We aimed to provide new reference data for C64 Hz-Rydel-Seiffer tuning fork Vibration Sensation Thresholds (VST) for the clinical diagnosis of Diabetic Sensorimotor Polyneuropathy (DSPN) and to evaluate the diagnostic performance when used in combination with other clinical tests as implemented in the Neuropathy Disability Score (NDS).

The study included 1,215 individuals with type 1 or type 2 diabetes and 207 with Normal Glucose Tolerance (NGT), who underwent clinical, electrophysiological, and Quantitative Sensory Tests (QST). Multiple regression analyses were used to determine VST in individuals with NGT. The diagnostic performance of tests to detect confirmed small or large fibre DSPN according to Toronto consensus criteria was assessed in 373 individuals with diabetes who underwent skin biopsies do determine intraepidermal nerve fibre density (IENFD).

The new age-dependent lower normative VST showed 73.5% sensitivity, 85.4% specificity, and 82.3% accuracy in diagnosing confirmed DSPN. Combining VST with the PinPrick test resulted in 83.4% sensitivity, 80.3% specificity, and 81.2% accuracy. The NDS incorporating VST was associated with nerve conduction indices, QST, and IENFD.

The new VST reference data shall enable clinicians to detect DSPN with higher accuracy in clinical practice, particularly when combined with a single small fibre test.

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.

Diabetic peripheral neuropathy (DPN) and neuropathic pain (NP) are common complications of type 1 diabetes that can greatly affect quality of life. Studying DNA methylation (DNAm) may help identify potential therapeutic targets; however, epigenome-wide association studies (EWAS) of DPN and NP are lacking. We thus performed prospective EWAS of 28 year DPN and NP incidence in the Pittsburgh Epidemiology of Diabetes Complications (EDC) study of childhood-onset (<17 years) type 1 diabetes.

DPN was defined as two or more of the following criteria: symptoms consistent with DPN; decreased tendon reflexes; or abnormal sensory examination. NP was reported as burning, aching or stabbing pain in the feet during an EDC examination or on the Michigan Neuropathy Screening Instrument (MNSI). The time of the first available blood-derived DNA specimen collected between 1988-1998 was considered the analytic 'baseline' (mean age 27 years; diabetes duration 19 years). After quality control, DNAm (EPIC array) at 683,597 CpGs was analysed in Cox models for time-to-DPN in 282 individuals free of DPN at baseline and time to NP in 365 individuals free of NP at baseline. False discovery rate (FDR) <0.05 was considered statistically significant. We also identified differentially methylated regions (DMRs), functional interaction networks and genetic variants associated with DNAm (methylation quantitative trait loci [meQTLs]), and performed Mendelian randomisation (MR) to assess evidence of causality.

Over 28 years, 154 individuals (54.6%) developed DPN and 148 (40.5%) developed NP. Greater methylation at three CpGs was significantly associated (FDR≤0.05) with reduced hazard of DPN: cg06163904 (CHMP6); cg10835127 (CACNA1B); and cg18945945 (PKNOX1). CpG associations with DPN remained similar after adjustment for clinical risk factors. We identified 75 meQTLs for cg18945945 in the PKNOX1 region, 59 of which were validated in an external diabetes cohort. One-sample MR provided nominal evidence for a potentially causal association between cg18945945 and DPN (p=0.01). While no individual CpGs were significantly associated with NP, there were 49 NP-associated DMRs.

Our study identified associations between DNAm and 28 year incidence of DPN and NP at several biologically plausible loci. Most notably, we identified a novel association between DNAm of PKNOX1 and future DPN, including evidence of a genetic influence on PKNOX1 methylation that was validated in an external diabetes cohort. PKNOX1 has previously been implicated in drug-induced neuropathy; our results provide strong evidence that epigenetic regulation of PKNOX1 may also play a functional role in the development of diabetic neuropathy. Our results suggest that epigenetic modification of the identified loci warrants further study to inform potential targets for prevention of DPN.

Endogenous carbonyl stress leads to the formation of advanced glycation end products (AGEs). AGEs represent a potential target to prevent or treat diabetic sensorimotor polyneuropathy (DSPN). The current study aimed to characterize cutaneous carbonyl stress, oxidative stress, immune cells, and endothelial cell damage in early type 2 diabetes compared with normal glucose tolerance (NGT) using novel cutaneous biomarkers.

Included were 160 individuals recently (≤12 months) diagnosed with type 2 diabetes and 144 with NGT from the German Diabetes Study baseline cohort. Nerve function was assessed using electrophysiological, quantitative sensory, and clinical testing. Skin biopsies were obtained to analyze intraepidermal nerve fiber density, AGE autofluorescence, argpyrimidine area, and endothelial cell area. In addition, skin autofluorescence was measured noninvasively using the AGE reader. A subgroup with type 2 diabetes (n = 80) was reassessed 5 years later.

After adjustment for sex, age, HbA1c, LDL cholesterol, and BMI, argpyrimidine area (17.5 ± 18.8 vs. 11.7 ± 12.7%) was higher in recent-onset type 2 diabetes than in NGT (P < 0.05). AGE autofluorescence was inversely correlated with nerve conduction (e.g., peroneal motor nerve conduction velocity: r = -0.346) and positively with AGE reader measurements in type 2 diabetes (r = 0.358, all P < 0.05), but not in NGT. Higher baseline AGE autofluorescence and lower endothelial cell area predicted the deterioration of clinical and neurophysiological measures after 5 years.

Cutaneous AGE markers were associated with neurophysiological deficits in recent-onset type 2 diabetes and predicted their progression after 5 years, substantiating the role of carbonyl stress in the development of early DSPN.

While recent studies suggested a potential causal link between type 1 diabetes mellitus (T1DM) but not type 2 diabetes mellitus (T2DM) and idiopathic pulmonary fibrosis (IPF), the involved mechanism remains unclear. Here, using a Mendelian randomization (MR) approach, we verified the causal relationship between the two types of diabetes mellitus and IPF and investigated the possible role of inflammation in the association between diabetes mellitus and IPF. Based on genome-wide association study (GWAS) summary data of T1DM, T2DM, and IPF, the univariable MR, multivariable MR (MVMR), and mediation MR were successively used to analyze the causal relationship. Inverse variance weighted was used as the main method to infer the causal effect, together with a series of sensitivity analyses. The univariable MR showed that only T1DM increased the risk of IPF, and there was no significant causal relationship between T2DM and IPF. The MVMR further verified that there was an independent direct causal effect of T1DM on IPF. Further mediation analysis showed that this effect was partly mediated by increasing C-X-C motif chemokine ligand 10 (CXCL10) and interleukin-12 subunit beta (IL-12B). In conclusion, T1DM is related to an increased risk of IPF. Notably, the causal effect was partially mediated by CXCL10 and IL-12B. Hence, monitoring T1DM patients may help in the early detection and prevention of IPF.

This study investigated the role of brain-derived neurotrophic factor (BDNF) in patients with degenerative lumbar stenosis, focusing on its expression and correlation with pain intensity. The study examined 96 patients with lumbar stenosis and 85 control participants. BDNF levels in the yellow ligamentum flavum were measured using reverse transcription quantitative polymerase chain reaction (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), and western blot analysis. The results showed significantly higher BDNF expression at both messenger ribonucleic acid (mRNA; fold change = +1.35 ± 0.23; p < 0.05) and protein levels in patients (28.98 ± 6.40 pg/mg) compared to controls (4.56 ± 1.98 pg/mg; p < 0.05). Furthermore, BDNF levels correlated positively with pain intensity reported by patients, with higher expression observed in those experiencing more severe pain. The study also explored the influence of lifestyle factors, such as smoking and alcohol consumption, and related diseases, such as diabetes, on BDNF expression. Smoking, alcohol use, and diabetes were associated with significantly elevated BDNF levels (p < 0.05). These findings suggest that BDNF could serve as a biomarker for pain severity in degenerative lumbar stenosis at the protein level, although this was not consistently observed at the mRNA level; this highlights the potential for BDNF-targeted therapies in managing pain. Future research should involve larger longitudinal studies to validate these findings and explore therapeutic interventions. This study underscores the importance of considering molecular and lifestyle factors in the treatment of degenerative lumbar stenosis, aiming to improve patient outcomes through comprehensive, targeted approaches.

The term "Diabetic neuropathy" refers to a collection of clinical and subclinical symptoms caused by problems with the peripheral nervous system. Diabetes, which affects approximately 381 million people worldwide, is the source of dysfunction due to the emergence of microvascular complications. It is anticipated that in the next ten years, Diabetic neuropathy will manifest in about 50% of patients who are currently diagnosed with diabetes. Clinical diagnosis can be established by getting a thorough patient history and exploring the symptoms to rule out alternative causes. Although distal symmetrical polyneuropathy, or just, is the most common and well-researched variant of the disorder, this review will concentrate on it. The multifactorial pathogenesis is linked to various inflammatory, vascular, metabolic, and neurodegenerative illnesses. The three fundamental molecular alterations that lead to the development of diabetic neuropathic pain are oxidative stress, endothelial dysfunction, and chronic inflammation. These three elements are crucial in the development of polyneuropathy because their combination might result in direct axonal damage and nerve ischemia. The purpose of this article was to provide a narrative review of diabetic neuropathy. We provide an overview of the most recent data on biomarkers, the pathogenesis of the illness, the most recent epidemiology of diabetic neuropathy, and the existing screening and diagnosis outcome measures used in both clinical and research contexts.

Diabetic peripheral neuropathy (DPN) is a complication of diabetes that occurs in 40 - 60 million individuals worldwide and is associated with other chronic diseases. However, there are no review studies that present the state-of- the- art and technologies developed to circumvent this important health problem.

This review was conducted based on scientific papers and patents. The papers were retrieved from Lilacs, PubMed, and Web of Science databases, and the patents from INPI, ESPACENET, WIPO, and GOOGLE PATENTS. Thus, a sample consisting of 14 scientific articles and 667 patents was analyzed.

From the analysis of the data, we drew an overview of the development of biomedical technologies for DPN and detected the pioneering spirit of China, the USA, and Japan in the area, with a focus on the treatment of DPN. Based on this, we carried out a SWOT analysis to help direct future efforts in the area, which should focus primarily on developing technologies for prevention, early diagnosis, and, above all, cure of the disease to reduce the important impact of this disease in various sectors of society.

This study finds a concentration of diabetic peripheral neuropathy products, especially therapeutic drugs, in high-income countries. It highlights the need for global collaboration and strategic focus on therapeutic adherence and preventive strategies to effectively manage DPN.

Distal sensorimotor polyneuropathy (DSPN) is a common neurological disorder in elderly adults and people with obesity, prediabetes and diabetes and is associated with high morbidity and premature mortality. DSPN is a multifactorial disease and not fully understood yet.

Here, we developed the Interpretable Multimodal Machine Learning (IMML) framework for predicting DSPN prevalence and incidence based on sparse multimodal data. Exploiting IMMLs interpretability further empowered biomarker identification. We leveraged the population-based KORA F4/FF4 cohort including 1091 participants and their deep multimodal characterisation, i.e. clinical data, genomics, methylomics, transcriptomics, proteomics, inflammatory proteins and metabolomics.

Clinical data alone is sufficient to stratify individuals with and without DSPN (AUROC = 0.752), whilst predicting DSPN incidence 6.5 ± 0.2 years later strongly benefits from clinical data complemented with two or more molecular modalities (improved ΔAUROC > 0.1, achieved AUROC of 0.714). Important and interpretable features of incident DSPN prediction include up-regulation of proinflammatory cytokines, down-regulation of SUMOylation pathway and essential fatty acids, thus yielding novel insights in the disease pathophysiology.

These may become biomarkers for incident DSPN, guide prevention strategies and serve as proof of concept for the utility of IMML in studying complex diseases.

Diabetic Neuropathy (DN) is one of the most frequent chronic complications of diabetes mellitus. Its commonest form, distal symmetrical polyneuropathy (DSPN), is characterised by slowly progressing length-dependent nerve damage in the lower limbs, increasing the risk of foot ulcerations and leading to symptoms like tingling, pain, or numbness.

The aim of this review was to discuss the utility of cilostazol, a phosphodiesterase inhibitor with known antiplatelet, vasodilatory, anti-inflammation properties, in the treatment of DSPN.

Preclinical studies in animals have demonstrated the ability of cilostazol to improve nerve function and to protect from peripheral nerve disruption and central sensitisation. However, clinical trials in humans are very sparse and have so far not been encouraging.

Further research is needed to fully understand the mechanisms and potential efficacy of cilostazol in treating DSPN.

Pidanjiangtang (PDJT) is a traditional Chinese medicine formula empirically used to treat impaired glucose tolerance (IGT) based on the "Pidan" theory from the classic ancient book Nei Jing. However, the mechanism of PDJT intervention for IGT remains to be studied.

This study aims to explore the mechanism of PDJT granules intervention in IGT by integrating gut microbiome and UHPLC-MS untargeted metabolomics.

The IGT model was established in 6-week-old male Sprague-Dawley (SD) rats by feeding them a high-fat diet and using an STZ injection. The low, medium, and high doses of PDJT were used for six weeks. metformin (Glucophage) was used as the positive control drug. The efficacy of PDJT was evaluated using fasting blood glucose (FBG), blood glucose maximum (BGmax), blood lipid, and inflammatory factor levels. Finally, 16S rDNA gut microbiome sequencing with metabolomics analysis was used to explore the pharmacological mechanism of PDJT intervention in IGT.

PDJT could reverse the phenotype of IGT rats, reduce blood glucose levels, improve lipid metabolism disorder, and reduce inflammatory response. Gut microbiome analysis found that PDJT can improve gut microbiota composition and abundance of three phyla (Firmicutes, Bacteroidota, Desulfobacterota) and four genera (unclassified_f__Lachnospiraceae, Ruminococcus, Allobaculum, Desulfovibrio), which play an important role in the process of PDJT intervention on glucose metabolism and lipid metabolism in IGT rats. UHPLC-MS untargeted metabolomics showed that PDJT could regulate the levels of 258 metabolites in lipid metabolism pathways, inflammatory response pathways, fat and protein digestion, and absorption. The combined analysis of the two omics showed that improving the body's metabolism by gut microbes may be the possible mechanism of PDJT in treating IGT. Thus, this study provides a new method to integrate gut microbiome and UHPLC-MS untargeted metabolomics to evaluate the pharmacodynamics and mechanism of PDJT intervention in IGT, providing valuable ideas and insights for future research on the treatment of IGT with traditional Chinese medicine.

Autoimmune nodopathies comprise a newly-established subtype of immune-mediated peripheral neuropathies, characterized by circulating autoantibodies that target nodal-paranodal proteins, including contactin-1 (CNTN1), contactin-associated protein-1 (Caspr1), neurofascin-155 (NF155) and neurofascin-isoforms (NF140 and NF186). Emerging evidence suggests that diabetes mellitus (DM) may confer increased risk for autoimmune nodopathies.

A systematic search was performed including studies reporting on patients harboring nodal/paranodal antibodies (CNTN1, Caspr1, NF155, NF140 and NF186). We sought to evaluate: (1) the prevalence of DM among patients with autoimmune nodopathies; (2) the phenotype of DM-patients harboring different types of nodal/paranodal antibodies; (3) clinical features that allow distinction of autoimmune nodopathies from diabetic peripheral neuropathy (DPN).

Five cohort studies, 3 case-reports and one case-series study were identified comprising 114 patients with autoimmune nodopathies. DM prevalence was documented to range between 10.5 % and 60 %. DM-patients harbored mostly paranodal antibodies; CNTN1: 58.3 %, followed by pan-neurofascin: 33.3 %, and Caspr1: 25 % antibodies. No significant differences in clinical phenotype were uncovered between DM-patients and their non-DM counterparts. Overall, DM patients were refractory to intravenous-immunoglobulins (IVIG), but responded well to escalation immunotherapies. Compared to DPN, distinctive features of autoimmune nodopathy comprised: (i) severe ataxia, tremor, and cranial nerve involvement; (ii) neurophysiological findings indicative of nodal-paranodal pathology, including (reversible) conduction failure and conduction velocity slowing, often accompanied by reduced compound muscle and sensory nerve action potentials; and (iii) marked protein-elevation or albuminocytological dissociation in cerebrospinal fluid analysis.

DM patients fall under the typical clinical phenotype of autoimmune nodopathy, displaying predominantly paranodal antibodies. Early suspicion is crucial, as unlike DPN, diagnosis of autoimmune nodopathy unfolds therapeutic perspectives.

Oxidative stress is a risk factor for distal sensorimotor polyneuropathy (DSPN). Selenoprotein P is a protein with antioxidant properties but has not been investigated in the context of DSPN. This study aimed to assess the associations between selenoprotein P and DSPN in people without and with type 2 diabetes (T2D).

Cross-sectional and prospective analyses were based on 1053 (including 217 with T2D) and 513 participants (including 79 with T2D), respectively, aged 61-82 years from the population-based KORA F4 survey. DSPN at baseline (KORA F4) and in the follow-up survey KORA FF4 was defined based on the Michigan Neuropathy Screening Instrument. Serum levels of full-length selenoprotein P were quantified by ELISA. Associations between selenoprotein P and prevalent or incident DSPN were estimated using logistic regression analysis adjusting for multiple confounders.

Selenoprotein P levels were not associated with prevalent DSPN in the total sample. However, there was a significant interaction by diabetes status. Higher levels of selenoprotein P were associated with lower odds of prevalent DSPN in individuals without T2D (fully adjusted model: OR 0.825 [95 % CI 0.682, 0.998], p = 0.0476), but not in those with T2D (OR [95 % CI] 1.098 [0.829, 1.454], p = 0.5132; pinteraction = 0.0488). Selenoprotein P levels were not associated with incident DSPN over a follow-up of 6.5 years.

In individuals without T2D from the older general population, lower selenoprotein P levels were associated with a higher prevalence of DSPN. Whether the antioxidant properties of selenoprotein P are responsible for the observed associations remains to be elucidated in future research.

Diabetic peripheral neuropathy (DPN) is a prevalent and debilitating complication of diabetes, often leading to severe neuropathic pain. Although other diabetes-related complications have witnessed a surge of emerging treatments in recent years, DPN has seen minimal progression. This stagnation stems from various factors, including insensitive diagnostic methods and inadequate treatment options for neuropathic pain.

In this comprehensive review, we highlight promising novel diagnostic techniques for assessing DPN, elucidating their development, strengths, and limitations, and assessing their potential as future reliable clinical biomarkers and endpoints. In addition, we delve into the most promising emerging pharmacological and mechanistic treatments for managing neuropathic pain, an area currently characterized by inadequate pain relief and a notable burden of side effects.

Skin biopsies, corneal confocal microscopy, transcutaneous electrical stimulation, blood-derived biomarkers, and multi-omics emerge as some of the most promising new techniques, while low-dose naltrexone, selective sodium-channel blockers, calcitonin gene-related peptide antibodies, and angiotensin type 2 receptor antagonists emerge as some of the most promising new drug candidates.

Our review concludes that although several promising diagnostic modalities and emerging treatments exist, an ongoing need persists for the further development of sensitive diagnostic tools and mechanism-based, personalized treatment approaches.

Nearly half of patients with diabetes experience diabetic peripheral neuropathy (DPN), resulting in a mere 53% survival rate within 3 years. Aberrations in coagulation function have been implicated in the pathogenesis of microvascular complications, prompting the need for a thorough investigation into its role as a contributing factor in the development and progression of DPN.

Data were gathered from 1211 type 2 diabetes patients admitted to five centers from September 2018 to October 2022 in China. DPN was evaluated by symptoms and electromyography. Motor and sensory nerve conduction velocity (NCV) was appraised and the NCV sum score was calculated for the median, ulnar, and peroneal motor or sensory nerves.

Patients with DPN exhibited alterations in coagulation function. (i) Specifically, they exhibited prolonged thrombin time (p = 0.012), elevated fibrinogen (p < 0.001), and shortened activated partial thromboplastin time (APTT; p = 0.026) when compared to the control group. (ii) After accounting for potential confounders in linear regression, fibrinogen, and D-dimer were negatively related to the motor NCV, motor amplitude values, and mean velocity and amplitude. Also, fibrinogen was associated with higher Michigan neuropathy screening instrument (MNSI) scores (β 0.140; p = 0.001). This result of fibrinogen can be validated in the validation cohort with 317 diabetic patients. (iii) Fibrinogen was independently associated with the risk of DPN (OR 1.172; p = 0.035). In the total age group, DPN occurred at a slower rate until the predicted fibrinogen level reached around 3.75 g/L, after which the risk sharply escalated.

Coagulation function is warranted to be concerned in patients with type 2 diabetes to predict and prevent the occurrence of DPN in clinical practice.

Diabetic peripheral neuropathy (DPN) is the most dominant cause of neuropathy worldwide, and there has been no specific treatment until now. The aim of the current study was to assess the probable protective effect of empagliflozin in type 2 diabetics who are suffering from DPN.

Fifty eligible type 2 diabetes mellitus (T2DM) cases with diabetic peripheral neuropathy were recruited in this study and classified into 2 groups. Group I (n=25) (control group) received placebo tablets once daily. Group II (n=25) (empagliflozin group) received empagliflozin 25mg once daily for three months. Empagliflozin efficacy was evaluated using electrophysiological studies, and HbA1c levels, the brief pain inventory short-form item (BPI-SF) score, the diabetic neuropathy symptom (DNS) score, the atherosclerotic cardiovascular disease (ASCVD) risk score, and the serum levels of neuron-specific enolase (NSE), malondialdehyde (MDA) and calprotectin (Calpro), lipid profile, and random blood glucose level (RBG).

After three months, comparing the results of the empagliflozin arm to the control arm showed a significant improvement in the electrophysiological studies and a significant decrease in the BPI-SF score and the mean serum levels of NSE and MDA. However, no significant difference was determined in HbA1c, Calpro, lipid profile, and RBG levels. In addition, the DNS and ASCVD risk scores were not significantly different. The NSE and MDA levels were significantly negatively correlated with the electrophysiological parameters. However, the BPI-SF score showed a non-significant difference.

Empagliflozin may be a promising neuroprotective and therapeutic agent for diabetic peripheral neuropathy. Trial registration Identifier: NCT05977465.

The early diagnosis of diabetic neuropathy (DN) is fundamental in order to enact timely therapeutic strategies for limiting disease progression. In this work, we explored the suitability of standing balance task for identifying the presence of DN. Further, we proposed two diagnosis pathways in order to succeed in distinguishing between different stages of the disease. We considered a cohort of non-neuropathic (NN), asymptomatic neuropathic (AN), and symptomatic neuropathic (SN) diabetic patients. From the center of pressure (COP), a series of features belonging to different description domains were extracted. In order to exploit the whole information retrievable from COP, a majority voting ensemble was applied to the output of classifiers trained separately on different COP components. The ensemble of kNN classifiers provided over 86% accuracy for the first diagnosis pathway, made by a 3-class classification task for distinguishing between NN, AN, and SN patients. The second pathway offered higher performances, with over 97% accuracy in identifying patients with symptomatic and asymptomatic neuropathy. Notably, in the last case, no asymptomatic patient went undetected. This work showed that properly leveraging all the information that can be mined from COP trajectory recorded during standing balance is effective for achieving reliable DN identification. This work is a step toward a clinical tool for neuropathy diagnosis, also in the early stages of the disease.

Diabetic distal symmetric sensorimotor polyneuropathy (DSPN) is a common complication of diabetes with devastating consequences. Hyperglycaemia is the major aetiological factor, while emerging data demonstrate that cardiometabolic risk factors also contribute to its development. Diagnosis of DSPN involves interview of medical and neurological history, foot inspection, and sensory and motor function examination with specific tests such as temperature and pinprick perception for small nerve fibers, and vibration and light touch assessments for large nerve fibers. Management includes optimised glycaemic control, treatment of cardiovascular risk factors, and symptomatic treatment aiming at improving life quality. This article provides an overview on epidemiology, risk factors, classification, diagnosis and current treatment of DSPN.

Advances in soft materials, miniaturized electronics, sensors, stimulators, radios, and battery-free power supplies are resulting in a new generation of fully implantable organ interfaces that leverage volumetric reduction and soft mechanics by eliminating electrochemical power storage. This device class offers the ability to provide high-fidelity readouts of physiological processes, enables stimulation, and allows control over organs to realize new therapeutic and diagnostic paradigms. Driven by seamless integration with connected infrastructure, these devices enable personalized digital medicine. Key to advances are carefully designed material, electrophysical, electrochemical, and electromagnetic systems that form implantables with mechanical properties closely matched to the target organ to deliver functionality that supports high-fidelity sensors and stimulators. The elimination of electrochemical power supplies enables control over device operation, anywhere from acute, to lifetimes matching the target subject with physical dimensions that supports imperceptible operation. This review provides a comprehensive overview of the basic building blocks of battery-free organ interfaces and related topics such as implantation, delivery, sterilization, and user acceptance. State of the art examples categorized by organ system and an outlook of interconnection and advanced strategies for computation leveraging the consistent power influx to elevate functionality of this device class over current battery-powered strategies is highlighted.

Diabetic foot ulcer is a serious and common complication of diabetes that often leads to significant morbidity and even amputation if not properly treated. Current treatment options, such as wound dressing, have limitations in promoting efficient healing. There is a need for effective interventions that can expedite the healing process and enhance the time required for complete healing.

This prospective single-blinded randomized control trial studied diabetic mellitus type 2 patients with ulcer in their second-degree feet from February 2019 to February 2023 in the Diabetic Foot Center, King Fahad Specialist Hospital Al Qassim-KSA.

This study involved 120 patients with a mean age of 59.64 ± 10.21. And 63% to 52.5% of them were males and 57% to 47.5% were females. The mean healing time was about 12.76 ± 4.08 days. Cases were divided into 4 equal groups with altered treatment procedures: honey alone, hydrogel alone, honey, and hydrogel combination alternately (3 intervention groups), and fucidin ointment or cream alone (1 control group), with 30 participants in each group. We revealed that the mean healing times for honey alone, hydrogel alone, and honey and hydrogel alternately were 12.20, 13.97, and 10.83 days, respectively. While it was 14.03 days in the control Fucidin ointment or cream [significantly P < .05 (P = .004)].

From the findings of the present study, we noticed that faster healing time among diabetic foot cases could be accomplished by treatment with a combination of honey and hydrogel alternately. Therefore, this therapy is effective in reducing the risk of diabetic foot ulcers.

Huangqi Guizhi Wuwu Decoction (HGWD) is a classic traditional Chinese herbal formula from "Synopsis of Golden Chamber," which is used to treat blood stagnation and has been used for alleviating diabetic peripheral neuropathy (DPN) in the clinic. However, the mechanisms of HGWD intervention DPN are still to be discovered.

This study aims to explore the mechanism of HGWD intervention DPN by integrating plasma metabolomics and gut microbiome.

BKS Cg-m+/+Leprdb/J (db/db) mice with DPN were at 16 weeks of age. The indices of DPN phenotypes in db/db mice, pathomorphology of the sciatic nerve, intraepithelial nerve fibers (IENF) of the foot pad, levels of blood lipids and oxidative stress, and inflammatory reaction were used to appraise the HGWD efficacy. Finally, the pharmacological mechanisms of HGWD intervening DPN were explored by metabolomics and 16S rRNA gene sequencing.

HGWD reversed DPN phenotypes in db/db mice, improved peripheral nerve structure, ameliorated the level of blood lipids and nerve growth factor in plasma, enhanced antioxidant capacity, and alleviated inflammatory responses. Plasma metabolomics disclosed that HGWD remarkably regulated the unusual levels of thirty-seven metabolites involved in sphingolipid metabolism, biosynthesis of unsaturated fatty acids, arachidonic acid metabolism, and amino acid biosynthesis pathways. The gut microbiome showed that nine bacteria were highly correlated with the efficacy of HGWD in DPN. Integrating analysis of microbiome and metabolomics demonstrated that the interaction of four bacteria with four metabolic pathways might be the significant mechanism of HGWD intervention in DPN.

The mediation of gut microbiota and plasma metabolism may be the potential mechanism of HGWD ameliorating DPN in db/db mice. The interaction of Lactobacillus, Alloprevotella, Bacteroides, and Desulfovibio with four metabolic pathways might be the critical mechanism for HGWD treating DPN.

The field of biomarker discovery is rapidly expanding. The introduction of ultrasensitive immunoassays and the growing precision of genetic technologies are poised to revolutionise the assessment and monitoring of many diseases. Given the difficulties in imaging and tissue diagnosis, there is mounting interest in serum and cerebrospinal fluid biomarkers of peripheral neuropathy. Realised and potential fluid biomarkers of peripheral nerve disease include neuronal biomarkers of axonal degeneration, glial biomarkers for peripheral demyelinating disorders, immunopathogenic biomarkers (such as the presence and titre of antibodies or the levels of cytokines) and genetic biomarkers. Several are already starting to inform clinical practice, whereas others remain under evaluation as potential indicators of disease activity and treatment response. As more biomarkers become available for clinical use, it has become increasingly difficult for clinicians and researchers to keep up-to-date with the most recent discovery and interpretation. In this review, we aim to inform practising neurologists, neuroscientists and other clinicians about recent advances in fluid biomarker technology, with a focus on single molecule arrays (Simoa), chemiluminescent enzyme immunoassays (CLEIA), electrochemiluminescence (ECL), proximity extension assays (PEA), and microfluidic technology. We discuss established and emerging fluid biomarkers of peripheral neuropathy, their clinical applications, limitations and potential future developments.

Diabetes is a chronic disease that can lead to a variety of complications and even cause death. The signal characteristics of the photoplethysmography signals (PPG) and electrocardiogram signals (ECG) can reflect the autonomic and vascular aspects of the effects of diabetes on the body.

Based on the complex mechanism of interaction between PPG and ECG, a set of ensemble empirical mode decomposition-independent component analysis (EEMD-ICA) fusion multi-scale percussion entropy index (MSPEI) method was proposed to analyze cardiovascular function in diabetic patients.

Firstly, the original signal was decomposed into multiple Intrinsic Mode Function (IMFs) by ensemble empirical mode decomposition EEMD, principal components of IMF were extracted by independent component analysis (ICA), then the extracted principal components were reconstructed to eliminate the complex high and low frequency noise of physiological signals. In addition, the MSPEI was calculated for the ECG R-R interval and PPG amplitude sequence.(RRI and Amp) The results showed that, compared with EEMD method, the SNR of EEMD-ICA method increases from 2.1551 to 11.3642, and the root mean square error (RMSE) decreases from 0.0556 to 0.0067. This algorithm can improve the performance of denoising and retain more feature information. The large and small scale entropy of MSPEI (RRI,Amp) was significantly different between healthy and diabetic patients (p< 0.01).

Compared with arteriosclerosis index (AI) and multi-scale cross-approximate entropy (MCAE): MSPEISS (RRI,Amp) indicated that diabetes can affect the activity of human autonomic nervous system, while MSPEILS (RRI,Amp) indicated that diabetes can cause or worsen arteriosclerosis.

Multi-scale Percussion Entropy algorithm has more advantages in analyzing the influence of diabetes on human cardiovascular and autonomic nervous function.

Type 2 diabetes mellitus (T2DM) is characterized by tissue-specific insulin resistance and pancreatic β-cell dysfunction, which result from the interplay of local abnormalities within different tissues and systemic dysregulation of tissue crosstalk. The main local mechanisms comprise metabolic (lipid) signalling, altered mitochondrial metabolism with oxidative stress, endoplasmic reticulum stress and local inflammation. While the role of endocrine dysregulation in T2DM pathogenesis is well established, other forms of inter-organ crosstalk deserve closer investigation to better understand the multifactorial transition from normoglycaemia to hyperglycaemia. This narrative Review addresses the impact of certain tissue-specific messenger systems, such as metabolites, peptides and proteins and microRNAs, their secretion patterns and possible alternative transport mechanisms, such as extracellular vesicles (exosomes). The focus is on the effects of these messengers on distant organs during the development of T2DM and progression to its complications. Starting from the adipose tissue as a major organ relevant to T2DM pathophysiology, the discussion is expanded to other key tissues, such as skeletal muscle, liver, the endocrine pancreas and the intestine. Subsequently, this Review also sheds light on the potential of multimarker panels derived from these biomarkers and related multi-omics for the prediction of risk and progression of T2DM, novel diabetes mellitus subtypes and/or endotypes and T2DM-related complications.

Diabetic peripheral neuropathy (DPN) is found in around one third of people with diabetes, but remains inadequately diagnosed and treated. Its management includes three cornerstones: 1) causal treatment with lifestyle modification, intensive diabetes therapy aimed at near-normoglycemia, and multifactorial cardiovascular risk intervention, 2) pathogenesis-oriented pharmacotherapy, and 3) symptomatic pain relief. Since symptomatic analgesic monotherapy only relieves the pain without targeting the underlying neuropathy and both has limited efficacy and is associated with adverse events, there is an unmet need for additional approaches derived from the pathogenetic concepts of DPN. Preclinical studies have suggested that diabetic neuropathy can be prevented or improved through the use of various agents that interfere with the pathophysiology of the underlying condition. Some of these encouraging findings could be translated successfully into the clinical setting. Efficacy and excellent safety were demonstrated in several meta-analyses (α-lipoic acid) and randomized clinical trials (benfotiamine, actovegin, epalrestat) in the treatment of symptomatic DPN. The NATHAN 1 trial demonstrated an improvement of neuropathic signs (deficits, impairments) after four years in asymptomatic DPN. These compounds are currently authorized for treatment of DPN in several countries. Long-term pivotal clinical trials should further establish their value as mono- and combination therapies in DPN.

Introduction: Diabetic distal symmetric polyneuropathy (DDSP) is the most prevalent form of diabetic peripheral neuropathy, and 25% of patients develop pain in their toes. DDSP is associated with increased cutaneous microvessel density (MVD), reduced skin blood flow, endothelial dysfunction, and impaired fluid filtration with vasodilation. The Piezo family of mechanosensitive channels is known to be involved in the control of vascular caliber by converting mechanical force into intracellular signals. Furthermore, Piezo2 is particularly involved in peripheral pain mechanisms of DDSP patients. To date, very little is known about the number, structure, and PIEZO expression in cutaneous blood vessels (BVs) of individuals with DDSP and their relation with pain and time span of diabetes. Methods and results: We studied microvessels using endothelial markers (CD34 and CD31) and smooth cell marker (α-SMA) by indirect immunohistochemical assay in sections of the glabrous skin of the toes from patients and controls. MVD was assessed through CD34 and CD31 immunoreaction. MVD determined by CD34 is higher in short-term DDSP patients (less than 15 years of evolution), regardless of pain. However, long-term DDSP patients only had increased BV density in the painful group for CD31. BVs of patients with DDSP showed structural disorganization and loss of shape. The BVs affected by painful DDSP underwent the most dramatic structural changes, showing rupture, leakage, and abundance of material that occluded the BV lumen. Moreover, BVs of DDSP patients displayed a Piezo1 slight immunoreaction, whereas painful DDSP patients showed an increase in Piezo2 immunoreaction. Discussion: These results suggest that alterations in the number, structure, and immunohistochemical profile of specific BVs can explain the vascular impairment associated with painful DDSP, as well as the temporal span of diabetes. Finally, this study points out a possible correlation between increased vascular Piezo2 immunostaining and pain and decreased vascular Piezo1 immunostaining and the development of vasodilation deficiency.

To investigate the relationship between neurofilament light chain (NfL) and the presence and severity of diabetic polyneuropathy (DPN).

We performed cross-sectional analysis of data from 178 participants of the ADDITION-Denmark cohort of people with screen-detected type 2 diabetes and 32 healthy controls. Biobank serum samples were analyzed for NfL using single-molecule array. DPN was defined by Toronto criteria for confirmed DPN. Original and axonal nerve conduction study (NCS) sum z-scores were used as indicators of the severity of DPN and peripheral nerve damage.

39 (21.9%) participants had DPN. Serum NfL (s-NfL) was significantly higher in participants with DPN (18.8 ng/L [IQR 14.4; 27.9]) than in participants without DPN (15.4 ng/L [IQR 11.7; 20.1]). There were no unadjusted s-NfL differences between controls (17.6 ng/L [IQR 12.7; 19.8]) and participants with or without DPN. Higher original and axonal NCS sum z-scores were associated with 10% higher s-NfL (10.2 and 12.1% [95% CI's 4.0; 16.8 and 6.6; 17.9] per 1 SD). The AUC of s-NfL for DPN was 0.63 (95% CI 0.52; 0.73).

S-NfL is unlikely to be a reliable biomarker for the presence of DPN. S-NfL is however associated tothe severity of the nerve damage underlying DPN.

Neuropathy is among the most often reported consequences of diabetes and the biggest cause of morbidity and mortality in people suffering from this life-long disease. Although different therapeutic methods are available for diabetic neuropathy, it is still the leading cause of limb amputations, and it significantly decreases patients' quality of life.

This study investigates potential novel therapeutic options that could ameliorate symptoms of DN.

Research and review papers from the last 10 years were taken into consideration.

There are various traditional drugs and non-pharmacological methods used to treat this health condition. However, the research in the area of pathogenic-oriented drugs in the treatment of DN showed no recent breakthroughs, mostly due to the limited evidence about their effectiveness and safety obtained through clinical trials. Consequently, there is an urgent demand for the development of novel therapeutic options for diabetic neuropathy.

Some of the latest novel diagnostic methods for diagnosing diabetic neuropathy are discussed as well as the new therapeutic approaches, such as the fusion of neuronal cells with stem cells, targeting gene delivery and novel drugs.

Diabetic neuropathy (DN) is the most prevalent complication of diabetes. Pharmacological treatments for DN are often limited in efficacy, so the development of new agents to alleviate DN is essential. The aim of this study was to evaluate the effects of rolipram, a selective phosphodiesterase-4 inhibitor (PDE-4I), and pentoxifylline, a general PDE inhibitor, using a rat model of DN. In this study, a diabetic rat model was established by i.p. injection of STZ (55 mg/kg). Rats were treated with rolipram (1 mg/kg), pentoxifylline (100 mg/kg), and combination of rolipram (0.5 mg/kg) and pentoxifylline (50 mg/kg), orally for 5 weeks. After treatments, sensory function was assessed by hot plate test. Then rats were anesthetized and dorsal root ganglion (DRG) neurons isolated. Cyclic adenosine monophosphate (cAMP), adenosine triphosphate (ATP, adenosine diphosphate and mitochondrial membrane potential (MMP) levels, Cytochrome c release, Bax, Bcl-2, caspase-3 proteins expression in DRG neurons were assessed by biochemical and ELISA methods, and western blot analysis. DRG neurons were histologically examined using hematoxylin and eosin (H&E) staining method. Rolipram and/or pentoxifylline significantly attenuated sensory dysfunction by modulating nociceptive threshold. Rolipram and/or pentoxifylline treatment dramatically increased the cAMP level, prevented mitochondrial dysfunction, apoptosis and degeneration of DRG neurons, which appears to be mediated by inducing ATP and MMP, improving cytochrome c release, as well as regulating the expression of Bax, Bcl-2, and caspase-3 proteins, and improving morphological abnormalities of DRG neurons. We found maximum effectiveness with rolipram and pentoxifylline combination on mentioned factors. These findings encourage the use of rolipram and pentoxifylline combination as a novel experimental evidence for further clinical investigations in the treatment of DN.

Metabolic disorders are a public health issue because of the complications they cause, but they are also a major risk factor for the onset of gout.

Dolastatin 16, a marine cyclic depsipeptide, was initially isolated from the sea hare Dolabella Auricularia by Pettit et al. Due to the lack of information regarding its bioactivity, target identification becomes an indispensable strategy for revealing the potential targets and mechanisms of action of Dolastatin 16. Network pharmacology was utilized to identify targets associated with the disease, gene ontology, and KEGG pathways. The results highlighted Matrix Metalloproteinase-9 (MMP9) as a potential target of Dolastatin 16 through network pharmacology analysis. This target was found to be primarily involved in the TNF signaling pathway and in foot ulceration-associated diabetic polyneuropathy. Furthermore, the binding mode and dynamic behavior of the complex were investigated through molecular docking and molecular dynamics studies. In the docking study, a native ligand (a hydroxamate inhibitor) and (R)-ND-336 were employed as ligand controls, demonstrating binding energy values of - 6.6 and - 8.9 kcal/mol, respectively. The Dolastatin 16 complex exhibited a strong affinity for MMP9, with a binding energy value of - 9.7 kcal/mol, indicating its high potential as an inhibitor. Molecular dynamics also confirmed the stability of the MMP9-Dolastatin complex throughout the simulation process. Dolastatin 16 has the potential to act as an MMP9 inhibitor, offering promise for accelerating the wound healing process in diabetic foot conditions.

The online version contains supplementary material available at 10.1007/s40203-023-00161-5.

The pathogenic mechanisms underlying distal symmetric polyneuropathy (DSPN), a common neuropathy in patients with diabetes mellitus (DM), are not fully understood. Here, we discover that the gut microbiota from patients with DSPN can induce a phenotype exhibiting more severe peripheral neuropathy in db/db mice. In a randomized, double-blind, and placebo-controlled trial (ChiCTR1800017257), compared to 10 patients who received placebo, DSPN was significantly alleviated in the 22 patients who received fecal microbiota transplants from healthy donors, independent of glycemic control. The gut bacterial genomes that correlated with the Toronto Clinical Scoring System (TCSS) score were organized in two competing guilds. Increased guild 1, which had higher capacity in butyrate production, and decreased guild 2, which harbored more genes in synthetic pathway of endotoxin, were associated with improved gut barrier integrity and decreased proinflammatory cytokine levels. Moreover, matched enterotype between transplants and recipients showed better therapeutic efficacy with more enriched guild 1 and suppressed guild 2. Thus, changes in these two competing guilds may play a causative role in DSPN and have the potential for therapeutic targeting.

To investigate the associations of a lifestyle score with various cardiovascular risk markers, indicators for fatty liver disease as well as MRI-determined total, subcutaneous and visceral adipose tissue mass in adults with new-onset diabetes.

This cross-sectional analysis included 196 individuals with type 1 (median age: 35 years; median body mass index (BMI): 24 kg/m²) and 272 with type 2 diabetes (median age: 53 years; median BMI: 31 kg/m²) from the German Diabetes Study. A healthy lifestyle score was generated based on healthy diet, moderate alcohol consumption, recreational activity, non-smoking and non-obese BMI. These factors were summed to form a score ranging from 0 to 5. Multivariable linear and non-linear regression models were used.

In total, 8.1% of the individuals adhered to none or one, 17.7% to two, 29.7% to three, 26.7% to four, and 17.7% to all five favorable lifestyle factors. High compared with low adherence to the lifestyle score was associated with more favorable outcome measures, including triglycerides (β (95% CI) -49.1 mg/dL (-76.7; -21.4)), low-density lipoprotein (-16.7 mg/dL (-31.3; -2.0)), and high-density lipoprotein cholesterol (13.5 mg/dL (7.6; 19.4)), glycated hemoglobin (-0.5% (-0.8%; -0.1%)), high-sensitivity C reactive protein (-0.4 mg/dL (-0.6; -0.2)), as well as lower hepatic fat content (-8.3% (-11.9%; -4.7%)), and visceral adipose tissue mass (-1.8 dm³ (-2.9; -0.7)). The dose-response analyses showed that adherence to every additional healthy lifestyle factor was associated with more beneficial risk profiles.

Adherence to each additional healthy lifestyle factor was beneficially associated with cardiovascular risk markers, indicators of fatty liver disease and adipose tissue mass. Strongest associations were observed for adherence to all healthy lifestyle factors in combination.

NCT01055093.

Diabetes sensory polyneuropathy (DSPN) is a significant complication of diabetes affecting up to 50% of patients in their lifetime and approximately 20% of patients suffer from painful diabetes neuropathic pain. DSPN - both painless and painful - leads to considerable morbidity including reduction of quality of life, increased lower limb amputations and is associated with worsening mortality. Significant progress has been made in the understanding of pathogenesis of DSPN and the last decade has seen newer techniques aimed at its earlier diagnosis. The management of painful DSPN remains a challenge despite advances made in the unravelling the pathogenesis of pain and its transmission. This article discusses the heterogenous clinical presentation of DSPN and the need to exclude key differential diagnoses. Furthermore, it reviews in detail the current diagnostic techniques involving both large and small neural fibres, their limitations and advantages and current place in the diagnosis of DSPN. Finally, the management of DSPN including newer pharmacotherapies are also discussed.

Vascular complications of diabetes pose a severe threat to human health. Prevention and treatment protocols based on a single vascular complication are no longer suitable for the long-term management of patients with diabetes. Diabetic panvascular disease (DPD) is a clinical syndrome in which vessels of various sizes, including macrovessels and microvessels in the cardiac, cerebral, renal, ophthalmic, and peripheral systems of patients with diabetes, develop atherosclerosis as a common pathology. Pathological manifestations of DPDs usually manifest macrovascular atherosclerosis, as well as microvascular endothelial function impairment, basement membrane thickening, and microthrombosis. Cardiac, cerebral, and peripheral microangiopathy coexist with microangiopathy, while renal and retinal are predominantly microangiopathic. The following associations exist between DPDs: numerous similar molecular mechanisms, and risk-predictive relationships between diseases. Aggressive glycemic control combined with early comprehensive vascular intervention is the key to prevention and treatment. In addition to the widely recommended metformin, glucagon-like peptide-1 agonist, and sodium-glucose cotransporter-2 inhibitors, for the latest molecular mechanisms, aldose reductase inhibitors, peroxisome proliferator-activated receptor-γ agonizts, glucokinases agonizts, mitochondrial energy modulators, etc. are under active development. DPDs are proposed for patients to obtain more systematic clinical care requires a comprehensive diabetes care center focusing on panvascular diseases. This would leverage the advantages of a cross-disciplinary approach to achieve better integration of the pathogenesis and therapeutic evidence. Such a strategy would confer more clinical benefits to patients and promote the comprehensive development of DPD as a discipline.

The prevalence of diabetic neuropathy is drastically increasing in the world. To halt the progression of diabetic neuropathy, there is an unmet need to have potential biomarkers for the diagnosis and new drug discovery.

To study various biomarkers involved in the pathogenesis of diabetic neuropathy.

The literature was searched with the help of various scientific databases and resources like PubMed, ProQuest, Scopus, and Google scholar from the year 1976 to 2020.

Biomarkers of diabetic neuropathy are categorised as inflammatory biomarkers such as MCP-1, VEGF, TRPV1, NF-κB; oxidative biomarkers such as adiponectin, NFE2L2; enzyme biomarkers like NADPH, ceruloplasmin, HO-1, DPP-4, PARP α; miscellaneous biomarkers such as SIRT1, caveolin 1, MALAT1, and microRNA. All biomarkers have a significant role in the pathogenesis of diabetic neuropathy.

These biomarkers have a potential role in the progression of diabetic neuropathy and can be considered as potential targets for new drug discovery.

Diabetic neuropathy is the most common microvascular complication of diabetes mellitus and a major risk factor for diabetes-related lower-extremity complications. Diffuse neuropathy is the most frequently encountered pattern of neurological dysfunction and presents clinically as distal symmetrical sensorimotor polyneuropathy. Due to the increasing public health significance of diabetes mellitus and its complications, screening for diabetic peripheral neuropathy is essential. Consequently, a review of the principles that guide screening practices, especially in resource-limited clinical settings, is urgently needed.

Numerous evidence-based assessments are used to detect diabetic peripheral neuropathy. In accordance with current guideline recommendations from the American Diabetes Association, International Diabetes Federation, International Working Group on the Diabetic Foot, and National Institute for Health and Care Excellence, a screening algorithm for diabetic peripheral neuropathy based on multiphasic clinical assessment, stratification according to risk of developing diabetic foot syndrome, individualized treatment, and scheduled follow-up is suggested for use in resource-limited settings.

Screening for diabetic peripheral neuropathy in resource-limited settings requires a practical and comprehensive approach in order to promptly identify affected individuals. The principles of screening for diabetic peripheral neuropathy are: multiphasic approach, risk stratification, individualized treatment, and scheduled follow-up. Regular screening for diabetes-related foot disease using simple clinical assessments may improve patient outcomes.

Peripheral neuropathy is common in diabetic patients and can lead to amputations or foot ulcers. microRNAs (miRNAs) possess crucial roles in diabetic peripheral neuropathy (DPN). This study aims to investigate the role miR-130a-3p played in DPN and its underlying molecular mechanisms. miR-130a-3p expression in clinical tissue samples, established DPN rat models, and extracellular vesicles (EVs) derived from adipose-derived stem cells (ADSCs) were determined. Schwann cells (SCs) were co-cultured with ADSC-derived EVs and treated with high glucose. The direct relationship and functional significance of miR-130a-3p, DNMT1, nuclear factor E2-related factor 2 (NRF2), hypoxia-inducible factor-1α (HIF1α), and skeletal muscle actin alpha 1 (ACTA1) was identified. The in vitro and in vivo implication of ADSC-derived EVs carrying miR-130a-3p was assessed. miR-130a-3p was poorly expressed in DPN patients and rats but highly expressed in ADSC-derived EVs. miR-130a-3p could be delivered to SCs through ADSC-derived EVs to inhibit SC apoptosis and promote proliferation under a high-glucose environment. miR-130a-3p activated NRF2/HIF1α/ACTA1 axis through down-regulating DNMT1. In vivo injection of ADSC-derived EVs activated NRF2/HIF1α/ACTA11 axis to promote angiogenesis in DPN rat model. These data together supported that ADSC-derived EVs carrying miR-130a-3p could alleviate DPN by accelerating SC proliferation and inhibiting apoptosis, providing a potential treatment against DPN.

Distal sensorimotor polyneuropathy (DSPN) is a common condition in older populations with high prevalence of obesity and type 2 diabetes. We hypothesised that the risk of DSPN is increased by multiple ubiquitous environmental risk factors, particularly in people with obesity. This study was based on 423 individuals aged 62-81 years without DSPN who participated in the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4 survey (2006-2008) in Southern Germany. During 6.5 years of follow-up, 188 participants developed clinical DSPN as assessed by the Michigan Neuropathy Screening Instrument. Environmental exposures, including air temperature, surrounding greenness (assessed with the normalized difference vegetation index [NDVI]), long-term road traffic noise and air pollution, were assessed at participants' residences. The cumulative risk index (CRI) evaluated the joint effects of co-occurring exposures on DSPN risk based on effect estimates from multi-exposure Poisson regression models. The models were adjusted for age, sex, height, waist circumference, smoking, alcohol consumption, physical activity, education and neighbourhood socioeconomic status. In the entire cohort, the co-occurrence of an interquartile range (IQR) decrease in temperature of the warm season and NDVI in a 100-m buffer and of an IQR increase in night-time average traffic noise and in annual average particle number concentration (PNC) was positively associated with incident DSPN (CRI [95 % CI] 1.39 [1.02, 1.91]). Effect estimates for exposure combinations were generally higher in individuals with obesity (CRI 1.34-2.01) than in those without obesity (CRI 0.90-1.33). The four-exposure model showed a twofold increased risk of DSPN among obese (CRI [95 % CI] 2.01 [1.10, 3.67]), but not among non-obese individuals (CRI [95 % CI] 1.18 [0.83, 1.67]). Thus, ubiquitous environmental exposures jointly augment the risk of DSPN in the older population. Lower air temperature in the warm season, less greenness, and higher noise levels and ultrafine particle concentrations identified people with obesity as a particularly vulnerable subgroup.