Axonal swellings are related to type 2 diabetes, but not to distal diabetic sensorimotor polyneuropathy

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  • Pall Karlsson
  • Sandra S Gylfadottir
  • Alexander G Kristensen
  • Juan D Ramirez, Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, United Kingdom; Department of Physics, University of Oxford, Oxford, United Kingdom; University of Oxford Centre for Clinical Magnetic Resonance Research, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
  • ,
  • Pedro Cruz, Department of Clinical Medicine, Faculty of Medicine, Aalborg University, Aalborg
  • ,
  • Nhu Le, Department of Medical Oncology, Radboud university medical centre and Radboud Institute for Molecular Life Sciences, Nijmegen
  • ,
  • Pallai R Shillo, Sheffield Teaching Hospitals NHS Foundation Trust
  • ,
  • Solomon Tesfaye, Sheffield Teaching Hospitals NHS Foundation Trust
  • ,
  • Andrew S C Rice, Imperial Coll London, Imperial College London, Imperial Clin Trials Unit
  • ,
  • Hatice Tankisi
  • Nanna B Finnerup
  • Jens R Nyengaard
  • Troels S Jensen
  • David L H Bennett, Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, United Kingdom; Department of Physics, University of Oxford, Oxford, United Kingdom; University of Oxford Centre for Clinical Magnetic Resonance Research, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
  • ,
  • Andreas C Themistocleous, Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, United Kingdom; Department of Physics, University of Oxford, Oxford, United Kingdom; University of Oxford Centre for Clinical Magnetic Resonance Research, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.

AIMS/HYPOTHESIS: Distal diabetic sensorimotor polyneuropathy (DSP) is a common complication of diabetes with many patients showing a reduction of intraepidermal nerve fibre density (IENFD) from skin biopsy, a validated and sensitive diagnostic tool for the assessment of DSP. Axonal swelling ratio is a morphological quantification altered in DSP. It is, however, unclear if axonal swellings are related to diabetes or DSP. The aim of this study was to investigate how axonal swellings in cutaneous nerve fibres are related to type 2 diabetes mellitus, DSP and neuropathic pain in a well-defined cohort of patients diagnosed with type 2 diabetes.

METHODS: A total of 249 participants, from the Pain in Neuropathy Study (UK) and the International Diabetic Neuropathy Consortium (Denmark), underwent a structured neurological examination, nerve conduction studies, quantitative sensory testing and skin biopsy. The study included four groups: healthy control study participants without diabetes (n = 45); participants with type 2 diabetes without DSP (DSP-; n = 31); and participants with evidence of DSP (DSP+; n = 173); the last were further separated into painless DSP+ (n = 74) and painful DSP+ (n = 99). Axonal swellings were defined as enlargements on epidermal-penetrating fibres exceeding 1.5 μm in diameter. Axonal swelling ratio is calculated by dividing the number of axonal swellings by the number of intraepidermal nerve fibres.

RESULTS: Median (IQR) IENFD (fibres/mm) was: 6.7 (5.2-9.2) for healthy control participants; 6.2 (4.4-7.3) for DSP-; 1.3 (0.5-2.2) for painless DSP+; and 0.84 (0.4-1.6) for painful DSP+. Swelling ratios were calculated for all participants and those with IENFD > 1.0 fibre/mm. When only those participants with IENFD > 1.0 fibre/mm were included, the axonal swelling ratio was higher in participants with type 2 diabetes when compared with healthy control participants (p < 0.001); however, there was no difference between DSP- and painless DSP+ participants, or between painless DSP+ and painful DSP+ participants. The axonal swelling ratio correlated weakly with HbA1c (r = 0.16, p = 0.04), but did not correlate with the Toronto Clinical Scoring System (surrogate measure of DSP severity), BMI or type 2 diabetes duration.

CONCLUSIONS/INTERPRETATION: In individuals with type 2 diabetes where IENFD is >1.0 fibre/mm, axonal swelling ratio is related to type 2 diabetes but is not related to DSP or painful DSP. Axonal swellings may be an early marker of sensory nerve injury in type 2 diabetes.

Original languageEnglish
JournalDiabetologia
Volume64
Issue4
Pages (from-to)923-931
Number of pages9
ISSN0012-186X
DOIs
Publication statusPublished - Apr 2021

    Research areas

  • Axonal swellings, Diabetes, Diabetic neuropathy, Neuropathic pain, Skin biopsy

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