Acta Neurol Belg DOI 10.1007/s13760-014-0304-0
ORIGINAL ARTICLE
Decreased serum vitamin D levels are associated with diabetic peripheral neuropathy in a rural area of Turkey Asuman Celikbilek • Ayse Yesim Gocmen • Nermin Tanik • Elif Borekci Mehmet Adam • Mehmet Celikbilek • Murat Suher • Namik Delibas
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Received: 15 December 2013 / Accepted: 25 April 2014 Ó Belgian Neurological Society 2014
Abstract Data examining the association between vitamin 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 neuropathy was confirmed or ruled out according to the electromyography findings and Douleur Neuropathique 4 questions. Serum vitamin D, VDBP and VDR levels were measured using commercial enzyme-linked immunosorbent A. Celikbilek (&) N. Tanik Department of Neurology, Medical School, Bozok University, 66200 Yozgat, Turkey e-mail: [email protected] 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
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 disorders, 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 hypovitaminosis 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 complication, which invariably results in a decreased quality of life [9, 10]. Vitamin D deficiency is more common in diabetics with symptoms of distal symmetrical polyneuropathy [11]. Recently, vitamin D insufficiency was associated with self-reported peripheral neuropathy symptoms
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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]. Consequently, a causal relationship between vitamin D deficiency and an increased risk of diabetic peripheral neuropathy has been proposed in multiple studies of various 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 diabetes 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 histories and performed the physical and neurological examinations. Dependent variables included systolic (SBP) and diastolic (DBP) blood pressure, and body mass index (BMI), which was calculated as weight in kilograms divided 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].
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Routine laboratory analyses were performed in our laboratory using standard methods. The study protocol was approved by the Bozok University 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 stimulated 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 subjects was maintained above 31–32 °C. Abnormal spontaneous 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, amplitude, and distal latency) and a score C4 on the Douleur Neuropathique 4 (DN4) questionnaire, peripheral neuropathy 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 retinopathy was diagnosed according to the presence of cotton wool spots, micro-aneurysms, and boat-shaped hemorrhages on direct ophthalmoscopy. Proliferative retinopathy was diagnosed according to the presence of neovascularization 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-proliferative 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.
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Biochemical analysis
Table 1 Demographic and laboratory data of control and diabetic patients
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 enzymelinked 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 calculated 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.
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
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 microvascular complications (peripheral neuropathy, retinopathy, and nephropathy). Values are expressed as frequencies and percentages, means and standard deviations, or medians and interquartile ranges. Analyses were conducted using SPSS ver. 15.0 (SPSS; Chicago, IL, USA). Statistical significance was set at p \ 0.05.
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)
Results Table 1 summarizes the demographic and laboratory data of the controls and diabetic patients. No significant difference 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
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 thyroid stimulating hormone, LDH lactate dehydrogenase, ALP alkaline phosphatase, VDBP vitamin D-binding protein, VDR vitamin D receptor
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
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Acta Neurol Belg Table 2 Associations among 25-hydroxyvitamin D, VDBP, VDR, diabetic characteristics, and diabetic microvascular complications in diabetic patients (n = 69)
25-Hydroxyvitamin D
VDBP
VDR
Disease duration (years)
NS
NS
NS
Fasting glucose (mg/dL)
NS
NS
NS
Glycosylated hemoglobin A1c (%)
NS
NS
NS
p = 0.032
NS
NS
Diabetic retinopathy (n = 18)
p = 0.003
NS
NS
Diabetic nephropathy (n = 4)
NS
NS
NS
Diabetic peripheral neuropathy Present (n = 24), 23.02 ng/mL (6.82–37.4) Absent (n = 45), 33.01 ng/mL (18.2–44.5) NS non significant, VDBP vitamin D-binding protein, VDR vitamin D receptor
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 indicate 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 recognized 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 sensitivity, 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
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neurotrophins, especially nerve growth factors, and defective calcium homeostasis leave nerves vulnerable to toxins, including hyperglycemia, which might contribute to the development of neurotrophic deficits as neuropathic changes in diabetes [30]. Second, the improvement in musculoskeletal 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 synthesized 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 vitamin 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 neuropathy in our study suggests that VDBP does not play a major role in the pathogenesis of diabetes. However,
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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 diabetics 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 demographic 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 constitutes 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 administering vitamin D in our diabetic group.
Conclusions In a racially homogeneous sample of the Turkey population, 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 neuropathy. Future large-scale longitudinal studies are needed to confirm our findings, as well as to evaluate the contributions 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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ORIGINAL ARTICLE
Decreased serum vitamin D levels are associated with diabetic peripheral neuropathy in a rural area of Turkey Asuman Celikbilek • Ayse Yesim Gocmen • Nermin Tanik • Elif Borekci Mehmet Adam • Mehmet Celikbilek • Murat Suher • Namik Delibas
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Received: 15 December 2013 / Accepted: 25 April 2014 Ó Belgian Neurological Society 2014
Abstract Data examining the association between vitamin 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 neuropathy was confirmed or ruled out according to the electromyography findings and Douleur Neuropathique 4 questions. Serum vitamin D, VDBP and VDR levels were measured using commercial enzyme-linked immunosorbent A. Celikbilek (&) N. Tanik Department of Neurology, Medical School, Bozok University, 66200 Yozgat, Turkey e-mail: [email protected] 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
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 disorders, 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 hypovitaminosis 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 complication, which invariably results in a decreased quality of life [9, 10]. Vitamin D deficiency is more common in diabetics with symptoms of distal symmetrical polyneuropathy [11]. Recently, vitamin D insufficiency was associated with self-reported peripheral neuropathy symptoms
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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]. Consequently, a causal relationship between vitamin D deficiency and an increased risk of diabetic peripheral neuropathy has been proposed in multiple studies of various 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 diabetes 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 histories and performed the physical and neurological examinations. Dependent variables included systolic (SBP) and diastolic (DBP) blood pressure, and body mass index (BMI), which was calculated as weight in kilograms divided 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].
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Routine laboratory analyses were performed in our laboratory using standard methods. The study protocol was approved by the Bozok University 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 stimulated 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 subjects was maintained above 31–32 °C. Abnormal spontaneous 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, amplitude, and distal latency) and a score C4 on the Douleur Neuropathique 4 (DN4) questionnaire, peripheral neuropathy 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 retinopathy was diagnosed according to the presence of cotton wool spots, micro-aneurysms, and boat-shaped hemorrhages on direct ophthalmoscopy. Proliferative retinopathy was diagnosed according to the presence of neovascularization 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-proliferative 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.
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Biochemical analysis
Table 1 Demographic and laboratory data of control and diabetic patients
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 enzymelinked 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 calculated 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.
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
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 microvascular complications (peripheral neuropathy, retinopathy, and nephropathy). Values are expressed as frequencies and percentages, means and standard deviations, or medians and interquartile ranges. Analyses were conducted using SPSS ver. 15.0 (SPSS; Chicago, IL, USA). Statistical significance was set at p \ 0.05.
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)
Results Table 1 summarizes the demographic and laboratory data of the controls and diabetic patients. No significant difference 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
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 thyroid stimulating hormone, LDH lactate dehydrogenase, ALP alkaline phosphatase, VDBP vitamin D-binding protein, VDR vitamin D receptor
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
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Acta Neurol Belg Table 2 Associations among 25-hydroxyvitamin D, VDBP, VDR, diabetic characteristics, and diabetic microvascular complications in diabetic patients (n = 69)
25-Hydroxyvitamin D
VDBP
VDR
Disease duration (years)
NS
NS
NS
Fasting glucose (mg/dL)
NS
NS
NS
Glycosylated hemoglobin A1c (%)
NS
NS
NS
p = 0.032
NS
NS
Diabetic retinopathy (n = 18)
p = 0.003
NS
NS
Diabetic nephropathy (n = 4)
NS
NS
NS
Diabetic peripheral neuropathy Present (n = 24), 23.02 ng/mL (6.82–37.4) Absent (n = 45), 33.01 ng/mL (18.2–44.5) NS non significant, VDBP vitamin D-binding protein, VDR vitamin D receptor
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 indicate 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 recognized 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 sensitivity, 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
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neurotrophins, especially nerve growth factors, and defective calcium homeostasis leave nerves vulnerable to toxins, including hyperglycemia, which might contribute to the development of neurotrophic deficits as neuropathic changes in diabetes [30]. Second, the improvement in musculoskeletal 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 synthesized 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 vitamin 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 neuropathy in our study suggests that VDBP does not play a major role in the pathogenesis of diabetes. However,
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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 diabetics 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 demographic 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 constitutes 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 administering vitamin D in our diabetic group.
Conclusions In a racially homogeneous sample of the Turkey population, 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 neuropathy. Future large-scale longitudinal studies are needed to confirm our findings, as well as to evaluate the contributions 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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