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October2014 Vol.51 Issue:      4 Table of Contents
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Effect of Serum Vitamin D Level on Severity of Diabetic Polyneuropathy

Mohamad Saad1, Wael Gabr1,4, Enaase Barakat2, Mohammed M.H. Al-Gayyar3

Departments of Neurology1, Internal Medicine2; Faculty of Medicine; Department of Clinical Biochemistry3; Faculty of Pharmacy; Mansoura University, Mansoura; Egypt; Riyadh National Hospital4; KSA



ABSTRACT

Background: Polyneuropathy is the commonest chronic and disabling complication of diabetes mellitus. Vitamin D insufficiency is common among diabetic patients, however, the link between vitamin D level and the presence of, and the severity of diabetic neuropathy is poorly understood, Objective: This study aimed at clarifying the link between vitamin D level and the diagnosis, and the severity of diabetic neuropathy. Methods: Fifty-eight diabetic patients were included, they were assessed clinically for neuropathy using neuropathy Michigan score, Toronto clinical score system (TCSS) and nerve conduction study of sural nerve, popliteal nerve and ulnar nerve. Control of diabetes was assessed by measuring HbA1c, Vitamin D status was determined by measuring 25-dihydroxyvitamin D. Results: Thirty-eight patients with diabetic polyneuropathy completed the study, compared to 20 control patients with diabetes and no neuropathy. Serum vitamin D level was lower among patient with proven diabetic neuropathy compared to controls (14.97±7.32 and 35.70±8.79 respectively), and was correlated to severity of neuropathy measured by TCSS irrespective to glycemic control, Moreover, vitamin D level correlates directly with the nerve conduction velocity and amplitude in sural nerve, popliteal nerve and ulnar nerve. Conclusion: Vitamin D level was found to correlate to the presence, and severity of neuropathy among diabetic patients, however, further studies are required to confirm if Vitamin D supplementation could prevent or delay the onset of neuropathy in such patients. [Egypt J Neurol Psychiat Neurosurg.  2014; 51(4): 465-470]

 

Key Words: Peripheral diabetic neuropathy, Vitamin D deficiency, Vitamin D insufficiency, diabetes mellitus.

Correspondence to Wael M. Gabr. Department of Neurology, University of Mansoura, Mansoura, Egypt.

Tel: +966500322107+966500322107.    E-mails: waaael@gmail.com




 

 


INTRODUCTION

 

Polyneuropathy affects 54 per 100,000 people a year in the community1, and up to 50% of diabetic patients2, representing the third most common neurological disorder, surpassed only by cerebrovascular events and shingles1, and predisposes patients to severe functional limitations through symptoms of unremitting pain and unsteadiness.2

The prevalence of diabetic neuropathy is directly related to diabetes duration, patient age, and metabolic control. Approximately 20% of diabetic patients will develop clinically significant neuropathy within 10 years of diabetes onset, and this proportion can increase to 50% after 10 or 15 years.3

There is reasonable evidence, extending over 40 years, that hypovitaminosis D predisposes to diabetes and cardiovascular disease.4 Vitamin D insufficiency is common among those diagnosed with diabetes5,6, as well as diabetic neuropathy patients.7 Several studies have suggested that adequate intake of vitamin D may prevent or delay the onset of diabetes, as well as reduce complications for those who have already been diagnosed.5,7-9

Vitamin D has been experimentally linked to the regulation of neurotrophin levels and neuronal Ca2+ homeostasis, both of which may provide a neuroprotective effect.10 The influence of vitamin D on nerve function is supported in an animal model of diabetic rats with deficiencies in nerve growth factor synthesis, treatment of these rats with vitamin D increased nerve growth factor production and prevented neurotrophic deficit.11 The data in humans regarding vitamin D insufficiency and diabetic neuropathy are limited and the use of vitamin D for treatment of neuropathic pain needs further study.7

Aim of work: To clarify the link between vitamin D level and the diagnosis, and the severity of diabetic neuropathy.

 

PATIENTS AND METHODS

 

This study was conducted in the neurology and internal medicine departments at Riyadh National Hospital, Riyadh, Saudi Arabia, a database was created of 65 patients with Diabetes Mellitus, which have been further subdivided into 2 groups; group 1 included 43 patients with diabetic neuropathy, and group 2 (control group) included 22 patients with diabetes without neuropathy.

Patients included in this study should satisfy the following criteria; (a) diagnosis of Type 2 diabetes mellitus according to World Health Organization 1999 criteria, and (b) willingness to sign informed consent form. Exclusion criteria included patients with other causes of neuropathy rather than diabetic (history of nerve root compression, cerebral vascular disease, hypothyroidism, pernicious anemia, alcoholism and using of drugs that is may cause neuropathy).

The study had been approved by the scientific committee at Riyadh National Hospital and with the Helsinki Declaration of 1975, as revised in 1983. Informed consent was taken from the patients to participate in this study.

Glycemic control was assessed via HbA1c levels. Body mass index (BMI) was calculated using the equation [weight in kilogram/(height in meter)2]. Categorized as normal (<25 kg/m2), overweight (25-30 kg/m2) and obese (>30 kg/m2).

Vitamin D status in the serum is evaluated based on the Diasorin 25-OH-D assay, which measures 25- OH-D. This is the predominant circulating form of vitamin D in the normal population and is the most commonly used to determine vitamin D status. Although there is no consensus on optimal levels of 25-OH-D, data suggests that levels 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 having vitamin D deficiency and vitamin D insufficiency, respectively.8

A data collecting sheet was filled by the internal medicine doctor to record demographic data and relevant medical history, then were screened for diabetic peripheral neuropathy. A neurologist performed the screening for diabetic peripheral neuropathy (DPN) using Michigan Neuropathy Screening Instrument (MNSI). It consists of a two-step program: The first part assessed a neuropathic symptom by a history questionnaire consists of 15 "yes or no" questions on foot sensation including pain, numbness and temperature sensitivity. The second part is 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 >2.0 on the MNSI examination, thresholds defined by prior validation studies.12

The screening method for fine touch sensation, vibration perception and ankle reflex using 10-g SWM, 128-Hz tuning fork and reflex hummer was followed the practical guideline from Michigan Diabetes Research and Training Center.13

Sensory testing was performed on the first toe. Symptom scores: present = 1, absent = 0. Reflex scores: absent = 2, reduced = 1, normal = 0. Sensory test score: abnormal = 1. normal = 0. Total scores range from normal = 0 to maximum of 19. a score ≤5 was recorded as showing no neuropathy, 6–8 mild, 9–11 moderate, and >11 equated to severe neuropathy

The nerve conduction study (NCSs) were performed with standard electrophysiological and electromyographic equipment provided by major manufacturers (Nicolet®, Teca®, and Disa®). Digital skin thermometers accurate to 0.1°C to ensure that skin temperatures were at least 32°C. Examinations were performed by trained electrophysiologists. 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 overlying the dorsal surface of the foot for the sural nerve, at the fifth finger for the ulnar nerve and overlying the extensor digitorum brevis muscle for the peroneal nerve.

 

Statistical Analysis

For descriptive statistics the frequency and percentage were calculated for qualitative variables, the mean values ±standard deviation (SD), and range were used for quantitative variables. For comparison between two groups student t-test was calculated. For correlation, Pearson correlation was used. Statistical computations were done using the computer software Statistical Package for the Social Sciences (SPSS) version 16 (Chicago, IL, USA). Statistical significance was predefined as P ≤0.05.

 

RESULTS

 

Sixty-five subjects diabetic patients were screened, of whom 43 (66.2%) had a diabetic poly neuropathy (DPN group) and 22 patients with diabetes without neuropathy (control group). Of the total number of patients, 58 patients have completed the study to its end (38 patients with DPN, and 20 patients in the control group), 23 patients were females (60.5%) and 15 were males (39.5%). Ages varied from 36 years to 68 years (mean ±SD, 54.0±7.7 years). Clinical characteristics of the patients and controls are summarized in table 1.

Age, BMI, and HbA1c within the last 3 months, were comparable among patients and controls. Patients with clinically proven diabetic neuropathy had remarkably lower serum 25-hydroxyvitamin D levels compared to the controls. Male patients had slightly lower 25-hydroxyvitamin D levels than female patients in diabetic polyneuropathy group but of no statistical significance. However, the 25-hydroxyvitamin D levels in female controls were lower than male (Table 2).

The glycemic control did not differ between diabetic patients with vitamin D insufficiency or deficiency as compare to diabetic with normal vitamin D level. That means, the effect of vitamin D on diabetic neuropathy did not depend on the glycemic control.

In addition, serum vitamin D correlates with the severity of diabetic neuropathy measured by Toronto clinical score system (TCSS) (Table 3). There is a significant difference in mean TCSS in neuropathic patient with vitamin D insufficiency and deficiency compared to diabetic patient with normal vitamin D level (12.75±2.35, 6.44±2.85, and 3.43±1.60 respectively). Moreover, vitamin D level correlates with changes in the NCS in the examined nerves; table 4 and 5.

The relationship between the severity of DPN as provided by the TCSS and the vitamin D serum levels was investigated by univariate correlation analysis. The Pearson correlation for the total TCSS and vitamin D was -0.850 (P≤0.001). The vitamin D serum level was significantly correlated with the TCSS (Figure 1). In addition, there are a significant correlation between the TCSS and amplitude and conduction velocities of the sural, popliteal and ulnar nerves (Tables 4 and 5).


 

 

 

 

Figure 1. Toronto clinical score system versus Serum vitamin D Level in the study patients.

 

Table 1. Clinical characteristics of diabetic neuropathy and control subjects among both sexes.

 

 

Patient (N=38)

Control (N=20)

P-value

Female (N=23)

Male (N=15)

0.418

Male (N=8)

Age (yr)

52.61 ±8.02

56.13 ±7.00

0.299

53.88 ±7.26

0.418

DM Duration (yr)

13.96 ±5.71

15.93 ±5.57

0.000

16.88 ±2.90

0.299

Neuropathy Duration (yr)

5.46 ±4.57

5.87 ±3.42

0.000

0.00 ±0.00

0.001

Toronto CSS

11.78 ±2.94

11.40 ±2.72

0.000

4.00 ±0.93

0.001

BMI (kg/m2)

33.76 ±4.16

33.08 ±3.12

0.761

32.9 5±5.14

0.761

Waist Circumference (Cm)

100.20 ±5.44

110.70 ±5.65

0.569

109.19 ±6.48

0.551

HbA1c (%)

9.61 ±2.31

9.97 ±1.85

0.551

10.65 ±1.91

0.569

Data are expressed as mean ±SD, P-value calculated by comparing diabetic and control groups.

Yr years,

Table 2. Serum vitamin D levels in diabetic neuropathy patients and control subjects (ng/dl).

 

 

Diabetic neuropathy subjects

(n=38)

Control subjects

(n=20)

P-value

Female

14.98± 7.86 (5-29)

34.00±8.98 (21-50)

0.001*

Male

15.73± 6.61 (5-23)

38.25±8.40 (26-51)

0.001*

Total

14.97±7.32 (5-29)

35.70±8.79 (21- 51)

0.001*

Data are mean +SD with range in parenthesis for the female and male patients separately and combined.

*significant at P<0.01

 

Table 3. Effect of Serum vitamin D levels on diabetic neuropathy severity measured by TCSS.

 

 

Vitamin D deficiency

(n=16)

Vitamin D insufficiency

(n=28)

Normal vitamin D

(n=14)

TCSS  (mean ±SD)

12.75 ±2.35*

6.44 ±2.85*

3.43 ±1.60

TCSS Toronto clinical score system

*significant at P<0.01

 

Table 4. Effect of serum vitamin D level on Toronto CSS (mean±SD).

 

 

Vitamin D insufficiency

(n=28)

Vitamin D deficiency

(n=16)

Normal vitamin D

(n=14)

Sural nerve CV

29.09 ±17.49

36.23 ±18.08

42.9 7±12.56a

Sural nerve Amp

3.11 ±2.09

4.61 ±2.79*

5.93 ±2.09 a

Lateral popliteal nerve CV

40.87 ±4.39

42.86 ±2.65*

45.34 ±1.46 ab

Lateral popliteal nerve Amp

5.44 ±0.93

5.86 ±1.26

6.510.87 ab

Ulnar nerve CV

45.87 ±12.16

61.4 ±3.95*

56.19 ±15.23 a

Ulnar nerve Amp

6.2 ±2.11

9.89 ±4.11*

9.35 ±3.82 a

,a Compared with vitamin D insufficiency patients (p<0.05), b Compared with vitamin D deficiency patients (p<0.05)

CV Conduction Velocity, Amp compound motor action potential amplitude

 

Table 5. Correlation between vitamin D and severity of DPN.

 

 

Sural CV

Sural Amplitude

Lateral popliteal CV

Lateral popliteal Amp

Ulnar CV

Ulnar Amp

Vitamin D

Pearson Correlation

0.378*

0.424**

0.340*

0.370*

0.686**

0.696**

2-tailed

0.019

0.008

0.037

0.022

0.000

0.000

CV Conduction Velocity, Amp compound motor action potential amplitude

*Correlation is significant at the 0.05 level (2-tailed), **Correlation is significant at the 0.01 level (2-tailed).

 

 


DISCUSSION

 

Epidemiologic evidence suggests that an adequate intake of vitamin D may prevent or delay the onset of diabetes, and also may reduce some of the diabetic complications including the peripheral neuropathies.14 In addition, vitamin D deficiency is often diagnosed in those with established diabetes.5

Findings from this study show that Patients with clinically proven diabetic neuropathy had statistically significant lower serum 25-hydroxyvitamin D levels compared to the controls, this association remains after adjusting for demographic factors, obesity, co-morbidities, and diabetes duration. Currently there is no clear mechanism that can explain this finding.

 

Vitamin D is known to impact diabetes control14, so it could be expected that some of the beneficial effects may be attributable to improved disease control, but our results revealed that glycemic control did not differ between diabetic patients with vitamin D insufficiency or deficiency as compare to diabetic with normal vitamin D level. That means that the effect of vitamin D on diabetic neuropathy did not depend on the glycemic control (Figure 1).

On the other hand vitamin D may be acting solely as a marker of good health and may not be directly involved in nerve function.15 In addition, we found that the serum vitamin D level correlates with the severity of diabetic neuropathy measured by TCSS (Table 4), which suggest a direct impact of vitamin D level on nerve function, but further studies are needed to evaluate this effect and explore the possible mechanisms of this affection.

Our results failed to detect a significant differences between both sexes in patient group as regard the neuropathy severity measured by TCSS (Table 4), also there is no significant difference in vitamin D level which in most study was more in female compared to male this may be attributed to the fact that in Saudi Arabia, the exposure of people generally to the sun is limited, despite of abundant sunlight due to high daytime temperature.16-18

The estimated dietary vitamin D intake in Saudis is low in comparison to the recommended Western daily dietary allowance of 400IU, also skin pigmentation, which is known to reduce the capacity of skin to synthesize vitamin D319, may contribute by decreasing the usefulness of the little sunlight to which our subjects are exposed.20

The results conducted from the nerve conduction studies on sural, popliteal and ulnar nerves also support a significant relationship between vitamin D level and diabetic neuropathy with direct relationship between vitamin D level and nerve conduction velocity and compound motor action potential amplitude (Table 4 and 5). This is in concordance with animal studies of Nickander and colleagues, who find that vitamin D deficiency was associated with induced or worsened nerve conduction abnormalities in both sciatic-tibial and caudal nerves.21

 

Conclusion

Diabetic patients with vitamin D deficiency have an increased risk for diabetic peripheral neuropathy. Practitioners should therefore actively inquire about vitamin D level when assessing diabetic neuropathy in their patients. Because of the impact of diabetic neuropathy on quality of life, novel interventions that are safe, low in cost and effective are needed. It is unclear whether supplementation with vitamin D could help decrease the severity of symptoms caused by diabetic neuropathy or whether a low level of vitamin D is a marker for other factors that could increase the severity of symptoms.

Further studies are needed not only to evaluate the value of vitamin D supplementation as a novel intervention but also to understand the role of vitamin D in diabetic neuropathy patient. Finally, this paper opens the research gate to answer another important question about the efficacy of vitamin D supplementation to prevent or delay the onset of diabetic neuropathy.

 

[Disclosure: Authors report no conflict of interest]

 

REFERENCES

 

1.      Ziegler D, Rathmann W, Dickhaus T, Meisinger C, Mielck A. Prevalence of polyneuropathy in pre-diabetes and diabetes is associated with abdominal obesity and macroangiopathy: the MONICA/KORA Augsburg Surveys S2 and S3. Diabetes Care. 2008; 31:464-9.

2.      Vileikyte L, Leventhal H, Gonzalez JS, Peyrot M, Rubin RR, Ulbrecht JS, et al. Diabetic peripheral neuropathy and depressive symptoms: the association revisited. Diabetes Care. 2005; 28:2378-83.

3.      Rathur HM, Boulton AJ. Recent advances in the diagnosis and management of diabetic neuropathy. J Bone Joint Surg Br. 2005; 87:1605-10.

4.      Hitman GA. Vitamin D, diabetic neuropathy and supplementation post-gestational diabetes. Diabet Med. 2012; 29:1.

5.      Pittas AG, Lau J, Hu FB, Dawson-Hughes B. The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. J Clin Endocrinol Metab. 2007; 92:2017-29.

6.      Sugden JA, Davies JI, Witham MD, Morris AD, Struthers AD. Vitamin D improves endothelial function in patients with Type 2 diabetes mellitus and low vitamin D levels. Diabet Med. 2008; 25:320-5.

7.      Penckofer S, Kouba J, Wallis DE, Emanuele MA. Vitamin D and diabetes: let the sunshine in. Diabetes Educ. 2008; 34:939-44.

8.      Pittas AG, Dawson-Hughes B, Li T, Van Dam RM, Willett WC, Manson JE, et al. Vitamin D and calcium intake in relation to type 2 diabetes in women. Diabetes Care. 2006; 29:650-6.

9.      Danescu LG, Levy S, Levy J. Vitamin D and diabetes mellitus. Endocrine. 2009; 35:11-7.

10.    Garcion E, Wion-Barbot N, Montero-Menei CN, Berger F, Wion D. New clues about vitamin D functions in the nervous system. Trends Endocrinol Metab. 2002; 13:100-5.

11.    Riaz S, Malcangio M, Miller M, Tomlinson DR. A vitamin D(3) derivative (CB1093) induces nerve growth factor and prevents neurotrophic deficits in streptozotocin-diabetic rats. Diabetologia. 1999; 42:1308-13.

12.    Feldman EL, Stevens MJ, Thomas PK, Brown MB, Canal N, Greene DA. A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care. 1994; 17:1281-9.

13.      Michigan Neuropathy Screening Instrument [Internet]. The Michigan Diabetes Research and Training Center (MDRTC) [cited 2014 Oct 1]. Availble from:

http://www.med.umich.edu/borc/profs/survey.html

14.    Penckofer S, Kouba J, Wallis DE, Emanuele MA. Vitamin D and diabetes: let the sunshine in. Diabetes Educ. 2008; 34:939-44.

15.    Soderstrom LH, Johnson SP, Diaz VA, Mainous AG. III. Association between vitamin D and diabetic neuropathy in a nationally representative sample: results from 2001-2004 NHANES. Diabet Med. 2012; 29:50-5.

16.    Sedrani SH. Vitamin D status of Saudi men. Trop Geogr Med. 1984; 36:181-7.

17.    Sedrani SH, Elidrissy AW, El Arabi KM. Sunlight and vitamin D status in normal Saudi subjects. Am J Clin Nutr. 1983; 38:129-32.

18.    Sedrani SH. Low 25-hydroxyvitamin D and normal serum calcium concentrations in Saudi Arabia: Riyadh region. Ann Nutr Metab. 1984; 28:181-5.

19.    Clemens TL, Adams JS, Henderson SL, Holick MF. Increased skin pigment reduces the capacity of skin to synthesise vitamin D3. Lancet. 1982; 1:74-6.

20.    Fonseca V, Tongia R, el-Hazmi M, Abu-Aisha H. Exposure to sunlight and vitamin D deficiency in Saudi Arabian women. Postgrad Med J. 1984; 60:589-91.

21.    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.


 

 

الملخص العربى

 

تأثير مصل فيتامين د على مستوى شدة اعتلال الأعصاب السكري

 

اعتلال الأعصاب هو أكثر المضاعفات المزمنة شيوعا لداء السكري., نقص فيتامين د أمر شائع بين مرضى السكري، ومع ذلك، فإنه لم يسبق دراسة الصلة بين مستوى فيتامين (د) و وجود، وشدة الاعتلال العصبي السكري بطريقه كافيه, ولذلك فقد أجريت هذه الدراسة لتوضيح الصلة بين مستوى فيتامين د وتشخيص، وشدة الاعتلال العصبي السكري.

تضمنت هذه الدراسة ثمانية وخمسين مريض للسكري، تم تقييمهم سريريا لتشخيص الاعتلال العصبي باستخدام مقياس متشجن و تورونتو ودراسة التوصيل العصبي من العصب الربلي، العصب المأبضية والعصب الزندي. وجرى تقييم السيطرة على مرض السكري عن طريق قياس نسبة مخزون السكر بالدم، مستوى فيتامين (د) بالدم تم تحديده عن طريق قياس ثنائي هيدروكسي قيتامين د بالدم.

ثمانية وثلاثون مريض من المرضى الذين تم دراستهم استكملوا الدراسة وتم عقد المقارنة بينهم مع 20 مريضا يعانون من مرض السكري فقط بدون الاعتلال العصبي (المجموعة الضابطة), أثبتت الدراسة وجود مستوي اقل من فيتامين د في مرضى الاعتلال العصبي السكري مقارنة مع المجموعة الضابطة، وقد ارتبط مستوى قصور فيتامين د مع شدة اعتلال الأعصاب بغض النظر إلى مستوى السيطرة على سكر الدم، علاوة على ذلك، وجد أن مستوى فيتامين (د) يرتبط بشكل مباشر مع سرعة التوصيل العصبي والسرعة في العصب الربلي، العصب المأبضية والعصب الزندي., ولذلك فمن الممكن ان يكون مستوى فيتامين د بالدم له عل


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