Metabolic correction in the management of diabetic peripheral neuropathy: improving clinical results beyond symptom control

Abstract

Current Clinical Management Guidelines of Diabetic Peripheral Neuropathy (DPN) are based on adequate glucose control and symptomatic pain relief. However, meticulous glycemic control could delay the onset or slow the progression of diabetic neuropathy in patients with DM type 2, but it does not completely prevent the progression of the disease. Complications of DPN as it continues its natural course, produce increasing pain and discomfort, loss of sensation, ulcers, infections, amputations and even death. In addition to the increased suffering, disability and loss of productivity, there is a very significant economic impact related to the treatment of DPN and its complications. In USA alone, it has been estimated that there are more than 5,000,000 patients suffering from DPN and the total annual cost of treating the disease and its complications is over $10,000 million dollars. In order to be able to reduce complications of DPN, it is crucial to improve or correct the metabolic conditions that lead to the pathology present in this condition. Pathophysiologic mechanisms implicated in diabetic neuropathy include: increased polyol pathway with accumulation of sorbitol and reduced Na+/K+-ATPase activity, microvascular damage and hypoxia due to nitric oxide deficit and increased oxygen free radical activity. Moreover, there is a decrease in glutathione and increase in homocysteine. Clinical trials in the last two decades have demonstrated that the use of specific nutrients can correct some of these metabolic derangements, improving symptom control and providing further benefits such as improved sensorium, blood flow and nerve regeneration. We will discuss the evidence on lipoic acid, acetyl-L-carnitine, benfotiamine and the combination of active B vitamins L-methylfolate, methylcobalamin and piridoxal-6-phosphate. In addition, we discuss the role of metformin, an important drug in the management of diabetes, and the presence of specific polymorphic genes, in the risk of developing DPN and how metabolic correction can reduce these risks.

Fig. (1)

Metabolism of folic acid, homocysteine and nitric oxide (NO). Folic acid conversion to active 5-methyl THF requires several enzymes, adequate liver and gastro-intestinal function and B3, B6, B2, vitamin C and zinc as co factors. 50% individuals unable to fully convert folic acid into 5-methyl THF. ^aMTHFR C677T polymorphism seems to be involved, leading to hyperhomocysteinemia. MTHFR, methylenetetrahydrofolate reductase; 5, 10-MTHF, 5, 10 methy1ene-tetrahydrofolate; DHF, dehydrofolate; THF, tetrahydrofolate; NOS, nitric oxide synthase; BH4, tetrahydrobiopterin.

Fig. (2)

Microphotographs of baseline skin punch biopsy at right calf (left panel) and after receiving 6-month of twice daily LMF-MC-PP treatment (right panel) [147]. Arrows indicate epidermal nerve fiber density, whereas arrow heads represent nerve fibers. Patient average increase of 3.02 nerve fibers per mm after treatment.