Patterns of cutaneous nerve fibre loss and regeneration in type 2 diabetes with painful and painless polyneuropathy
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.
KeywordsNerve regeneration Neuropathic pain Neuropathy Skin biopsy Type 2 diabetes
Dermal nerve fibre length
Diabetic sensorimotor polyneuropathy
Painful diabetic sensorimotor polyneuropathy
Painless diabetic sensorimotor polyneuropathy
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
The authors wish to thank the staff of the Research Group Neuropathy, Institute for Clinical Diabetology at the German Diabetes Center (DDZ), Düsseldorf, Germany, especially F. Battiato, N. Reuß and M. Schroers-Teuber, for their excellent work. The GDS Group consists of A.E. Buyken (Department of Sports and Health, Paderborn University, Paderborn, Germany), G. Geerling (Department of Ophthalmology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany), J. Eckel, H. Al-Hasani, C. Herder, A. Icks, J. Kotzka, O. Kuss, E. Lammert, D. Markgraf, K. Müssig, W. Rathmann, J. Szendroedi, D. Ziegler and M. Roden (speaker) (all DDZ). Some of the data were presented as an abstract at the 52nd EASD Annual Meeting in Munich in 2016.
The data sets generated during and/or analysed during the current study are not publicly available, since they are subject to national data protection laws and restrictions imposed by the ethics committee to ensure data privacy of the study participants. However, they can be applied for through an individual project agreement with PROPANE and/or GDS.
The GDS was initiated and financed by the German Diabetes Center, which is funded by the German Federal Ministry of Health (Berlin, Germany), the Ministry of Innovation, Science, Research and Technology of the state North Rhine-Westphalia (Düsseldorf, Germany), grants from the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD), and partly funded through an EFSD award supported by Novartis to DZ and AS. The PROPANE study was initiated by the PROPANE consortium and received funding from the European Union Seventh Framework Programme FP7/2007-2013 (grant no. 602273).
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
All authors were involved in revising the manuscript critically for important intellectual content and gave final approval of the version to be published. GJB contributed to acquisition, analysis and interpretation of data and wrote the manuscript. AS and SP contributed to the acquisition, analysis and interpretation of data, BR and JB contributed to the acquisition of data. KB, KM, JS and MR contributed to the analysis and interpretation of data. DZ contributed to conception and design of the study and to the analysis and interpretation of data. DZ is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
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