Diabetologia

, Volume 60, Issue 12, pp 2495–2503 | Cite as

Patterns of cutaneous nerve fibre loss and regeneration in type 2 diabetes with painful and painless polyneuropathy

  • Gidon J. Bönhof
  • Alexander Strom
  • Sonja Püttgen
  • Bernd Ringel
  • Jutta Brüggemann
  • Kálmán Bódis
  • Karsten Müssig
  • Julia Szendroedi
  • Michael Roden
  • Dan Ziegler
Article

Abstract

Aims/hypothesis

The determinants and mechanisms of the development of diabetic sensorimotor polyneuropathy as a painful (DSPN+p) or painless (DSPN-p) entity remain unclear. We examined the degree of cutaneous nerve fibre loss and regeneration in individuals with type 2 diabetes with DSPN+p or DSPN-p compared with individuals with recent-onset type 2 diabetes and corresponding healthy volunteers.

Methods

In this cross-sectional study, skin biopsies taken from the distal lateral calf were obtained from individuals with recent-onset type 2 diabetes (n = 32) from the German Diabetes Study, with DSPN+p (n = 34) and DSPN-p (n = 32) from the PROPANE study, and volunteers with normal glucose tolerance (n = 50). Double immunofluorescence staining for protein gene product 9.5 (PGP9.5) (pan-neuronal marker) and growth-associated protein 43 (GAP-43) (nerve regeneration marker) was applied to assess intraepidermal nerve fibre density (IENFD) and length (IENFL) and dermal nerve fibre length (DNFL). DSPN was diagnosed using the modified Toronto Consensus (2011) criteria, while neuropathic pain was assessed using an 11-point Numerical Rating Scale.

Results

After adjustment for age, sex, BMI and HbA1c, IENFD and IENFL were reduced for both markers in individuals with recent-onset diabetes and both DSPN groups compared with control participants (all p < 0.05), but did not differ between the DSPN groups. The DNFL GAP-43/PGP9.5 ratio was higher in the DSPN+p and DSPN-p groups compared with control participants (1.18 ± 0.28 and 1.07 ± 0.10 vs 1.02 ± 0.10; p ≤ 0.05) and in the DSPN + p group compared with DSPN-p (p < 0.05). Correlation analyses showed distinct inverse associations between the DNFL GAP-43/PGP9.5 ratio and PGP9.5 positive IENFD as well as DNFL (IENFD: β = −0.569, DNFL: β = −0.639; both p < 0.0001) in individuals with type 2 diabetes, but not in the control group. A similar pattern was found for correlations between the DNFL GAP-43/PGP9.5 ratio and peripheral nerve function tests.

Conclusions/interpretation

Dermal nerve fibre regeneration is enhanced in DSPN, particularly in DSPN+p, and increases with advancing intraepidermal nerve fibre loss. These data suggest that, despite progressive epidermal fibre loss, dermal nerve repair is preserved, particularly in DSPN+p, but fails to adequately counteract epidermal neurodegenerative processes.

Keywords

Nerve regeneration Neuropathic pain Neuropathy Skin biopsy Type 2 diabetes 

Abbreviations

DNFL

Dermal nerve fibre length

DSPN

Diabetic sensorimotor polyneuropathy

DSPN+p

Painful diabetic sensorimotor polyneuropathy

DSPN-p

Painless diabetic sensorimotor polyneuropathy

GAP-43

Growth-associated protein-43

GDS

German Diabetes Study

IENFD

Intraepidermal nerve fibre density

IENFL

Intraepidermal nerve fibre length

NCV

Nerve conduction velocity

NDS

Neuropathy Disability Score

NRS

Numerical Rating Scale

NSS

Neuropathy Symptom Score

PGP9.5

Protein gene product 9.5

PROPANE

Probing the Role of Sodium Channels in Painful Neuropathies

SFN

Small fibre neuropathy

SNAP

Sensory nerve action potential

TDT

Thermal detection threshold

VPT

Vibration perception threshold

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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Gidon J. Bönhof
    • 1
  • Alexander Strom
    • 1
    • 2
  • Sonja Püttgen
    • 1
  • Bernd Ringel
    • 1
  • Jutta Brüggemann
    • 1
  • Kálmán Bódis
    • 1
  • Karsten Müssig
    • 1
    • 2
    • 3
  • Julia Szendroedi
    • 1
    • 2
    • 3
  • Michael Roden
    • 1
    • 2
    • 3
  • Dan Ziegler
    • 1
    • 2
    • 3
  1. 1.Institute for Clinical Diabetology, German Diabetes Center (DDZ)Leibniz Center for Diabetes Research at Heinrich Heine UniversityDüsseldorfGermany
  2. 2.German Center for Diabetes Research (DZD)MunichGermany
  3. 3.Division of Endocrinology and Diabetology, Medical FacultyHeinrich Heine UniversityDüsseldorfGermany

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