weight the Smart Low-Carb Way and The Rotation Diet Planner software. She has shared her passion for nutrition from the podium at professional and public seminars and on radio and TV. Bettina is an alumna of the State University of New York College at Buffalo and was a founding member of the board of directors of Adipsy, a 501(c)(3) dedicated to providing respites away from the difficulties of cancer.
James McGuire, DPM, PT, LPed, FAPWHc
Temple University School of Podiatric Medicine
Leonard S. Abrams Center for Advanced Wound Healing
Dr. James McGuire is the director of the Leonard S. Abrams Center for Advanced Wound Healing and a Professor Clinician Scholar in the Departments of Podiatric Medicine and Biomechanics at the Temple University School of Podiatric Medicine in Philadelphia.
Dr. McGuire is a board-certified podiatrist and wound care specialist. His DPM degree is from the former Pennsylvania College of Podiatric Medicine, now part of Temple University. He completed a residency in podiatric surgery at the Maryland Podiatry Residency Program in Baltimore. A fellow and founding member of the American Professional Wound Care Association, and the Academy for Physicians in Wound Healing, he also serves on the board of the Council for Medical Education and Testing. Dr. McGuire is also a licensed physical therapist and pedorthist, and is certified in wound care by the Council for Medical Education and Testing. He is also board certified by both the American Board of Podiatric Surgery and the American Board of Podiatric Medicine.
Dr. McGuire left 10 years of private practice in Rutland, Vermont, to become a member of the Temple University faculty in 1992. He has more than 30 years of experience in wound management, has published extensively, and has participated in several research trials involving the diabetic foot and wound healing. Dr. McGuire has lectured both nationally and internationally in the areas of wound healing, diabetic foot management, off-loading, and biomechanics of the at-risk foot.
Patricia M. O’Connell, BSc, MBA
Patricia M. O’Connell, BSc, MBA, currently Lead Technical Writer for XYMOGEN/WholeScripts, is a health and wellness executive with 15 years in the food and dietary supplements industry. Starting with a dual degree in biochemistry and environmental biology from Saint Xavier University in Chicago, she has intertwined her knowledge of plant chemistry and mammalian biochemistry with the rigors of manufacturing, quality, and safety. Through the unique lenses of evolution and biochemical interaction, Patricia has honed her ability to identify botanicals, vitamins, and minerals as bioagents and explain their pharmacological effects through technical writing and presentation storytelling. Patricia’s mid-career MBA from Hough Graduate School of Business at the University of Florida has provided her with deeper insight into how to commercialize these bioagents to scale and perfect the message that nutritional intervention works. Patricia’s career has included Coca-Cola, Ball Horticultural Company, Nephron Pharmaceuticals Corporation, Valensa International, Curaleaf, and XYMOGEN/WholeScripts.