Nerve and Vascular Biomarkers in Skin Biopsies Differentiate Painful From Painless Peripheral Neuropathy in Type 2 Diabetes
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-...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2021-10-01
|
| Series: | Frontiers in Pain Research |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fpain.2021.731658/full |
| _version_ | 1819289641006661632 |
|---|---|
| author | Pallai Shillo Yiangos Yiangou Philippe Donatien Marni Greig Dinesh Selvarajah Iain D. Wilkinson Praveen Anand Solomon Tesfaye |
| author_facet | Pallai Shillo Yiangos Yiangou Philippe Donatien Marni Greig Dinesh Selvarajah Iain D. Wilkinson Praveen Anand Solomon Tesfaye |
| author_sort | Pallai Shillo |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-24T03:10:04Z |
| format | Article |
| id | doaj.art-9cd47bec165d41d88d07d8724f042f33 |
| institution | Directory Open Access Journal |
| issn | 2673-561X |
| language | English |
| last_indexed | 2024-12-24T03:10:04Z |
| publishDate | 2021-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pain Research |
| spelling | doaj.art-9cd47bec165d41d88d07d8724f042f332022-12-21T17:17:50ZengFrontiers Media S.A.Frontiers in Pain Research2673-561X2021-10-01210.3389/fpain.2021.731658731658Nerve and Vascular Biomarkers in Skin Biopsies Differentiate Painful From Painless Peripheral Neuropathy in Type 2 DiabetesPallai Shillo0Yiangos Yiangou1Philippe Donatien2Marni Greig3Dinesh Selvarajah4Iain D. Wilkinson5Praveen Anand6Solomon Tesfaye7Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United KingdomPeripheral Neuropathy Unit, Hammersmith Hospital, Imperial College London, London, United KingdomPeripheral Neuropathy Unit, Hammersmith Hospital, Imperial College London, London, United KingdomDiabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United KingdomDiabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United KingdomAcademic Unit of Radiology, University of Sheffield, Sheffield, United KingdomPeripheral Neuropathy Unit, Hammersmith Hospital, Imperial College London, London, United KingdomDiabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United KingdomPainful 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.https://www.frontiersin.org/articles/10.3389/fpain.2021.731658/fullpainbiomarkersskinvascularpainful diabetic neuropathyvon Willebrand Factor |
| spellingShingle | Pallai Shillo Yiangos Yiangou Philippe Donatien Marni Greig Dinesh Selvarajah Iain D. Wilkinson Praveen Anand Solomon Tesfaye Nerve and Vascular Biomarkers in Skin Biopsies Differentiate Painful From Painless Peripheral Neuropathy in Type 2 Diabetes Frontiers in Pain Research pain biomarkers skin vascular painful diabetic neuropathy von Willebrand Factor |
| title | Nerve and Vascular Biomarkers in Skin Biopsies Differentiate Painful From Painless Peripheral Neuropathy in Type 2 Diabetes |
| title_full | Nerve and Vascular Biomarkers in Skin Biopsies Differentiate Painful From Painless Peripheral Neuropathy in Type 2 Diabetes |
| title_fullStr | Nerve and Vascular Biomarkers in Skin Biopsies Differentiate Painful From Painless Peripheral Neuropathy in Type 2 Diabetes |
| title_full_unstemmed | Nerve and Vascular Biomarkers in Skin Biopsies Differentiate Painful From Painless Peripheral Neuropathy in Type 2 Diabetes |
| title_short | Nerve and Vascular Biomarkers in Skin Biopsies Differentiate Painful From Painless Peripheral Neuropathy in Type 2 Diabetes |
| title_sort | nerve and vascular biomarkers in skin biopsies differentiate painful from painless peripheral neuropathy in type 2 diabetes |
| topic | pain biomarkers skin vascular painful diabetic neuropathy von Willebrand Factor |
| url | https://www.frontiersin.org/articles/10.3389/fpain.2021.731658/full |
| work_keys_str_mv | AT pallaishillo nerveandvascularbiomarkersinskinbiopsiesdifferentiatepainfulfrompainlessperipheralneuropathyintype2diabetes AT yiangosyiangou nerveandvascularbiomarkersinskinbiopsiesdifferentiatepainfulfrompainlessperipheralneuropathyintype2diabetes AT philippedonatien nerveandvascularbiomarkersinskinbiopsiesdifferentiatepainfulfrompainlessperipheralneuropathyintype2diabetes AT marnigreig nerveandvascularbiomarkersinskinbiopsiesdifferentiatepainfulfrompainlessperipheralneuropathyintype2diabetes AT dineshselvarajah nerveandvascularbiomarkersinskinbiopsiesdifferentiatepainfulfrompainlessperipheralneuropathyintype2diabetes AT iaindwilkinson nerveandvascularbiomarkersinskinbiopsiesdifferentiatepainfulfrompainlessperipheralneuropathyintype2diabetes AT praveenanand nerveandvascularbiomarkersinskinbiopsiesdifferentiatepainfulfrompainlessperipheralneuropathyintype2diabetes AT solomontesfaye nerveandvascularbiomarkersinskinbiopsiesdifferentiatepainfulfrompainlessperipheralneuropathyintype2diabetes |