, 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



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.


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.


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.


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.


Nerve regeneration Neuropathic pain Neuropathy Skin biopsy Type 2 diabetes 



Dermal nerve fibre length


Diabetic sensorimotor polyneuropathy


Painful diabetic sensorimotor polyneuropathy


Painless diabetic sensorimotor polyneuropathy


Growth-associated protein-43


German Diabetes Study


Intraepidermal nerve fibre density


Intraepidermal nerve fibre length


Nerve conduction velocity


Neuropathy Disability Score


Numerical Rating Scale


Neuropathy Symptom Score


Protein gene product 9.5


Probing the Role of Sodium Channels in Painful Neuropathies


Small fibre neuropathy


Sensory nerve action potential


Thermal detection threshold


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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