Evaluation of small nerve fiber dysfunction in type 2 diabetes

Ekman, Linnéa; Thrainsdottir, Soley; Englund, Elisabet; Thomsen, Niels; Rosén, Ingmar; Hazer, Derya Burcu; Petersson, Jesper; Eriksson, Kerstin; Dahlin, Lars B.

doi:10.1111/ane.13171

Cited by 16 publications

(34 citation statements)

References 47 publications

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“…Subcutaneous injection of this vector attenuated diabetes-induced hyperalgesia and restored normal TNF mRNA levels in the skin (160). Numerous rodent models of DPN have reported progressive declines in IENF density (162)(163)(164). In contrast, a recent study showed increased density of dermal peptidergic (SP+/CGRP+) fibers in human patients with painful DPN compared to painless DPN and healthy controls (165).…”

Section: Diabetic Polyneuropathymentioning

confidence: 99%

Cutaneous Neuroimmune Interactions in Peripheral Neuropathic Pain States

2021

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Bidirectional interplay between the peripheral immune and nervous systems plays a crucial role in maintaining homeostasis and responding to noxious stimuli. This crosstalk is facilitated by a variety of cytokines, inflammatory mediators and neuropeptides. Dysregulation of this delicate physiological balance is implicated in the pathological mechanisms of various skin disorders and peripheral neuropathies. The skin is a highly complex biological structure within which peripheral sensory nerve terminals and immune cells colocalise. Herein, we provide an overview of the sensory innervation of the skin and immune cells resident to the skin. We discuss modulation of cutaneous immune response by sensory neurons and their mediators (e.g., nociceptor-derived neuropeptides), and sensory neuron regulation by cutaneous immune cells (e.g., nociceptor sensitization by immune-derived mediators). In particular, we discuss recent findings concerning neuroimmune communication in skin infections, psoriasis, allergic contact dermatitis and atopic dermatitis. We then summarize evidence of neuroimmune mechanisms in the skin in the context of peripheral neuropathic pain states, including chemotherapy-induced peripheral neuropathy, diabetic polyneuropathy, post-herpetic neuralgia, HIV-induced neuropathy, as well as entrapment and traumatic neuropathies. Finally, we highlight the future promise of emerging therapies associated with skin neuroimmune crosstalk in neuropathic pain.

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Section: Diabetic Polyneuropathymentioning

confidence: 99%

Cutaneous Neuroimmune Interactions in Peripheral Neuropathic Pain States

2021

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“…Characteristics of the subjects ( n = 15) are presented in Table 1, previously published by Thomsen et al and Ekman et al 3,4,22 Median age [quartiles] was 74 [74–77] and 72 [68–75] for subjects with ( n = 9) and without ( n = 6) diabetes, respectively ( p = 0.04; Table 1). Median HbA 1c was significantly higher among type 2 diabetes subjects compared to control, 40 [29–62] mmol/mol (5.8 [4.8–7.8] %) vs. 29 [26–32] mmol/mol (4.8 [4.5–5.1] %) ( p = 0.028; Table 1).…”

Section: Resultsmentioning

confidence: 97%

Quantitative proteomic analysis of human peripheral nerves from subjects with type 2 diabetes

et al. 2021

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Aims Diabetic peripheral neuropathy (DPN) is a common and severe complication to type 2 diabetes. The pathogenesis of DPN is not fully known, but several pathways and gene polymorphisms contributing to DPN are described. DPN can be studied using nerve biopsies, but studies on the proteome of the nerve itself, and its surrounding tissue as a whole, are lacking. Studies on the posterior interosseous nerve (PIN) have proposed PIN a useful indicator of DPN. Methods A quantitative mass spectrometry‐based proteomics analysis was made of peripheral nerves from age‐ and gender‐matched living human male tissue donors; nine type 2 diabetes subjects, with decreased sural nerve action potentials indicating DPN, and six controls without type 2 diabetes, with normal electrophysiology results. Results A total of 2617 proteins were identified. Linear regression was used to discover which proteins were differentially expressed between type 2 diabetes and controls. Only soft signals were found. Therefore, clustering of the 500 most variable proteins was made to find clusters of similar proteins in type 2 diabetes subjects and healthy controls. Conclusions This feasibility study shows, for the first time, that the use of quantitative mass spectrometry enables quantification of proteins from nerve biopsies from subjects with and without type 2 diabetes, which may aid in finding biomarkers of importance to DPN development.

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“…Mice Fed with CAF Diet and Injected with Multiple Low-Doses of STZ Showed a Reduced IENF Density Intraepidermal nerve fibers (IENF) are directly associated with functional innervation of the skin, and the reduction of IENF density constitutes one of the main histological features in T2DM patients (Ekman et al, 2020). In fact, quantification of epidermal innervation is considered as a reliable and minimally invasive methods of diagnosing and staging diabetic neuropathy (Beiswenger et al, 2008).…”

Section: Diabetic Mice Slowly Developed Mechanical Allodyniamentioning

confidence: 99%

Characterization of Mechanical Allodynia and Skin Innervation in a Mouse Model of Type-2 Diabetes Induced by Cafeteria-Style Diet and Low-Doses of Streptozotocin

Castañeda-Corral

Velázquez-Salazar

et al. 2021

Front. Pharmacol.

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Background: Painful distal symmetrical polyneuropathy (DPN) is a frequent complication of type-2 diabetes mellitus (T2DM) that commonly presents as neuropathic pain and loss of skin nerve fibers. However, there are limited therapies to effectively treat DPN and many of the current animal models of T2DM-induced DPN do not appear to mirror the human disease. Thus, we validated a DPN mouse model induced by a cafeteria-style diet plus low-doses of streptozotocin (STZ).Methods: Female C57BL/6J mice were fed either standard (STD) diet or obesogenic cafeteria (CAF) diet for 32 weeks, starting at 8 weeks old. Eight weeks after starting diets, CAF or STD mice received either four low-doses of STZ or vehicle. Changes in body weight, blood glucose and insulin levels, as well as oral glucose- and insulin-tolerance tests (OGTT and ITT) were determined. The development of mechanical hypersensitivity of the hindpaws was determined using von Frey filaments. Moreover, the effect of the most common neuropathic pain drugs was evaluated on T2DM-induced mechanical allodynia. Finally, the density of PGP -9.5+ (a pan-neuronal marker) axons in the epidermis from the hindpaw glabrous skin was quantified.Results: At 22–24 weeks after STZ injections, CAF + STZ mice had significantly higher glucose and insulin levels compared to CAF + VEH, STD + STZ, and STD + VEH mice, and developed glucose tolerance and insulin resistance. Skin mechanical sensitivity was detected as early as 12 weeks post-STZ injections and it was significantly attenuated by intraperitoneal acute treatment with amitriptyline, gabapentin, tramadol, duloxetine, or carbamazepine but not by diclofenac. The density of PGP-9.5+ nerve fibers was reduced in CAF + STZ mice compared to other groups.Conclusion: This reverse translational study provides a painful DPN mouse model which may help in developing a better understanding of the factors that generate and maintain neuropathic pain and denervation of skin under T2DM and to identify mechanism-based new treatments.

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Evaluation of small nerve fiber dysfunction in type 2 diabetes

Cited by 16 publications

References 47 publications

Cutaneous Neuroimmune Interactions in Peripheral Neuropathic Pain States

Cutaneous Neuroimmune Interactions in Peripheral Neuropathic Pain States

Quantitative proteomic analysis of human peripheral nerves from subjects with type 2 diabetes

Characterization of Mechanical Allodynia and Skin Innervation in a Mouse Model of Type-2 Diabetes Induced by Cafeteria-Style Diet and Low-Doses of Streptozotocin

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