The impact of vitamin D supplementation on peripheral neuropathy in a sample of Egyptian prediabetic individuals

Introduction

Diabetes mellitus (DM), a significant world health problem, is a metabolic disease, which occurs due to a defect in insulin release and or insulin resistance¹. Globally, the prevalence of type 2 diabetes (T2DM) is high and rising across all regions².

There is a higher frequency of idiopathic polyneuropathy, small fiber neuropathy and painful sensory neuropathy among prediabetics. These findings suggest an involvement of the small unmyelinated nerve fibers that carry pain, temperature, and regulate autonomic function during prediabetes, before the development of diabetes³.

Vitamin D, which is a fat-soluble hormone, has multiple physiological roles, which extends far beyond calcium metabolism⁴. Vitamin D deficiency is a worldwide health problem, patients with prediabetes, T2DM, gestational diabetes and obesity represent a high-risk group⁵.

Recently, a lot of studies have been done to assess the association between vitamin D level and the diabetic peripheral neuropathy in patients with diabetes mellitus and to study the effect of vitamin D on painful neuropathy, but there is a lack of data concerning prediabetic individuals¹.

The aim of this work was to determine the association of vitamin D deficiency with peripheral neuropathy severity and evaluate the effect of vitamin D supplementation on peripheral neuropathy in prediabetics with hypovitaminosis D.

Methods

An analytic case-control followed by an interventional one arm clinical trial design (quasi experiment) were performed to fulfill the preset objectives. The case-control study included 89 prediabetic patients with peripheral neuropathy (Group A) and 89 prediabetics without peripheral neuropathy (Group B).

Study Participants and Case Definition: Prediabetic individuals were diagnosed, according to the American Diabetes Association 2019, with impaired fasting (100–125 mg/dl) and/or impaired glucose tolerance (140–199 mg/dl), and/or glycated haemoglobin (5.7–6.4%)⁶ (they were all ages between 18–60 years old). Participants were recruited from the National Institute of Diabetes and Endocrinology (NIDE), Cairo, Egypt, in the period from September 2018 to March 2019 after proven informed written consent.

Ethical Considerations: A written informed consent was obtained from all patients. All data were made confidential and an ethical approval on study conduction was obtained from the Local Research Ethical Committee (REC) of the Faculty of Medicine, Ain Shams University. FWA 000017858.

All participants were subjected to full medical history including smoking habits, alcohol consumption, drug history, thorough clinical examination including blood pressure, weight, height and BMI.

Results

Comparison between the two studied groups regarding clinical and laboratory characteristics is shown in Table 1. 20.2% of patients in group A (With PN) reported vitamin D insufficiency (N=18), while deficiency was evident in 79.8% (N=71) and none reported normal level of vitamin D. While group B (Without PN): 9 (10.1%) were insufficient, 80 (89.9%) were deficient and none were sufficient (Table 2); with a non-significant difference in the mean level of vitamin D level between the two groups (13.957 ± 6.3603 ng/ml (group A) vs 14.594 ± 3.9318 ng/mL (group B) (P>0.05) (Table 1).

Vitamin D level showed a negative but statistically insignificant correlation with the severity of peripheral neuropathy (assessed by SF-MPQ) (r= 0.032, p= 0.766) and pain score (assessed by DN4 questionnaire) (r= 0.052, p= 0.629)

Neuropathic pain score and its severity

A statistically significant improvement in neuropathic pain severity was observed by the SF-MPQ (28.3±7.2 before and 17±6.3 after vitamin D supplementation, P≤0.001). There was also a statistically significant reduction in the DN4 questionnaire score from 6.39 ±1.64 to 2.5 ± 0.9, ≤0.001 (≥4 denote neuropathic pain) with an improvement of neuropathic pain in 82% of patients (73 out of 89) (P≤0.001) (Figure 1).

Figure 1. Neuropathic pain score assessed by Douleur Neuropathic 4 score and severity of peripheral neuropathy assessed by the Short-Form McGill Pain Questionnaire score of group A (prediabetic patients with peripheral neuropathy) before and after vitamin D supplementation.

Discussion

Diabetic peripheral neuropathy in recently diagnosed diabetic patients may reach about 8% and more than 50% in patients with long-standing diabetes¹¹. Recently, the American Diabetes Association stated that there is no strong evidence that supports the lifestyle management or efficacy of glycemic control in the treatment of neuropathic pain, which means that pharmaceutical interventions such as pregabalin, duloxetine, or tapentadol are the only way of treatment¹². Accordingly, we aimed to demonstrate the association of vitamin D status with peripheral neuropathy and determine the effect of vitamin D supplementation on painful neuropathy in prediabetics.

Even with our sunny country, none of our patients (0%) had sufficient vitamin D level.

Kuchay et al., 2015 in their study found that prediabetes patients were 54.3% vitamin D deficient, 21.3% were insufficient and only 24.4% were sufficient despite abundant sunshine in India¹³.

Kuchay et al., (2015) demonstrated an association between vitamin D status and prevalence of diabetes, with low prevalence in people with high vitamin D status and a belief that a serum 25(OH) vitamin D level of 15 ng/mL or less may be a threshold at which vitamin D deficiency confers negative effect on insulin sensitivity¹³. This was confirmed when nearly 50% of patients with prediabetes had serum 25(OH) vitamin D levels below 15 ng/mL¹³. On the contrary, Rolim et al., (2016) found the association between HbA1c and 25(OH) vitamin D controversial and glycemic control was not associated with vitamin D level¹⁴. Luo et al., (2009) stated that there was no impact of hypovitaminosis D on metabolic syndrome status and HbA1c¹⁵.

The association between vitamin D status and prevalence of diabetes can be explained through the effect of vitamin D on pancreatic β‐cell function and plasma calcium. Vitamin D deficiency decreases serum calcium, which regulates insulin synthesis and release¹⁶.

On the other hand, administration of vitamin D causes increase in serum calcium, decrease in circulating free fatty acid levels, increase in insulin release and improvement in glucose levels¹⁷.

Shehab et al., (2012) study on 210 diabetic patients, from which 87 had peripheral neuropathy, first found that vitamin D deficiency was significantly associated with diabetic peripheral neuropathy¹⁸. In agreement with Shillo et al., (2019) who reported that serum vitamin D levels were lower in patients with painful DPN than in those with painless DPN, and pain scores were negatively correlated with serum vitamin D levels¹⁹.

On the contrary, Basit et al., (2016) acknowledged that there was no significant correlation between 25 (OH) vitamin D status with either total McGill pain location, McGill pain score, DN4 or positive symptoms²⁰ and this was inconsistent with the present study. Studies by Usluogullari et al., (2015) also found no difference in the prevalence of vitamin D deficiency between diabetic peripheral neuropathy patients and controls²¹.

However, Shehab et al., (2012) study confirmed that vitamin D was the only independent risk factor for diabetic peripheral neuropathy¹⁸. While in China, He et al., (2017) declared that deficiency of vitamin D is an independent risk factor for diabetic peripheral neuropathy and can be considered a potential biomarker for peripheral neuropathy in diabetic Chinese patients²².

On the other hand, Alkhatatbeh et al., (2019) showed that the only significant predictor for neuropathic pain was female gender, while vitamin D level, BMI, age, FBG, duration of T2DM, DBP and SBP were not²³. The divergence in the results of previous studies may be due to the use of different methods to assess neuropathy and because the studies were directed on different populations.

Injection of vitamin D 200.000 IU intramuscular every month for three successive months is in accordance with the guidelines for vitamin D supplementation and treatment of deficiency in Central Europe individuals with proved vitamin D deficiency which require higher doses of vitamin D than doses recommended for the general population. The therapeutic dose in severe deficiency should be 1.000–10.000 IU/day (~50.000 IU/week), depending on the patient’s body weight and age. The duration of the treatment varies from 1–3 months, depending on the degree of vitamin D deficiency²⁴. Our patients showed significant improvement and reduction in neuropathy severity score and also showed clinical improvement by monofilament and tuning fork. This is in line with Bell (2012) who found great improvement in neuropathic symptoms after supplementation with 50.000 IU of vitamin D₂ every week in a case report of a patient suffering from diabetic peripheral neuropathy. The patient had been refractory to different types of treatment like tricyclic's, gabapentin, oxycodone and pregabalin²⁵. As well, Shehab et al., (2015) in their study applied vitamin D replacement therapy as a single intramuscular vitamin D dose of 300.000 IU and this application significantly enhanced the DN4 questionnaire scores of the patients with diabetic neuropathy²⁶. Correspondingly, Lee and Chen (2008) showed that oral cholecalciferol resulted in an approximate 50% reduction in painful neuropathic symptoms and a significant reduction in SF-MPQ score from 32.1 to 19.4; however, this study had neither a placebo group nor was randomized, leaving it open to considerable bias²⁷.

Possible explanation of previous studies was demonstrated in vitro by Fukuoka et al., (2001) and in vivo by Riaz et al., (1999) who considered vitamin D as a neurotrophic substance, which modulates neuronal growth and differentiation, and neuromuscular functions^28,29. Its exact role in diabetic neuropathic pain is uncertain; insufficiency of vitamin D may increase damage of diabetic nerve and may affect the function of nociceptors leading to pain at a higher threshold of serum 25 (OH) vitamin D concentration higher than that in the non-diabetic individuals²⁷.

Therefore, the results of previous studies corroborate our findings that vitamin D supplementation improves peripheral neuropathy and can be used as a safe treatment for peripheral neuropathy in prediabetic patients with hypovitaminosis D.

Opposing previous results, a study by Alam et al., (2016) reported no significant decrease in neuropathic pain scores after vitamin D administration³⁰. This study was based on all or none values instead of assessing the quantity of pain score, which may have led to a failure of observing a reduction in pain scoring.

Glycemic parameters of our patients showed significant improvement after the administration of 200.000 IU of vitamin D every four weeks for 12 weeks, which was the same result found by Kuchay et al., (2015) who revealed that correcting vitamin D deficiency in people with prediabetes significantly reduces FBG, two hours plasma glucose and A1C levels in 12 months¹³. However, contrary to our findings, He et al., (2018) proclaimed in their meta-analysis that vitamin D supplementation did not improve fasting glucose levels or insulin resistance, nor did it prevent T2DM in non-diabetics³¹. Furthermore, Moreira-Lucas et al., (2017) confirmed that vitamin D supplementation did not improve fasting or post challenge measures of insulin sensitivity, β-cell function or HbA1c³².

Among the limitations of the study were a small sample size compared to previous studies. Our study is the first to discuss the effect of vitamin D supplementation on peripheral neuropathy in prediabetic individuals whereas other studies have discussed the effect on diabetic patients. Finding prediabetic participants with peripheral neuropathy to include in the study was challenging.

Conclusion

This study found that vitamin D supplementation in prediabetics with peripheral neuropathy and hypovitaminosis D improves neuropathy in those patients as assessed by McGill and DN4 scores, as well as glycemic parameter namely HbA1c, FBG and 2h-PPG.

Data availability

Consent statement

Written informed consent was obtained from all individual participants included in our study.