Dr. Allie is the Director of Cardiothoracic and Endovascular Surgery at the Cardiovascular Institute of the South in Lafayette, Louisiana.

The true relevance, natural history, clinical impact, and social and economic costs of diabetic neuropathy are not well documented because of inconsistencies in the objective diagnostic criteria. Certainly, the incidence must be significant with the increasing incidence of diabetes (14–16 million), obesity, peripheral arterial disease (PAD), and elderly population. The cardiovascular complications of diabetes are staggering with end-stage lower-extremity PAD and diabetes resulting in the development of critical limb ischemia (CLI), which causes 220,000–240,000 amputations yearly in the United States and Europe.1–6 The patient with diabetes is at 7–40 times greater risk for amputation than the patient without diabetes, and increasingly, diabetic neuropathy is being implicated as a contributing factor.6
The etiological pathophysiologic mechanism of diabetic neuropathy is considered multifactorial and includes direct metabolic injury to the nerve fiber, impaired neuropathic regeneration, and neurovascular insufficiency including direct endothelial injury and dysfunction caused by reduced nitric oxide (NO) availability and disrupted normal cellular oxidation. Homocysteine, a sulfhydryl amino acid, has been strongly associated with cardiovascular disease, especially PAD, and most recently has been implicated in diabetic neuropathy. Elevated homocysteine levels are also associated with endothelial dysfunction, decreased NO, and, therefore, impaired wound and tissue healing because optimal NO bioavailability is necessary for angiogenesis, collagen deposition, and granulation tissue formation.7–11 Normal homocysteine metabolism requires remethylation and transulfuration with vitamin B6, vitamin B12, and folate as essential cofactors. Hyperhomocysteinemia can be inherited (a TT-genotype, which reduces folic acid metabolism) or acquired due to nutritional (vitamin) deficiencies. Cigarette smoking and excessive caffeine consumption have been associated with hyperhomocysteinemia.
Clinically, diabetic neuropathy has been associated with the duration of diabetes, insulin dependency, and poor glycemic control (elevated HbA1c).12 Optimizing insulin therapy has shown modest improvements by vibratory sensitivity and nerve conduction velocity but in general medical and surgical treatment for diabetic neuropathy can be characterized as poor, and it is considered irreversible in most cases. The recent understanding of the role of NO, homocysteine metabolism, and its cofactors has given rise to several novel medical strategies to treat diabetic neuropathy, PAD, and impaired wound healing.13 Oral 6(S)-methyltetrahydrofolate (L-MTHF), the active form of folic acid, has been shown to increase NO synthesis therefore reducing superoxide generation with improved endothelial function. L-methylfolate has several distinct advantages over oral folic acid administration including being 7 times more bioavailable with a significant superiority (3 times) in lowering serum homocysteine.13,14 These advantages are achieved as the metabolically active L-methylfolate avoids the complex 4-step conversion process oral folic acid must go through for activation. Additionally, 40–50% of the patient population exhibits a genetic polymorphism in which folic acid is incompletely converted to L-methylfolate.14–17 Pyridoxal 5’-phosphate (vitamin B6) and methylcobalamin (vitamin B12) are important in maintaining neurofunctions, including myelinogenesis, nerve repair, and nerve regeneration, which are impaired in severe diabetic neuropathy.10
Serum vitamin levels have been associated with serum homocysteine levels. A strong inverse relationship exists between plasma homocysteine and both folic acid and vitamin B12 therefore creating an opportunity for a medical (nutritional) strategy for treating diabetic neuropathy. Metanx (Pamlab, L.L.C., Covington, La) has combined 2.8 mg L-methylfolate, 25 mg pyridoxal 5’-phosphate, and 2 mg methylcobalamin into 1 novel supplement, optimizing a strategy to treat hyperhomocysteinemia and its clinical sequelae, including diabetic neuropathy, with potential for far reaching benefits in other diabetic complications including cardiovascular disease, PAD, and even CLI. Several illustrative clinical cases are presented using these novel treatment strategies in treating diabetic neuropathy.