Nerve regeneration following traumatic peripheral nerve injuries and neuropathies is a complex process modulated by diverse factors and intricate molecular mechanisms. Past studies have focused on factors that stimulate axonal outgrowth and myelin regeneration. However, recent studies have highlighted the pivotal role of autophagy in peripheral nerve regeneration, particularly in the context of traumatic injuries. Consequently, autophagy-targeting modulation has emerged as a promising therapeutic approach to enhancing peripheral nerve regeneration. Our current understanding suggests that activating autophagy facilitates the rapid clearance of damaged axons and myelin sheaths, thereby enhancing neuronal survival and mitigating injury-induced oxidative stress and inflammation. These actions collectively contribute to creating a favorable microenvironment for structural and functional nerve regeneration. A range of autophagy-inducing drugs and interventions have demonstrated beneficial effects in alleviating peripheral neuropathy and promoting nerve regeneration in preclinical models of traumatic peripheral nerve injuries. This review delves into the regulation of autophagy in cell types involved in peripheral nerve regeneration, summarizing the potential drugs and interventions that can be harnessed to promote this process. We hope that our review will offer novel insights and perspectives on the exploitation of autophagy pathways in the treatment of peripheral nerve injuries and neuropathies.

Diabetic peripheral neuropathy (DPN), as one of the most prevalent complications of diabetes, leads to significant pain and financial burden to patients. Currently, there was no effective treatment for DPN since the glucose control was just a prevention and the drug therapy only relieved the DPN pain. As a non-invasive physical therapy, low-intensity pulsed ultrasound (LIPUS) is utilized in the musculoskeletal and nerve injuries therapy. Studies revealed that LIPUS could regenerate nerves by the mechanical stimulation via oxidative stress pathway, which was thought as the important factor for DPN, and might have potential in the DPN therapy. This study aimed to identify a new therapeutic strategy for DPN using LIPUS. We analyzed the therapy effect and explored the therapeutic mechanism of LIPUS on DPN in mice. This study involved animal experiments and C57BL/6J mice were randomly assigned to DPN model and Sham groups. The DPN model group was fed a high-fat chow diet and injected with streptozotocin (STZ) for 3 consecutive days (40 mg/kg/d), whereas the Sham group was fed a normal diet and injected with an equal volume of sodium citrate buffer. After the DPN model confirmed with the 84-day modeling process, the DPN mice were randomly allocated into the DPN group and the LIPUS group. The LIPUS group underwent ultrasound treatments with a center frequency of 1 MHz, a duty cycle of 20 %, and a spatial average temporal average intensity (ISATA) of 200 mW/cm2 for 20 min/d, 5 d/w. After the 56-day treatment, all mice were euthanized. LIPUS therapeutic effects were evaluated through measurements of fasting blood glucose (FBG), behavioral tests, oxidative stress tests, morphological analysis, immunofluorescence, and western blot analysis. The results indicated that DPN mice had significantly higher FBG levels (28.77 ± 2.95 mmol/L) compared with sham mice (10.31 ± 1.49 mmol/L). Additionally, DPN mice had significantly lower mechanical threshold (4.13 ± 0.92 g) and higher thermal latency (16.20 ± 2.39 s) compared with the sham mice (7.31 ± 0.83 g, 11.67 ± 1.21 s). After receiving LIPUS treatment, the glucose tolerance tests (GTT) suggested that LIPUS treatment improved glucose tolerance, which was shown by a decrease in the area under the curve (AUC) for glucose in the LIPUS group (AUC = 2452 ± 459.33 min*mmol/L) compared with the DPN group (AUC = 3271 ± 420.90 min*mmol/L). Behavioral tests showed that LIPUS treatment significantly alleviated DPN-induced abnormalities by improving the mechanical threshold from 2.79 ± 0.79 g in the DPN group to 5.50 ± 1.00 g in the LIPUS group, and significantly decreasing thermal latency from 12.38 ± 1.88 s in the DPN group to 9.49 ± 2.31 s in the LIPUS group. Morphological observations revealed that DPN mice had a thinning and irregularly shaped myelin sheath, with 61.04 ± 5.60 % of abnormal nerve fibers in the sciatic nerve in LIPUS group, compared with 49.76 ± 4.88 % of abnormal nerve fibers in the LIPUS-treated group. Additionally, LIPUS treatment increased the mean fluorescence intensity of the associated nerve regeneration protein (i.e., Nf200) from 27.81 ± 0.32 arbitrary units in the DPN group to 37.62 ± 0.36 arbitrary units in the LIPUS group. Western blot and immunofluorescence analysis showed that LIPUS treatment significantly reduced Keap1 expression to 0.04 ± 0.06 relative units, compared with 0.17 ± 0.30 in the DPN group. Furthermore, immunofluorescence analysis revealed that LIPUS treatment promoted the production of its downstream antioxidant protein, heme oxygenase-1 (HO-1), with an increase in the fluorescence intensity from 27.81 ± 0.32 arbitrary units in the DPN group to 37.62 ± 0.36 arbitrary units in the LIPUS-treated group. The fluorescence intensity of Nrf2 was significantly higher in the LIPUS group, increasing from 4.90 ± 0.25 arbitrary units in the DPN group to 15.18 ± 2.13 arbitrary units in the LIPUS-treated group. Additionally, the malondialdehyde (MDA) levels, an indicator of oxidative stress, were significantly reduced in the serum, from 5.40 ± 0.48 nmol/ml in the DPN group to 4.64 ± 0.16 nmol/ml in the LIPUS-treated group, and in the sciatic nerve, from 16.17 ± 5.88 nmol/mg protein to 4.67 ± 2.10 nmol/mg protein, suggesting the oxidative stress was inhibited by LIPUS. This study demonstrated for the first time that LIPUS could relive DPN through anti-oxidative stress process. This study suggests that LIPUS might be a new therapy strategy for DPN.

Diabetic peripheral neuropathic pain (DPNP), a common diabetic mellitus (DM) complication, may result from the activation of satellite glial cells (SGCs) in the dorsal root ganglion (DRG), potentially enhancing peripheral sensitization. The N-methyl-D-aspartate receptor (NMDAR) subtype NR2A and Toll-like receptor (TLR)2 play key roles in neuroimmune interactions. However, their roles in SGCs of DRG and the precise mechanisms mediating peripheral sensitization in DPNP remain unclear. Here, we found that the expression of glial fibrillary acidic protein (GFAP), NR2A, and TLR2 in SGCs from DRG significantly increased under increased glucose and NMDA stimulation in vitro. Additionally, upregulation of interleukin (IL)-6 and nerve growth factor (NGF) was observed. Notably, lentivirus-induced NR2A knockdown (KD) and C29 (TLR2 inhibitor) significantly blocked the above SGCs changes induced by NMDA and increased glucose. Behavior tests showed mechanical and thermal sensitivities induced by sciatic nerve ligation (SNL) were more obvious in DM background related to streptozotocin (STZ) injection than non-DM background mice, which were significantly alleviated by NR2A conditional knockout (CKO) in SGCs and TLR2 KO. Moreover, immunofluorescence (IF) results revealed the co-expression of NR2A and TLR2 in neurons and SGCs in the DRG. Following SNL in DM mice, the upregulation of NR2A, TLR2, GFAP, β-catenin, p-GSK-3β, p-nuclear factor kappa (NF-κ)-B, IL-6, NGF, Bcl-2-associated X protein (Bax), and Caspase 3, and the significant downregulation of Bcl-2 were consistent with the changes observed after increased glucose and NMDA treatment. The upregulation of TLR2 was blocked by NR2A CKO and Wnt signal pathway inhibition. Additionally, the activation of SGCs, upregulated IL-6 as well as NGF secretion and increased apoptosis, associated with nerve injury in DM background were altered by TLR2 KO and NF-κB pathway inhibition. In conclusion, the activation of the NR2A-Wnt-TLR2 signaling axis mediated peripheral sensitization in the DRG by influencing SGCs' activation, and the synthesis and secretion of pro-inflammatory cytokines and NGF, promoting SGCs' apoptosis, thus exacerbating a peripheral nerve injury related-NP in DM background. Our study provided insights into the role of NR2A-Wnt-TLR2 signaling axis of SGCs in mediating the generation and maintenance of DPNP and suggested targeting this signaling axis may be a promising therapeutic approach for DPNP.

Tryptophan (Trp), an essential amino acid obtained through dietary sources, plays a crucial role in various physiological processes. The metabolism of Trp branches into three principal pathways: the serotonin pathway, the kynurenine pathway, and the indole pathway. The kynurenine and serotonin pathways are host pathways while the indole pathway is solely the result of bacterial metabolism. Trp metabolites extend their influence beyond protein biosynthesis to affect a spectrum of pathophysiological mechanisms including, but not limited to, neuronal function, immune modulation, inflammatory responses, oxidative stress regulation, and maintenance of intestinal health. This review focuses on indole derivatives and their impact on vascular health. Trp-containing dipeptides are highlighted as a targeted nutraceutical approach to modulate Trp metabolism, enhance beneficial metabolite production, and mitigate risk factors for vascular diseases. The importance of optimizing Trp intake and dietary strategies to harness the benefits of Trp-derived metabolites for vascular health is underscored, bringing to light the need for further research to refine these therapeutic approaches.

Diabetic neuropathy (DN) is a prevalent and debilitating complication of diabetes mellitus, significantly impacting patient quality of life and contributing to morbidity and mortality. Affecting approximately 50% of patients with diabetes, DN is predominantly characterized by distal symmetric polyneuropathy, leading to sensory loss, pain, and motor dysfunction, often resulting in diabetic foot ulcers and lower-limb amputations. The pathogenesis of DN is multifaceted, involving hyperglycemia, dyslipidemia, oxidative stress, mitochondrial dysfunction, and inflammation, which collectively damage peripheral nerves. Despite extensive research, disease-modifying treatments remain elusive, with current management primarily focusing on symptom control. This review explores the complex mechanisms underlying DN and highlights recent advances in diagnostic and therapeutic strategies. Emerging insights into the molecular and cellular pathways have unveiled potential targets for intervention, including neuroprotective agents, gene and stem cell therapies, and innovative pharmacological approaches. Additionally, novel diagnostic tools, such as corneal confocal microscopy and biomarker-based tests, have improved early detection and intervention. Lifestyle modifications and multidisciplinary care strategies can enhance patient outcomes. While significant progress has been made, further research is required to develop therapies that can effectively halt or reverse disease progression, ultimately improving the lives of individuals with DN. This review provides a comprehensive overview of current understanding and future directions in DN research and management.

Background: Diabetic peripheral neuropathy is associated with morbidity and mortality in people with diabetes mellitus. Aims: In this study, we determined relationships of the body-mass index (BMI), systolic blood pressure, diastolic blood pressure, fasting blood glucose, HbA1c, and ankle-brachial index (ABI) with diabetic peripheral neuropathy risk. Methods: A cross-sectional study was conducted with 1088 Indonesians and data collected using self-reported questionnaires, laboratory examinations, and physical examinations. Instruments included a digital scale, height measurement device, digital sphygmomanometer, Doppler ultrasound, 10-g monofilament, and a 128-Hz tuning fork. Data analysis used the Chi-square test, Fisher Exact, and multiple logistic regression test with significance p < .05. Results: The BMI (p < .001), blood pressure (p < .001), ABI (p < .001), fasting blood glucose (p = .016), and HbA1c (p < .001) were significantly related to peripheral neuropathy risk. The conditions of obesity, hypertension, high ABI, high fasting blood glucose, and high HbA1c significantly increased the risk of peripheral neuropathy. Moreover, participants with ≥4 co-occurring abnormal levels of the BMI, systolic blood pressure, diastolic blood pressure, fasting blood glucose, HbA1c, and ABI had significantly synergistically increased risks of peripheral neuropathy, and the more abnormal conditions there were, the higher the risk of peripheral neuropathy. Conclusions: Abnormalities of the BMI, blood pressure, fasting blood glucose, HbA1c, and ABI significantly and synergistically increased the risk of peripheral neuropathy and can be considered predictors of peripheral neuropathy. Nurses are expected to be aware of these predictors so that they can immediately take appropriate steps if they encounter abnormal conditions by optimizing their role as educators.

The microenvironment of diabetic wounds is complicated and characterized by hyperglycemia, hyperinflammation, persistent infection, hypoxia, and ischemia, making wound restoration and healing extremely challenging. Therefore, functional hydrogel dressings with the ability to regulate the microenvironment of diabetic wounds are a promising strategy for the treatment of diabetic wounds. In this study, a pH/glucose dual-responsive hydrogel based on phenylboric acid-modified carboxymethyl chitosan (CMCSPBA), aldehyde-terminated polyethylene glycol (PEGCHO), and polyvinyl alcohol (PVA) has been developed for diabetic wound treatment via Schiff base and phenylboric ester interactions. Glucose oxidase (GOX), catalase (CAT), and deferoxamine mesylate (DFO) are incorporated into the hydrogel to endow it with multi-functionality. In the hyperglycemic environment of diabetic wounds, a benign feedback loop is formed through the synergistic action of each component of the hydrogel, which enables the reshaping of the microenvironment of diabetic wounds by adjusting the pH and glucose, alleviating oxidative stress and hypoxia, regulating the inflammatory response, inhibiting bacterial infection, and promoting angiogenesis, thus accelerating diabetic wound healing in streptozotocin (STZ)-induced diabetic mice.

Peripheral neuropathy (PN) is a common disease among adults that can lead to severe clinical outcomes; Life's Simple 7(LS7) is recommended to reduce the risk of cardiovascular disease and stroke. However, the association between LS7 and PN has not been well studied yet.

We enrolled 4634 adults aged 40 to 85 years from the National Health and Nutrition Examination Survey (NHANES) 1999-2004. We used univariable and multivariable logistic regression models to evaluate the association between the LS7 score and PN. The LS7 score was treated as a continuous variable and divided into three groups: inadequate (0-7), average (8-10), and optimal (11-14). Subgroup analyses were also performed.

The average age of the participants was 55.28(0.24) years, and 684(11.59%) of those were diagnosed with PN. In three models, the inverse associations between LS7 and PN were found. In Model 3, a point increase in the LS7 score was associated with a 9% decreased incidence of PN, the odds ratio (OR) was 0.91, and the 95% confidence interval (CI) was 0.86 to 0.97. Compared with the inadequate LS7 score group, participants in the average and optimal groups were less likely to have PN, and the OR and 95%CI were 0.75(0.59,0.96) and 0.47(0.28,0.79), respectively. No significant interactions were found in the subgroup analyses.

An increased LS7 score is inversely associated with the likelihood of PN. This benefit was observed predominantly in participants who had the optimal LS7 score.

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes arising in part from glycemic damage to neurons and Schwann cells (SC). While the pathogenic mechanisms of DPN are complex, mitochondrial dysfunction and endoplasmic reticulum (ER) stress contribute to the development of DPN and serve as therapeutic targets for disease modification. Cemdomespib is an orally bioavailable small molecule which alleviates clinical indices of DPN that correlate with improvements in neuronal oxidative stress and mitochondrial bioenergetics. However, the contribution of SC ER stress in the onset of DPN and the therapeutic efficacy of cemdomespib remains unknown. To address this issue, mice expressing a conditional deletion of protein kinase RNA-like ER kinase (PERK) in myelinating SCs (SC-cPERK KO) and control SC-PERKf/f mice were rendered diabetic with streptozotocin. Diabetic SC-PERKf/f and SC-cPERK KO mice developed a similar magnitude of DPN as quantified by the onset of a thermal/mechanical hypoalgesia, decreases in nerve conduction velocity (NCV) and intraepidermal fiber density (iENFD). After 8 weeks of diabetes, daily treatment with 1 mg/kg cemdomespib for an additional 8 weeks significantly improved thermal/mechanical hypoalgesia, NCV, iENFD and decreased markers of ER stress in diabetic SC-PERKf/f mice, but the drug had no effect in diabetic SC-cPERK KO mice. Nrf2 is a PERK substrate and studies using rat SCs subjected to ER stress demonstrated that cemdomespib increased Nrf2 activity. Collectively, these data suggest that activation of SC PERK by diabetes is not necessary for the onset of DPN, but serves as a target in the action of cemdomespib, potentially by increasing Nrf2 activity.

This study investigated the correlation between metformin use and diabetic peripheral neuropathy (DPN) risk in patients with type 2 diabetes mellitus (T2DM) and its dose-dependent relationship. The study included new-onset T2DM patients from 2002 to 2013. Patients were divided into two groups based on metformin treatment, and DPN risk was assessed at 2- and 5-year follow-ups. After adjusting for various factors, two logistic models, metformin cumulative defined daily dose (cDDD) and metformin treatment intensity (defined daily dose [DDD]/month), evaluated the metformin-DPN risk association. Results showed that patients with metformin cDDD < 300, 300-500, and > 500 had higher DPN risk at both follow-ups. Odds ratios (ORs) and confidence intervals (CIs) for DPN were 1.74 (1.69-1.79), 2.05 (1.81-2.32), and 2.36 (1.34-4.16) at 2 years and 1.63 (1.60-1.65), 1.82 (1.69-1.96), and 2.17 (1.56-3.03) at 5 years. Similarly, patients with < 10, 10-25, and > 25 DDD/month had higher DPN risk at both follow-ups. Metformin use correlated with DPN risk in T2DM patients, with a dose-dependent relationship. Higher metformin cDDD or treatment intensity increased DPN risk. However, the absence of vitamin B12 data limits the understanding of the underlying mechanisms. Well-designed, large-scale studies are required to evaluate the potential risks of metformin therapy for DPN in patients with T2DM.

Diabetic neuropathic pain (DNP) is one of the most prevalent complications of diabetes, characterized by a high global prevalence and a substantial affected population with limited effective therapeutic options. Although DNP is closely associated with hyperglycemia, an increasing body of research suggests that elevated blood glucose levels are not the sole inducers of DNP. The pathogenesis of DNP is intricate, involving the release of inflammatory mediators, alterations in synaptic plasticity, demyelination of nerve fibers, and ectopic impulse generation, yet the precise mechanisms remain to be elucidated. The spinal dorsal horn coordinates dynamic interactions between peripheral and central pain pathways, wherein dorsal horn neurons, microglia, and astrocytes synergize with Schwann cell-derived signals to process nociceptive information flow. Abnormally activated neurons can alter signal transduction by modifying the local microenvironment, compromising myelin integrity, and diminishing trophic support, leading to neuronal sensitization and an amplifying effect on peripheral pain signals, which in turn triggers neuropathic pain. Ion channels play a pivotal role in signal conduction, with the modulation of sodium, potassium, and calcium channels being particularly crucial for the regulation of pain signals. In light of the rising incidence of diabetes and the current scarcity of effective DNP treatments, a thorough investigation into the interactions between neurons and glial cells, especially the mechanisms of ion channel function in DNP, is imperative for identifying potential drug targets, developing novel therapeutic strategies, and thereby enhancing the prospects for DNP management.

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes. Although studies have previously investigated metabolic disruptions in the peripheral nervous system (PNS), the exact metabolic mechanisms underlying DPN remain largely unknown. Herein, a specific form of metabolic remodeling involving aberrant ketogenesis within Schwann cells (SCs) in streptozotocin (STZ)-induced type I diabetes mellitus is identified. The PNS adapts poorly to such aberrant ketogenesis, resulting in disrupted energy metabolism, mitochondrial damage, and homeostatic decompensation, ultimately contributing to DPN. Additionally, the maladaptive peripheral ketogenesis is highly dependent on the cannabinoid type-1 receptor (CB1R)-Hmgcs2 axis. Silencing CB1R reprogrammed the metabolism of SCs by blocking maladaptive ketogenesis, resulting in rebalanced energy metabolism, reduced histopathological changes, and improved neuropathic symptoms. Moreover, this metabolic reprogramming can be induced pharmacologically using JD5037, a peripheral CB1R blocker. These findings revealed a new metabolic mechanism underlying DPN, and promoted CB1R as a promising therapeutic target for DPN.

Intraepidermal nerve fiber (IENF) density is commonly evaluated to diagnose peripheral neuropathy. However, conventional two-dimensional (2D) analysis using rodent models shows high interstudy variability. Three-dimensional (3D) IENF analysis has been proposed for human skin biopsies because the spatial location of each nerve can be easily determined. However, no studies have compared 2D and 3D analyses of mouse cutaneous nerve fibers under the same conditions. We aimed to establish a more accurate analysis method for mouse cutaneous nerve fibers. We used the glabrous plantar metatarsal skin of male C57BL/6J mice. The middle area of the plantar skin was used for 2D and 3D analyses, and the marginal area was also investigated in the 3D analysis. Tissue transparency, nerve fiber-specific antibodies, confocal microscopy, and IMARIS software were used for the 3D analysis. The 3D analysis clearly defined branching points and continuity, allowing accurate IENF density measurement. Conversely, the 2D analysis could not accurately determine IENF density because it could not detect the continuity of the nerve from the dermis to epidermis. Thus, the actual IENF density from the 3D analysis was significantly less than that from the 2D analysis. In addition, the density and length of IENFs in the middle area were significantly higher than those in the marginal area. This 3D approach enables the precise capture of IENF trajectories with various parameters, establishing a standard method for evaluating peripheral neuropathy models. Furthermore, our findings indicate that comparative studies aiming to analyze mouse IENF need to consider the site of skin sampling.

Sympathetic dysfunction in skin is well known in diabetic peripheral neuropathy. This produces dry, cracked, peeling skin susceptible to infection and also epidermal microcirculation insufficiency. Impaired autonomic neurovascular control opens dermal arterio-venous anastomoses and shunts microcirculation away from the epidermis and impairs skin oxygenation and nutrition. Few recognise that diabetic neuropathy includes swelling-induced entrapment neuropathy. Multiple peripheral nerves, swollen by the secondary polyol metabolic pathway, suffer local compressions at fibro-osseous tunnels. This includes the C-fibres controlling autonomic functions which constitute most of the nerve axons. No current standard of care therapy addresses the sympathetic-regulated neurovascular impairment of skin microcirculation in diabetes. Epineurolysis surgery for peripheral nerve decompression relieves local axonal compressions and generates recovery of sub-epidermal capillary flow. Clinical and animal diabetes studies have demonstrated objective improvements to epidermal hypoxia, demyelination and axonal histology. Seven surgery studies find an average 1.39% recurrence and zero amputations after prior Risk Class 3 wound healing in a mean of 1.78 years of follow-up. Deficits of electrophysiology, transcutaneous oxygenation and vasa nervorum circulation also improve. Surgically improved microcirculation is physiology-based. Nerve decompression minimises diabetic peripheral neuropathy, avoids initial diabetic foot ulcers, promotes neuropathic diabetic foot ulcer healing and minimises ulcer recurrences and subsequent amputation. The observational studies of these important benefits suggest wide application to the complications of diabetes neuropathy and beg for academic attention to Level 1 EBM confirmation.

Diabetic neuropathy (DN) is a debilitating complication of diabetes mellitus (DM), characterized by progressive neuronal damage, sensory dysfunction, and impaired quality of life. Recent advances in exosome research have elucidated their crucial role in DN's pathogenesis, diagnosis, and treatment. Exosomes-nanoscale extracellular vesicles-function as vehicles for molecular cargo, including microRNAs (miRNAs), proteins, and lipids, which mediate intercellular communication and regulate key biological processes. Pathologically, hyperglycemia and hyperlipidemia induce the release of exosomes enriched with pathogenic miRNAs, such as miR-130a and miR-20b-3p, which disrupt neuronal function, axonal regeneration, and inflammatory pathways. Conversely, diagnostic studies highlight the utility of exosomal biomarkers like miR-7 and miR-221 in the early detection and monitoring of DN. Therapeutically, Schwann cell-derived and mesenchymal stromal cell (MSC)-derived exosomes demonstrate neuroprotective and reparative effects by enhancing mitochondrial function, modulating inflammation, and promoting axonal repair. Emerging approaches, including engineered exosomes and miRNA-enriched vesicles, further expand their therapeutic potential. Despite these advances, challenges such as standardization, large-scale production, and clinical validation remain in translating these findings into clinical practice. This review underscores the multifaceted roles of exosomes in DN and highlights their potential as innovative tools for precision diagnostics and targeted therapies, paving the way for future research and clinical applications.

Diabetic peripheral neuropathy (DPN) is a prevalent complication of diabetes mellitus (DM), significantly contributing to the risk of amputation and mortality. Reactive oxygen species (ROS) can induce both neurological and structural harm through direct impact and pyroptosis, underscoring the critical role of ROS regulation in mitigating DPN. In this research endeavor, we propose harnessing the inherent antioxidant properties of sulfhydryl groups by grafting them onto gold nanodots through an amidation reaction, resulting in the creation of ROS-responsive AuNDs. Additionally, we aim to synthesize AuNDs-VEGF, wherein VEGF is attached to AuNDs via electrostatic interactions, as a therapeutic strategy for addressing DPN in rat models. The results of in vivo experiments showed that AuNDs and AuNDs-VEGF nanoparticles could increase the nerve conduction velocity, shorten the latency of nerve conduction in the sciatic nerve, promote the regeneration of nerve trophectodermal vessels, improve the structure and function of the sciatic nerve, reduce the apoptosis of neural cells, and alleviate the atrophy of the gastrocnemius muscle. Thus, VEGF-loaded ROS-responsive nanodots present a promising avenue for ameliorating diabetic peripheral neuropathy. This innovative approach not only extends the application possibilities of nanodots but also introduces a novel avenue for the treatment of diabetic neuropathy.

Diabetic Peripheral Neuropathy (DPN) is a prevalent complication of Type 2 Diabetes Mellitus (T2DM), leading to hand function impairments that affect daily activities and quality of life. Despite its significance, no culturally adapted tool exists for assessing hand-related activity limitations in the Malay-speaking population. This study aimed to translate, culturally adapt and validate the Duruöz Hand Index (DHI) for Malaysians with DPN.

A cross-sectional study was conducted in two phases: (1) translation and cultural adaptation of the DHI into Malay and (2) evaluation of its psychometric properties. Content validity was assessed by a panel of nine experts using the Content Validity Index (CVI). Face validity was evaluated through a pilot test with 10 individuals with DPN. Internal consistency (Cronbach's alpha) and test-retest reliability (Intraclass Correlation Coefficient, ICC) were measured in 30 participants with DPN. Known-group validity was examined by comparing DPN participants with healthy individuals.

The content validity of the Malay-DHI was excellent and face validity confirmed that the Malay-DHI was clear and comprehensible. Internal consistency was strong across all categories (α = 0.84-0.97). Test-retest reliability demonstrated excellent stability (ICC = 0.996-1.000). Known-group validity showed a significant difference between individuals with DPN and healthy individuals (Z = -6.93, p < .001).

The Malay version of the DHI demonstrated strong validity and reliability, making it a culturally relevant and robust tool for assessing hand function in individuals with DPN. This tool may facilitate targeted rehabilitation interventions and improve clinical outcomes.

Diabetic peripheral neuropathy (DPN) is a prevalent and disabling complication of diabetes, with painful diabetic peripheral neuropathy (PDPN) being its most severe subtype due to chronic pain and resistance to treatment. Satellite glial cells (SGCs), critical for maintaining dorsal root ganglion (DRG) homeostasis, undergo significant structural and functional changes under pathological conditions. This study investigated the role of galactosylceramide (GalCer), a key sphingolipid, in SGC dysfunction and neuron-glia interactions during DPN progression. Using a rat model of PDPN, we employed single-cell RNA sequencing (scRNA-seq), targeted mass spectrometry, and immunofluorescence analysis. The PDPN group exhibited transcriptional activation and structural reorganization of SGCs, characterized by increased SGC abundance and glial activation, evidenced by elevated Gfap expression. Functional enrichment analyses revealed disruptions in sphingolipid metabolism, including marked reductions in GalCer levels. Subclustering identified vulnerable SGC subsets, such as Cluster a, with dysregulated lipid metabolism. The depletion of GalCer impaired SGC-neuron communication, destabilizing DRG homeostasis and amplifying neurodegeneration and neuropathic pain. These findings demonstrate that GalCer depletion is a central mediator of SGC dysfunction in PDPN, disrupting neuron-glia interactions and exacerbating neuropathic pain. This study provides novel insights into the molecular mechanisms of DPN progression and identifies GalCer metabolism as a potential therapeutic target.

For Diabetic polyneuropathy, the most prevalent form of polyneuropathy, there is a lack of evidence-based treatment options. Current approaches include pain management, alpha-lipoic acid, and antidepressants. Physical interventions, such as electrical stimulation (four-chamber galvanic bath) have been suggested but have limited supporting evidence. Heated granular stone therapy is another option to consider.

An unblinded randomized controlled trials was conducted in 68 diabetic patients with distal sensorimotor polyneuropathy undergoing rehabilitation for diabetes mellitus as a primary or secondary diagnosis in the Paracelsus-Harz-Clinic (Quedlinburg, Germany). Patients were randomized into either the intervention group receiving heated granulated stone footbaths, or the control group receiving four-chamber galvanic baths. The primary endpoint was the assessment of any change in polyneuropathy using a vibration sensation test (Rydel-Seiffer scale, 8/8) from admission to discharge, analyzed by t-test and multivariable regression. Additionally, serum TNF-α and IL-6 as potential markers for polyneuropathy were compared over time using paired t-test.

The mean age of the patients was 66.8 ± 7.8 years; 63.2% were male and mean BMI was 32.2 ± 6.4 kg/m2. Of the patients, 98.5% suffered from type 2 diabetes (one patient with type I diabetes); 82.4% were receiving oral antidiabetic medication; and 58.8% were insulin dependent. Distal sensorimotor polyneuropathy improved in both groups. The sum score increased from 16.7 to 22.6 in the study group and from 20.3 to 23.6 in the control group. A t-test showed a non-significant difference in the change of sum score between the treatment groups (2.6 points, p = 0.092), but adjusting for potential risk factors favors the intervention group (p = 0.043). Both analyzed markers decreased over time in each treatment group with IL-6 showing a clinical and significant reduction in the control group (p = 0.03).

Diabetic patients with distal sensorimotor polyneuropathy benefit from physical treatment with administration of electrical stimulation (four-chamber galvanic bath) or a therapy with heated granulated stones three times a week. Our results indicate that heated stone therapy may be a potential treatment option. However, further research is required to understand the underlying biological processes.

The study was registered in clinical trials.gov (identifier: NCT05622630, registration date: 18/11/2022).

Diabetic autonomic neuropathy (DAN) is a severe complication of diabetes that affects the autonomic nervous system, impacting cardiovascular, gastrointestinal, genitourinary, and other systems. This study examines the levels of three potential biomarkers-DEFA1, progranulin, and NRG4-to assess their diagnostic and prognostic value in DAN patients.

This observational, single-center study included 80 patients with type 2 diabetes. Clinical data and laboratory results were collected, and serum levels of DEFA1, progranulin, and NRG4 were measured using ELISA. The presence of DAN was assessed using Ewing's tests. Statistical analyses included t-tests, Pearson's correlations, and ROC analysis to explore associations and the predictive values of the biomarkers.

Progranulin levels were significantly elevated in patients with DAN compared to those without (p < 0.05), showing a positive correlation with diabetes duration (r = 0.375; p = 0.01) and a significant predictive value for DAN (AUC = 0.666; p = 0.013). DEFA1 and NRG4 levels did not differ significantly between the groups. Progranulin was also higher in patients who were treated with sulfonylureas and GLP-1 receptor agonists and in those with coronary artery disease.

Progranulin emerges as a potential biomarker for the presence and severity of DAN, correlating with disease duration and autonomic dysfunction. While DEFA1 and NRG4 showed no significant association, the findings underscore the importance of further exploring the inflammatory pathways in DAN. Progranulin measurement could enhance early diagnosis and personalized management of autonomic neuropathy in diabetes.

Obesity and the metabolic syndrome (MetS) are major global health challenges that contribute significantly to the rising prevalence of type 2 diabetes (T2D) and neuropathy. Neuropathy, a common and disabling complication of T2D, is characterized by progressive distal-to-proximal axonal degeneration, driven in part by mitochondrial dysfunction in both neurons and axons. Recent evidence points to the toxic effects of saturated fatty acids on peripheral nerve health, with studies demonstrating that these fats impair mitochondrial function and bioenergetics, leading to distal axonal loss. Conversely, monounsaturated fatty acids are found to be neuroprotective, restoring mitochondrial function and preventing neuropathy. These findings suggest that dietary factors play a crucial role in the pathogenesis of neuropathy associated with metabolic dysregulation and emphasize the need for lifestyle interventions and therapies that target these newly identified mechanisms.

Diabetic neuropathy (DN) is one of the major complications of diabetes and the most common cause of neuropathic pain. Although the underlying pathological mechanisms remain unclear, several studies have produced conflicting results regarding the link between magnesium (Mg) concentration and DN. This ambiguity raises questions about the potential benefits of Mg supplementation in individuals with DN. Therefore, this comprehensive review summarizes and discusses the evidence from clinical, in vitro, and in vivo studies on the association between Mg and DN. Several findings indicate that Mg depletion is linked to the presence of neuropathy in diabetic patients. Additionally, low Mg concentration may contribute to the onset or worsening of DN by promoting axonal degeneration through various pathways. Furthermore, multiple studies have shown that Mg supplementation can have neuroprotective effects. These findings suggest potential as an alternative or complementary therapy for preventing and treating DN in the future.

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes mellitus. Early identification of individuals at high risk of DPN is essential for successful early intervention. Traditional Chinese medicine (TCM) tongue diagnosis, one of the four diagnostic methods, lacks specific algorithms for TCM symptoms and tongue features. This study aims to develop machine learning (ML) models based on TCM to predict the risk of diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes mellitus (T2DM).

A total of 4723 patients were included in the analysis (4430 with T2DM and 293 with DPN). TFDA-1 was used to obtain tongue images during a questionnaire survey. LASSO (least absolute shrinkage and selection operator) logistic regression model with fivefold cross-validation was used to select imaging features, which were then screened using best subset selection. The synthetic minority oversampling technique (SMOTE) algorithm was applied to address the class imbalance and eliminate possible bias. The area under the receiver operating characteristic curve (AUC) was used to evaluate the model's performance. Four ML algorithms, namely logistic regression (LR), random forest (RF), support vector classifier (SVC), and light gradient boosting machine (LGBM), were used to build predictive models for DPN. The importance of covariates in DPN was ranked using classifiers with better performance.

The RF model performed the best, with an accuracy of 0.767, precision of 0.718, recall of 0.874, F-1 score of 0.789, and AUC of 0.77. With a value of 0.879, the LGBM model appeared to be the best regarding recall Age, sweating, dark red tongue, insomnia, and smoking were the five most significant RF features. Age, yellow coating, loose teeth, smoking, and insomnia were the five most significant features of the LGBM model.

This cross-sectional study demonstrates that the RF and LGBM models can screen for high-risk DPN in T2DM patients using TCM symptoms and tongue features. The identified key TCM-related features, such as age, tongue coating, and other symptoms, may be advantageous in developing preventative measures for T2DM patients.

Peripheral neuropathy caused by diabetes is closely related to the vicious cycle of oxidative stress and mitochondrial dysfunction resulting from metabolic abnormalities. The effects mediated by the silent information regulator type 2 homolog-1 (SIRT1)/peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) axis present new opportunities for the treatment of type 2 diabetic peripheral neuropathy (T2DPN), potentially breaking this harmful cycle.

To validate the effectiveness of electroacupuncture (EA) in the treatment of T2DPN and investigate its potential mechanism based on the SIRT1/PGC-1α axis.

The effects of EA were evaluated through assessments of metabolic changes, morphological observations, and functional examinations of the sciatic nerve, along with measurements of inflammation and oxidative stress. Proteins related to the SIRT1/PGC-1α axis, involved in the regulation of mitochondrial biogenesis and antioxidative stress, were detected in the sciatic nerve using Western blotting to explain the underlying mechanism. A counterevidence group was created by injecting a SIRT1 inhibitor during EA intervention to support the hypothesis.

In addition to diabetes-related metabolic changes, T2DPN rats showed significant reductions in pain threshold after 9 weeks, suggesting abnormal peripheral nerve function. EA treatment partially restored metabolic control and reduced nerve damage in T2DPN rats. The SIRT1/PGC-1α axis, which was downregulated in the model group, was upregulated by EA intervention. The endogenous antioxidant system related to the SIRT1/PGC-1α axis, previously inhibited in diabetic rats, was reactivated. A similar trend was observed in inflammatory markers. When SIRT1 was inhibited in diabetic rats, these beneficial effects were abolished.

EA can alleviate the symptoms of T2DNP in experimental rats, and its effects may be related to the mitochondrial biogenesis and endogenous antioxidant system mediated by the SIRT1/PGC-1α axis.

Diabetic neuropathy (DN) is a prevalent and painful complication of diabetes; however, the mechanisms underlying its pathogenesis remain unclear, and effective clinical treatments are lacking. This study aims to explore the role of peroxisomes in Schwann cells in DN.

The abundance of peroxisomes in the sciatic nerves of mice or Schwann cells was analyzed using laser confocal super-resolution imaging and western blotting. The RFP-GFP-SKL (Ser-Lys-Leu) probe was utilized to assess pexophagy (peroxisomes autophagy) levels. To evaluate the palmitoylation of PEX11B, the acyl-resin assisted capture (acyl-RAC) assay and the Acyl-Biotin Exchange (ABE) assay were employed. Additionally, MR (Mendelian randomization) analysis was conducted to investigate the potential causal relationship between DN and MS (Multiple sclerosis).

There was a decrease in peroxisomal abundance in the sciatic nerves of diabetic mice, and palmitic acid (PA) induced a reduction in peroxisomal abundance by inhibiting peroxisomal biogenesis in Schwann cells. Mechanistically, PA induced the palmitoylation of PEX11B at C25 site, disrupting its self-interaction and impeding peroxisome elongation. Fenofibrate, a PPARα agonist, effectively rescued peroxisomal dysfunction caused by PA and restored the peroxisomal abundance in diabetic mice. Lastly, MR analysis indicates a notable causal influence of DN on MS, with its onset and progression intricately linked to peroxisomal dysfunction.

Targeting the peroxisomal biogenesis pathway may be an effective strategy for preventing and treating DN, underscoring the importance of addressing MS risk at the onset of DN.

Diabetes mellitus is a chronic disorder that progressively induces complications, compromising daily independence. Among these, diabetic neuropathy is particularly prevalent and contributes to substantial neuromuscular impairments in both types 1 and 2 diabetes. This condition leads to structural damage affecting both the central and peripheral nervous systems, resulting in a significant decline in sensorimotor functions. Alongside neuropathy, diabetic myopathy also contributes to muscle impairment and reduced motor performance, intensifying the neuromuscular decline. Diabetic neuropathy typically implicates neurogenic muscle atrophy, motoneuron loss and clustering of muscle fibres as a result of aberrant denervation-reinervation processes. These complications are associated with compromised neuromuscular junctions, where alterations occur in pre-synaptic vesicles, mitochondrial content and post-synaptic signalling. Neural damage is intensified by chronic hyperglycaemia and oxidative stress, exacerbating vascular dysfunction and reducing oxygen delivery. These complications imply a severe decline in neuromuscular performance, evidenced by reductions in maximal force and power output, rate of force development and muscle endurance. Furthermore, diabetes-related complications are compounded by age-related degenerative changes in long-term patients. Aerobic and resistance training offer promising approaches for managing blood glucose levels and neuromuscular function. Aerobic exercise promotes mitochondrial biogenesis and angiogenesis, supporting metabolic and cardiovascular health. Resistance training primarily enhances neural plasticity, muscle strength and hypertrophy, which are crucial factors for mitigating sarcopenia and preserving functional independence. This topical review examines current evidence on the physiological mechanisms underlying diabetic neuropathy and the potential impact of physical activity in counteracting this decline.

Humans are perhaps evolutionarily engineered to get deeply addicted to sugar, as it not only provides energy but also helps in storing fats, which helps in survival during starvation. Additionally, sugars (glucose and fructose) stimulate the feel-good factor, as they trigger the secretion of serotonin and dopamine in the brain, associated with the reward sensation, uplifting the mood in general. However, when consumed in excess, it contributes to energy imbalance, weight gain, and obesity, leading to the onset of a complex metabolic disorder, generally referred to as diabetes. Type 2 diabetes mellitus (T2DM) is one of the most prevalent forms of diabetes, nearly affecting all age groups. T2DM is clinically diagnosed with a cardinal sign of chronic hyperglycemia (excessive sugar in the blood). Chronic hyperglycemia, coupled with dysfunctions of pancreatic β-cells, insulin resistance, and immune inflammation, further exacerbate the pathology of T2DM. Uncontrolled T2DM, a major public health concern, also contributes significantly toward the onset and progression of several micro- and macrovascular diseases, such as diabetic retinopathy, nephropathy, neuropathy, atherosclerosis, and cardiovascular diseases, including cancer. The current review discusses the epidemiology, causative factors, pathophysiology, and associated comorbidities, including the existing and emerging therapies related to T2DM. It also provides a future roadmap for alternative drug discovery for the management of T2DM.

Diabetic polyneuropathy (DPN) is a multifactorial disease associated not only with hyperglycaemia but also with circulatory disturbances such as hypertension. A close interaction between the immune system and hypertension is known. It remains unclear whether the inflammatory response is associated with hypertension in the pathology of human DPN. Autopsied patients were evaluated: 7 non-diabetic patients (nDM), 11 non-diabetic patients with hypertension (nDMHT), 6 patients with diabetes (DM) and 9 patients with hypertension and diabetes (DMHT). Intraepidermal nerve fibre density (IENFD) was examined by immunofluorescent staining. Dissected sural nerve (SNs) were morphometrically quantified. Dermal and endoneurial macrophage infiltration was evaluated by double immunostaining using anti-CD68 and anti-CD206 antibodies. IENFD was significantly decreased in DM compared to nDM (p < 0.05) and was further decreased in DMHT (p < 0.05). Myelinated nerve fibre density (MNFD) in the SN was significantly decreased in DM compared with nDM (p < 0.05) and further decreased in DMHT (p < 0.01 vs. DM). The infiltration of CD206-/CD68+ proinflammatory macrophages in the SN was significantly increased in DM compared to nDM (p < 0.05), whilst the number of CD206+/CD68+ anti-inflammatory macrophages was decreased in DM (p < 0.05). Hypertension had no impact on macrophage infiltration. The ratio of CD206- and CD206+ macrophage was negatively correlated with MNFD (r = 0.42, p < 0.05) but not IENFD (r = 0.30, p = 0.09). Dermal CD206+ macrophage infiltration was similar amongst all groups. Diabetes complicated by hypertension significantly increased the total diffusion barrier thickness (p < 0.01 vs. DM). Total diffusion barrier thickness was inversely correlated with both IENFD (r = -0.59, p < 0.01) and MNFD (r =-0.62, p < 0.01). Our results suggest that vascular factors and inflammation might be synergistically involved in pathological changes in human diabetic patients through different mechanisms.

The present study aimed to evaluate the effects of 12-week resistance training (RT) on muscle strength, dynamic balance, glycemic control and the lipid profile.

The Laboratory of Movement Studies in the University of São Paulo, Brazil, developed this longitudinal study between 2021 and 2023. It assessed 62 males with type 2 diabetes mellitus pre and post an RT protocol. The participants, who were 69.8 (±3.9) years old, took part in a 12-week twice-weekly RT program. Three sets of eight to twelve repetitions each were executed for eight exercises targeting the large muscle groups. The intensity was set between 7 and 8 out of 10 for perceived effort, according to the Omni Resistance Exercise Scale. All participants were evaluated pre and post in knee extensor and flexor strength by isokinetic dynamometry, handgrip strength by manual dynamometry and dynamic postural balance by a force platform, as well as blood tests to determine the lipid and glycemic profiles. For comparison, paired t or Wilcoxon tests were used at an alpha of 5%.

There was an improvement in muscular strength by handgrip restricted to the non-dominant side (p = 0.033) and for the bilateral knee flexors (p < 0.001) and extensors (p < 0.001), as determined by isokinetic dynamometry. There was no improvement in dynamic postural balance, glycemic control or lipid control.

The 12-week RT promoted improved muscle strength in knee extension and flexion and non-dominant grip pressure but did not affect dynamic balance, glycemic control or the lipid profile.

Type 2 diabetes mellitus (T2DM), a prevalent chronic disease affecting over 400 million people globally, is driven by genetic and environmental factors. The pathogenesis involves insulin resistance and β-cell dysfunction, mediated by mechanisms such as the dedifferentiation of β-cells, mitochondrial dysfunction, and oxidative stress. Treatment should be based on non-pharmacological therapy. Strategies such as increased physical activity, dietary modifications, cognitive-behavioral therapy are important in maintaining normal glycemia. Advanced therapies, including SGLT2 inhibitors and GLP-1 receptor agonists, complement these treatments and offer solid glycemic control, weight control, and reduced cardiovascular risk. Complications of T2DM, such as diabetic kidney disease, retinopathy, and neuropathy, underscore the need for early diagnosis and comprehensive management to improve patient outcomes and quality of life.

About one out of two diabetic patients develop diabetic neuropathy (DN), of these 20% experience neuropathic pain (NP) leading to individual, social, and health-economic burden. Risk factors for NP are largely unknown; however, premature aging was recently associated with several chronic pain disorders. DNA methylation-based biological age (DNAm) is associated with disease risk, morbidity, and mortality in different clinical settings. The purpose of this work was to study, for the first time, whether biological age is involved in pain development in a huge cohort of DN patients with neuropathy assessed by anatomopathological assay (99 painful (PDN), 132 painless (PLDN) patients, 84 controls (CTRL)). Six subsets of DNAm biomarkers were calculated to evaluate NP-associated changes in epigenetic aging, telomere shortening, blood cell count estimates, and plasma protein surrogates. We observed pain-related acceleration of epigenetic age (DNAmAgeHannum, DNAmGrimAgeBasedOnPredictedAge, DNAmAgeSkinBloodClock), pace of aging (DunedinPoAm), and shortening of telomeres between PDN and PLDN patients. PDN showed decreased predicted counts of B lymphocytes, naive and absolute CD8 T cells, and increased granulocyte counts. Several surrogates of plasma proteins were significantly different (GHR, MMP1, THBS2, PAPPA, TGF-α, GDF8, EDA, MPL, CCL21) in PDNs compared to PLDNs. These results provide the first evidence of an acceleration of biological aging in patients with painful compared to painless DN. This achievement has been possible thanks to the state of the art clinical phenotyping of the enrolled patients. Our findings indicate that the aging process may be directly involved in the PDN progression and in general health degeneration in the T2DM patients. Therefore, it is possible to hypothesize that the administration of effective antiaging drugs could slow down or even block the disease advancement.

Schwann cells, as crucial regenerative cells, possess the ability to facilitate axon growth following peripheral nerve injury. However, the regeneration efficiency dominated by Schwann cells is impaired by factors such as the severity of peripheral nervous injury, aging, and metabolic disease. Cause the limitations of clinical treatments, it is necessary to urgently search for new substances that could reinforce the functionality of Schwann cells and promote nerve regeneration. We represented the first evidence that isoviolanthin possesses the capability to enhance Schwann cell proliferation and migration. Then, transcriptome sequencing was employed to examine the Differential Expressed Genes (DEGs), resulting in the identification of 193 DEGs. Following this, the expression levels of the top 5 up-regulated genes were confirmed through RT-qPCR, with Fhl3 demonstrating the most significant up-regulation. Schwann cells were transduced with virus particles made in HEK-293T/17 cells by transfection with lentivirus packaging plasmids containing Fhl3. A notable enhancement in Schwann cell proliferation and migration was observed following transduction. Furthermore, the Fhl3-up group exhibited a significant upregulation of Vimentin expression compared to the control group. These results suggested that isoviolanthin plays a positive role in enhancing Schwann cells' activity via increasing Fhl3 expression, and the mechanism may be related to the EMT(epithelial-mesenchymal transition)-like process.

Diabetes mellitus (DM) has become a public health problem, which is associated with high morbidity and mortality, due to the chronic complications, such as diabetic neuropathy. Current recommendations for the treatment of neuropathic pain achieve a reduction of 30% in only 30% of cases. Therefore, it is necessary to identify new therapeutic approaches to improve the quality of life of diabetic patients.

This work evaluated the antinociceptive effect of intranasal administration of the combination of dextro-ketamine (keta), a non-competitive glutamatergic receptor antagonist, and dexmedetomidine (DEX), a selective alpha2-adrenergic agonist, in rats with neuropathic pain induced by streptozotocin-DM.

The thermal hyperalgesia and mechanical allodynia observed in DM model are reduced with the intranasal administration of the combination of keta and DEX (200 + 0.10 μg/kg) after 3 days of treatment. The antinociceptive action could be due to reduction of Ca2+ influx with lower glutamate release and reduced excitability through the activation of alpha2-adrenergic receptors by DEX and reduction of NMDA receptor activation by glutamate with lower excitability due to the antagonism produced by keta. DM induced increased expression of glial fibrillary acid protein (GFAP) and tumor necrosis factor-alpha (TNF-alpha) detected by immunohistochemistry, indicating greater astrocyte activity and intense inflammatory response. Intranasal administration for 10 days of the combination of low doses of keta and DEX promoted an intense decrease in the expression of both GFAP and TNF-alpha, indicating lower activation of astrocytes in the spinal cord and reduced production and release of TNF-alpha, favoring the reduction of inflammation.

Intranasal administration of low doses of keta with DEX could be a new therapeutic approach to reduce neuropathic pain and consequently improve the quality of life of diabetic patients.

Diabetic neuropathy, also known as diabetic peripheral sensorimotor neuropathy (DPN), is a consequential complexity of diabetes, alongside diabetic nephropathy, diabetic cardiomyopathy, and diabetic retinopathy. It is characterized by signs and symptoms of peripheral nerve damage in diabetes patients after ruling out other causes. Approximately 20% of people with diabetes are affected by this painful and severe condition. The development of diabetic neuropathy is influenced by factors such as impaired blood flow to the peripheral nerves and metabolic issues, including increased polyol pathway activation, myo-inositol loss, and nonenzymatic glycation. The present review article provides a brief overview of the pathological changes in diabetic neuropathy and the mechanisms and types of DPN. Various diagnostic tests and biomarkers are available to assess nerve damage and its severity. Pharmacotherapy for neuropathic pain in diabetic neuropathy is complex. This review will explore current treatment options and potential future developments to improve the quality of life for patients suffering from diabetic neuropathy.

Advillin is an actin-binding protein involved in regulating the organization of actin filaments and the dynamics of axonal growth cones. In mice, advillin is exclusively expressed in somatosensory neurons, ubiquitously expressed in all neuron subtypes during neonatal ages and particularly enriched in isolectin B4-positive (IB4 + ) non-peptidergic neurons in adulthood. We previously showed that advillin plays a key role in axon regeneration of somatosensory neurons during peripheral neuropathy. Mice lacking advillin lost the ability to recover from neuropathic pain induced by oxaliplatin, chronic compression of the sciatic nerve, and experimental autoimmune encephalitis. However, the role of advillin in painful diabetic neuropathy remains unknown. Diabetic neuropathy, a prevalent complication of types 1 and 2 diabetes mellitus, poses significant treatment challenges because of the limited efficacy and adverse side effects of current analgesics. Here we probed the effect of advillin knockout on neuropathic pain in a diabetic mouse model induced by multiple low doses of streptozotocin (STZ). STZ-induced cold allodynia was resolved in 8 weeks in wild-type ( Avil +/+ ) mice but could last more than 30 weeks in advillin-knockout ( Avil -/- ) mice. Additionally, Avi -/- but not Avil +/+ mice showed STZ-induced mechanical hypersensitivity of muscle. Consistent with the prolonged and/or worsened STZ-induced neuropathic pain, second-line coping responses to pain stimuli were greater in Avil -/- than Avil +/+ mice. On analyzing intraepidermal nerve density, STZ induced large axon degeneration in the hind paws but with distinct patterns between Avil +/+ and Avil -/- mice. We next probed whether advillin knockout could disturb capsaicin-induced axon regeneration ex vivo because capsaicin is clinically used to treat painful diabetic neuropathy by promoting axon regeneration. In a primary culture of dorsal root ganglion cells, 10-min capsaicin treatment selectively promoted neurite outgrowth of IB4 + neurons in Avil +/+ but not Avil -/- groups, which suggests that capsaicin could reprogram the intrinsic axonal regeneration by modulating the advillin-mediated actin dynamics. In conclusion, advillin knockout prolonged STZ-induced neuropathic pain in mice, which may be associated with the impaired intrinsic capacity of advillin-dependent IB4 + axon regeneration.

The present review aimed to provide an update on the scientific progress of the role of epigenetic modifications on diabetic peripheral neuropathic pain (DPNP). DPNP is a devastating and troublesome complication of diabetes mellitus (DM), which affects one third of patients with DM and causes severe hyperalgesia and allodynia, leading to challenges in the treatment of these patients. The pathophysiology of DPNP is multifactorial and is not yet fully understood and treatment options for this disease are currently unsatisfactory. The underlying mechanisms and pathophysiology of DPNP have largely been explored in animal models and a mechanism‑derived approach might offer a potential therapeutic‑target for attenuating certain phenotypes of DPNP. Altered gene expression levels within the peripheral or central nervous systems (CNS) are a crucial mechanism of DPNP, however, the transcriptional mechanisms of these genes have not been fully elucidated. Epigenetic modifications, such as DNA methylation and histone modifications (methylation, acetylation, or phosphorylation), can alter gene expression levels via chromatin remodeling. Moreover, it has been reported that altering gene expression via epigenetic modifications within the peripheral or CNS, contributes to the changes in both pain sensitivity and pharmacological efficacy in DPNP. Therefore, the present review summarized the findings of relevant literature on the epigenetic alterations in DPNP and the therapeutic potential for targeting these alterations in the future treatment of this disease.

Diabetic peripheral neuropathy (DPN) affects approximately half of the 500 million people with type 2 diabetes worldwide. Previous studies have suggested that glucagon-like peptide-1 (GLP-1) receptors in the peripheral nervous system may be a suitable target for DPN treatment. Fourteen participants were consecutively recruited after being prescribed either semaglutide or dulaglutide as part of standard clinical care for type 2 diabetes. Participants underwent clinical assessment, nerve conduction studies, and axonal excitability assessment at baseline and at 3 mo following commencement of GLP-1 receptor agonist (GLP-1RA) therapy. These data were combined with 10 participants who had previously received exenatide therapy, and mathematical modeling of excitability data was undertaken. Clinical neuropathy scores improved at 3 mo following commencement of GLP-1 (baseline TNS 3.7 ± 4.5, posttreatment TNS 2.3 ± 3.4, P = 0.005). Nerve conduction studies demonstrated an improvement in sural amplitude at 3 mo (baseline 11.9 ± 8.5 μV, posttreatment 14.2 ± 9.2 μV; P = 0.013). Axonal excitability studies revealed changes consistent with improvements in Na+/K+-ATPase pump function and Na+ permeability, and this was supported by mathematical modeling. GLP-1RA therapy improves clinical and neurophysiological outcomes in DPN. Treatment with GLP-1RA may reverse axonal dysfunction by improving Na+/K+-ATPase pump function.NEW & NOTEWORTHY Diabetic peripheral neuropathy is known to be relentlessly progressive and irreversible. Prospective studies in 24 participants with diabetic peripheral neuropathy (DPN) treated with glucagon-like peptide-1 receptor agonists (GLP-1RA) demonstrated improvements in clinical neuropathy scores, nerve conduction studies, and axonal excitability recordings. Analysis of axonal excitability recordings revealed the mechanism for GLP-1RA improvement in DPN were changed consistent with improvements in Na+/K+-ATPase pump function, and this was supported by mathematical modeling.

Lesioned fascicles (LFs) in the sciatic nerves of individuals with diabetic neuropathy (DN) correlate with clinical symptom severity. This study aimed to characterize the structural and molecular composition of these lesions to better understand DN pathogenesis. Sciatic nerves from amputees with and without type 2 diabetes (T2D) were examined using ex vivo magnetic resonance neurography, in vitro imaging, and proteomic analysis. Lesions were only found in T2D donors and exhibited significant structural abnormalities, including axonal degeneration, demyelination, and impaired blood-nerve barrier (BNB). Although non-LFs from T2D donors showed activation of neuroprotective pathways, LFs lacked this response and instead displayed increased complement activation via the classical pathway. The detection of liver-derived acute-phase proteins suggests that BNB disruption facilitates harmful interorgan communication between the liver and nerves. These findings reveal key molecular mechanisms contributing to DN and highlight potential targets for therapeutic intervention.

to investigate the early consequences of type 1 diabetes (T1D) on the neural strategies of muscle force production.

motor unit (MU) activity was recorded from the vastus lateralis muscle with High-Density surface Electromyography during isometric knee extension at 20 and 40% of maximum voluntary contraction (MVC) in 8 T1D (4 males, 4 females, 30.5 ± 3.6 years) and 8 matched control (4 males, 4 females, 27.3 ± 5.9 years) participants. Muscle biopsies were also collected from vastus lateralis for fiber type analysis, including myosin heavy chain (MyHC) isoform content via protein and mRNA expression.

MVC was comparable between groups as well as MU conduction velocity, action potentials' amplitude and proportions of MyHC protein isoforms. Nonetheless, MU discharge rate, relative derecruitment thresholds and mRNA expression of MyHC isoform I were lower in T1D.

young people with uncomplicated T1D present a different neural control of muscle force production. Furthermore, differences are detectable non-invasively in absence of any functional manifestation (i.e., force production and fiber type distribution). These novel findings suggest that T1D has early consequences on the neuromuscular system and highlights the necessity of a better characterization of neural control in this population.

Diabetic limb ischemia (DLI) is a frequent complication of diabetes and the leading cause of non-traumatic amputation. Traditional treatments like stent placement and bypass surgery may not suit all patients. Exosome transplantation has emerged as a promising therapy. Netrin1, a protective cardiovascular factor, has an unclear role in DLI. This study investigates the role of Netrin1 in DLI patients and evaluates the therapeutic potential of exosomes derived from Netrin1-overexpressing adipose-derived stem cells (N-ADSCs). The expression of Netrin1 is significantly decreased in both endothelial cells and serum of DLI patients, highlighting its potential as a biomarker or therapeutic target. In vitro, Netrin1-enriched exosomes (N-Exos) promoted human umbilical vein endothelial cell (HUVEC) proliferation, migration, tube formation, and increased resistance to apoptosis under high glucose conditions. These protective effects are mediated through PI3K/AKT/eNOS and MEK/ERK pathways, and N-Exos further facilitated macrophage polarization from M1 to M2. In vivo, N-Exos demonstrates superior therapeutic effects over ADSC exosomes (Exos), including enhanced angiogenesis, improved collateral artery remodeling, reduced inflammation, and muscle protection. Collectively, these findings identify Netrin1 as a critical factor in DLI and underscore its significance in disease progression and therapeutic strategies. N-Exos offers a promising non-cellular therapeutic approach for the treatment of DLI.