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Deficits in systemic biomarkers of neuroinflammation and growth factors promoting nerve regeneration in patients with type 2 diabetes and polyneuropathy
  1. Dan Ziegler1,2,3,
  2. Alexander Strom1,2,
  3. Gidon J Bönhof1,3,
  4. Julia M Kannenberg1,2,
  5. Margit Heier4,
  6. Wolfgang Rathmann2,5,
  7. Annette Peters2,4,
  8. Christina Meisinger6,7,
  9. Michael Roden1,2,3,
  10. Barbara Thorand2,4,
  11. Christian Herder1,2,3
  1. 1Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
  2. 2German Center for Diabetes Research (DZD), München-Neuherberg, Germany
  3. 3Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
  4. 4Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
  5. 5Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
  6. 6Independent Research Group Clinical Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
  7. 7Chair of Epidemiology, Ludwig-Maximilians-Universität München am UNIKA-T Augsburg, Augsburg, Germany
  1. Correspondence to Professor Dan Ziegler; dan.ziegler{at}ddz.de

Abstract

Introduction The determinants and mechanisms contributing to diabetic sensorimotor polyneuropathy (DSPN) remain unclear. Since neuroinflammation and altered nerve regeneration have been implicated in the pathogenesis of both DSPN and neuropathic pain, we hypothesized that the corresponding biomarkers could be associated with DSPN in general and could have the potential to discriminate between the painful and painless DSPN entities.

Methods In a cross-sectional study using multimarker proximity extension assay technology we assessed 71 serum biomarkers including cytokines, chemokines, growth factors, receptors, and others in patients with type 2 diabetes with DSPN (DSPN+) (n=304) or without DSPN (DSPN−) (n=158) and persons with normal glucose tolerance (NGT) without polyneuropathy (n=354).

Results After adjustment for multiple testing and sex, age, body mass index, HbA1c, and smoking, the serum levels of 17 biomarkers (four cytokines, five chemokines, four growth factors, two receptors, two miscellaneous) were lower in DSPN+ than in DSPN− and NGT. In DSPN+, six of these biomarkers were associated with peripheral nerve function. The concentrations of 15 other biomarkers differed between NGT and both DSPN+ and DSPN−, but not between DSPN+ and DSPN−. No differences in biomarker levels were found between patients with painful (n=164) and painless DSPN (n=140).

Conclusions Deficits in systemic cytokines, chemokines, and growth factors promoting nerve regeneration in patients with type 2 diabetes are linked to polyneuropathy in general but not specifically to the painful or painless entity.

Trial registration number NCT02243475.

  • type 2 diabetes
  • inflammation and complications
  • biomarkers
  • peripheral neuropathy

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Footnotes

  • Contributors DZ designed the study and wrote the manuscript. AS, GJB, JMK, MH, and CH researched the data. AS, GJB, JMK, MH, WR, AP, CM, MR, BT, CH, and DZ contributed to the discussion and reviewed and edited the manuscript. DZ is the guarantor of this study, 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.

  • Funding The study was funded in part by grants from the European Union Seventh Framework Programme FP7/2007-2013 (PROPANE consortium; grant number 602273), the German Federal Ministry of Education and Research to the German Center for Diabetes Research (DZD; to CH and BT), and from the German Diabetes Association (Deutsche Diabetes Gesellschaft, DDG; to GJB). This work was also supported by the Ministry of Culture and Science of the State of North Rhine-Westphalia and the German Federal Ministry of Health. The KORA study was initiated and financed by the Helmholtz Zentrum München–German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval All participants provided written informed consent according to the Declaration of Helsinki. The PROPANE study was approved by the local ethics committee of Heinrich Heine University, Düsseldorf, Germany. The KORA study was approved by the ethics board of the Bavarian Chamber of Physicians (Munich, Germany).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

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