Comparison of therapeutic effects of N-Acetylcysteine with pregabalin in improving the clinical symptoms of painful diabetic neuropathy: a randomized, double-blind clinical trial.

OBJECTIVES: Painful diabetic neuropathy (PDN) is highly prevalent and annoyingly in patients with diabetes. The aim of this study was to investigate the effects of oral N-acetylcysteine (NAC) compared to pregabalin in PDN. METHODS: One hundred two eligible patients with type 2 diabetes and PDN were randomly recievied pregabalin (150 mg/day) or N-Acetylcysteine (NAC) (600 mg/ twice a day) for 8 weeks. Mean pain score, Sleep interference score (SIS), Patient Global Impression of Change (PGIC), Clinical Global Impression of Change (CGIC), and also, serum levels of total antioxidant capacity (TAC), total thiol groups (TTG), catalase activity (CAT), nitric oxide (NO), and malondialdehyde (MDA) were assessed at baseline and at the end of the study. RESULTS: NAC was well tolerated in all patients. The decrease in mean pain scores and increase in SIS was similar between two groups. More improvement in PGIC and CGIC from the baseline was reported in NAC group. NAC, significantly, decreased serum levels of MDA, and NO, but increased TAC, TTG, and CAT. Pregabalin, significantly, decreased serum levels of MDA, and NO and increased TAC. DISCUSSION: NAC is efficacious in alleviate symptoms of PDN which is probably related to its antioxidant effects. TRIAL REGISTRATION: The research protocol received approval from the Ethics Committee of Hamadan University of Medical Sciences (IR.UMSHA.REC.1397.137). The trial registry URL and number in Iranian Registry of Clinical Trials (IRCT): https://www.irct.ir/trial/33313 , IRCT20180814040795N2 (Registration date: 2019-01-21, Retrospectively registered).

A Systematic Guideline by the ASPN Workgroup on the Evidence, Education, and Treatment Algorithm for Painful Diabetic Neuropathy: SWEET.

Introduction: Painful diabetic neuropathy (PDN) is a leading cause of pain and disability globally with a lack of consensus on the appropriate treatment of those suffering from this condition. Recent advancements in both pharmacotherapy and interventional approaches have broadened the treatment options for PDN. There exists a need for a comprehensive guideline for the safe and effective treatment of patients suffering from PDN. Objective: The SWEET Guideline was developed to provide clinicians with the most comprehensive guideline for the safe and appropriate treatment of patients suffering from PDN. Methods: The American Society of Pain and Neuroscience (ASPN) identified an educational need for a comprehensive clinical guideline to provide evidence-based recommendations for PDN. A multidisciplinary group of international experts developed the SWEET guideline. The world literature in English was searched using Medline, EMBASE, Cochrane CENTRAL, BioMed Central, Web of Science, Google Scholar, PubMed, Current Contents Connect, Meeting Abstracts, and Scopus to identify and compile the evidence for diabetic neuropathy pain treatments (per section as listed in the manuscript) for the treatment of pain. Manuscripts from 2000-present were included in the search process. Results: After a comprehensive review and analysis of the available evidence, the ASPN SWEET guideline was able to rate the literature and provide therapy grades for most available treatments for PDN utilizing the United States Preventive Services Task Force criteria. Conclusion: The ASPN SWEET Guideline represents the most comprehensive review of the available treatments for PDN and their appropriate and safe utilization.

Improvement of diabetes-induced spinal cord axon injury with taurine via nerve growth factor-dependent Akt/mTOR pathway.

Diabetic neuropathy (DN) is a common neurological complication caused by diabetes mellitus (DM). Axonal degeneration is generally accepted to be the major pathological change in peripheral DN. Taurine has been evidenced to be neuroprotective in various aspects, but its effect on spinal cord axon injury (SCAI) in DN remains barely reported. This study showed that taurine significantly ameliorated axonal damage of spinal cord (SC), based on morphological and functional analyses, in a rat model of DN induced by streptozotocin (STZ). Taurine was also found to induce neurite outgrowth in cultured cerebral cortex neurons with high glucose exposure. Moreover, taurine up-regulated the expression of nerve growth factor (NGF) and neurite outgrowth relative protein GAP-43 in rat DN model and cultured cortical neurons/VSC4.1 cells. Besides, taurine increased the activating phosphorylation signals of TrkA, Akt, and mTOR. Mechanistically, the neuroprotection by taurine was related to the NGF-pAKT-mTOR axis, because either NGF-neutralizing antibody or Akt or mTOR inhibitors was found to attenuate its beneficial effects. Together, our results demonstrated that taurine promotes spinal cord axon repair in a model of SCAI in STZ-induced diabetic rats, mechanistically associating with the NGF-dependent activation of Akt/mTOR pathway.

Understanding the Clinical Relationship Between Diabetic Retinopathy, Nephropathy, and Neuropathy: A Comprehensive Review.

Diabetic retinopathy, nephropathy, and neuropathy are significant microvascular complications of diabetes mellitus, contributing to substantial morbidity and mortality worldwide. This comprehensive review examines the clinical relationship between these complications, focusing on shared pathophysiological mechanisms, bidirectional relationships, and implications for patient management. The review highlights the importance of understanding the interconnected nature of diabetic complications and adopting a holistic approach to diabetes care. Insights gleaned from this review underscore the necessity for early detection, timely intervention, and integrated care models involving collaboration among healthcare professionals. Furthermore, the review emphasizes the need for continued research to elucidate underlying mechanisms, identify novel therapeutic targets, and assess the efficacy of integrated care strategies in improving patient outcomes. By fostering interdisciplinary collaboration and knowledge exchange, future research endeavors hold the potential to advance our understanding and management of diabetic complications, ultimately enhancing patient care and quality of life.

Wearable Movement Exploration Device with Machine Learning Algorithm for Screening and Tracking Diabetic Neuropathy-A Cross-Sectional, Diagnostic, Comparative Study.

BACKGROUND: Diabetic neuropathy is one of the most common complications of diabetes mellitus. The aim of this study is to evaluate the Moveo device, a novel device that uses a machine learning (ML) algorithm to detect and track diabetic neuropathy. The Moveo device comprises 4 sensors positioned on the back of the hands and feet accompanied by a mobile application that gathers data and ML algorithms that are hosted on a cloud platform. The sensors measure movement signals, which are then transferred to the cloud through the mobile application. The cloud triggers a pipeline for feature extraction and subsequently feeds the ML model with these extracted features. METHODS: The pilot study included 23 participants. Eleven patients with diabetes and suspected diabetic neuropathy were included in the experimental group. In the control group, 8 patients had suspected radiculopathy, and 4 participants were healthy. All participants underwent an electrodiagnostic examination (EDx) and a Moveo examination, which consists of sensors placed on the feet and back of the participant's hands and use of the mobile application. The participant performs six tests that are part of a standard neurological examination, and a ML algorithm calculates the probability of diabetic neuropathy. A user experience questionnaire was used to compare participant experiences with regard to both methods. RESULTS: The total accuracy of the algorithm is 82.1%, with 78% sensitivity and 87% specificity. A high linear correlation up to 0.722 was observed between Moveo and EDx features, which underpins the model's adequacy. The user experience questionnaire revealed that the majority of patients preferred the less painful method. CONCLUSIONS: Moveo represents an accurate, easy-to-use device suitable for home environments, showing promising results and potential for future usage.

Clinical effects of combined use of carbamazepine and amitriptyline in the treatment of diabetic neuropathy with concurrent diabetic foot.

OBJECTIVE: This study aims to analyze the clinical effects of combining carbamazepine and amitriptyline in the treatment of diabetic neuropathy with concurrent diabetic foot. METHODS: A total of 120 diabetic neuropathy patients treated at our hospital from June 2022 to November 2023 were included in the study. Patients meeting the inclusion criteria were registered, and their basic data were collected. The patients were randomly divided into two groups: the control group treated with amitriptyline and the study group treated with a combination of carbamazepine and amitriptyline. RESULTS: The study group demonstrated significantly better clinical efficacy compared to the control group (p < 0.05). There were no significant differences in psychological status and pain perception before treatment between the two groups (p > 0.05). However, post-treatment, the study group showed improved psychological status, reduced pain perception, and overall better quality of life in both physiological and psychological dimensions compared to the control group (p < 0.05). CONCLUSION: The combined use of carbamazepine and amitriptyline in the treatment of diabetic neuropathy with concurrent diabetic foot yields positive clinical outcomes. It effectively alleviates symptoms, improves psychological well-being, reduces pain sensation, and enhances overall quality of life. These findings can guide physicians in adopting a more evidence-based treatment approach and provide patients with more effective individualized treatment strategies.

Efficacy of electro-acupuncture versus sham acupuncture for diabetic peripheral neuropathy: study protocol for a three-armed randomised controlled trial.

INTRODUCTION: Specific treatment for diabetic peripheral neuropathy (DPN) is still lacking, and acupuncture may relieve the symptoms. We intend to investigate the efficacy and safety of electro-acupuncture (EA) in alleviating symptoms associated with DPN in diabetes. METHODS AND ANALYSIS: This multicentre, three-armed, participant- and assessor-blind, randomised, sham-controlled trial will recruit 240 eligible participants from four hospitals in China and will randomly assign (1:1:1) them to EA, sham acupuncture (SA) or usual care (UC) group. Participants in the EA and SA groups willl receive either 24-session EA or SA treatment over 8 weeks, followed by an 8-week follow-up period, while participants in the UC group will be followed up for 16 weeks. The primary outcome of this trial is the change in DPN symptoms from baseline to week 8, as rated by using the Total Symptom Score. The scale assesses four symptoms: pain, burning, paraesthesia and numbness, by evaluating the frequency and severity of each. All results will be analysed with the intention-to-treat population. ETHICS AND DISSEMINATION: The protocol has been approved by the Ethics Committee of the Beijing University of Chinese Medicine (Identifier: 2022BZYLL0509). Every participant will be informed of detailed information about the study before signing informed consent. The results of this trial will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ChiCTR2200061408.

Prevalence of Metabolic Syndrome and Its Risk Factors Influence on Microvascular Complications in Patients With Type 1 and Type 2 Diabetes Mellitus.

BACKGROUND: Diabetes mellitus (DM) long-term macrovascular and microvascular complications pose significant health risks and increase mortality. In DM patients, metabolic syndrome (MetSy) either precedes or coexists with the condition. Central obesity, poor glycemic control, hypertension, elevated triglycerides (TG), and low high-density lipoproteins (HDL-C) are the components of MetSy. The purpose of this study is to investigate related diabetic microvascular complications in type 1 DM (T1DM) by comparing them with type 2 DM (T2DM), determine potential risk factors, and estimate prevalence based on the diagnosis of MetSy. METHODOLOGY: This study included 160 T1DM and 160 T2DM patients, totaling 320 DM patients. It was carried out from April 20, 2022, to September 31, 2023, at the Sheikh Zayed Hospital, Rahim Yar Khan, in the Outdoor Diabetic Clinic and Medicine Department. A unique questionnaire was utilized to gather socio-demographic, general, clinical, and laboratory data for the MetSy criteria set forth by the International Diabetes Federation (IDF). The blood pressure, BMI, and waist circumference (WC) were measured, while venous fasting blood was used to assess biochemical markers such as HDL-C, TG, and fasting blood sugar. The microvascular diabetes complications were identified using abdominal ultrasound, fundus ophthalmoscopy, and routine laboratory tests. We quantified and analyzed these variables individually for T1DM and T2DM patients with or without MetSy and compared them in the presence or absence of diabetes microvascular complications. RESULTS: MetSy prevalence was 25.62% (41, n=160) for T1DM and 60.62% (97, n=160) for T2DM, totaling 43.12%. Among T1DM patients with MetSy, the majority were married males, aged 36-49 years, with a BMI of 26.69±2.20 kg/m2 and a WC of 85.12±4.23, and 67.5% (108) patients had diabetes microvascular complications. Comparatively, in T2DM with MetSy, the majority were married females aged 50-59 years with a BMI of 29.79 ± 4.65 kg/m² and a large WC of 93.43±4.49, and 75% (123) patients had diabetes microvascular complications. Overall, this study noted significant p-values for hypertension, elevated TG, low HDL-c, high WC, obesity, female gender in T2DM, and above 36 years of age in both groups with MetSy. Diabetic retinopathy (DR) at 32.4% (p<0.001) was the most prevalent T1DM microvascular complication, followed by nephropathy (30.6%), neuropathy (DN) at 28.1%, and gastroparesis (DG) at 22.3%. Whereas in T2DM, the prevalence of DN was 36.3% (p<0.001), followed by DKD (29.3%), DG (28.9%), and DR (24.9%). CONCLUSION: Nearly a quarter of T1DM patients had MetSy, with increasing percentages of overweight and obese patients who are more likely to have DR, DKD, or DN. MetSy affects two-thirds of T2DM patients, with married obese females aged 50-59 being more susceptible than males, who are more likely to suffer DN, DKD, or DG. Risk factors that contribute to the MetSy burden in T1DM and T2DM include hypertension, poor glycemic management, low HDL-C, high TG, and a higher BMI or WC. Increasing age, female gender in T2DM, longer diabetes duration, and co-morbid hypertension were independent predictors of microvascular complications. DR, DN, DKD, and gastroparesis are the most prevalent diabetic microvascular sequelae. The clinical management of diabetic patients with healthy lifestyle adaptations, good glycemic control, antihypertensives, and statins will contribute greatly to MetSy prevention.

SIRT3 alleviates painful diabetic neuropathy by mediating the FoxO3a-PINK1-Parkin signaling pathway to activate mitophagy.

INTRODUCTION: Painful diabetic neuropathy (PDN) is a common complication of diabetes. Previous studies have implicated that mitochondrial dysfunction plays a role in the development of PDN, but its pathogenesis and mechanism have not been fully investigated. METHODS: In this study, we used high-fat diet/low-dose streptozotocin-induced rats as a model of type 2 diabetes mellitus. Behavioral testing, whole-cell patch-clamp recordings of dorsal root ganglion (DRG) neurons, and complex sensory nerve conduction velocity studies were used to assess peripheral neuropathy. Mitochondrial membrane potential (MMP), ATP, tissue reactive oxygen species, and transmission electron microscopy were used to evaluate the function and morphology of mitochondria in DRG. Real-time PCR, western blot, and immunofluorescence were performed to investigate the mechanism. RESULTS: We found that damaged mitochondria were accumulated and mitophagy was inhibited in PDN rats. The expression of sirtuin 3 (SIRT3), which is an NAD+-dependent deacetylase in mitochondria, was inhibited. Overexpression of SIRT3 in DRG neurons by intrathecally administered LV-SIRT3 lentivirus ameliorated neurological and mitochondrial dysfunctions. This was evidenced by the reversal of allodynia and nociceptor hyperexcitability, as well as the restoration of MMP and ATP levels. Overexpression of SIRT3 restored the inhibited mitophagy by activating the FoxO3a-PINK1-Parkin signaling pathway. The effects of SIRT3 overexpression, including the reversal of allodynia and nociceptor hyperexcitability, the improvement of impaired mitochondria and mitophagy, and the restoration of PINK1 and Parkin expression, were counteracted when FoxO3a siRNA was intrathecally injected. CONCLUSION: These results showed that SIRT3 overexpression ameliorates PDN via activation of FoxO3a-PINK1-Parkin-mediated mitophagy, suggesting that SIRT3 may become an encouraging therapeutic strategy for PDN.

MOTS-c is an effective target for treating streptozotocin induced painful diabetic neuropathy through induction of AMPK/PGC-1α -mediated mitochondrial biogenesis.

Painful Diabetic Neuropathy (PDN) is a common diabetes complication that frequently causes severe hyperalgesia and allodynia and presents treatment challenges. MOTS-c, a novel mitochondrial-derived peptide, has been shown to regulate glucose metabolism, insulin sensitivity, and inflammatory responses. This study aimed to evaluate the effects of MOTS-c in streptozocin (STZ)-induced PDN model and investigate the putative underlying mechanisms. We found that endogenous MOTS-c levels in plasma and spinal dorsal horn were significantly lower in STZ-treated mice than in control animals. Accordingly, MOTS-c treatment significantly improves STZ-induced weight loss, elevation of blood glucose, mechanical allodynia, and thermal hyperalgesia; however, these effects were blocked by dorsomorphin, an AMPK inhibitor. In addition, MOTS-c treatment significantly enhanced AMPKα1/2 phosphorylation and PGC-1α expression in the lumbar spinal cord of PDN mice. Mechanistic studies indicated that MOTS-c significantly restored mitochondrial biogenesis, inhibited microglia activation, and decreased the production of pro-inflammatory factors, which contributed to the alleviation of pain. Moreover, MOTS-c decreased STZ-induced pain hypersensitivity in PDN mice by activating AMPK/PGC-1α signaling pathway. This provides the pharmacological and biological evidence for developing mitochondrial peptide-based therapeutic agents for PDN.

A study on prevalence of diabetic peripheral neuropathy in diabetic patients attending a rural health and training centre.

Introduction: Diabetic neuropathy is a common complication, affecting up to half the diabetics. Diabetic peripheral neuropathy (DPN) predominantly affects the hands and lower limbs. It leads to loss of protective sensation, resulting in continuous injury to insensitive feet. The early detection of DPN using an objective screening test followed by its appropriate management is important, as up to 50% of diabetic peripheral neuropathies may be asymptomatic. Objectives: To screen diabetic patients attending a Rural Health and Training Centre of a medical college in Tamil Nadu for DPN. To assess the association between DPN and sociodemographic factors, duration of diabetes, glycemic control, physical activity, body mass index, smoking and habit of alcohol consumption. Materials and Methods: The study was conducted among 206 diabetic patients attending a Rural Health and Training Centre. Participants were assessed using the Michigan Neuropathy Screening Instrument (MNSI), which involves using a questionnaire followed by a physical examination. Results: Of the 206 patients, 61.2% were male, and 38.8% were female. The mean age was 50.86 years (standard deviation [SD] = 12.26 years). The mean duration of diabetes was 8.3 years (SD = 5.5 years). The proportion of diabetics who were screened positive for peripheral neuropathy was 16.5% and 21.8% using the MNSI questionnaire and examination, respectively. Age of 60 years and above was significantly associated with DPN.(OR = 3.982, P value = 0.0001). Duration of more than 5 years of diabetes was also significantly associated with DPN.(OR = 6.01, P value = 0.003). Conclusion: A high proportion of diabetics were screened positive for peripheral neuropathy, and many of them were unaware of having the complication. Many risk factors associated with DPN were reported in this study. Thus, early diagnosis and management with MNSI or any other validated screening tool in health care institutions is essential.

Humanin's impact on pain markers and neuronal viability in diabetic neuropathy model.

OBJECTIVE: This study investigates the impact of chronic humanin (HN) treatment on pain-related markers (NMDA, substance P, TRPV1, and IL-1ß) in diabetic mice's dorsal root ganglia (DRG). Additionally, we assess the effects of HN on cellular viability in DRG neurons. METHODS: In vivo experiments involved 15 days of HN administration (4 mg/kg) to diabetic mice (n = 10). Protein levels of NMDA, IL-1ß, TRPV1, and substance P were measured in diabetic DRG. In vitro experiments explored HN's impact on apoptosis and cellular viability, focusing on the JAK2/STAT3 pathway. RESULTS: Humanin significantly reduced the elevated expression of NMDA, IL-1ß, TRPV1, and substance P induced by diabetes (p < .05). Furthermore, HN treatment increased cellular viability in DRG neurons through JAK2/STAT3 pathway activation (p < .05). CONCLUSION: These findings highlight the significance of understanding mitochondrial function and pain markers, as well as apoptosis in diabetes. The study provides insights for managing the condition and its complications.

Gastrointestinal symptom burden in diabetic autonomic and peripheral neuropathy - A Danes cohort study.

OBJECTIVE: We investigated associations between gastrointestinal symptoms - evaluated as a combined weighted symptom score (CWSS) - Diabetic autonomic neuropathy (DAN), and distal symmetrical polyneuropathy (DSPN) in type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS: Cross-sectional study in a tertiary outpatient clinic. CWSS was calculated based on questionnaires: gastroparesis composite symptom index (GCSI) and gastrointestinal symptom rating score (GSRS). DAN and DSPN were addressed using the composite autonomic symptom score 31 (COMPASS-31) questionnaire, cardiac autonomic reflex tests (CARTs), electrochemical skin conductance (ESC), vibration perception threshold (VPT), Michigan Neuropathy Screening Instrument (MNSI), pain- and thermal sensation. Analyses were adjusted for age, sex, diabetes duration, smoking, LDL-cholesterol, HbA1C and systolic blood pressure. Type 1 and type 2 diabetes were evaluated separately. RESULTS: We included 566 with type 1 diabetes and 377 with type 2 diabetes. Mean ± SD age was 58 ± 15 years and 565 (59.9 %) were women. A high CWSS was present in 143 (25 %) with type 1 and 142 (38 %) with type 2 diabetes. The odds of DAN by COMPASS-31 (p < 0.001) were higher in the high score group. For type 1 diabetes, odds of cardiac autonomic neuropathy were higher in the high CWSS group. The odds of DSPN by VPT and MNSI in type 1 diabetes, and by ESC, VPT and pain sensation in type 2 diabetes were higher in the high CWSS group. CONCLUSIONS: A high symptom score was associated with neuropathy by COMPASS-31 and vibration perception. Gastrointestinal symptom burden associated inconsistently with other neuropathy tests between diabetes types.

Therapeutic Effect of Schwann Cell-Like Cells Differentiated from Human Tonsil-Derived Mesenchymal Stem Cells on Diabetic Neuropathy in db/db Mice.

BACKGROUND: Diabetic neuropathy (DN) is the most common complication of diabetes, and approximately 50% of patients with this disease suffer from peripheral neuropathy. Nerve fiber loss in DN occurs due to myelin defects and is characterized by symptoms of impaired nerve function. Schwann cells (SCs) are the main support cells of the peripheral nervous system and play important roles in several pathways contributing to the pathogenesis and development of DN. We previously reported that human tonsil-derived mesenchymal stem cells differentiated into SCs (TMSC-SCs), named neuronal regeneration-promoting cells (NRPCs), which cells promoted nerve regeneration in animal models with peripheral nerve injury or hereditary peripheral neuropathy. METHODS: In this study, NRPCs were injected into the thigh muscles of BKS-db/db mice, a commonly used type 2 diabetes model, and monitored for 26 weeks. Von Frey test, sensory nerve conduction study, and staining of sural nerve, hind foot pad, dorsal root ganglia (DRG) were performed after NRPCs treatment. RESULTS: Von Frey test results showed that the NRPC treatment group (NRPC group) showed faster responses to less force than the vehicle group. Additionally, remyelination of sural nerve fibers also increased in the NRPC group. After NRPCs treatment, an improvement in response to external stimuli and pain sensation was expected through increased expression of PGP9.5 in the sole and TRPV1 in the DRG. CONCLUSION: The NRPCs treatment may alleviate DN through the remyelination and the recovery of sensory neurons, could provide a better life for patients suffering from complications of this disease.

Metformin improves diabetic neuropathy by reducing inflammation through up-regulating the expression of miR-146a and suppressing oxidative stress.

PURPOSE: Diabetic neuropathy (DN) is a notable complication of diabetes mellitus. The potential involvement of miR-146a in DN regulation is presently under investigation. Metformin, a commonly prescribed medication for diabetes, is the primary therapeutic intervention. This study aimed to unveil the potential protective effects of metformin on diabetic neuropathy and explore the mechanisms underlying its action. METHOD: Six-weeks male Sprague Dawley rats (n = 40) were randomly divided into 5 groups. The rat model of diabetic neuropathy (DN) was established by administering streptozotocin (STZ). To investigate the effects on the sciatic nerve and resident Schwann cells (RSCs), metformin and miR-146a mimics were administered, and our research explored the potential underlying mechanism. RESULT: The sciatic nerve samples obtained from diabetic rats exhibited noticeable morphological damage, accompanied by decreased miR-146a expression (2.61 ± 0.11 vs 5.0 ± 0.3, p < 0.01) and increased inflammation levels (p65: 1.89 ± 0.04 vs 0.82 ± 0.05, p < 0.01; TNF-α: 0.93 ± 0.03 vs 0.33 ± 0.03, p < 0.01). Notably, the administration of metformin effectively ameliorated the structural alterations in the sciatic nerve by suppressing the inflammatory pathway (p65: 1.15 ± 0.05 vs 1.89 ± 0.04, p < 0.01; TNF-α: 0.67 ± 0.04 vs 0.93 ± 0.03, p < 0.01) and reducing oxidative stress (NO: 0.062 ± 0.004 vs 0.154 ± 0.004umol/mg, p < 0.01; SOD: 3.08 ± 0.09 vs 2.46 ± 0.09 U/mg, p < 0.01). The miR-146a mimics intervention group exhibited comparable findings. CONCLUSION: This study's findings implied that metformin can potentially mitigate diabetic neuropathy in rats through the modulation of miR-146a expression.

Behavior of neuropathy symptom score and neuropathy disability score in patients with and without peripheral diabetic neuropathy: A retrospective cohort study.

BACKGROUND: This study aimed to stablish cut-off of early diagnosis of diabetic polyneuropathy (PDN) based on neuropathy symptom score (NSS) and neuropathy disability score (NDS); to determine the behavior of NDD and NDS in patients with and without PDN; and to verify the association between clinical and demographic variables with both tests. METHODS: This retrospective cohort included 86 patients with diabetes. The NSS and NDS evaluations were collected in medical records in two moments: initial (entry into service) and final (after three years). Individuals were categorized in three groups: G1- PDN in both evaluations (N = 27); G2- PDN only in the final evaluation (N = 16); G3-individuals without PDN (N = 43). A ROC curve was performed to evaluate the sensitivity and specificity of NSS and NDS for PDN diagnosis. ANOVA was used to compare NSS and NDS between groups and evaluations, and multiple regression was performed to find predictors of PDN. RESULTS: The NSS and NDS showed excellent sensitivity and specificity (NDS ≥1.5 and NSS ≥6.5) for PDN diagnosis. There was a significant difference between groups in initial (p = 0.000) and final (p = 0.000) NDS and NSS evaluations. There was an association between peripheral arterial disease (PAD) and increase in NSS (p = 0.024) in G2; and association between loss of protective sensation (LOPS) and increase in NSS in G3 (p < 0.001). CONCLUSION: NSS and NDS tests showed excellent sensitivity and specificity for early PDN diagnosis. Behavior of both tests can differ patients with and without PDN. Furthermore, PAD and LOPS can be a predictor of PDN evolution.

Predicting Postsurgical Complications of Peripheral Nerve Decompression: NSQIP Analysis of Frailty Measures Versus Historic Proxies.

Background: Peripheral nerve decompression (PND) is generally safe, and newer techniques allow frail patients to undergo PND at less common sites. Current literature suggests patient frailty measures may more accurately predict postsurgical complications versus other proxies, but no current literature examines frailty in PND. Methods: The authors reviewed data from the National Surgical Quality Improvement Program for patients who underwent PND outside the most common sites from 2013 to 2019. The modified 5-Item Frailty Index (mFI-5) and modified Charlson Comorbidity Index (mCCI) scores were calculated, and complications data were gathered. Age, body mass index (BMI), major comorbidities, American Society of Anesthesiologists class, and frailty were compared as predictors of all-cause 30-day complications, 30-day surgical site complications, length of stay, and complication severity, using univariate and multivariate logistic regression. Results: Of 1120 patients, the mean age was 51.3 (15.4) years and mean BMI was 30.6 (7.0) kg/m2. Patients were predominantly white and healthy. The complication rate was 3.4%. All-cause complications were predicted by ≥3 major comorbidities (odds ratio [OR], 95% confidence interval [CI]: 6.26, 1.36-21.32; P = .007), followed by mFI-5 score and mCCI score. Complication severity was associated with major comorbidities and mFI-5 score, while length of stay was most strongly predicted by age ≥ 65 years (OR, 95% CI: 2.17, 1.37-3.42; P = .0008) and mCCI score of 3 (OR, 95% CI: 1.77, 1.01-3.05; P = 0.041). The only risk factor for readmission was mFI-5 score of 1 (OR, 95% CI: 7.00, 1.68-47.16; P = .016). Conclusions: Frailty and risk proxies may predict postoperative complications in PND at uncommon sites. Use of frailty indices may expand the age range of patients offered PND. Further research is necessary to delineate contributing risk factors and to clarify 24-hour observation and admissions.

Ginkgolide B can alleviate spinal cord glymphatic system dysfunction and provide neuroprotection in painful diabetic neuropathy rats by inhibiting matrix metalloproteinase-9.

The glymphatic system plays a crucial role in maintaining optimal central nervous system (CNS) function by facilitating the removal of metabolic wastes. Aquaporin-4 (AQP4) protein, predominantly located on astrocyte end-feet, is a key pathway for metabolic waste excretion. ß-Dystroglycan (ß-DG) can anchor AQP4 protein to the end-feet membrane of astrocytes and can be cleaved by matrix metalloproteinase (MMP)-9 protein. Studies have demonstrated that hyperglycemia upregulates MMP-9 expression in the nervous system, leading to neuropathic pain. Ginkgolide B (GB) exerts an inhibitory effect on the MMP-9 protein. In this study, we investigated whether inhibition of MMP-9-mediated ß-DG cleavage by GB is involved in the regulation of AQP4 polarity within the glymphatic system in painful diabetic neuropathy (PDN) and exerts neuroprotective effects. The PDN model was established by injecting streptozotocin (STZ). Functional changes in the glymphatic system were observed using magnetic resonance imaging (MRI). The paw withdrawal threshold (PWT) was measured to assess mechanical allodynia. The protein expressions of MMP-9, ß-DG, and AQP4 were detected by Western blotting and immunofluorescence. Our findings revealed significant decreases in the efficiency of contrast agent clearance within the spinal glymphatic system of the rats, accompanied by decreased PWT, increased MMP-9 protein expression, decreased ß-DG protein expression, and loss of AQP4 polarity. Notably, GB treatment demonstrated the capacity to ameliorate spinal cord glymphatic function by modulating AQP4 polarity through MMP-9 inhibition, offering a promising therapeutic avenue for PDN.

Skin keratinocyte-derived SIRT1 and BDNF modulate mechanical allodynia in mouse models of diabetic neuropathy.

Diabetic neuropathy is a debilitating disorder characterized by spontaneous and mechanical allodynia. The role of skin mechanoreceptors in the development of mechanical allodynia is unclear. We discovered that mice with diabetic neuropathy had decreased sirtuin 1 (SIRT1) deacetylase activity in foot skin, leading to reduced expression of brain-derived neurotrophic factor (BDNF) and subsequent loss of innervation in Meissner corpuscles, a mechanoreceptor expressing the BDNF receptor TrkB. When SIRT1 was depleted from skin, the mechanical allodynia worsened in diabetic neuropathy mice, likely due to retrograde degeneration of the Meissner-corpuscle innervating Aß axons and aberrant formation of Meissner corpuscles which may have increased the mechanosensitivity. The same phenomenon was also noted in skin-keratinocyte specific BDNF knockout mice. Furthermore, overexpression of SIRT1 in skin induced Meissner corpuscle reinnervation and regeneration, resulting in significant improvement of diabetic mechanical allodynia. Overall, the findings suggested that skin-derived SIRT1 and BDNF function in the same pathway in skin sensory apparatus regeneration and highlighted the potential of developing topical SIRT1-activating compounds as a novel treatment for diabetic mechanical allodynia.

Diabetic Neuropathic Pain: Directions for Exploring Treatments.

Diabetic neuropathic pain (DNP) is one of the common and severe late-stage complications of diabetes mellitus, which could greatly influence the patients' quality of life. Patients with DNP often experience spontaneous pain and evoked pain such as mechanical allodynia and thermal hyperalgesia, meaning that their physical and psychological health are severely impaired. Unfortunately, the mechanisms of DNP remain highly elusive, so substantial breakthrough in effective DNP targeted treatments is still clinically challenging. This article will hence summarise the main mechanisms currently known to underlie DNP pathogenesis, along with describing some of the current and potential treatment methods against diabetic neuropathic pain.