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Vitamin D and Diabetic Peripheral Neuropathy: The Research Continues

May 19, 2020
Vitamin D replacement therapy, in addition to glucose-lowering diabetes treatment, could address deficiencies experienced by those with neuropathic pain symptoms and balance impairment.

Diabetic peripheral neuropathy (DPN) is a common complication of type 2 diabetes, affecting up to 50% of patients and often resulting in foot and hand muscle weakness, balance disturbance, and neuropathic pain. The pain is often severe and leads to depression, anxiety, sleep disorders, and reduced quality of life. Diabetic neuropathy involves both small and large nerve fibers. The small fibers include C-fibers associated with electric shock or burning symptoms, while large fiber impairments affect balance.

According to a recent position statement from the American Diabetes Association, there is no compelling evidence that supports the efficacy of glycemic control or lifestyle management in the treatment of neuropathic pain, which leaves only pharmaceutical interventions, such as pregabalin, duloxetine, or tapentadol.1

Vitamin D deficiency is now known to be prevalent in patients with type 2 diabetes, particularly those with symptoms of DPN, and studies have shown that low serum vitamin D levels are an independent predictor of DPN development.2,3 Would supplementation of vitamin D, therefore, improve pain in these patients?


Image: iStock (nadisja)Study scores after vitamin D treatment indicated an improvement in small fibers, while the Berg balance scale improvements suggested an improvement in the large nerve fibers.

Vitamin D Deficiency Affects Neuropathic Pain and Balance

In a randomized, placebo-controlled study of patients with DPN and low vitamin D levels, Sari and colleagues examined the effects of vitamin D replacement therapy on neuropathic pain and balance.4 They based their study on research that showed vitamin D-associated improvements in axon regeneration and myelination following nerve injury,5 as well as increases in nerve growth factor synthesis and prevention of neuronal degeneration.6

Other studies have looked at the reduction of neuropathic pain following vitamin D supplementation, but this was the first investigation of the effect of vitamin D on balance disturbances in patients with DPN, possibly through a beneficial effect on the central nervous system and muscle tissue.7

In their study, Sari and colleagues administered a one-time injection of 300,000 IU vitamin D in a liquid formulation to patients with low levels of circulating 25-hydroxyvitamin D (25(OH)-D) (<30 ng/mL) who had polyneuropathy that was confirmed with electromyography.  Neuropathic pain was assessed at baseline and after 12 weeks using the Douleur Neuropathique in 4 questions (DN4), a patient questionnaire, and balance was assessed using the Berg Balance Scale, a functional balance test.

Results showed that after 12 weeks, patients’ questionnaire scores reflected a significant decrease in neuropathic pain compared to baseline, and balance test scores were significantly improved. Patients also showed a significant decrease in scores measuring electric shock and burning sensations from baseline to the end of the study. These scores indicated an improvement in small fibers, while the Berg balance scale improvements suggested an improvement in the large nerve fibers, according to the investigators. The results confirmed the findings of previous research showing that decreased levels of circulating 25(OH)-D may contribute to increased risk of large fiber neuropathy, as shown in nerve conduction velocity studies, in patients with type 2 diabetes.8


Numerous Factors are Involved

Sari and colleagues attributed the improvement in balance scores primarily to axonal regeneration. In a follow-up letter to the editor, Celikbilek noted that although the neurotrophic effects of vitamin D on nerve function could be the primary reason for improvements in patients with DPN who receive supplementation, other cellular factors may also play a role by regulating the amount of activated vitamin D delivered to the muscle and pancreatic beta cells.9 He notes that vitamin D may might also elevate the pain threshold through a nociceptor repair function.

As research continues, studies show that vitamin D seems to influence a broad range of metabolic systems by complex signaling pathways. In a recent meta-analysis, Yammine and colleagues examined four studies including 364 patients with type 2 diabetes and DPN to assess whether vitamin D supplementation would improve pain.2 Results of the individual studies showed increases in serum vitamin D levels along with improvements in McGill Pain Questionnaire scores, although there was a lack of correlation between pain scores and changes in vitamin D serum levels.  

In an interview with PPM, Dr. Yammine, who is head of the Diabetic Foot Clinic and Diabetic Foot Research Center at the Lebanese American University Medical Center-Rizk Hospital in Beirut, Lebanon,  said, “Our results suggest that attaining an absolute serum level of vitamin D could be the necessary step to perceptibly reduce pain, rather than a significant level increase following supplementation.”

Biochemical changes in calcium signaling, neurotrophic factors, and production of active metabolites might explain the lack of correlation between pain scores and vitamin D serum level changes. “It could be that pain improvement would be correlated to a threshold of vitamin D value rather than the change from baseline,” he added. Thus, it seems likely that attaining such a threshold may require a personalized medicine approach.


Agreement on the Benefits of Vitamin D Replacement Therapy

While the research on DPN and vitamin D continues, investigators do agree that vitamin D replacement therapy in addition to glucose-lowering diabetes treatment could address any deficiencies that may be causing neuropathic pain symptoms and balance impairment associated with DPN.

Dr. Yammine concluded that vitamin D supplementation could further add value to the treatment of painful peripheral diabetic neuropathy. Although there is a general level of caution about supplementation among investigators and clinicians, Dr. Yammine believes it is due to a lack of knowledge, rather than resistance. “I have never seen a case of vitamin D toxicity. When searching in the literature, toxicity is extremely rare,” he added.

Last updated on: June 17, 2020
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