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Low brain-derived neurotrophic factor protein levels and single-nucleotide polymorphism Val66Met are associated with peripheral neuropathy in type II diabetic patients

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Abstract

Background

Studies by our group demonstrated brain-derived neurotrophic factor (BDNF) levels in blood and BDNF-Val66met-SNP as potential biomarkers in chemotherapy-induced peripheral neuropathy. Here, we evaluate symptoms of peripheral neuropathy (PN) and depression in patients with type II diabetes mellitus in search of an association with serum BDNF levels and the Val66Met-SNP.

Methods

In total, 90 patients enrolled in the study; 23 (25.6%) had known PN, as determined by nerve conduction studies (NCS–PN), and 67 (74.4%) were not diagnosed with PN (U-PN). PN symptoms were assessed and graded in these groups using the total neuropathy score (TNSr) and DN4 scales. Small nerve fiber testing of sensitivity thresholds to cold, warm and hot pain signals was performed using the Q-sense device. Depression was assessed using the PHQ9 questionnaire. BDNF protein levels and Val66Met-SNP were determined with ELISA and Sanger sequencing, respectively.

Results

NCS–PN patients showed lower serum BDNF levels alongside significantly higher TNSr, DN4 and PHQ9 scores and lower hot pain sensitivity thresholds as compared to U-PN patients. Patients with Met-BDNF-SNP showed increased TNSr scores and lower hot pain sensitivity thresholds as compared to patients with Val-BDNF-SNP. Depression showed a weaker correlation with sensitivity thresholds to hot pain signals as compared to TNSr and DN4 scores.

Conclusions

Diminished peripheral BDNF resources and Met-BDNF-SNP genotype are associated with augmented symptoms of PN in patients with type II diabetes mellitus. Sensitivity thresholds to hot pain signals may be less influenced by depression and possibly more accurately detect PN symptoms in diabetic patients.

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Acknowledgements

We wish to thank Rivka Sharon for designing PCR analysis of BDNF and the Israel Ministry of Galilee Development for their support of editing the final manuscript and preparing the layout. This work was supported by grant from D-cure.

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Authors and Affiliations

  1. Hematology Unit and Laboratories, Galilee Medical Center, P.O. Box 21, 22100, Naharia, Israel

    David Azoulay, Ortal Sheleg & Ety Shaoul

  2. Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel

    David Azoulay, Ety Shaoul, Mona Shehadeh & Amir Bashkin

  3. Department of Geriatric Medicine, Galilee Medical Center, Naharia, Israel

    Sean Abed & Edward Kaykov

  4. Department of Neurology, Galilee Medical Center, Naharia, Israel

    Akram Sfadi

  5. Biochemistry and Endocrinology Laboratory, Galilee Medical Center, Naharia, Israel

    Mona Shehadeh

  6. Diabetes, Endocrinology and Metabolism Unit, Galilee Medical Center, Naharia, Israel

    Marina Nodelman & Amir Bashkin

Authors
  1. David Azoulay
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  2. Sean Abed
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  3. Akram Sfadi
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  4. Ortal Sheleg
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  9. Amir Bashkin
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Contributions

DA designed the study, performed experiments, analyzed the data, interpreted the data and wrote the manuscript. AS and SA recruited patients to the study and performed neurological assessment of PN symptoms and depression. OS performed PCR analysis for BDNF-SNP genotyping. MS performed vitamin B12 analysis in patients. ES, MN and EK helped design the study and interpret the data. Amir Bashkin advised the clinical aspects of the study, recruited patients to the study and interpret the data.

Corresponding author

Correspondence to David Azoulay.

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Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

This study have been reviewed by the appropriate ethics committee and have therefore been performed in accordance with ethical standards laid down in appropriate version of the 1964 Declaration of Helsinki (Galilee Medical Center approval # 0061-15-NHR, April 2nd 2015).

Informed consent

All persons gave their informed consent prior to their inclusion in the study.

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592_2020_1508_MOESM1_ESM.pptx

Figure 1: TNSr, DN4 and hot-pain sensitivity threshold in patients with depression. A. The graph presents the overall TNSr and DN4 scores of patients with minimal symptoms of depression (white bars) and patients with depression (black bars). Bars represent mean (± SEM) scores. *p value < 0.05. B. The bars show the mean (± SEM) hot-pain temperature thresholds of patients with minimal symptoms of depression and patients with depression. *p value < 0.05. (PPTX 46 kb)

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Azoulay, D., Abed, S., Sfadi, A. et al. Low brain-derived neurotrophic factor protein levels and single-nucleotide polymorphism Val66Met are associated with peripheral neuropathy in type II diabetic patients. Acta Diabetol 57, 891–898 (2020). https://doi.org/10.1007/s00592-020-01508-6

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  • DOI: https://doi.org/10.1007/s00592-020-01508-6

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