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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 53  |  Issue : 2  |  Page : 102-106

The effect of hypovitaminosis D normalization on diabetic neuropathy


1 Department of Neurology, Mansoura University, Mansoura, Egypt
2 Department of Neurology, Mansoura University, Mansoura, Egypt; Department of Neurology, Riyadh National Hospital, Riyadh, Saudi Arabia
3 Department of Internal Medicine, Mansoura University, Mansoura, Egypt

Date of Submission21-Jan-2016
Date of Acceptance03-Apr-2016
Date of Web Publication2-Jun-2016

Correspondence Address:
Wael M Gabr
MD, Department of Neurology, Faculty of Medicine, University of Mansoura, Mansoura, Egypt

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-1083.183436

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  Abstract 

Background
Few data on the association between vitamin D levels and peripheral nerve function are available from human studies, although diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus. Unfortunately, pharmacological treatment is often partially effective or accompanied by unacceptable side effects, and a new concept for the management of DPN is imperative. The purpose of this study was to clarify the impact of hypovitaminosis D correction on DPN in type 2 diabetic (DM2) patients.
Materials and methods
Fifty patients with a mean age of 54.72 ± 9.00 years with DM2 (disease duration 14.62 ± 5.95 years) were recruited. They were assessed clinically for neuropathy using the Michigan Neuropathy Screening Instrument, the Toronto Clinical Score System, and nerve conduction study (NCS) of the sural, popliteal, and ulnar nerves. At same sitting, vitamin D was assessed by measuring 25-dihydroxy, and then repeat Toronto Clinical Score System and NCS were carried out after vitamin D correction.
Results
Neuropathy severity was significantly improved after vitamin D supplementation. The mean ± SD neuropathy severity was 11.60 ± 2.90 before treatment and 10.82 ± 3.31 after treatment. Moreover, there was improvement of NCS in mild DPN after vitamin D correction but failed to show the same effect in moderate and severe cases.
Conclusion
Normalization of low vitamin D level has a potential beneficial effect in reducing neuropathy severity in DM2, and hence serum 25-hydroxyvitamin D level should be tested and low levels should be corrected to improve neuropathy symptoms. Further studies in a larger scale are required to confirm these results and re-evaluate patients with severe and moderate DPN.

Keywords: Diabetes mellitus, peripheral diabetic neuropathy, vitamin D deficiency, vitamin D insufficiency


How to cite this article:
Saad M, Gabr WM, Barakat E, Enein AF. The effect of hypovitaminosis D normalization on diabetic neuropathy. Egypt J Neurol Psychiatry Neurosurg 2016;53:102-6

How to cite this URL:
Saad M, Gabr WM, Barakat E, Enein AF. The effect of hypovitaminosis D normalization on diabetic neuropathy. Egypt J Neurol Psychiatry Neurosurg [serial online] 2016 [cited 2021 Apr 21];53:102-6. Available from: http://www.ejnpn.eg.net/text.asp?2016/53/2/102/183436


  Introduction Top


The WHO estimates that the global prevalence of diabetes is currently approaching 5%; thus, this disease can be called an epidemic of the 21st century [1]. Diabetic peripheral neuropathy (DPN) is common, under or misdiagnosed, causes substantial morbidity with increased mortality [2], and it develops in more than half of all diabetic patients [3].

The pathogenesis of DPN is complicated and remains poorly understood [1]. It is associated with glucose metabolic pathways through direct neuronal metabolic injury or microvascular injury. The postulated mechanisms include increased free radical generation by enhanced activation of the polyol pathway and reductive stress, which could potentially account for advanced glycation end-products accumulation, hexosamine formation, and protein kinase C activation [4]. Recently, there is accumulating evidence that hypovitaminosis D is highly prevalent in patients with type 2 diabetes (DM2) [5] and associated with DPN [6].

Vitamin D has traditionally been associated with calcemic activities - namely, phosphorus and calcium homeostasis. However, recent evidence from various lines of research suggested nontraditional roles of vitamin D in human health [7].

There are several mechanisms through which vitamin D can affect the nervous system. The downregulation of the expression of L-type voltage-sensitive calcium-channels by vitamin D has been shown to reduce the influx and excitotoxic effects of calcium to neurons [8]. Moreover, vitamin D increases the production of neurotrophins, which support the survival of existing neurons and encourage the growth and differentiation of new neurons and synapses [9],[10],[11],[12],[13]. These biological effects suggest that vitamin D could influence and augment DPN and that its supplementation may have a role in the improvement of DPN symptoms [14]. Both in-vitro and in-vivo studies revealed that vitamin D has a neurotrophic effect but its role in DPN pain is uncertain [9].

Vitamin D receptors exist on peripheral nerves and Schwann cells. Animal studies on diabetic rats support its influence on nerve function, with deficiencies in nerve growth factor synthesis in cases of hypovitaminosis D. Normalization of vitamin D in these rats increased nerve growth factor production and prevented neurotrophic deficit [6]. Lee and Chen [5] showed that vitamin D supplementation over 3 months in diabetic patients with hypovitaminosis D improved neuropathic symptoms by 50%. Thus far, there has only been limited and contradictory data available on the impact of vitamin D correction on DPN.


  Aim of work Top


Our objective was to evaluate the effect of vitamin D repletion on DPN in patients with DM2 and low vitamin D.


  Materials and methods Top


All patients with DM2 and vitamin D deficiency or insufficiency were recruited from the outpatients attending the neurology and internal medicine clinics at Riyadh National Hospital, Riyadh, Saudi Arabia.

The internal medicine doctor recorded demographic data and relevant medical history and filled a data collection sheet. Thereafter, patients were screened for DPN using the Michigan Neuropathy Screening Instrument (MNSI). It consists of a two-step program: the first step includes assessment of a neuropathic symptom using a history questionnaire comprising 15 'yes or no' questions on foot sensation, including pain, numbness, and temperature sensitivity, and the second step includes a brief physical examination involving an inspection of the feet and evaluation of ankle reflexes, vibration sensation, and fine touch. Neuropathy is defined operationally as seven or more positive responses on the MNSI questionnaire or a score greater than 2.0 on the MNSI examination; thresholds were defined by prior validation studies [15],[16]. The screening method for fine touch sensation, vibration perception, and ankle reflex using 10 g SWM, 128 Hz tuning fork, and reflex hummer, respectively, was followed according to the practical guideline from Michigan Diabetes Research and Training Center [17].

The DPN severity was assessed using the Toronto Clinical Neuropathy Scoring System (TCSS) [18]. Sensory testing was performed on the first toe and scored as follows: symptom scores: present = 1 and absent = 0; reflex scores: absent = 2, reduced = 1, and normal = 0; and sensory test score: abnormal = 1 and normal = 0. Total scores range from normal = 0 to a maximum of 19. A score of 5 or less was recorded as showing no neuropathy, 6-8 as mild, 9-11 as moderate, and a score greater than 11 was equated to severe neuropathy.

Nerve conduction studies (NCSs) were performed with standard electromyographic and electrophysiological equipment provided by major manufacturers (Nicolet-EDX Viking IOM system; Pleasanton, California, USA). Digital skin thermometers were used to ensure that skin temperatures were at least 32°C. Velocity was determined for the distal sural and ulnar sensory nerves and for the peroneal motor nerve (knee to ankle) unilaterally on the nondominant side. Response amplitude was measured over the dorsal surface of the foot for the sural nerve, over the extensor digitorum brevis muscle for the peroneal nerve, and at the fifth finger for the ulnar nerve. All data were collected using specified anatomical landmarks and standard surface techniques for both recording and stimulation sites. Over a period of 3 months, hypovitamnosis D was corrected and the NCS were repeated again.

The study protocol was reviewed and approved by the scientific committee at Riyadh National Hospital and was in accordance with the principles of Helsinki Declaration of 1975, as revised in 1983. Informed consent was obtained from the patients to participate in this study.

Inclusion criteria were as follows:

  1. Diagnosis of DM2 according to the WHO 1999 criteria,
  2. Presence of vitamin D deficiency or insufficiency,
  3. Presence of diabetic DPN, and
  4. Willingness to sign the informed consent form.


Exclusion criteria included the following:

  1. Causes of neuropathy other than diabetes (history of nerve root compression, cerebral vascular disease, hypothyroidism, pernicious anemia, alcoholism, and using of drugs that may cause neuropathy);
  2. Past history of stroke, as it can cause neuropathy;
  3. Pregnancy, because of possible temporary changes in blood chemistry, circulation, and pain sensitivity; and
  4. Presence of elevated serum vitamin D level and ruling out of both vitamin B12 deficiency and a paraproteinemia as a cause of DPN.


A large number of patients did not meet the inclusion and hence were excluded. Eligible patients (193 patients) were invited to participate in the trial, but 136 of them declined to participate and seven patients did not show up. Finally, 50 patients participated in the study.

Levels of 25-hydroxyvitamin D (25-OH-D) were measured from blood obtained at the same visit at which NCS were performed. We used the direct, competitive chemiluminescence immunoassay with the DiaSorin LIAISON25-OH Vitamin D TOTAL assay. Although there is no consensus on optimal levels of 25-OH-D, data suggest that levels of 30 ng/ml can be considered an indication of sufficient vitamin D. Thus, individuals with 25-OH-D levels below 20 ng/ml and ranging from 20 to 29 ng/ml were characterized as having vitamin D deficiency and vitamin D insufficiency, respectively.

Statistical analysis

For descriptive statistics, the frequency and percentage were calculated for qualitative variables and the mean values ± SD and range were used for quantitative variables. For comparison between two groups two sample t-tests were used and, when adjustments were required, analysis of covariance was used. Statistical computations were carried out using the SPSS software, version 17 (SPSS Inc., Chicago, Illinois, USA). Statistical significance was predefined as P value of 0.05 or less.


  Results Top


Fifty patients received vitamin D therapy and completed the study. They were between 36 and 81 years of age (mean ± SD, 54.72 ± 9.00 years) and the majority of them were female (64%). The clinical characteristics of the patients are summarized in [Table 1].
Table 1: Clinical characteristics of diabetic peripheral neuropathy patients

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The mean NCS for the sural, lateral popliteal, and ulnar nerves showed no statistically significant difference in patients before and after normalization of vitamin D levels [Table 2]. Patients were further divided into subgroups according to neuropathy severity using the TCSS into the mild, moderate, and severe groups. On comparing these groups, there was a significant improvement in NCS in the mild DPN group [Table 3].
Table 2: Effect of vitamin D correction on nerve conduction studies

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Table 3: Effect of vitamin D correction on NCS among different diabetic neuropathy

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In moderate and severe DPN, there were no significant changes in NCS before and after correction of serum vitamin D level. Moreover, the compound muscle action potential amplitude was improved after correction of low vitamin D in moderate and severe diabetic neuropathy, but this improvement failed to reach statistical significance [Table 3].

As shown in [Table 4], there was a significant reduction in the DPN severity after normalization of low serum vitamin D level. This improvement was noticed as significant difference in mean TCSS in neuropathic patients, in all patients and in all DPN subgroups [Table 4].
Table 4: Effect of vitamin D correction on TCSS (mean ± SD)

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  Discussion Top


In this study, short-term supplementation with vitamin D for normalization of low serum vitamin D level in DPN patients improved the neuropathy severity; there is only some pieces of evidence from the literature concerning the effect of vitamin D on DPN. Bell reported an evident improvement with vitamin D supplementation in a 38-year-old type 1 diabetic patient who had diabetes for 27 years and neuropathic symptoms in both hands and feet for 10 years. Marked improvement in his neuropathic symptoms was noticed after correction of his low serum vitamin D [19].

These results are in agreement with data from the National Health and Nutrition Examination Survey, which demonstrated that hypovitaminosis D is associated with higher neuropathic pain scores among diabetic participants [6]. Moreover, Lee and Chen [5] found that, among 51 patients with DPN, vitamin D supplementation resulted in significant improvement in neuropathic pain scores. An improvement in neuropathy is explained in the light of the induction of nerve growth factor synthesis by vitamin D derivatives as shown in vitro in fibroblasts and astrocytes and in vivo in rat brain [20]. In addition, pain thresholds of multiple etiologies have been reported to be decreased with hypovitaminosis D and increased when the vitamin D deficiency is corrected [19].

The results from the NCS on the sural, lateral popliteal, and ulnar nerves revealed improvement in the electrophysiological function of the examined nerves after vitamin D normalization and showed a direct relationship between vitamin D level and nerve conduction velocity and the compound muscle action potential amplitude of the nerve. These differences were statistically significant in all examined nerves among patients with mild DPN, whereas in patients with moderate and severe DPN the differences still did not reach a statistical significance after treatment.

Few data on the association of peripheral nerve function and vitamin D levels are available from human studies. However, our results are supported by the study of McDermott et al. [14], who found significant associations of low vitamin D levels with slower peroneal and sural nerve conductions. Moreover, Shehab et al. [21] found that vitamin D levels were not only inversely proportional to a neuropathy symptom score but also significantly associated with slower nerve conduction velocities after correction for diabetic duration and levels of HbA1c, urinary albumin, and LDL. Moreover, in animal studies conducted by Nickander et al. [22], they found that hypovitaminosis D was associated with worsened or induced nerve conduction abnormalities in both sciatic-tibial and caudal nerves.


  Conclusion Top


We conclude that correction of hypovitaminosis D improves neuropathic symptoms in diabetic patients with DPN and therefore it is recommended to investigate diabetic patients for the serum vitamin D level as a possible treatable cause for DPN. Further studies are needed to evaluate the effect of vitamin D supplementation on peripheral nerves in DPN patients and explore the possible mechanisms of this effect. Moreover, the possibility that early vitamin D replacement may prevent or delay the onset of diabetic complications, mainly DPN, must be investigated.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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Brewer LD, Thibault V, Chen KC, Langub MC, Landfield PW, Porter NM. Vitamin D hormone confers neuroprotection in parallel with downregulation of L-type calcium channel expression in hippocampal neurons. J Neurosci 2001; 21 :98-108.  Back to cited text no. 8
    
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Naveilhan P, Neveu I, Wion D, Brachet P. 1,25-dihydroxyvitamin D3, an inducer of glial cell line-derived neurotrophic factor. Neuroreport 1996; 7 :2171-2175.  Back to cited text no. 9
    
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Neveu I, Naveilhan P, Baudet C, Brachet P, Metsis M. 1,25-dihydroxyvitamin D3 regulates NT-3, NT-4 but not BDNF mRNA in astrocytes. Neuroreport 1994; 6 :124-126.  Back to cited text no. 10
    
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Neveu I, Naveilhan P, Jehan F, Baudet C, Wion D, De Luca HF, Brachet P. 1,25-dihydroxyvitamin D3 regulates the synthesis of nerve growth factor in primary cultures of glial cells. Brain Res Mol Brain Res 1994; 24 :70-76.  Back to cited text no. 11
    
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Wang Y, Chiang YH, Su TP, Hayashi T, Morales M, Hoffer BJ, Lin SZ. Vitamin D(3) attenuates cortical infarction induced by middle cerebral arterial ligation in rats. Neuropharmacology 2000; 39 :873-880.  Back to cited text no. 13
    
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McDermott MM, Liu K, Ferrucci L, Tian L, Guralnik J, Kopp P, et al. Vitamin D status and functional performance in peripheral artery disease. Vasc Med 2012; 17 :294-302.  Back to cited text no. 14
    
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Bril V, Perkins BA. Validation of the Toronto Clinical Scoring System for diabetic polyneuropathy. Diabetes Care 2002; 25 :2048-2052.  Back to cited text no. 18
    
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Bell DS. Reversal of the symptoms of diabetic neuropathy through correction of vitamin D deficiency in a type 1 diabetic patient. Case Rep Endocrinol 2012; 2012 : 2012:165056.  Back to cited text no. 19
    
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Pfeifer M, Begerow B, Minne HW, Abrams C, Nachtigall D, Hansen C. Effects of a short-term vitamin D and calcium supplementation on body sway and secondary hyperparathyroidism in elderly women. J Bone Miner Res 2000; 15 :1113-1118.  Back to cited text no. 20
    
21.
Shehab D, Al-Jarallah K, Mojiminiyi OA, Al Mohamedy H, Abdella NA. Does vitamin D deficiency play a role in peripheral neuropathy in type 2 diabetes? Diabet Med 2012; 29 :43-49.  Back to cited text no. 21
    
22.
Nickander KK, Schmelzer JD, Rohwer DA, Low PA. Effect of alpha-tocopherol deficiency on indices of oxidative stress in normal and diabetic peripheral nerve. J Neurol Sci 1994; 126 :6-14.  Back to cited text no. 22
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]


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