Low Vitamin D Levels in Painful Diabetic Peripheral Neuropathy

Becky McCall

September 06, 2018

Lower vitamin D (25-hydroxyvitamin D) levels are found in patients with painful diabetic peripheral neuropathy (DPN) compared to those with painless DPN, patients with diabetes without any neuropathy, and healthy people, shows a study unique for its rigorous control for seasonal sunlight and physical activity.

"This is the first time a study has corrected for these confounders [sunlight and physical activity]. The findings have major clinical significance because painful DPN is distressing and disabling," said lead author Solomon Tesfaye, MD, consultant endocrinologist at the Royal Hallamshire Hospital, Sheffield, UK, who discussed the findings with Medscape Medical News in an interview.

Not only have previous studies failed to robustly control for seasonal sunlight exposure and physical activity, which have a significant impact on vitamin D levels, most have not differentiated between people with painful and painless DPN. In addition, these prior studies have lacked detailed assessment of peripheral neuropathy including measurement of skin intra-epidermal nerve density.

"The finding is a big deal because it opens up a whole new area of research," asserted Tesfaye. "It's a very common disorder with 25% of patients with diabetes having neuropathic pain, many of whom are undiagnosed and suffering in silence because they believe it is just part of the aging process," he explained.

He added that the small proof-of-principle study was a borne out of anecdotal findings that vitamin D supplements or injections given to patients with painful DPN improved their pain.

The article was published online August 13 in Diabetic Medicine.

Differentiating Between Painful and Painless DPN

In total, 45 white Europeans with type 2 diabetes and 14 healthy volunteers participated in the study. Those with type 2 diabetes were then divided into three further groups (17 with painful DPN, 14 with painless DPN, and 14 with no DPN).

Seasonal sunlight exposure and daily activity were measured, a lower limb skin biopsy was performed, and 25-hydroxyvitamin D was measured from July to September (summer season) in all patients. The relationship of vitamin D with measures of small and large nerve fiber function was also assessed using quantitative sensory testing, skin biopsy, and nerve conduction studies.

Essentially, after adjusting for age, body mass index, activity score, and sunlight exposure, vitamin D levels were significantly lower in those with painful DPN (34.9 nmol/L) than healthy volunteers (62.1 nmol/L), those with no DPN (49.6 nmol/L), and those with painless DPN (53.1 nmol/L). Vitamin D was the only independent variable found to be significant with an inverted odds ratio of 1.11, write the researchers.

Explaining the results with regard to the measurement of peripheral neuropathy, Tesfaye said they found that lower vitamin D levels correlated with a lower (more abnormal) cold detection threshold (r = 0.39, P = .02) using quantitative sensory testing (QST). On skin biopsy, considered the gold standard for diagnosing and assessing small fiber neuropathy, lower subepidermal nerve fiber densities also correlated with lower levels of vitamin D (= 0.42, = .01).

"Patients with painful DPN were found to have less sensitivy, i.e., only detected cold at 11°C and had low numbers of small nerve fibers," reported the endocrinologist, who is an expert in the field of DPN.

The findings suggest that vitamin D deficiency may contribute to the development of painful DPN by playing a role in the pathogenesis of small-fiber neuropathy particularly affecting nociceptors, he and his coauthors explain.

He highlighted that not only is painful DPN underdiagnosed, but even when it is identified there is a paucity of effective medication available.

Current therapies, typically amitriptyline or gabapentin among others, work in just one third of patients and only improve pain by approximately 50%.

Side effects can be considerable and common. "These drugs kill the pain but 'kill' the patient too. If we have something that is physiologically active and improves pain without the side effects then the finding here is a major triumph." 

However, he cautions that this is a small, early study and much more research is needed to prove causality between low vitamin D levels and painful DPN. "A randomized, double-blind, prospective clinical trial is needed, and I'm going to apply to do it."

"If causality is confirmed, this will have a significant impact on clinical practice as there would be a clear rationale for early screening and treatment for low vitamin D in people with painful DPN."

Diabet Med. Published online August 13, 2018. Abstract

Tesfaye has reported no relevant financial relationships.

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