Abstract
Aims/hypothesisDistal 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.MethodsA 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.ResultsMedian (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/interpretationIn 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.Graphical abstract
Highlights
Diabetic sensorimotor polyneuropathy (DSP) is a common complication of diabetes, which typically presents as a distal symmetric polyneuropathy with sensory loss or pain in the feet and hands [1, 2]
The axonal swelling ratio was higher in study participants with type 2 diabetes, irrespective of whether DSP was present, when compared with healthy control (HC) participants
Our key findings are that where Intraepidermal nerve fibre density (IENFD) > 1.0 fibre/mm, the axonal swelling ratio is increased in type 2 diabetes when compared with HC participants; axonal swelling ratio did not differ between study participants with or without painless DSP+, or between painless DSP+ and painful DSP+
Summary
Diabetic sensorimotor polyneuropathy (DSP) is a common complication of diabetes, which typically presents as a distal symmetric polyneuropathy with sensory loss or pain in the feet and hands [1, 2]. Skin nerve fibre morphometric analysis offers potential insights, as differences are observed between individuals with painless and painful DSP [5]. There is some uncertainty as to whether IENFD differentiates between patients with painless and painful DSP, as some studies report an inverse correlation between IENFD and pain [9], while others report no correlation [10]. Morphometric analysis of nerve fibres detects a change in axonal structures termed axonal swellings, a degenerative change that contains watery axoplasm, neurofilaments and abnormal mitochondria [11]. In one study an increase of axonal swellings was found in patients with painful DSP [5]; in another study axonal swellings did not differentiate between patients with painful and painless DSP [14]. Axonal swellings were higher in participants with DSP when compared with participants with diabetes but without DSP, and with healthy control (HC) participants
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