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  • Review Article
  • Published:

Schwann cell interactions with axons and microvessels in diabetic neuropathy

Nature Reviews Neurology volume 13, pages 135–147 (2017)Cite this article

Subjects

Key Points

  • Peripheral neuropathy is a serious but often neglected complication of diabetes mellitus

  • Schwann cells support the structural and functional integrity of nerves, so their damage as a result of the metabolic consequences of diabetes adversely affects axons

  • High polyol pathway flux, oxidative stress and inflammation are the main pathways activated in Schwann cells during diabetic neuropathy

  • Disruption of Schwann cell metabolism by hyperglycaemia and/or dyslipidaemia results in accumulation of neurotoxic intermediates that confer axonal and vascular vulnerability to injury

  • Microvascular changes within the endoneurium create a hypoxic environment that has the potential to disrupt Schwann cell function, promoting activation of inflammatory cascades that lead to neurodegeneration

Abstract

The prevalence of diabetes worldwide is at pandemic levels, with the number of patients increasing by 5% annually. The most common complication of diabetes is peripheral neuropathy, which has a prevalence as high as 50% and is characterized by damage to neurons, Schwann cells and blood vessels within the nerve. The pathogenic mechanisms of diabetic neuropathy remain poorly understood, impeding the development of targeted therapies to treat nerve degeneration and its most disruptive consequences of sensory loss and neuropathic pain. Involvement of Schwann cells has long been proposed, and new research techniques are beginning to unravel a complex interplay between these cells, axons and microvessels that is compromised during the development of diabetic neuropathy. In this Review, we discuss the evolving concept of Schwannopathy as an integral factor in the pathogenesis of diabetic neuropathy, and how disruption of the interactions between Schwann cells, axons and microvessels contribute to the disease.

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Figure 1: Pathogenesis of diabetic neuropathy.
Figure 2: Hyperglycaemia-driven Schwann cell stress and neurodegeneration.

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Acknowledgements

The authors gratefully acknowledge Dr Páll Karlsson from the Danish Pain Research Center, Department of Clinical Medicine, Aarhus University, for providing the pictures of unmyelinated fibres from the human skin biopsy samples. We would also like to thank Ken Kragsfeldt from the Clinical Institute, Aarhus University, for the graphical design. This work has been made possible thanks to a challenge grant from the Novo Nordisk Foundation (NNF14OC0011633) and an NIH grant (NS081082).

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Authors and Affiliations

  1. The International Diabetic Neuropathy Consortium (IDNC), Aarhus University, Aarhus C, 8000, Nørrebrogade, Denmark

    Nádia P. Gonçalves

  2. Department of Biomedicine, Danish Research Institute of Translational Neuroscience DANDRITE, Nordic-EMBL Partnership, Aarhus University, Ole Worms Alle 3, Aarhus C, 8000, Denmark

    Christian B. Vægter

  3. Department of Neurology, Danish Pain Research Center and IDNC, Aarhus University Hospital, Aarhus C, 8000, Nørrebrogade, Denmark

    Henning Andersen & Troels S. Jensen

  4. Department of Neuroradiology and Center for Functionally Integrative Neuroscience, Aarhus University Hospital, Aarhus C, 8000, Nørrebrogade, Denmark

    Leif Østergaard

  5. Department of Pathology, University of California San Diego, Gilman Drive, La Jolla, 92093, California, USA

    Nigel A. Calcutt

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  1. Nádia P. Gonçalves
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Contributions

N.P.G., C.B.V, L.Ø., N.A.C. and T.S.J. researched data for the article and wrote the article. N.P.G., C.B.V, H.A., N.A.C. and T.S.J. made substantial contributions to discussion of the content of the article. All authors reviewed the manuscript before submission.

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Correspondence to Nádia P. Gonçalves.

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Glossary

Prediabetes

A condition in which blood glucose levels are higher than normal but not high enough to be considered as type 2 diabetes; individuals with prediabetes often develop diabetic neuropathy.

Dependence receptors

Proteins that mediate apoptosis by monitoring the absence of certain trophic factors.

Basal lamina

Sheets of extracellular matrix that are secreted by Schwann cells and surround a nerve.

Endoneurium

A layer of interstitial connective tissue that surrounds all axons, thereby separating individual nerve fibres.

Radial sorting

The process that underlies selection of one axon for myelination by a Schwann cell during development.

Capillary dysfunction

A state of dysregulated capillary blood flow patterns, in which oxygen, glucose and other diffusible molecules cannot be extracted efficiently by the tissue; uptake of these molecules can become critically impaired, although reduced tissue blood supply is not obvious.

C-peptide

A short polypeptide that is cleaved from proinsulin in the production of insulin, and can be measured in the blood.

Coupled respiration

A process in which oxygen uptake is dependent on the presence of ADP and phosphate.

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Gonçalves, N., Vægter, C., Andersen, H. et al. Schwann cell interactions with axons and microvessels in diabetic neuropathy. Nat Rev Neurol 13, 135–147 (2017). https://doi.org/10.1038/nrneurol.2016.201

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