Danish Pain Research Centre, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Core Centre for Molecular Morphology, Section for Stereology for Microscopy, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Diabetologia. 2021 Apr;64(4):923-931. doi: 10.1007/s00125-020-05352-9. Epub 2021 Jan 23.
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.
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.
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 HbA (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.
目的/假设：远端糖尿病感觉运动多发性神经病（DSP）是糖尿病的常见并发症，许多患者的表皮内神经纤维密度（IENFD）减少，皮肤活检是评估 DSP 的一种经过验证且敏感的诊断工具。轴突肿胀比是 DSP 中改变的形态学定量。然而，尚不清楚轴突肿胀是否与糖尿病或 DSP 有关。本研究的目的是在明确诊断为 2 型糖尿病的患者中，研究皮肤神经纤维中的轴突肿胀与 2 型糖尿病、DSP 和神经性疼痛之间的关系。
共有 249 名参与者参加了英国疼痛性神经病变研究（Pain in Neuropathy Study，UK）和国际糖尿病神经病变联合会（International Diabetic Neuropathy Consortium，丹麦），他们接受了结构化的神经学检查、神经传导研究、定量感觉测试和皮肤活检。该研究包括四个组：无糖尿病的健康对照组参与者（n=45）；无 DSP 的 2 型糖尿病参与者（DSP-；n=31）；有 DSP 证据的参与者（DSP+；n=173）；最后一组进一步分为无痛性 DSP+（n=74）和疼痛性 DSP+（n=99）。轴突肿胀定义为表皮穿透纤维的扩张，直径超过 1.5μm。轴突肿胀比通过将轴突肿胀的数量除以表皮内神经纤维的数量来计算。
健康对照组参与者的中位数（IQR）IENFD（纤维/mm）为：6.7（5.2-9.2）；DSP-参与者为 6.2（4.4-7.3）；无痛性 DSP+参与者为 1.3（0.5-2.2）；疼痛性 DSP+参与者为 0.84（0.4-1.6）。计算了所有参与者和 IENFD>1.0 纤维/mm 的参与者的肿胀比。当仅包括 IENFD>1.0 纤维/mm 的参与者时，与健康对照组参与者相比，2 型糖尿病患者的轴突肿胀比更高（p<0.001）；然而，DSP-和无痛性 DSP+参与者之间，或无痛性 DSP+和疼痛性 DSP+参与者之间没有差异。轴突肿胀比与 HbA 呈弱相关（r=0.16，p=0.04），但与多伦多临床评分系统（DSP 严重程度的替代测量）、BMI 或 2 型糖尿病病程无关。
结论/解释：在 IENFD>1.0 纤维/mm 的 2 型糖尿病患者中，轴突肿胀比与 2 型糖尿病有关，但与 DSP 或疼痛性 DSP 无关。轴突肿胀可能是 2 型糖尿病感觉神经损伤的早期标志物。
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