ORIGINAL ARTICLE

Decreased serum vitamin D levels are associated with diabeticperipheral neuropathy in a rural area of Turkey

Asuman Celikbilek • Ayse Yesim Gocmen • Nermin Tanik • Elif Borekci •

Mehmet Adam • Mehmet Celikbilek • Murat Suher • Namik Delibas

Received: 15 December 2013 / Accepted: 25 April 2014

� Belgian Neurological Society 2014

Abstract Data examining the association between vita-

min D and diabetic peripheral neuropathy are limited. This

study investigated the serum levels of vitamin D, vitamin

D-binding protein (VDBP), and vitamin D receptor (VDR)

in diabetics in the Yozgat region of Turkey, and assessed

their relationships with diabetic peripheral neuropathy. 69

diabetic patients and 49 age- and sex-matched control

subjects were enrolled in this clinical prospective study. All

the diabetics underwent conventional sensory and motor

nerve conduction studies, and diabetic peripheral neuropa-

thy was confirmed or ruled out according to the electro-

myography findings and Douleur Neuropathique 4

questions. Serum vitamin D, VDBP and VDR levels were

measured using commercial enzyme-linked immunosorbent

assay kits. The serum vitamin D levels (p = 0.001) were

significantly lower, while the VDR levels (p = 0.003) were

higher, in diabetics than in controls. The serum VDBP

levels were similar in both groups (p [ 0.05). The serum

vitamin D levels were significantly lower in diabetics with

diabetic peripheral neuropathy than in those without

(p = 0.032), whereas the serum VDBP and VDR levels

were similar in these two groups (p [ 0.05). The lower

serum vitamin D levels in diabetics, especially in those with

peripheral neuropathy, may suggest a neurotrophic effect of

vitamin D.

Keywords Diabetes � Diabetic peripheral neuropathy �Vitamin D � Vitamin D-binding protein � Vitamin D

receptor

Introduction

Recently, in addition to bone health, associations have been

found between vitamin D deficiency and numerous disor-

ders, including cancer, multiple sclerosis, microbial and

cardiometabolic diseases, hypertension, and diabetes [1–4].

There is evidence of relationships between low vitamin D

and types 1 [5, 6] and 2 [7, 8] diabetes. Although hypo-

vitaminosis D is prevalent in patients with type 2 diabetes,

few studies have examined its relationship with diabetic

peripheral neuropathy.

Diabetic peripheral neuropathy affects more than 50 %

of type 2 diabetics and is a major microvascular compli-

cation, which invariably results in a decreased quality of

life [9, 10]. Vitamin D deficiency is more common in

diabetics with symptoms of distal symmetrical polyneu-

ropathy [11]. Recently, vitamin D insufficiency was asso-

ciated with self-reported peripheral neuropathy symptoms

A. Celikbilek (&) � N. Tanik

Department of Neurology, Medical School, Bozok University,

66200 Yozgat, Turkey

e-mail: asunebioglu@yahoo.com

A. Y. Gocmen � N. Delibas

Department of Biochemistry, Medical School,

Bozok University, 66200 Yozgat, Turkey

E. Borekci

Department of Internal Medicine, Medical School,

Bozok University, 66200 Yozgat, Turkey

M. Adam

Department of Ophthalmology, Medical School,

Bozok University, 66200 Yozgat, Turkey

M. Celikbilek

Department of Gastroenterology, Medical School,

Bozok University, 66200 Yozgat, Turkey

M. Suher

Department of Endocrinology and Metabolism, Medical School,

Bozok University, 66200 Yozgat, Turkey

123

Acta Neurol Belg

DOI 10.1007/s13760-014-0304-0

in a nationally representative sample of adults diagnosed

with diabetes [12]. More recently, Shehab et al. [13]

reported that vitamin D deficiency is an independent risk

factor for diabetic peripheral neuropathy in type 2 diabetes.

This was confirmed by Skalli et al. [14], who found an

association between vitamin D deficiency and diabetic

peripheral neuropathy. Vitamin D supplementation has also

been suggested as an effective ‘‘analgesic’’ for relieving

neuropathic pain in patients with diabetes [11, 15]. Con-

sequently, a causal relationship between vitamin D defi-

ciency and an increased risk of diabetic peripheral

neuropathy has been proposed in multiple studies of vari-

ous ethnic groups [16]. However, no clinical study has

examined the Turkish population. Therefore, this study

investigated the serum levels of vitamin D, vitamin

D-binding protein (VDBP), and vitamin D receptor (VDR)

in diabetic patients, and assessed their relationships with

diabetic peripheral neuropathy, in the Yozgat region of

Turkey.

Methods

Study population

This prospective clinical study included 69 patients with

type 2 diabetes mellitus and 49 age- and sex-matched

control subjects of Caucasian origin, ranging from 30 to

70 years of age. It was conducted in the Yozgat region of

Turkey known as central Anatolia, in the winter of 2012.

Type 2 diabetes mellitus was identified by the presence of

fasting glucose levels C126 mg/dL or postprandial glucose

levels C200 mg/dL concomitant with symptoms of diabe-

tes or the treatment of previously diagnosed diabetes with

insulin or oral hypoglycemic agents [17]. Patients with

malignancies; chronic liver or kidney diseases, which

plausibly affect vitamin D metabolism; thyroid disease;

cardiovascular or connective tissue disease; inflammatory

or autoimmune disease and osteoporosis were excluded.

Additionally, those who were pregnant; morbidly obese;

current smokers; or current consumers of alcohol and those

with use of drugs known to interfere with the vitamin D

metabolism (e.g., vitamin D supplements, anticonvulsants,

rifampicin, and antiretroviral drugs) were excluded.

The same neurologist took the patients’ medical histo-

ries and performed the physical and neurological examin-

ations. Dependent variables included systolic (SBP) and

diastolic (DBP) blood pressure, and body mass index

(BMI), which was calculated as weight in kilograms divi-

ded by the square of height in meters [18]. Fasting venous

blood samples were taken from all subjects in winter

(January and February), as a short timeframe to avoid

seasonal variation in the serum vitamin D levels [19].

Routine laboratory analyses were performed in our labo-

ratory using standard methods.

The study protocol was approved by the Bozok Uni-

versity Research Ethics Committee, and written informed

consent was obtained from all participants.

Assessment of peripheral neuropathy

All diabetic patients underwent conventional sensory and

motor nerve conduction studies performed by the same

neurologist, who was blinded to the results. The median,

ulnar, deep peroneal, and tibial motor nerves and median,

ulnar, and sural sensory nerves in both limbs were stimu-

lated using a Medelec Synergy electromyography (EMG)

machine (Medelec Synergy, Oxford Instruments, Surrey,

UK). The filter settings used a 20–2,000 Hz bandpass for

the sensory nerve studies and a 2–10,000 Hz bandpass for

the motor nerve studies. The limb temperature of all sub-

jects was maintained above 31–32 �C. Abnormal sponta-

neous activity, increased number of long-duration motor

unit potentials, and decreased recruitment patterns were

determined to be indicators of neuropathic changes. Based

on the EMG findings (nerve conduction velocity, ampli-

tude, and distal latency) and a score C4 on the Douleur

Neuropathique 4 (DN4) questionnaire, peripheral neurop-

athy was confirmed or ruled out for each patient [20]. Of

the diabetic patients, 24 (34.8 %) were found to have

peripheral neuropathy with axonal subtype in all.

Assessment of retinopathy

Retinopathy status was assessed by funduscopic eye

examinations performed by the same ophthalmologist, who

was blinded to the patient status. Non-proliferative reti-

nopathy was diagnosed according to the presence of cotton

wool spots, micro-aneurysms, and boat-shaped hemor-

rhages on direct ophthalmoscopy. Proliferative retinopathy

was diagnosed according to the presence of neovasculari-

zation in the retina [21]. Of the diabetic patients, 18

(26.1 %) were found to have retinopathy: four patients had

the proliferative type and the remainder had the non-pro-

liferative type.

Assessment of nephropathy

Nephropathy was diagnosed according to the presence of

microalbuminuria, macroalbuminuria, or a creatinine

clearance \90 mL/min. Micro- and macroalbuminuria

were diagnosed based on the urinary albumin: creatinine

ratio [21]: 30–300 mg albumin per gram of creatinine for

microalbuminuria and [300 mg for macroalbuminuria.

Four patients with diabetes were found to have

nephropathy.

Acta Neurol Belg

123

Biochemical analysis

All blood samples were centrifuged for 10 min at

3,000 rpm, after which the supernatant was removed

quickly and kept frozen at -80 �C until assayed by an

investigator blind to patient status. Commercial enzyme-

linked immunosorbent assay (ELISA) kits were used to

measure the serum vitamin D (EIA-5396, DRG, Marburg,

Germany), VDBP (K2314, Immundiagnostik, Bensheim,

Germany), and VDR (Cusabio, Wuhan, China) levels using

appropriate wavelengths on a microplate reader

(EL 9 800 TM, BioTek Instruments, Winooski, VT, USA)

following the assay instructions. Concentrations were cal-

culated over the standard curves. The detectable ranges for

vitamin D, VDBP, and VDR were 30–100, 20–55 ng\mL,

and 6.25–400 pg/mL, respectively.

Statistical analysis

The Shapiro–Wilk test, histograms, and q–q plots were

used to test the normality of the data, and Levene’s test was

used to assess variance homogeneity. Independent samples

t tests and Mann–Whitney U tests were used to compare

differences between continuous variables, and Chi-square

(v2) analyses were used to assess differences between

categorical variables. Pearson correlations were used to

examine relationships among vitamin D, VDBP, VDR,

diabetic characteristics (disease duration, fasting glucose,

and glycosylated hemoglobin A1c), and diabetic micro-

vascular complications (peripheral neuropathy, retinopa-

thy, and nephropathy). Values are expressed as frequencies

and percentages, means and standard deviations, or medi-

ans and interquartile ranges. Analyses were conducted

using SPSS ver. 15.0 (SPSS; Chicago, IL, USA). Statistical

significance was set at p \ 0.05.

Results

Table 1 summarizes the demographic and laboratory data

of the controls and diabetic patients. No significant dif-

ference was found between the groups with respect to age

or gender (p [ 0.05). All the routine laboratory results,

except for the fasting glucose (p \ 0.001), were similar

between the diabetics and controls (p [ 0.05). The serum

vitamin D levels (p = 0.001) were significantly lower in

the diabetic patients than in the controls, while the VDR

levels (p = 0.003) were higher (Table 1). The serum

VDBP levels were similar in both groups (p [ 0.05). There

was no correlation between vitamin D, VDBP, VDR, and

diabetic characteristics in the diabetics (p [ 0.05, Table 2).

However, there was a significant decrease in serum vitamin

D levels in diabetics with diabetic peripheral neuropathy

than in those without, whereas the serum VDBP and VDR

levels were similar between these groups (p = 0.032 and

p [ 0.05, respectively; Table 2).

Discussion

Two main findings emerged from this study. First, the

serum vitamin D levels were significantly lower, while the

VDR levels were higher in the diabetics than in the

Table 1 Demographic and laboratory data of control and diabetic

patients

Variables Control (n = 49) Diabetic (n = 69) p

Age (years) 58.6 ± 10.9 56 ± 9.5 0.164

Gender (female/male) 33 (67.3)/16 (32.7) 49 (71)/20 (29) 0.670

BMI (kg/m2) 31.9 ± 5.5 31.5 ± 4.9 0.665

SBP (mmHg) 120 (110–130) 120 (110–130) 0.970

DBP (mmHg) 70 (60–80) 70 (60–80) 0.894

WBC (103/mm3) 7.9 ± 1.4 7.8 ± 1.2 0.727

Hemoglobin (mg/dL) 14.1 (13.1–15.3) 14 (13.2–15.2) 0.889

Platelet (103/mm3) 264.3 ± 67.6 262.1 ± 70 0.869

Fasting glucose

(mg/dL)

90 (86–93.5) 168 (134–217.5) \0.001

Creatinine (mg/dL) 0.7 (0.6–0.8) 0.7 (0.6–0.85) 0.314

AST (IU/L) 20.1 ± 6.2 18.7 ± 5.5 0.211

ALT (IU/L) 18 (13–25) 20 (15–27.5) 0.146

TC (mg/dL) 216 ± 37.1 210.9 ± 49.4 0.544

TG (mg/dL) 149 (103–200) 149 (105–207) 0.539

HDL-C (mg/dL) 42 (39.5–48) 43 (37–46.5) 0.658

LDL-C (mg/dL) 137.7 ± 28.4 131.5 ± 34.4 0.305

TSH (uIU/mL) 1.4 (0.9–2) 1.5 (0.9–2.6) 0.354

B12 vitamin (pg/mL) 356 (296.5–460.5) 355 (298–504.5) 0.810

Folat (ng/mL) 11 (10–13) 12 (10–15) 0.077

Albumin (g/dL) 4.2 (4–4.4) 4.3 (4.1–4.5) 0.237

LDH (IU/L) 128 (116.5–143) 121 (113–138) 0.116

ALP (IU/L) 62 (55–71) 60 (53–69) 0.199

Calcium (mg/dL) 9.49 ± 0.37 9.36 ± 0.39 0.086

Phosphorus (mg/dL) 3.5 (3.1–4.1) 3.6 (3.1–4) 0.747

Magnesium (mg/dL) 1.9 (1.8–2) 1.9 (1.8–2.1) 0.326

Parathormone

(pg/mL)

41.5 (34.1–55.5) 46.1 (36.6–60.1) 0.159

25-hydroxyvitamin

D (ng/mL)

42.96 (27.01–63.13) 23.08 (14.63–39.45) 0.001

VDBP (ng/mL) 39.86 (32.13–44.85) 38.2 (28.04–45.47) 0.733

VDR (pg/mL) 52.81 (47.03–87.47) 89.12 (61.33–97.09) 0.003

Values are expressed as n(%), mean ± SD or median(25th–75th percentiles)

BMI body mass index, SBP systolic blood pressure, DBP diastolic blood

pressure, WBC white blood cell, AST aspartate aminotransferase, ALT alanine

aminotransferase, TC total cholesterol, TG triglyceride, HDL-C high-density

lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, TSH thy-

roid stimulating hormone, LDH lactate dehydrogenase, ALP alkaline phos-

phatase, VDBP vitamin D-binding protein, VDR vitamin D receptor

Acta Neurol Belg

123

controls; the VDBP levels were similar in both groups.

Second, the serum vitamin D levels were significantly

lower, while the serum VDR and VDBP levels were similar

in diabetics with peripheral neuropathy compared with

those without peripheral neuropathy.

Vitamin D can be ingested in the diet or formed in the

skin by ultraviolet B exposure; it is hydroxylated into

25-hydroxy vitamin D (25-OHD) in the liver; and then,

metabolized in the kidneys by the enzyme 1a-hydroxylase

into its active form, 1,25-OHD [1]. 25-OHD is used to

determine a patient’s vitamin D status owing to its longer

half-life in plasma, and forms a circulating reservoir of

vitamin D [22]. There is no consensus on the optimal

25-OHD levels [1]. Vitamin D levels [30 ng/mL are

usually considered sufficient; levels of 20–30 ng/mL indi-

cate insufficiency, while vitamin D deficiency is considered

when the serum level is \20 ng/mL [1]. Vitamin D status

alters glucose metabolism [23, 24]. It is currently recog-

nized that type 2 diabetes is associated with systemic

inflammation, which has been linked primarily to insulin

resistance [25]. Since vitamin D has anti-inflammatory and

immunoregulatory effects, it can ameliorate low-grade

chronic inflammation by modulating the generation of

cytokines [24, 26]. Vitamin D might also stimulate insulin

release by pancreatic beta cells, and improve insulin sen-

sitivity, and hence glycemic control, in patients with type 2

diabetes [27, 28]. This suggests a role for vitamin D in the

pathogenesis of type 2 diabetes [29]. In this study, the

diabetic group had vitamin D insufficiency, and this was

worse in those with peripheral neuropathy (23.02 vs

33.01 ng/mL). Our results were similar to reports that

vitamin D deficiency is an independent risk factor for

diabetic peripheral neuropathy [13, 14].

Two mechanisms for this can be considered. First, this

may be explained by the neurotrophic effects of vitamin D

on nerve function [11, 14]. Animal models have linked

vitamin D to the regulation of neurotrophin levels and

neuronal calcium homeostasis, both of which might confer

neuroprotective effects [30, 31]. A decrease in

neurotrophins, especially nerve growth factors, and defec-

tive calcium homeostasis leave nerves vulnerable to toxins,

including hyperglycemia, which might contribute to the

development of neurotrophic deficits as neuropathic chan-

ges in diabetes [30]. Second, the improvement in muscu-

loskeletal pain with the correction of vitamin D deficiency

[32], together with the relief of neuropathic symptoms after

topical vitamin D application to the affected areas [33],

suggest a new nociceptor repair function for vitamin D,

which elevates the pain threshold.

Currently, it is not clear whether the improvement in

symptoms is due to a resolution of nerve damage or the

elevated pain threshold. The serum vitamin D levels did

not correlate with diabetic characteristics such as disease

duration, fasting glucose, and glycosylated hemoglobin

A1c, in diabetics. The reason for this is unclear; however,

the majority of the participants in our sample had vitamin

D insufficiency, whereas markedly deficient levels might

lead to different correlations.

To our knowledge, no clinical study has investigated the

serum VDBP and VDR levels in diabetics. VDBP is a

highly polymorphic single-chain serum glycoprotein syn-

thesized and secreted by the liver [34]. VDBP functions as

a specific transporter of circulating vitamin D metabolites,

which include 25-OHD and 1,25-OHD, and is essential for

vitamin D endocytosis and metabolism [35]. VDBP binds

88 % of serum 25-OHD and 85 % of serum 1,25-OHD,

leaving 0.40 % ‘free’ and the remainder associated with

other serum proteins, such as globular actin and fatty acids

[35]. It has been suggested that the different VDBP variants

bind the diverse vitamin D metabolites with varying

affinity, thereby affecting the amount of intracellular vita-

min D in beta cells [35]. In experimental diabetic rats, the

altered serum VDBP concentration is usually paralleled by

changes in the serum vitamin D levels [36]. However, the

lack of associations between VDBP and diabetic patients

and between diabetics with and without peripheral neu-

ropathy in our study suggests that VDBP does not play a

major role in the pathogenesis of diabetes. However,

Table 2 Associations among

25-hydroxyvitamin D, VDBP,

VDR, diabetic characteristics,

and diabetic microvascular

complications in diabetic

patients (n = 69)

NS non significant, VDBP

vitamin D-binding protein, VDR

vitamin D receptor

25-Hydroxyvitamin D VDBP VDR

Disease duration (years) NS NS NS

Fasting glucose (mg/dL) NS NS NS

Glycosylated hemoglobin A1c (%) NS NS NS

Diabetic peripheral neuropathy

Present (n = 24), 23.02 ng/mL (6.82–37.4) p = 0.032 NS NS

Absent (n = 45), 33.01 ng/mL (18.2–44.5)

Diabetic retinopathy (n = 18) p = 0.003 NS NS

Diabetic nephropathy (n = 4) NS NS NS

Acta Neurol Belg

123

activated vitamin D functions by binding to a nuclear

receptor, the VDR [31]. Recent data have demonstrated

that VDR is expressed in many tissues, including those

involved in the regulation of glucose metabolism, such as

muscle and pancreatic beta cells [37, 38]. Given the ability

of the islets to express 1a-hydroxylase, thereby activating

25-OHD, VDR itself can promote insulin secretion directly

[39, 40].

In our study, the serum VDR levels were higher in

diabetic patients, possibly in response to the lower vitamin

D levels. However, the VDR levels were similar in dia-

betics with and without peripheral neuropathy. Although

this finding cannot be explained fully, it has been suggested

that vitamin D, like other steroid hormones, influences a

wide range of metabolic systems by transmitting signals

via both genomic and non-genomic pathways outside the

cell nucleus [41]. The mechanism underlying the low

vitamin D and unchanged VDR proteins in the serum

samples of diabetics with peripheral neuropathy depends

on complex signaling pathways, since the genomic and

non-genomic pathways are closely linked [31, 41].

Despite the gender and racial homogeneity, it is clearly

unrealistic to homogenize all environmental and demo-

graphic factors that significantly affect the serum vitamin D

levels besides season and latitude, for all enrolled subjects

such as ethnic habits of covering the body, cultural food

traditions, and the degree of skin pigmentation; this con-

stitutes the greatest limitation of these studies. Other

drawbacks of our research include the following: (1) this

study was cross-sectional, therefore a causal link between

vitamin D status and diabetes is unclear; (2) regarding

diabetic peripheral neuropathy, more sensitive assessments

of nerve fiber damage, such as quantitative sensory testing,

were not available; and (3) it would be more informative if

the diabetic neuropathic symptoms resolved after admin-

istering vitamin D in our diabetic group.

Conclusions

In a racially homogeneous sample of the Turkey popula-

tion, hypovitaminosis D was greater in patients with type 2

diabetes, especially in those with peripheral neuropathy.

This suggests a possible neurotrophic effect of vitamin D,

which leads one to ask whether vitamin D supplementation

has a role in the management of diabetic peripheral neu-

ropathy. Future large-scale longitudinal studies are needed

to confirm our findings, as well as to evaluate the contri-

butions of VDBP and VDR proteins to the development of

diabetic peripheral neuropathy.

Conflict of interest The authors declare no conflict of interest.

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