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A Medicinal Food Provides Food for Thought in Managing Diabetic Neuropathy

      SEE RELATED ARTICLE p. 141
      In this issue of the Journal, Fonseca et al
      • Fonseca V.A.
      • Lavery L.A.
      • Thethi T.K.
      • et al.
      Metanx in type 2 diabetes with peripheral neuropathy: a randomized trial.
      report on the effects of Metanx (Pamlab LLC, Covington, La), a nutritional food comprised of methylcobalamin (2 mg), L-methylfolate (3 mg), and pyridoxal 5 phosphate (35 mg) (LMF-MC-PLP), given daily in a 24-week, double-blind, placebo-controlled, multisite study to 24 individuals with established diabetic peripheral neuropathy.
      The primary end point of the study was vibration perception threshold, which failed to achieve significance. However, the Neuropathy Total Symptom Score-6 (NTSS-6),
      • Bastyr E.
      • Zhang D.
      • Bril V.
      The MBBQ Study Group
      Neuropathy Total symptom Score-6 Questionnaire (NTSS-6) is a valid instrument for asessing the positive symptoms of diabetic peripheral neuropathy (DPN).
      which is a composite quantification of numbness, tingling, and aching, burning, or lancinating pain; and allodynia improved significantly at week 16 (P=.013 vs placebo) and week 24 (P=.033). Moreover, there were significant improvements in the Mental Health component of the Short Form (36) Health Survey, which includes Happiness (feelings of peace, happiness and calm all of the time), Role Emotional (no problems with work or other daily activities), Social Function (performing normal social activities without interference due to physical or emotional problems), and Vitality (feeling full of pep and energy all of the time).
      This response to the Metanx occurred with <2% adverse events, which were mainly rash and gastrointestinal upset and were no greater than placebo. Metanx has been shown to improve sensory nerve conduction and skin nerve fiber density in Zucker diabetic fatty rats.
      • Obrosova I.
      • Shevalye H.
      Metanx alleviates diabetes-induced large and small fiber neuropathies and promotes small sensory nerve fiber regeneration.
      Small, uncontrolled, but longer-term pilot studies of LMF-MC-PLP have shown improvements in tactile and discriminatory static test results as well as nerve fiber density and symptoms in patients with diabetic neuropathy.
      • Jacobs A.M.
      • Cheng D.
      Management of diabetic small-fiber neuropathy with combination L-methylfolate, methylcobalamin, and pyridoxal 5′-phosphate.
      • Walker Jr, M.J.
      • Morris L.M.
      • Cheng D.
      Improvement of cutaneous sensitivity in diabetic peripheral neuropathy with combination L-methylfolate, methylcobalamin, and pyridoxal 5′-phosphate.
      These improvements have also been observed in small studies of topiramate (which is not approved for diabetic neuropathy)
      • Boyd A.L.
      • Barlow P.M.
      • Pittenger G.L.
      • Simmons K.F.
      • Vinik A.I.
      Topiramate improves neurovascular function, epidermal nerve fiber morphology, and metabolism in patients with type 2 diabetes mellitus.
      and ruboxistaurin, an investigational agent.
      • Boyd A.
      • Casellini C.
      • Vinik E.
      • Vinik A.
      Quality of life and objective measures of diabetic neuropathy in a prospective placebo controlled trial of ruboxistaurin and topiramate.
      Nerve conduction studies have also improved with the investigational agents ranirestat, epalrestat, and actovegin,
      • Bril V.
      • Buchanan R.A.
      Long-term effects of ranirestat (AS-3201) on peripheral nerve function in patients with diabetic sensorimotor polyneuropathy.
      • Hotta N.
      • Akanuma Y.
      • Kawamori R.
      • et al.
      Long-term clinical effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy: the 3-year, multicenter, comparative Aldose Reductase Inhibitor-Diabetes Complications Trial.
      • Ziegler D.
      • Movsesyan L.
      • Mankovsky B.
      • Gurieva I.
      • Abylaiuly Z.
      • Strokov I.
      Treatment of symptomatic polyneuropathy with actovegin in type 2 diabetic patients.
      while results with the antioxidant α-lipoic acid have been promising.
      • Ziegler D.
      • Low P.A.
      • Litchy W.J.
      • et al.
      Efficacy and safety of antioxidant treatment with alpha-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial.
      Currently, however, the only agents approved for the treatment of symptomatic diabetic peripheral neuropathy in the US are duloxetine and pregabalin, which do not affect nerve conduction, have mechanisms of action unrelated to the pathophysiology of diabetic neuropathy, and which only address pain relief.
      • Vinik A.
      The approach to the management of the patient with neuropathic pain.
      Of greater relevance is the question of whether the nutritional food LMF-MC-PLP is able to correct the underlying defects in diabetic peripheral neuropathy. The failure to meet the primary endpoints of improved vibration perception is due to poor study design or an inadequate endpoint.
      • Vinik A.I.
      Diabetic neuropathies: evaluation, management and controversies in treatment options.
      As expected, levels of folate and its active product 5-methyltetrahydrofolate, vitamin B12, and PLP increased, while methylmalonic acid (MMA) decreased, as did homocysteine, with Metanx treatment. The responses to the symptom score (NTSS6) were related to the baseline folic acid and homocysteine levels despite lack of evidence of B12 deficiency, nor were surrogate markers of abnormal B12 levels, such as elevated MMA and homocysteine, present. There is evidence that B12 supplementation can reduce nerve damage in patients with diabetes by a mechanism involving the reduction of peroxynitrite and superoxide and restoring glutathione levels to normal. These effects were quite possibly due to the other components in LMF-MC-PLP. LMF restores the coupling of endogenous nitric acid synthase, reducing nitrosative and oxidative stress and therefore improves microvascular function. In addition, PLP decreases levels of receptor for advanced glycation end products, potentially improving microvascular disease.
      • Obrosova I.
      • Shevalye H.
      Metanx alleviates diabetes-induced large and small fiber neuropathies and promotes small sensory nerve fiber regeneration.
      A more cogent argument in this case is the fact that the use of metformin, which inhibits absorption of cobalamin, increased the likelihood of response to LMF-MC-PLP. Because metformin has become the mainstay of managing type 2 diabetes, even in children,
      American Diabetes Association
      Standards of medical care in diabetes—2010.
      we are likely to see an explosion in the occurrence in nerve dysfunction.
      Recent studies have shown that the threshold for neurologic dysfunction in the elderly is seen with B12 levels 460 pg/mL, not the level of 250 pg/mL, which has been accepted in the past.
      • Vinik A.I.
      • Strotmeyer E.S.
      Diabetic neuropathy in older adults.
      It behooves us to continue our studies in metformin-treated patients to determine their thresholds for the development of symptoms and use objective measures of neuropathy to evaluate the responses to methylcobalamin. Circulating levels achieved with the natural food far exceed those when B12 is given by injection, and there may be a gain or even potential harm of these very high levels of methylcobalamin for sustained time periods. Methylcobalamin has been shown to improve neuropathy symptoms in humans,
      • Ang C.D.
      • Alviar M.J.
      • Dans A.L.
      • et al.
      Vitamin B for treating peripheral neuropathy.
      • Yaqub B.A.
      • Siddique A.
      • Sulimani R.
      Effects of methylcobalamin on diabetic neuropathy.
      whereas elevated levels of homocysteine and MMA are associated with metformin and neuropathy in diabetes.
      • Wile D.J.
      • Toth C.
      Association of metformin, elevated homocysteine, and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy.
      Functional cobalamin deficiency (elevated MMA levels) is increased in patients with type 2 diabetes and is associated with a tripling of neuropathy frequency.
      • Solomon L.R.
      Diabetes as a cause of clinically significant functional cobalamin deficiency.
      A substantial proportion of cobalamin deficiency in diabetes can be traced to metformin use,
      • Wile D.J.
      • Toth C.
      Association of metformin, elevated homocysteine, and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy.
      • Bell D.S.
      Metformin-induced vitamin B12 deficiency presenting as a peripheral neuropathy.
      and subclinical deficiency can be determined using homocysteine and MMA levels.
      • Green R.
      Indicators for assessing folate and vitamin B12 status and for monitoring the efficacy of intervention strategies.
      In the current study, the negative scores between NTSS-6 and metformin use suggest that the cobalamin treatment effect was reversing a metformin-induced deficiency. However, the independent effect of pyridoxal in the vasculature and nervous system and the inverse relationship between baseline pyridoxal levels and the NTSS-6 symptom scores suggest that the improvement may have been due to pyridoxal replacement.
      • Ang C.D.
      • Alviar M.J.
      • Dans A.L.
      • et al.
      Vitamin B for treating peripheral neuropathy.
      • McCann V.J.
      • Davis R.E.
      Serum pyridoxal concentrations in patients with diabetic neuropathy.
      • Levin E.R.
      • Hanscom T.A.
      • Fisher M.
      • et al.
      The influence of pyridoxine in diabetic peripheral neuropathy.
      Undoubtedly there needs to be controlled trials of the individual components to determine which accounts for the beneficial effects. The active form of folic acid, 5-methyltetrahydrofolate, reverses uncoupling of NO synthase and restores NO synthesis, leading to vasodilation and improved endothelial function.
      • Mangoni A.A.
      • Sherwood R.A.
      • Asonganyi B.
      • Swift C.G.
      • Thomas S.
      • Jackson S.H.
      Short-term oral folic acid supplementation enhances endothelial function in patients with type 2 diabetes.
      • Title L.M.
      • Cummings P.M.
      • Giddens K.
      • Genest Jr, J.J.
      • Nassar B.A.
      Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease.
      • Doshi S.N.
      • McDowell I.F.
      • Moat S.J.
      • et al.
      Folate improves endothelial function in coronary artery disease: an effect mediated by reduction of intracellular superoxide?.
      Theoretically, improvement of nerve blood flow would improve nerve function. The animal studies on LMF-MC-PLP clearly show improvements in sensory but not motor nerve conduction and an increase in intraepidermal nerve fiber in the Zucker fatty diabetic rat.
      • Obrosova I.
      • Shevalye H.
      Metanx alleviates diabetes-induced large and small fiber neuropathies and promotes small sensory nerve fiber regeneration.
      This unique effect has also been reported with 12-lipoxygenase, but not 5-lipoxygenase, knockout animals,
      • Obrosova I.G.
      • Stavniichuk R.
      • Drel V.R.
      • et al.
      Different roles of 12/15-lipoxygenase in diabetic large and small fiber peripheral and autonomic neuropathies.
      thus highlighting the fact that the pathogenesis of small- and large-fiber neuropathies are quite different and may well require specific treatments and the use of appropriate end points in further trials of the medical food LMF-MC-PLP. The use of a quality-of-life tool such as the Norfolk Quality of Life–Diabetic Neuropathy, sensitive to changes in small- and large-fiber neuropathies, may well have distinguished these effects of the food supplement.
      • Boyd A.
      • Casellini C.
      • Vinik E.
      • Vinik A.
      Quality of life and objective measures of diabetic neuropathy in a prospective placebo controlled trial of ruboxistaurin and topiramate.
      • Vinik E.J.
      • Hayes R.P.
      • Oglesby A.
      • et al.
      The development and validation of the Norfolk QOL-DN, a new measure of patients' perception of the effects of diabetes and diabetic neuropathy.
      The study design in the Fonseca trial was not such that these differences could have been detected. Interestingly, the study of a medicinal food has given us food for thought!!!

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