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 assess the association of vitamin D deficiency with peripheral neuropathy severity and determine the effect of vitamin D supplementation on peripheral neuropathy in prediabetics.

Methods

An interventional case-control study was conducted on 178 prediabetic individuals aged 18–60 years 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. 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 approval of the study 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.

Upon assessment of vitamin D status among our patients we found that 27 (15%) patients were insufficient, 151 (85%) were deficient and none were sufficient. Regarding group (A): 18 (20.2%) were insufficient, 71 (79.8%) were deficient and none were sufficient; while group (B): 9 (10.1%) were insufficient, 80 (89.9%) were deficient and none were sufficient (Table 2); with a non-significant difference in 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).

A highly significant negative correlation was found between vitamin D level and the severity of peripheral neuropathy score (r = -0.472) (P ≤ 0.001) (Figure 1a), as shown by the SF-MPQ. We also found a highly significant negative correlation between vitamin D level and the DN4 questionnaire score (pain score) (r = -0.647) (P ≤ 0.001) (Figure 1b).

Figure 1a. Correlation between vitamin D level and severity of peripheral neuropathy assessed by the Short-Form McGill Pain Questionnaire in group (A) before vitamin D injection.

Figure 1b. Correlation between vitamin D level and Douleur Neuropathique 4 score of neuropathic pain in group (A) before vitamin D injection.

Linear regression analysis showing correlations between the SF-MPQ and different parameters in the studied group showed that 25 (OH) vitamin D, Serum HbA1c, 2 hours PP are predictors of neuropathy severity after adjustment of age, sex, BMI and other lab parameters (OR -0.178, 95% CI -0.32– -0.03) (OR 4.846, 95% CI 0.19–9.5) (OR 0.05, 95% CI 0.005–0.104) (P≤0.05).

Neuropathic pain score and its severity

We found a highly significant improvement in neuropathic pain severity as shown by the SF-MPQ (P≤0.001), there was also a significant reduction in the DN4 questionnaire score from (6.39 ±1.64) to (2.5 ±0.9) (≥4 denote neuropathic pain) with an improvement of neuropathic pain of about 82% and a total number of patients having a DN4 score less than 4 was 73 out of 89 prediabetic patients with peripheral neuropathy (P≤0.001) (Figure 2).

Figure 2. Comparison between 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 diabetes¹³. 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 treatment¹⁴. 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, while 85% (151 patients) were deficient and 15% (27 patients) were insufficient.

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 India¹⁵.

A negative correlation was found between serum 25 (OH) vitamin D and serum HbA1c, FBS and two hours post 75 g. Consistently, 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 sensitivity¹⁵ This was confirmed when nearly 50% of patients with prediabetes had serum 25(OH) vitamin D levels below 15 ng/mL¹⁵. 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 level¹⁶. Luo et al., (2009) stated that there was no impact of hypovitaminosis D on metabolic syndrome status and HbA1c¹⁷.

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 release¹⁸.

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 levels¹⁹.

Hypovitaminosis D in our patients was interestingly linked with the severity of peripheral neuropathy score elicited by the SF-MPQ scoring, DN4 questionnaire scoring and clinically by using 10 g monofilament, tuning fork and pinprick in nearly half of the patients, after adjusting for demographic data and other co-morbidities. Confirming these findings, 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 neuropathy²⁰. 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 levels²¹.

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 symptoms²². Studies by Usluogullari et al., (2015) also found no difference in the prevalence of vitamin D deficiency between diabetic peripheral neuropathy patients and controls²³.

Vitamin D level and two-hour post 75 g glucose were the independent predictors for neuropathy severity in our study, whereas Shehab et al., (2012) study confirmed that vitamin D was the only independent risk factor for diabetic peripheral neuropathy²⁰. 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 patients²⁴.

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 not²⁵. 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 deficiency²⁶. 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 pregabalin²⁷. 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 neuropathy²⁸. 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 bias²⁹.

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^30,31. 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 individuals²⁹.

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.

Opposing previous results, a study by Alam et al., (2016) reported no significant decrease in neuropathic pain scores after vitamin D administration³². 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 months¹⁵. 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-diabetics³³. 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 HbA1c³⁴.

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 deficiency can be considered an independent risk factor for peripheral neuropathy in prediabetic individuals. Also, correction of vitamin D deficiency improves glycemic parameters, lipid profile, peripheral neuropathy score and severity.

Data availability

Consent statement

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