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Introduction: Diabetic polyneuropathy (DPN), a common complication of diabetes, can manifest as small, large, or mixed fiber neuropathy (SFN, LFN, and MFN, respectively), depending on the type of fibers involved. Despite evidence indicating small fiber involvement prior to large fiber involvement in type 1 diabetes mellitus (T1DM)-associated DPN, no evidence has been produced to determine the more prevalent subtype. We aim to determine the more prevalent type of nerve fiber damage-SFN, LFN, and MFN-in T1DM-associated DPN, both with and without pain., Research Design and Methods: In this cross-sectional study, participants (n=216) were divided into controls; T1DM; T1DM with non-painful DPN (NP-DPN); and T1DM with painful DPN (P-DPN). DPN was further subgrouped based on neuropathy severity. The more prevalent type of fiber damage was determined applying small and large fiber-specific tests and three diagnostic models: model 1 (≥1 abnormal test); model 2 (≥2 abnormal tests); and model 3 (≥3 abnormal tests)., Results: MFN showed the highest prevalence in T1DM-associated DPN. No differences in neuropathy subtype were found between NP-DPN and P-DPN. DPN, with prevalent SFN plateaus between models 2 and 3. All models showed increased prevalence of MFN according to DPN severity. Model 3 showed increased DPN with prevalent LFN in early neuropathy. DPN with prevalent SFN demonstrated a similar, but non-significant pattern., Conclusions: DPN primarily manifests as MFN in T1DM, with no differentiation between NP-DPN and P-DPN. Additionally, we propose model 2 as an initial criterion for diagnosing DPN with a more prevalent SFN subtype in T1DM. Lastly, the study suggests that in mild stages of DPN, one type of nerve fiber (either small or large) is more susceptible to damage., Competing Interests: Competing interests: PK has received personal fees from Grünenthal, Alnylam, and Vertex Pharmaceuticals, and has received a research grant from Merck outside the submitted work., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims/hypothesis: Our aim was to investigate structural changes of cutaneous Schwann cells (SCs), including nociceptive Schwann cells (nSCs) and axons, in individuals with diabetic polyneuropathy. We also aimed to investigate the relationship between these changes and peripheral neuropathic symptoms in type 1 diabetes., Methods: Skin biopsies (3 mm) taken from carefully phenotyped participants with type 1 diabetes without polyneuropathy (T1D, n=25), type 1 diabetes with painless diabetic polyneuropathy (T1DPN, n=30) and type 1 diabetes with painful diabetic polyneuropathy (P-T1DPN, n=27), and from healthy control individuals (n=25) were immunostained with relevant antibodies to visualise SCs and nerve fibres. Stereological methods were used to quantify the expression of cutaneous SCs and nerve fibres., Results: There was a difference in the number density of nSCs not abutting to nerve fibres between the groups (p=0.004) but not in the number density of nSCs abutting to nerve fibres, nor in solitary or total subepidermal SC soma number density. The overall dermal SC expression (measured by dermal SC area fraction and subepidermal SC process density) and peripheral nerve fibre expression (measured by intraepidermal nerve fibre density, dermal nerve fibre area fraction and subepidermal nerve fibre density) differed between the groups (all p<0.05): significant differences were seen in participants with T1DPN and P-T1DPN compared with those without diabetic polyneuropathy (healthy control and T1D groups) (all p<0.05). No difference was found between participants in the T1DPN and P-T1DPN group, nor between participants in the T1D and healthy control group (all p>0.05). Correlational analysis showed that cutaneous SC processes and nerve fibres were highly associated, and they were weakly negatively correlated with different neuropathy measures., Conclusions/interpretation: Cutaneous SC processes and nerves, but not SC soma, are degenerated and interdependent in individuals with diabetic polyneuropathy. However, an increase in structurally damaged nSCs was seen in individuals with diabetic polyneuropathy. Furthermore, dermal SC processes and nerve fibres correlate weakly with clinical measures of neuropathy and may play a partial role in the pathophysiology of diabetic polyneuropathy in type 1 diabetes., (© 2023. The Author(s).)

Background and Objectives: Diabetic polyneuropathy (DPN) is a complication of diabetes characterized by pain or lack of peripheral sensation, but the underlying mechanisms are not yet fully understood. Recent evidence showed increased cutaneous macrophage infiltration in patients with type 2 diabetes and painful DPN, and this study aimed to understand whether the same applies to type 1 diabetes., Methods: The study included 104 participants: 26 healthy controls and 78 participants with type 1 diabetes (participants without DPN [n = 24], participants with painless DPN [n = 29], and participants with painful DPN [n = 25]). Two immune cells, dermal IBA1 + macrophages and epidermal Langerhans cells (LCs, CD207 + ), were visualized and quantified using immunohistological labeling and stereological counting methods on skin biopsies from the participants. The IBA1 + macrophage infiltration, LC number density, LC soma cross-sectional area, and LC processes were measured in this study., Results: Significant difference in IBA1 + macrophage expression was seen between the groups ( p = 0.003), with lower expression of IBA1 in participants with DPN. No differences in LC morphologies (LC number density, soma cross-sectional area, and process level) were found between the groups (all p > 0.05). In addition, IBA1 + macrophages, but not LCs, correlated with intraepidermal nerve fiber density, Michigan neuropathy symptom inventory, (questionnaire and total score), severity of neuropathy as assessed by the Toronto clinical neuropathy score, and vibration detection threshold in the whole study cohort., Discussion: This study showed expressional differences of cutaneous IBA1 + macrophages but not LC in participants with type 1 diabetes-induced DPN compared with those in controls. The study suggests that a reduction in macrophages may play a role in the development and progression of autoimmune-induced diabetic neuropathy., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)