Nerve and Vascular Biomarkers in Skin Biopsies Differentiate Painful From Painless Peripheral Neuropathy in Type 2 Diabetes.

Pallai Shillo,Marni Greig,Solomon Tesfaye,Praveen Anand,Iain D Wilkinson,Yiangos Yiangou,Philippe Donatien,Dinesh Selvarajah

doi:10.3389/fpain.2021.731658

Abstract

Painful diabetic peripheral neuropathy can be intractable with a major impact, yet the underlying pain mechanisms remain uncertain. A range of neuronal and vascular biomarkers was investigated in painful diabetic peripheral neuropathy (painful-DPN) and painless-DPN and used to differentiate painful-DPN from painless-DPN. Skin biopsies were collected from 61 patients with type 2 diabetes (T2D), and 19 healthy volunteers (HV). All subjects underwent detailed clinical and neurophysiological assessments. Based on the neuropathy composite score of the lower limbs [NIS(LL)] plus seven tests, the T2D subjects were subsequently divided into three groups: painful-DPN (n = 23), painless-DPN (n = 19), and No-DPN (n = 19). All subjects underwent punch skin biopsy, and immunohistochemistry used to quantify total intraepidermal nerve fibers (IENF) with protein gene product 9.5 (PGP9.5), regenerating nerve fibers with growth-associated protein 43 (GAP43), peptidergic nerve fibers with calcitonin gene-related peptide (CGRP), and blood vessels with von Willebrand Factor (vWF). The results showed that IENF density was severely decreased (p < 0.001) in both DPN groups, with no differences for PGP9.5, GAP43, CGRP, or GAP43/PGP9.5 ratios. There was a significant increase in blood vessel (vWF) density in painless-DPN and No-DPN groups compared to the HV group, but this was markedly greater in the painful-DPN group, and significantly higher than in the painless-DPN group (p < 0.0001). The ratio of sub-epidermal nerve fiber (SENF) density of CGRP:vWF showed a significant decrease in painful-DPN vs. painless-DPN (p = 0.014). In patients with T2D with advanced DPN, increased dermal vasculature and its ratio to nociceptors may differentiate painful-DPN from painless-DPN. We hypothesized that hypoxia-induced increase of blood vessels, which secrete algogenic substances including nerve growth factor (NGF), may expose their associated nociceptor fibers to a relative excess of algogens, thus leading to painful-DPN.

Highlights

Painful diabetic peripheral neuropathy affects up to a quarter of all patients with diabetes [1] and can lead to a significant curtailment of quality of life [2]
We reported significant nerve fiber loss in distal leg skin biopsies from patients with diabetic peripheral neuropathy (DPN) using PGP9.5, calcitonin gene-related peptide (CGRP), and growth-associated protein 43 (GAP43) nerve fiber immunostaining
This was apparent for intraepidermal nerve fibers (IENF) and sub-epidermal nerve fiber (SENF) density in both painful-DPN and painless-DPN groups, compared with the healthy volunteers (HV) group, and patients without the No-DPN group

Summary

Introduction

Painful diabetic peripheral neuropathy affects up to a quarter of all patients with diabetes [1] and can lead to a significant curtailment of quality of life [2]. Patients present with a range of sensory symptoms, including burning, aching and “electric shock-like” pains in their feet and legs [3]. Night-time exacerbations of pain and contact hypersensitivity to bedclothes result in loss of sleep, and painful diabetic peripheral neuropathy (painful-DPN) can be disabling [4]. The pathophysiology of painful-DPN is complex, and there are no generally accepted disease-modifying treatments for the condition [4]. There is a need to understand the underlying mechanisms of pain in DPN to help advance its treatment

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Results

Conclusion