Vitamin D and painful diabetic neuropathy: missing link or innocent bystander?

Abstract

277 ISSN 1758-1907 10.2217/DMT.13.28 © 2013 Future Medicine Ltd Diabetes Manage. (2013) 3(4), 277–279 Painful diabetic neuropathy is an extremely disabling condition that may be present in at least a fifth of diabetic patients [1]. The etiology of painful diabetic neuropathy is complex with peripheral somatic [2,3], autonomic [4] and central thalamic perfusion defects identified in these patients [5]. The characteristic symptoms include symmetrical paresthesia, dysesthesia, electric shock-like pains and allodynia in the feet with nocturnal exacerbation. The treatment of this condition has remained unsatisfactory with a ‘good’ response to conventional medication rated at between 30–50% pain relief [6]. There are many available treatments, all are at best moderately effective, and their use is limited by side effects. Currently, there are only two US FDA-approved treatments, duloxetine and pregabalin, based on proven efficacy in randomized placebo-controlled trials; however, neither are entirely effective, particularly as patients can have a poor response and/or tolerability to both medications [7]. Furthermore, recent studies of novel drugs in the treatment of painful diabetic neuropathy have dramatically failed [8,9], with active treatment being barely superior to placebo. Therefore, there is a need to establish potential new mechanisms and, hence, treatments for painful diabetic neuro pathy. It is, therefore, intriguing that a recent study has shown elevated levels of methylglyoxal in diabetic patients with painful neuropathy, and has shown that it mediates its effects by depolarizing sensory neurons and inducing post-translational modification of the voltage-gated sodium channel Na v 1.8, which is associated with increased electrical excitability, facilitating firing of nociceptive neurons [10]. Gain-offunction variants of the sodium channel Na v 1.7 and, more recently, Na v 1.8 have been found in a significant proportion of patients with painful neuropathy [11]. While these observations are of potential relevance, translation to clinically effective therapies is likely to take several years. Vitamin D deficiency is highly prevalent in diabetic populations [12] and those with deficiencies are likely to have common characteristics to those with painful diabetic neuropathy. Three recent studies have found an association between vitamin D deficiency and diabetic neuropathy [13–15]; however, all have failed to assess the differences between positive (hyperalgesia and allodynia) and negative (paresthesia and