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Preclinical studies indicate that diverse muscarinic receptor antagonists, acting via the M1 sub-type, promote neuritogenesis from sensory neurons in vitro and prevent and/or reverse both structural and functional indices of neuropathy in rodent models of diabetes. We sought to translate this as a potential therapeutic approach against structural and functional indices of diabetic neuropathy using oxybutynin, a muscarinic antagonist approved for clinical use against overactive bladder. Studies were performed using sensory neurons maintained in vitro, rodent models of type 1 or type 2 diabetes and human subjects with type 2 diabetes and confirmed neuropathy. Oxybutynin promoted significant neurite outgrowth in sensory neuron cultures derived from adult normal rats and STZ-diabetic mice, with maximal efficacy in the 1-100 nmol/l range. This was accompanied by a significantly enhanced mitochondrial energetic profile as reflected by increased basal and maximal respiration and spare respiratory capacity. Systemic (3-10 mg/kg/day s.c.) and topical (3% gel daily) oxybutynin reversed paw heat hypoalgesia in the STZ and db/db mouse models of diabetes and reversed paw tactile allodynia in STZ-diabetic rats. Loss of nerve profiles in the skin and cornea of db/db mice was also prevented by daily topical delivery of 3% oxybutynin for 8 weeks. A randomized, double-blind, placebo-controlled interventional trial was performed in subjects with type 2 diabetes and established peripheral neuropathy. Subjects received daily topical treatment with 3% oxybutynin gel or placebo for 6 months. The a priori designated primary endpoint, significant change in intra-epidermal nerve fibre density (IENFD) in skin biopsies taken before and after 20 weeks of treatments, was met by oxybutynin but not placebo. Secondary endpoints showing significant improvement with oxybutynin treatment included scores on clinical neuropathy, pain and quality of life scales. This proof-of-concept study indicates that muscarinic antagonists suitable for long-term use may offer a novel therapeutic opportunity for treatment of diabetic neuropathy. Trial registry number: NCT03050827.

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.

Objective: To assess the efficacy and safety of stem cell therapy in human studies for diabetic peripheral neuropathy (DPN). Methods: A comprehensive literature review was performed across multiple databases, including Ovid MEDLINE ALL, Embase via Ovid SP, Scopus, Web of Science Core Collection, and Cochrane CENTRAL, up to January 31, 2024. Keywords and controlled vocabularies related to diabetic neuropathy and stem cell therapy were used. Inclusion criteria encompassed all controlled trials examining stem cell therapy for DPN, excluding animal or in vitro studies, review papers, conference abstracts, and editor letters. Data extraction and risk of bias assessment were independently performed by multiple reviewers using standardized tools. Results: Out of 5431 initial entries, seven were included. Stem cell therapies included bone marrow-derived mononuclear cells and umbilical cord-derived mesenchymal stem cells, administered mainly via intramuscular transplantation. Meta-analysis indicated significant improvements in motor nerve conduction velocity (weighted mean differences (WMD): 2.2, 95% CI 1.6–2.8) and sensory nerve conduction velocity (WMD: 1.9, 95% CI 1.1–2.6). Vibration perception threshold and Toronto Clinical Scoring System scores decreased significantly (WMD: − 2.9, 95% CI − 4.0, − 1.8, and WMD: − 3.6, 95% CI − 5.0, − 2.2, respectively). Sensitivity analysis and subgroup analysis confirmed the robustness and specificity of these findings. The complications were pain and swelling at the injection sites, which disappeared in a few days. Conclusion: Stem cell therapy shows significant promise in improving clinical outcomes for DPN, with evident benefits in nerve conduction and sensory parameters. Further research is needed to consolidate these findings and optimize therapeutic protocols. [ABSTRACT FROM AUTHOR]

Identifying clinical features that are associated with recurrence of endometrioid endometrial carcinoma (EEC) in patients with diabetes mellitus (DM). A single-center retrospective cohort study was performed on patients with a diagnosis of both DM and Stage I EEC. Clinical and pathologic features were analyzed in relation to 5-year progression free survival (PFS). Kaplan-Meier Curves and Cox proportional hazard ratios were utilized to assess effect on 5-year PFS. A total of 539 patients were included, with biopsy proven recurrence in 86 (18 %), and 456 (82 %) with no evidence of recurrence. Age, BMI, HgbA1c, metformin use, number of antihyperglycemic medications, use of adjuvant radiation, and surgical approach were not associated with differences in PFS. Presence of end-organ complications associated with diabetes was correlated with worse PFS (HR 1.78, 95 % CI 1.1–2.9, P = 0.02), and specifically diabetic neuropathy was associated with higher rates of recurrence (HR 3.6, 95 % CI 2.1–6.2, P < 0.01). In this cohort, PFS was independently associated with extent of myoinvasion (HR 2.33, 95 % CI 1.4–3.7, P < 0.01) as well as both microsatellite instability (HR 3.43, 95 % CI 1.8–6.6, P < 0.01), and no specific molecular profile (HR 0.3, 95 % CI 0.2–0.6, P < 0.01) molecular subtypes. In patients with DM and EEC, extent of myoinvasion and TCGA molecular subtype correlated with worse PFS. Control of DM as evidenced by HgbA1c, BMI, and use of antihyperglycemic medications did not correlate with PFS in our cohort of patients with Stage I EEC, while the presence of diabetic neuropathy was associated with a higher risk of recurrence. These results highlight importance of evaluating diabetes severity and molecular subtype in endometrial cancer patients. • Diabetic neuropathy is associated with higher rates of endometrioid endometrial carcinoma (EEC) recurrence. • Obesity, hemoglobin A1C, and use of antihyperglycemic medications is not associated with EEC recurrence rates. • Myoinvasion, microsatellite instability, and no specific molecular subtype is associated with increased EEC recurrence. [ABSTRACT FROM AUTHOR]

Introduction. Diabetes mellitus is a significant global health issue, particularly due to its chronic complications, such as neuropathy and peripheral arterial disease (PAD), which can lead to debilitating outcomes like diabetic foot, ulcers, and amputations. These complications not only afflict the patient’s quality of life, but also present significant social and healthcare challenges. Traditional therapeutic approaches often provide only partial symptoms’ relief, prompting the exploration of alternative therapies to enhance disease management and patient’s quality of life. Ozone therapy has emerged as a promising adjuvant treatment for patients with diabetes. In clinical practice, ozone therapy has demonstrated encouraging results in reducing neuropathic and vascular symptoms and in improving overall quality of life. The therapeutic versatility of ozone is attributed to its ability to generate a cascade of biologically active compounds that target multiple pathological processes. These include cardiovascular, peripheral vascular, neurologic, and skin conditions, as well as enhanced wound healing, making it particularly beneficial for the complex and multifactorial nature of diabetes-related complications. Conclusions. Ozone therapy has demonstrated potential as a therapeutic option for managing neurovascular complications in diabetic patients. Clinical evidence shows an improvement in symptoms, as verified by specific diagnostic tests, suggesting that ozone therapy may serve as a valuable addition to the conventional treatment of diabetic neuropathy and peripheral arterial disease. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a leading cause of disability with adverse effects on the quality of life. It also affects occupational health by impacting several work-related parameters. This review discusses the relationship between diabetes and absenteeism, presenteeism, work impairment and unemployment. The association between work and diabetic complications such as neuropathic pain, diabetic foot, psychological issues and hypoglycemia due to treatment is also examined. Evidence points to a relationship between diabetes and absenteeism, reduced work productivity, and, thus, overall work impairment. A stronger negative impact on work performance is mediated by painful diabetic neuropathy and diabetic foot. In addition, psychological distress has been positively correlated with total workdays lost and frequency of absence. Depression in the diabetic population has also been linked with increased absenteeism, presenteeism, and work disability. Moreover, hypoglycaemia induced by antidiabetic medication may affect work attendance and performance. Finally, diabetes has been associated with inequality in the work environment, lower job satisfaction and higher unemployment rates, mainly because of its complications. [ABSTRACT FROM AUTHOR]

Introduction: Diabetic foot is one of the most devastating complications of diabetes and is the leading cause of lower limb amputations. Patients with a long-standing history of diabetes mellitus often experience symptoms of pain, burning sensation, numbness, and paraesthesia in the heel and feet. These symptoms may be due to compression of the medial plantar nerve, a branch of the tibial nerve, within the tarsal tunnel. Aim: To evaluate the incidence of Tarsal Tunnel Syndrome (TTS) in patients suffering from Type 2 Diabetes Mellitus (T2DM). Materials and Methods: This study was a cross-sectional analysis conducted at the Army Hospital (Research and Referral) in New Delhi, India, from October 2019 to April 2021. A total of 30 consecutive diabetic patients presenting with pain, burning, numbness, and paraesthesia in the heel or feet, with or without ulcers, were included. All patients were clinically evaluated using three-point sensory testing, Tinel's sign at the tarsal tunnel, and assessment for the presence of ulcers on the foot. All patients underwent Nerve Conduction Velocity (NCV) studies. Imaging studies in the form of Magnetic Resonance Imaging (MRI) were performed for a complete work-up of these patients and further diagnosis of TTS. The incidence of TTS was evaluated using clinical, radiological and electrodiagnostic studies. Results: Of the 30 patients enrolled, 20 were males (66.7%) and 10 were females (33.3%). The incidence of TTS among diabetic patients was found to be 14 (46.7%) based on electrodiagnostic criteria, 22 (73.3%) based on clinical evaluation, and 25 (83.3%) based on radiological findings. The mean HbA1c level was 8.5±1.04%. The most common imaging finding was oedema, observed in 83.3% of patients. Inflammation and ganglion cysts were seen in 13.3% and 10% of patients, respectively. Conclusion: TTS is difficult to diagnose. MRI is a useful imaging modality to support the diagnosis. Electrodiagnostic studies can help confirm the diagnosis. [ABSTRACT FROM AUTHOR]

Introduction: The pathogenesis of diabetic neuropathic pain (DNP) is complex involving various processes, which need exploring reliable biomarkers for its early detection and severity prediction. Methods: Study enrolled 181 patients diagnosed with diabetes, among which 74 patients developed DNP. Serum miR-34a-5p levels were compared between DNP patients and non-DNP patients by polymerase chain reaction (PCR), and the potential of miR-34a-5p in predicting the risk and discriminating patients with DNP was evaluated. The regulatory effect of miR-34a-5p on the inflammation, proliferation, and polarization of microglia was evaluated in HMC3 cells treated with high glucose. Results: Upregulated miR-34a-5p was identified as a risk factor and discriminated DNP patients miR-34a-5p was positively correlated with the levels of triglyceride (r = 0.797), fasting blood glucose (r = 0.840), and glycated hemoglobin (r = 0.894) of DNP patients. In HMC3 cells, the high-glucose-induced inflammation, promoted cell growth and caused polarization. The knockdown of miR-34a-5p showed the significant protective effect of microglia activation by high glucose, which was reversed by silencing ENPP3. Discussion: miR-34a-5p served as a biomarker for the prediction and early detection of DNP and mediated microglia inflammation caused by DNP via modulating ENPP3. [ABSTRACT FROM AUTHOR]

The prevention of diabetic foot ulcers remains a critical challenge. This study evaluates a smart compression sock designed to address this issue by integrating temperature, plantar pressure, and blood oxygen sensors and monitoring data recorded by these sensors. The smart sock, developed with input from a certified Pedorthist, was tested on 20 healthy adult participants aged 16 to 53. It includes four temperature sensors and pressure sensors at common ulcer sites (first and fifth metatarsal heads, calcaneus, and hallux), and a blood oxygen sensor on the hallux. The sensors are monitored, and their transduced data are collected and stored through an app installed on a personal cell phone. The mobile app interface is user-friendly, providing intuitive navigation and easy access to the sensors' data. Using repeated measures ANOVA and post hoc tests, we analyzed the impact of various physical activities on physiological changes in the foot. The device effectively detected significant variations in blood oxygen, temperature, and pressure across six activities. Statistical analyses revealed significant differences based on activity type and sensor location. These results highlight the smart sock's sensitivity and accuracy, suggesting its potential to prevent diabetic foot ulcers. Further clinical trials are needed to evaluate its efficacy in a larger, more diverse population. [ABSTRACT FROM AUTHOR]

Diabetic neuropathy is one of the most serious and common complications of diabetes with a wide spectrum, affecting 30–50% of diabetic patients. However, the current treatments of this disorder, mainly based on controlling blood glucose level, show an inadequate clinical outcome. Better approaches are needed. In this fashion, it is noted that promoting nerve regeneration and preventing nerve degeneration should be focused on equally and appropriately. In this mini review, how more effective approaches are in targeting PI3K/AKT and MEK/ERK pathways in the treatment of peripheral diabetic neuropathy is discussed. Future treatment of peripheral diabetic neuropathy should consider these approaches. [ABSTRACT FROM AUTHOR]

Aim: To assess the likelihood of dementia in individuals with type 2 diabetes (T2D), distinguishing between those with and without microvascular diseases. Methods: Leveraging the National Health Insurance Research Database in Taiwan, we identified individuals newly diagnosed with T2D from 1 January 2009 through 31 December 2014. Multivariable Cox proportional hazard models were used to compare the risk of outcomes. Results: Individuals with microvascular disease had a significantly higher risk of all‐cause dementia (adjusted hazard ratio [95% confidence interval] 1.13 [1.09, 1.17]) compared with matched individuals without microvascular disease. In addition, individuals with diabetic kidney disease and diabetic neuropathy were associated with a significantly increased risk of Alzheimer's disease (1.16 [1.02, 1.32] and 1.14 [1.03, 1.27]), vascular dementia (1.21 [1.06, 1.38] and 1.14 [1.02, 1.28]) and other dementia (1.11 [1.04, 1.19] and 1.10 [1.04, 1.16]), respectively, compared with those without microvascular disease. Conclusions: This nationwide cohort study showed that patients with T2D and microvascular disease, particularly diabetic kidney disease and diabetic neuropathy, were associated with a significantly higher risk of Alzheimer's disease, vascular dementia, other dementia and all‐cause dementia than those without microvascular disease. [ABSTRACT FROM AUTHOR]

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Background: Diabetic peripheral neuropathy (DPN) is common and can go unnoticed until it is firmly developed. This study aims to establish a transformer-based deep learning algorithm (DLA) to classify corneal confocal microscopy (CCM) images, identifying DPN in diabetic patients. Methods: Our classification model differs from traditional convolutional neural networks (CNNs) using a Swin transformer network with a hierarchical architecture backbone. Participants included those with (DPN+, n = 57) or without (DPN-, n = 37) DPN as determined by the updated Toronto consensus criteria. The CCM image dataset (consisting of 570 DPN+ and 370 DPN- images, with five images selected from each participant's left and right eyes) was randomly divided into training, validation, and test subsets at a 7:1: 2 ratio, considering individual participants. The effectiveness of the algorithm was assessed using diagnostic accuracy measures, such as sensitivity, specificity, and accuracy, in conjunction with Grad-CAM visualization techniques to interpret the model's decisions. Results: In the DPN + group (n = 12), the transformer model successfully predicted all participants, while in the DPN- group (n = 7), one participant was misclassified as DPN+, with an area under the curve (AUC) of 0.9405 (95% CI 0.8166, 1.0000). Among the DPN + images (n = 120), 117 were correctly classified, and among the DPN- images (n = 70), 49 were correctly classified, with an AUC of 0.8996 (95% CI 0.8502, 0.9491). For single-image predictions, the transformer model achieved a superior AUC relative to the ResNet50 model (0.8761, 95% CI 0.8155, 0.9366), the Inception_v3 model (0.8802, 95% CI 0.8231, 0.9374), and the DenseNet121 model (0.8965, 95% CI 0.8438, 0.9491). Conclusion: Transformer-based networks outperform CNN-based networks in rapid binary DPN classification. Transformer-based DLAs have clinical DPN screening potential. [ABSTRACT FROM AUTHOR]

Diabetic Charcot neuroarthropathy (DCN), first described in 1936, occurs in less than 1% of diabetic patients, but in those diabetic subjects with distal symmetrical polyneuropathy, the overall incidence increases to 30% and the risk is even greater in those with type 1 diabetes. Factors that precipitate DCN are trauma, ischaemia due to arterio‐venous shunting, increased osteoclastic activity and inflammation. DCN usually presents with a painless swollen foot and/or ankle which is ‘hot to the touch’. These clinical findings are soon followed by characteristic magnetic resonance imaging (MRI) abnormalities and later X‐ray changes. The joints that are most typically involved in chronological order are the tarsometatarsals followed by the naviculocuniform, sub‐tarsal, talonavicular and metatarsal and tarsophalangeal. The cornerstone of therapy is prolonged (3–12 months) offloading with immobilization. Bisphosphonates may possibly accelerate recovery, whereas other unproven possible therapies include rhPTH, 1–34, calcitonin and methylprednisolone, which are not only ineffective but in some cases may also prolong the time to healing. Denosumab is potentially an efficacious, if unproven, therapy to accelerate healing. The risk of amputation is high and increases in the presence of a foot ulcer. DCN is associated with manifestations of autonomic neuropathy, including cardiac denervation, so that the risks of a cardiac event and heart failure are increased with DCN. Mortality is also increased with DCN, especially in the presence of a foot ulcer. To avoid the recurrence of DCN and especially to lower the risk of the recurrence of a foot ulcer recurrence reconstructive, surgery may be needed. [ABSTRACT FROM AUTHOR]

There is an increasing prevalence of diabetes mellitus (DM), particularly type 2 DM (T2DM), and its associated complications. T2DM is linked to insulin resistance, chronic inflammation, and oxidative stress, which can lead to both macrovascular and microvascular complications, including peripheral diabetic neuropathy (PDN). Inflammatory processes play a key role in the development and progression of T2DM and its complications, with specific markers like C-reactive protein (CRP), interleukins (ILs), and tumor necrosis factor (TNF)-α being associated with increased risk. Other key inflammatory markers such as nuclear factor kappa B (NF-κB) are activated under hyperglycemic and oxidative stress conditions and contribute to the aggravation of PDN by regulating inflammatory gene expression and enhancing endothelial dysfunction. Other important roles in the inflammatory processes are played by Toll-like receptors (TLRs), caveolin 1 (CAV1), and monocyte chemoattractant protein 1 (MCP1). There is a relationship between vitamin D deficiency and PDN, highlighting the critical role of vitamin D in regulating inflammation and immune responses. The involvement of macrophages in PDN is also suspected, emphasizing their role in chronic inflammation and nerve damage in diabetic patients. Vitamin D supplementation has been found to reduce neuropathy severity, decrease inflammatory markers, and improve glycemic control. These findings suggest that addressing vitamin D deficiency could offer therapeutic benefits for PDN. These molecular pathways are critical in understanding the pathogenesis of DM complications and may offer potential biomarkers or therapeutic targets including anti-inflammatory treatments, vitamin D supplementation, macrophage phenotype modulation, and lifestyle modifications, aimed at reducing inflammation and preventing PDN. Ongoing and more extensive clinical trials with the aim of investigating anti-inflammatory agents, TNF-α inhibitors, and antioxidants are needed to advance deeper into the understanding and treatment of painful diabetic neuropathy. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Corneal confocal microscopy (CCM) detects small nerve fiber loss and correlates with skin biopsy findings in diabetic neuropathy. In chronic idiopathic axonal polyneuropathy (CIAP) this correlation is unknown. Therefore, we compared CCM and skin biopsy in patients with CIAP to healthy controls, patients with painful diabetic neuropathy (PDN) and diabetics without overt neuropathy (DM). Methods: Participants with CIAP and suspected small fiber neuropathy (n = 15), PDN (n = 16), DM (n = 15), and healthy controls (n = 16) underwent skin biopsy and CCM testing. Inter‐center intraclass correlation coefficients (ICC) were calculated for CCM parameters. Results: Compared with healthy controls, patients with CIAP and PDN had significantly fewer nerve fibers in the skin (IENFD: 5.7 ± 2.3, 3.0 ± 1.8, 3.9 ± 1.5 fibers/mm, all p <.05). Corneal nerve parameters in CIAP (fiber density 23.8 ± 4.9 no./mm2, branch density 16.0 ± 8.8 no./mm2, fiber length 13.1 ± 2.6 mm/mm2) were not different from healthy controls (24.0 ± 6.8 no./mm2, 22.1 ± 9.7 no./mm2, 13.5 ± 3.5 mm/mm2, all p >.05). In patients with PDN, corneal nerve fiber density (17.8 ± 5.7 no./mm2) and fiber length (10.5 ± 2.7 mm/mm2) were reduced compared with healthy controls (p <.05). CCM results did not correlate with IENFD in CIAP patients. Inter‐center ICC was 0.77 for fiber density and 0.87 for fiber length. Discussion: In contrast to patients with PDN, corneal nerve parameters were not decreased in patients with CIAP and small nerve fiber damage. Therefore, CCM is not a good biomarker for small nerve fiber loss in CIAP patients. [ABSTRACT FROM AUTHOR]

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 Aβ 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. [ABSTRACT FROM AUTHOR]

The world is experiencing an enormous rise in the prevalence of diabetes, which is associated with massive healthcare costs that threaten to overwhelm many healthcare systems. Most of the diabetes expenditure is attributed to the management of chronic diabetes complications, including diabetic peripheral neuropathy (DPN)/diabetic foot complications, chronic kidney disease, sight‐threatening retinopathy and cardiovascular diseases. Of these complications, the most overlooked is DPN. Most consultations around the world do not even involve taking off shoes and socks to carry out a foot examination, and even when carried out, the peripheral neurological examination using the 10‐g monofilament diagnoses DPN when it is already at an advanced stage. Thus, all too often diabetes complications are diagnosed late, resulting in devastating outcomes, particularly in low‐ to middle‐income countries. There is, therefore, an urgent need to instigate new strategies to improve microvascular screening uptake using a holistic protocol for annual diabetes health checks outside the busy diabetes clinic. One such approach, the Sheffield One‐Stop Microvascular Screening Service, which involves modern point of care devices to diagnose DPN, has been shown to be feasible and effective, resulting in high uptake and early management of diabetes complications. This article outlines the advantages of this One‐Stop Microvascular Screening Service and a plan to trial an adapted version of this service to a resource‐limited country, the Philippines. If successful, this model has the potential for implementation in other countries around the world. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate the effects of an 8-week yoga intervention on muscle strength, proprioception, pain, concerns about falling, and quality of life in individuals diagnosed with diabetic neuropathy. Methods: A quasi-experimental design incorporating a pretest-posttest methodology and a control group was implemented in the present study. A total of 30 patients who were diagnosed with type 2 diabetes and neuropathy were recruited and randomly assigned to intervention (n = 15) or non-exercise control (n = 15). Yoga sessions were conducted for a duration of 60 min on three occasions per week, with participants requested to practice at home on other days. Results: The results showed significant main effects of time on the muscle strength (both flexor and extensor muscles, p <.001, ηp2 = 0.652 and p <.001, ηp2 = 0.539, respectively), proprioception error (p <.001, ηp2 = 0.807), pain intensity (p <.001, ηp2 = 0.538), concerns about falling (p <.001, ηp2 = 0.700), and overall score of quality of life (p <.001, ηp2 = 0.475). Moreover, there were significant group-by-time interactions for all variables (p <.001 for all). Conclusion: The study reveals that yoga intervention can be an effective alternative therapeutic approach to medication for individuals with diabetic neuropathy. Yet, future studies are needed on a larger sample size to strengthen the present understanding of the advantageous impact of yoga intervention in this population. [ABSTRACT FROM AUTHOR]

• Brain alterations have been described in type 1 diabetes and diabetic neuropathy. • Metabolic profiles of neuropathic phenotypes using relevant brain regions were explored. • Specific metabolic brain profiles were linked to phenotypes of diabetes, neuropathy, and neuropathic pain. • Metabolic brain profiles could be relevant for detailed understanding of central neuropathy. The study aimed to investigate brain metabolites in type 1 diabetes and the associations with disease characteristics. We explored the metabolic profiles predicting different neuropathic phenotypes using multiple linear regression analyses. We compared brain metabolites in 55 adults with type 1 diabetes (including painful diabetic peripheral neuropathy (DPN), painless DPN, without DPN) with 20 healthy controls. Proton magnetic resonance spectroscopy measurements (N-acetylaspartate (NAA), glutamate (glu), myo-inositol (mI), and glycerophosphocholine (GPC) were obtained in ratios to creatine (cre)) from the parietal region, anterior cingulate cortex and thalamus. The overall diabetes group revealed decreased parietal NAA/cre compared to healthy controls (1.41 ± 0.12 vs. 1.55 ± 0.13,p < 0.001) and increased mI/cre (parietal: 0.62 ± 0.08 vs. 0.57 ± 0.07,p = 0.025, cingulate: 0.65 ± 0.08 vs. 0.60 ± 0.08,p = 0.033). Reduced NAA/cre was associated with more severe DPN (all p ≤ 0.04) whereas increased mI/cre was associated with higher hemoglobin A 1c (HbA 1c) (p = 0.02). Diabetes was predicted from decreased parietal NAA/cre, increased parietal ml/cre, and decreased thalamic glu/cre. DPN was predicted from decreased parietal NAA/cre and increased GPC/cre. Painful DPN was predicted from increased parietal GPC/cre and thalamic glu/cre. Specific metabolic brain profiles were linked to the different phenotypes of diabetes, DPN and painful DPN. Assessment of metabolic profiles could be relevant for detailed understanding of central neuropathy in diabetes. [ABSTRACT FROM AUTHOR]

Introduction: With a high mortality rate, diabetes mellitus (DM) is the result of insulin deficiency during its secretion or action, more common in patients over 40 years old, being responsible for 95% of morbidity cases in Brazil. Well-planned physical therapy, with efficient interventions and exercises, aims to improve mobility and balance in individuals with peripheral diabetic neuropathy (PDN). Objective: The objective of this article is to describe the physical therapy interventions in patients with diabetic neuropathy. Methodology: The present work is a literature review, with data collection between August 2021 and May 2022, through a search in PubMed, SciELO and PEDro databases. Results and discussion: Considering the clinical repercussions of patients, professionals use treatment techniques with the objective of preventing the progression of symptoms and degeneration of neural function. Final Considerations: An isolated treatment considered the gold standard to be applied in patients with PDN was not found in the literature, transcutaneous electrical stimulation does not present among scholars a concession of applicability. [ABSTRACT FROM AUTHOR]

Covid-19 is an infectious disease that is part of a group of viruses responsible for causing severe acute respiratory syndromes, the Sars-Cov-2. To describe the persistence of symptoms in patients diagnosed with Sars-Cov-2 infection, the term Long-Covid has been used. Respiratory physiotherapy plays an important role in the face of persistent symptoms of Covid-19 in order to restore functionality impaired or lost by the pathology. The objective of the current research is to collect data from medical records and assemble a profile of patients with Long-Covid who sought physical therapy treatment. This is a research analysis of medical records with a diagnosis of Long-Covid who sought the sector to perform treatment between January/2021 and May/2022. A total of 55 medical records were collected and 11 were excluded for not meeting the inclusion criteria, including 20 males with an average age of 57 years and 24 females with an average age of 56 years. The main symptoms found in the research were tiredness, dyspnea and muscle pain. A population profile was found where the greatest demand for physiotherapeutic treatment was female, hypertensive individuals, who use continuous medication, and do not practice physical activities. Even most of the study population underwent hospitalizations, either in the ward or ICU, whose most persistent symptoms were fatigue, dyspnea and muscle pain, with mean blood pressure below expectations, a 6-minute walk test below ideal and average vital signs within the normal range. [ABSTRACT FROM AUTHOR]

Diabetic peripheral neuropathy (DPN) impairs glucose and fat metabolism and physical functioning. This study examined the effects of low-intensity resistance exercise training (LI-RT) and a lower limb conditioning program (LLCP) on physical function and lipid profile in DPN. Forty-five diabetic women with mild to moderate neuropathy (55.5 ± 3.1 y) were randomly assigned to one of three groups: LI-RT (n = 15), LLCP (n = 15), and control (n = 15). The LI-RT and LLCP groups trained 3 times/week (90 min/session) for 12 weeks. The LI-RT group completed 3 sets of 10 repetitions for ten exercises at 30-repetition maximum; the LLCP group performed 12 lower extremity motions designed for peripheral neuropathy; and the control group followed their routine daily activities. Physical function was assessed using the Timed Up and Go Test (TUG), Five Times Sit-to-Stand (FTSTS) test, and 6-min walking test (6MWT). Blood lipid profile was assessed. Both the LI-RT and LLCP groups significantly improved in TUG scores compared to the control group (p ≤ 0.05). No significant changes between groups were observed for the FTSTS and 6MWT. The LI-RT and LLCP groups, compared to the control group, showed a significant reduction in low-density lipoprotein (p ≤ 0.05), and triglycerides (p ≤ 0.001). High-density lipoproteins showed non-significant changes. Low intensity training involving resistance exercises or lower limb range of motion enhance physical function and lipid profile in patients with DPN. High intensity exercise could be risky and deter adherence. Hence, these gentler exercise programs offer viable options for enhancing health and fitness in DPN patients. [ABSTRACT FROM AUTHOR]

Peripheral Diabetic Neuropathy (PDN) is the major complication of diabetes, and sensory-motor impairments can compromise balance, increasing the risk of falls and consequently can lead to functional disability. Thus, this study aims to evaluate the sensory and motor aspects of balance in individuals with type 2 diabetes mellitus with and without PDN. This is a cross-sectional study which analyzed balance in 51 individuals, divided into three groups: G1 – individuals with Peripheral Diabetic Neuropathy; G2 - individuals with diabetics and without PDN; and G3 – individuals without Diabetes Mellitus. As for the instruments used to evaluate balance, specific tests based on model system approach were applied: MiniBESTest and the modified Clinical Test of Sensory Integration of Balance (mCTSIB). It was observed that individuals in G1 showed balance impairment in mCTSIB and MiniBESTest compared to G2 and G3. In individuals with diabetics without PDN (G2) there was a reduction in tandem position time on the unstable surface and worse anticipatory postural adjustments (APA) and reactive postural response (RPR) compared to individuals without diabetes (G3). PDN showed impairments in both static and dynamic balance, with alterations in sensory orientation, decreased anticipatory and reactive postural response. However, individuals with diabetes and without PDN also present worsening response in tandem position time on the unstable surface, APA and RPR tasks. [ABSTRACT FROM AUTHOR]

Charcot neuroarthropathy (CN) is a complex disease of the bone and joints that can lead to serious and life-threatening complications. This study investigates epidemiologic trends in diabetic CN in Texas and the impact of age on these values. A retrospective analysis was conducted using the Texas Department of State Health Services Hospital Discharge Data Public Use Data File. Using International Classification of Diseases, Ninth (ICD-9) and Tenth (ICD-10) Revision codes, we identified patients with diabetes and Charcot ankle or foot. Data extracted included diagnoses, race, and gender. Population rates were estimated using census data, calculated per 1000 population and standardized by age. Overall and age-standardized rates of CN increased each year from 2006 to 2016, except for a downward trend from 2014 to 2016. Poisson regression revealed significant increases in the incidence rate ratio compared to 2006 for each year from 2008 to 2016. When age group is included, all years except 2007 show a significant increase relative to 2006, and all age groups have increased rates relative to ages 18–44. Major and minor amputations in patients with CN have increased. The increasing rates of CN and amputations highlight the need for further research and standardized strategies for diagnosis and management. • Age-standardized rates of Charcot neuroarthropathy has increased in recent years. • Incidence rate ratio of Charcot neuroarthropathy significantly increased 2008–2016. • Major and minor amputations trended upward in Charcot patients from 2006 to 2016. [ABSTRACT FROM AUTHOR]

Background and Objectives: This study aimed to investigate the protective effect of diosmin and hesperidin in diabetic neuropathy using a rat model, focusing on their impact on nerve regeneration through the fibroblast growth factor 21 (FGF21) and galectin-3 (gal3) pathway. Materials and Methods: Forty adult male Wistar rats were used in this study. Diabetes was induced using streptozotocin (STZ), and the rats were divided into control, diabetes and saline-treated, diabetes and diosmin + hesperidin (150 mg/kg) treated, and diabetes and diosmin + hesperidin (300 mg/kg) treated groups. Electromyography (EMG) and inclined plane testing were performed to assess nerve function and motor performance. Sciatic nerve sections were examined histopathologically. Plasma levels of FGF21, galectin-3, and malondialdehyde (MDA) were measured as markers of oxidative stress and inflammation. Results: Diabetic rats treated with saline displayed reduced nerve conduction parameters and impaired motor performance compared to controls. Treatment with diosmin and hesperidin significantly improved compound muscle action potential (CMAP) amplitude, distal latency, and motor performance in a dose-dependent manner. Histopathological examination revealed decreased perineural thickness in treated groups. Additionally, treatment with diosmin and hesperidin resulted in increased plasma FGF21 levels and reduced plasma levels of galectin-3 and MDA, indicating decreased oxidative stress and inflammation. Conclusions: Diosmin and hesperidin exhibited protective effects in diabetic neuropathy by promoting nerve regeneration, enhancing nerve conduction, and improving motor performance. These effects were associated with modulation of the FGF21 and galectin-3 pathway. These findings suggest that diosmin and hesperidin may hold potential as adjunctive therapies for diabetic neuropathy. [ABSTRACT FROM AUTHOR]

Aim: To investigate the efficacy of Palmitoylethanolamide (PEA, 300 mg), Superoxide Dismutase (SOD, 70 UI), Alpha Lipoic Acid (ALA, 300 mg), vitamins B6 (1.5 mg), B1 (1.1 mg), B12 (2.5 mcg), E (7.5 mg), nicotinamide (9 mg), and minerals (Mg 30 mg, Zn 2.5 mg) in one tablet in people with Diabetic Neuropathy (DN). Patients–methods: In the present pilot study, 73 people (age 63.0 ± 9.9 years, 37 women) with type 2 Diabetes Mellitus (DMT2) (duration 17.5 ± 7.3 years) and DN were randomly assigned to receive either the combination of ten elements (2 tablets/24 h) in the active group (n = 36) or the placebo (n = 37) for 6 months. We used the Michigan Neuropathy Screening Instrument Questionnaire and Examination (MNSIQ and MNSIE), measured vibration perception threshold (VPT) with biothesiometer, and Cardiovascular Autonomic Reflex Tests (CARTs). Nerve function was assessed by DPN Check [sural nerve conduction velocity (SNCV) and amplitude (SNAP)]. Sudomotor function was assessed with SUDOSCAN, which measures electrochemical skin conductance in hands and feet (ESCH and ESCF). Pain score (PS) was assessed with Pain DETECT questionnaire. Quality of life was assessed by questionnaire. Results: In the active group, there was a large improvement of pain (PS from 20.9 to 13.9, p < 0.001). There was also a significant improvement of vitamin B12 (B12) levels, MNSIQ, SNCV, VPT, and ESCF (222.1 vs. 576.3 pg/ mL, p < 0.001; 6.1 vs. 5.9, p = 0.017; 28.8 vs. 30.4, p = 0.001; 32.1 vs. 26.7, p = 0.001; and 72.2 vs. 74.8, p < 0.001 respectively). In the placebo group, neither pain (21.6 vs. 21.7, p = 0.870) or any other aforementioned parameters changed significantly, and MNSIE worsened (2.9 vs. 3.4, p < 0.001). As a result, changes from baseline to follow-up in pain, B12 levels, VPT, and MNSIQ differed significantly between the two groups (p < 0.001, 0.025, 0.009, and <0.001, respectively). CARTs, SNAP, ESCH did not significantly change in either of the two groups. Conclusions: The combination of the ten elements in one tablet for 6 months at a daily dose of two tablets in people with DN significantly improves pain, vibration perception threshold, and B12 levels. [ABSTRACT FROM AUTHOR]

Diabetes is known to cause an array of central and peripheral neurological conditions. Among the neuropathic complications associated with diabetes are distal symmetrical polyneuropathy, amyotrophy, polyradiculopathy, autonomic neuropathy, and cranial mononeuropathies. Notably, brachial plexopathy has not been documented as a complication of diabetes. A 50-year-old man with a history of diabetes mellitus presented with severe pain and progressive weakness in his right upper limb. Laboratory investigations, immunopathological analyses, and cerebrospinal fluid examination yielded normal results. The electrodiagnosis and imaging studies were consistent with bilateral brachial plexus neuritis. This unique presentation does not align with the rare diabetic polyradiculopathy of the upper limbs commonly linked to diabetic amyotrophy. The association between diabetes mellitus and brachial plexopathy is uncommon, indicating a possible occurrence of a rare subtype within diabetic neuropathies. [ABSTRACT FROM AUTHOR]

Diabetic neuropathy is a common chronic complication of diabetes and is characterized by high incidence and disability rates. It is the result of various metabolic imbalances, including disorders of glucose metabolism, lipid metabolism, and insulin signaling abnormalities caused by insulin deficiency or resistance. The pathogenesis of diabetic neuropathy is closely related to lipid metabolism disorders. Disorders of lipid metabolism, especially abnormal changes in fatty acids, sphingolipids and cholesterol, are key causal factors and new therapeutic targets for diabetic neuropathy. This article reviews the disorder of lipid metabolism under diabetic conditions, and its role and mechanism in the occurrence and development of diabetic neuropathy, with the aim of providing new ideas for diabetic neuropathy treatment. [ABSTRACT FROM AUTHOR]

The transcription factor nuclear factor erythroid 2‐related factor 2 (NRF2) has multifarious action with its target genes having redox‐regulating functions and being involved in inflammation control, proteostasis, autophagy, and metabolic pathways. Therefore, the genes controlled by NRF2 are involved in the pathogenesis of myriad diseases, such as cardiovascular diseases, metabolic syndrome, neurodegenerative diseases, autoimmune disorders, and cancer. Amidst this large array of diseases, diabetic neuropathy (DN) occurs in half of patients diagnosed with diabetes and appears as an injury inflicted upon peripheral and autonomic nervous systems. As a complex effector factor, NRF2 has entered the spotlight during the search of new biomarkers and/or new therapy targets in DN. Due to the growing attention for NRF2 as a modulating factor in several diseases, including DN, this paper aims to update the recently discovered regulatory pathways of NRF2 in oxidative stress, inflammation and immunity. It presents the animal models that further facilitated the human studies in regard to NRF2 modulation and the possibilities of using NRF2 as DN biomarker and/or as target therapy. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effects of exercise therapy on neuropathic symptoms, signs, psychosocial aspects, and physical function in people with diabetic neuropathy (DN). Methods: A search in PubMed, Web of Science, Physiotherapy Evidence (PEDro), and Cochrane databases was performed from inception to Invalid Date NaN,. Randomized clinical trials (RCTs) were selected in patients with DN comparing exercise therapy with a control group. The studies' methodological quality was assessed with the PEDro scale. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the overall quality. Results: Eleven RCTs (n = 517 participants) were included. Nine studies showed high methodological quality. Mean (MD) and standardized mean differences (SMD) were observed in favor of exercise therapy for symptoms (MD = −1.05; confidence interval 95% = −1.90 to −0.20), signs (SMD = −0.66; confidence interval 95%= −1 to −0.32), and physical function (SMD = −0.45; confidence interval 95% = −0.66 to −0.24). No changes were found in psychosocial aspects (SMD = −0.37; confidence interval 95% = −0.92 to 0.18). The overall quality of evidence was very low. Conclusion: The quality of evidence suggesting that exercise therapy provides short-term benefits in neuropathic symptoms, signs, and physical function in patients with DN is very low. Furthermore, there were no effects found on psychosocial aspects. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the impact of denosumab on (i) the incidence of type 2 diabetes (T2D), and (ii) long‐term health outcomes (microvascular [neuropathy, retinopathy, nephropathy] and macrovascular [cardiovascular disease, cerebrovascular accident] complications, and all‐cause mortality) in patients with T2D, before (iii) combining results with prior studies using meta‐analysis. Methods: A retrospective analysis of data in a large global federated database (TriNetX; Cambridge, MA) was conducted from 331 375 patients, without baseline T2D or cancer, prescribed either denosumab (treatment, n = 45 854) or bisphosphonates (control, n = 285 521), across 83 healthcare organizations. Propensity score matching (1:1) of confounders was undertaken that resulted in 45 851 in each cohort. Secondary analysis further evaluated the impact of denosumab on long‐term health outcomes in patients with T2D. Additionally, we systematically searched prior literature that assessed the association between denosumab and T2D. Estimates were pooled using random‐effects meta‐analysis. Risk of bias and evidence quality were assessed using Cochrane‐endorsed tools. Results: Denosumab (vs. bisphosphonates) was associated with a lower risk of incident T2D over 5 years (hazard ratio 0.83 [95% confidence interval {CI} 0.78‐0.88]). Secondary analysis showed significant risk reduction in all‐cause mortality (0.79 [0.72‐0.87]) and foot ulceration (0.67 [0.53‐0.86]). Also, pooled results from four studies (three observational, one randomized controlled trial) following meta‐analysis showed a reduced relative risk (RR [95% CI]) for incident T2D in patients prescribed denosumab (0.83 [0.79‐0.87]) (I2 = 10.76%). Conclusions: This is the largest cohort study to show that denosumab treatment is associated with a reduced RR of incident T2D, as well as an associated reduced RR of all‐cause mortality and microvascular complications, findings that may influence guideline development in the treatment of osteoporosis, particularly in patients who are at a high risk of T2D. [ABSTRACT FROM AUTHOR]

Aims/Introduction: To investigate risk factors for diabetic peripheral neuropathy (DPN) and to explore the connection between insulin‐like growth factor‐1 (IGF‐1) and DPN in individuals with type 2 diabetes. Materials and Methods: A total of 790 patients with type 2 diabetes participated in a cross‐sectional study, divided into two groups: those with DPN (DPN) and those without DPN (non‐DPN). Blood samples were taken to measure IGF‐1 levels and other biochemical markers. Participants underwent nerve conduction studies and quantitative sensory testing. Results: Patients with DPN exhibited significantly lower levels of IGF‐1 compared with non‐DPN patients (P < 0.001). IGF‐1 was positively correlated with the average amplitude of both motor (P < 0.05) and sensory nerves (P < 0.05), but negatively correlated with the vibration perception threshold (P < 0.05). No significant difference was observed between IGF‐1 and nerve conduction velocity (P > 0.05), or the temperature detection threshold (P > 0.05). Multivariate regression analysis identified diabetes duration, HbA1c, and the low levels of IGF‐1 as independent risk factors (P < 0.001). Receiver operating characteristic analysis determined that at 8 years duration of diabetes, 8.5% (69.4 mmol/mol) HbA1c and 120 ng/mL IGF‐1, the optimal cut‐off points, indicated DPN (P < 0.001). Conclusions: A reduction of IGF‐1 in patients with DPN suggests a potential protective role against axon injury in large fiber nerves of type 2 diabetes patients. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus (DM), a multisystem disorder, is a known etiological entity, leading to several neurological disorders. Among them, nervous system is more commonly affected. In most of the diabetic polyneuropathy cases, sensory symptoms involving both general and special senses predominate. Due to gradual and non-homogenous manifestations, it is not easy to detect its onset. Till now no accepted gold standard has been available for its assessment and diagnosis. In this study, changes in vibration perception threshold (VPT) at different frequencies and auditory perception threshold have been investigated in diabetes patients and healthy controls. Aims and objectives: Determination of perception threshold of a general sense-vibration sense and a special sense-hearing in normal human subjects and patients of DM and evaluation of perception threshold of the human sensory system by VPT test and pure tone audiometry (PTA) as a diagnostic, prognostic and research tool for diabetic neuropathy. Materials and Methods: A case--control study, conducted in the department of physiology at medical college, Kolkata, after obtaining approval by the institutional research and ethics committee on 100 cases and 40 control subjects. Testing of vibration sensitivity was performed with the help of tuning forks of frequencies of 128 Hz, 256 Hz, and 512 Hz. Assessment of auditory perception threshold was done by Siemens SD 28 diagnostic audiometer. Results: All data obtained by the methods described here are tabulated. Graphs and charts are drawn and analyzed by standard statistical methods using Statistical Packages for the Social Sciences (version-16) and MATLAB (version-9). A P < 0.05 was considered as significant. A partial negative correlation was observed between the vibration sensitivity and fasting blood sugar and postprandial blood sugar level of the patient population of DM cases, with a "r" value (Pearson's correlation coefficient was around -0.5. By PTA, it was found the percentage of rise in auditory threshold is around 92-93% in 8000 Hz frequency, and the results of the t-test yield a very highly significant difference (P < 0.0001) between cases and controls. It was found that 128 Hz and 256 Hz vibration stimuli applied over maxillary prominence are highly sensitive and efficient tools for perception analysis. Pure tone auditory threshold evaluation showed preservation of the right-sided advantage of auditory sensitivity and frequency-dependent loss of hearing in the diabetic study population. Conclusion: Determination of perception threshold of vibration sense by tuning fork and auditory perception by PTA may be used as an effective, easily performed, and low-cost bedside and also outpatient department-based diagnostic tool in patients with DM. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus has emerged as a pressing global concern, with a notable increase in recent years. Despite advancements in treatment, existing medications struggle to halt the progression of diabetes and its associated complications. Increasing evidence underscores inflammation as a significant driver in the onset of diabetes mellitus. Therefore, perspectives on new therapies must consider shifting focus from metabolic stress to inflammation. High mobility group box (HMGB-1), a nuclear protein regulating gene expression, gained attention as an endogenous danger signal capable of sparking inflammatory responses upon release into the extracellular environment in the late 1990s. Purpose: Given the parallels between inflammatory responses and type 2 diabetes (T2D) development, this review paper explores HMGB-1's potential involvement in onset and progression of diabetes complications. Specifically, we will review and update the understanding of HMGB-1 and its inflammatory pathways in insulin resistance, diabetic nephropathy, diabetic neuropathy, and diabetic retinopathy. Conclusions: HMGB-1 and its receptors i.e. receptor for advanced glycation end-products (RAGE) and toll-like receptors (TLRs) present promising targets for antidiabetic interventions. Ongoing and future projects in this realm hold promise for innovative approaches targeting HMGB-1-mediated inflammation to ameliorate diabetes and its complications. [ABSTRACT FROM AUTHOR]

Objectives: The study aimed to compare the effects of separate and simultaneous application of Tecar therapy and low-level laser therapy on neurological symptoms of type 2 diabetic patients. Patients and methods: In this randomized control trial conducted between November 2021 and February 2022, 45 patients (30 females, 15 males; mean age: 65.7±7.6 years; range, 51 to 76 years) with type 2 diabetes and peripheral sensory neuropathy of the lower limbs were randomly divided into three groups: Tecar + sham laser (n=15), Tecar + laser (n=15), and laser + sham Tecar (n=15). Outcome measures for both right and left limbs included tibial motor nerve conduction velocity (MNCV), sural nerve amplitude, sole sensation, and ankle-brachial index (ABI) measured before and after 10 sessions and after a three-month follow-up. Results: In intergroup comparison, the Tecar + laser group significantly improved compared to the laser + sham Tecar group in terms of tibial MNCV in both limbs after 10 sessions and all measured outcomes after three months (p<0.05). In addition, comparison between the Tecar + laser and Tecar + sham laser groups for tibial MNCV (p=0.021 for the right limb and p=0.002 for the left limb) and ABI (p=0.001 for the right limb and p=0.002 for the left limb) in both limbs after three months was significant. In the intragroup comparison, a significant improvement was found in the laser + sham Tecar group for sole sensation (p<0.001) and ABI (p<0.001) of both limbs after three months compared to before the interventions, whereas in the other two groups, significant improvements were found in all four outcomes. Conclusion: A significant increase was found in neurological outcomes in all three groups after 10 sessions. Moreover, the use of combined Tecar therapy and laser compared to Tecar or laser alone could lead to a more lasting effect in improving the sensory symptoms of type 2 diabetic patients with peripheral neuropathy of the lower limbs. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a chronic metabolic disorder characterized by high blood sugar levels, which can lead to severe health issues if not managed effectively. Recent statistics indicate a significant global impact, with 463 million adults diagnosed worldwide and this projected to rise to 700 million by 2045. Type 1 diabetes is an autoimmune disorder where the immune system attacks pancreatic beta cells, reducing insulin production. Type 2 diabetes is primarily due to insulin resistance. Both types of diabetes are linked to severe microvascular and macrovascular complications if unmanaged. Microvascular complications, such as diabetic retinopathy, nephropathy, and neuropathy, result from damage to small blood vessels and can lead to organ and tissue dysfunction. Chronic hyperglycemia plays a central role in the onset of these complications, with prolonged high blood sugar levels causing extensive vascular damage. The emerging treatments and current research focus on various aspects, from insulin resistance to the intricate cellular damage induced by glucose toxicity. Understanding and intervening in these pathways are critical for developing effective treatments and managing diabetes long term. Furthermore, ongoing health initiatives, such as increasing awareness, encouraging early detection, and improving treatments, are in place to manage diabetes globally and mitigate its impact on health and society. These initiatives are a testament to the collective effort to combat this global health challenge. [ABSTRACT FROM AUTHOR]

Abstract Objective To assess the efficacy and safety of stem cell therapy in human studies for diabetic peripheral neuropathy (DPN). Methods A comprehensive literature review was performed across multiple databases, including Ovid MEDLINE ALL, Embase via Ovid SP, Scopus, Web of Science Core Collection, and Cochrane CENTRAL, up to January 31, 2024. Keywords and controlled vocabularies related to diabetic neuropathy and stem cell therapy were used. Inclusion criteria encompassed all controlled trials examining stem cell therapy for DPN, excluding animal or in vitro studies, review papers, conference abstracts, and editor letters. Data extraction and risk of bias assessment were independently performed by multiple reviewers using standardized tools. Results Out of 5431 initial entries, seven were included. Stem cell therapies included bone marrow-derived mononuclear cells and umbilical cord-derived mesenchymal stem cells, administered mainly via intramuscular transplantation. Meta-analysis indicated significant improvements in motor nerve conduction velocity (weighted mean differences (WMD): 2.2, 95% CI 1.6–2.8) and sensory nerve conduction velocity (WMD: 1.9, 95% CI 1.1–2.6). Vibration perception threshold and Toronto Clinical Scoring System scores decreased significantly (WMD: − 2.9, 95% CI − 4.0, − 1.8, and WMD: − 3.6, 95% CI − 5.0, − 2.2, respectively). Sensitivity analysis and subgroup analysis confirmed the robustness and specificity of these findings. The complications were pain and swelling at the injection sites, which disappeared in a few days. Conclusion Stem cell therapy shows significant promise in improving clinical outcomes for DPN, with evident benefits in nerve conduction and sensory parameters. Further research is needed to consolidate these findings and optimize therapeutic protocols.

ABSTRACT Diabetic neuropathy is one of the most serious and common complications of diabetes with a wide spectrum, affecting 30–50% of diabetic patients. However, the current treatments of this disorder, mainly based on controlling blood glucose level, show an inadequate clinical outcome. Better approaches are needed. In this fashion, it is noted that promoting nerve regeneration and preventing nerve degeneration should be focused on equally and appropriately. In this mini review, how more effective approaches are in targeting PI3K/AKT and MEK/ERK pathways in the treatment of peripheral diabetic neuropathy is discussed. Future treatment of peripheral diabetic neuropathy should consider these approaches.

AIM: To observe the changes in corneal subepithelial nerve fibers (CNFs) and Langerhans cells (LCs) in patients with type 2 diabetes using corneal laser confocal microscopy (CLCM). METHODS: A total of 60 patients (64 eyes), including 40 patients with type 2 diabetes (DM group) and 20 subjects without diabetes (control group) were included with CLCM. Neuron J plugin of Image J software were used for quantitative analysis of CNF length (CNFL), CNF density (CNFD), corneal nerve branch fiber density (CNBD), main branch length density, branch length density, corneal nerve fiber tortuosity (NT) score, and LCs density. An independent samples t-test to analyze the variability between the two groups was performed, and Pearson correlation analysis was used to analyze the relationships between CNF and multiple biochemical indicators in the DM group. The predictive power of CNF for type 2 diabetes was assessed using the receiver operating characteristic (ROC) curve. RESULTS: There were significant differences in the CNFL, CNFD, and main branch length density between two groups. The results of Pearson correlation analysis showed a significant negative correlation between CNFD and the duration of diabetes as well as triglyceride levels and total cholesterol, and a significant positive correlation between CNFD and serum albumin. In addition, the NT score showed a positive correlation and urea nitrogen, similar to the positive correlation observed between LC density and glycosylated hemoglobin (HbA1c) levels. CNFD showed the highest area under the curve (AUC of ROC) value, followed by main branch length density and CNFL. The AUC of the ROC curve under the logistic regression model also demonstrated good predictive values. The cut-off values of CNFD, CNFL, and main branch length density for diabetes showed 31.25, 18.85, and 12.56, respectively. CONCLUSION: In patients with type 2 diabetes, there is a notable reduction in both CNFL and CNFD. These measurements can be influenced by various blood biochemical factors. However, the compromised nerve fibers can serve as valuable indicators for predicting the onset of type 2 diabetes and also as biomarkers for detecting diabetic neuropathy and its related complications.

Background and purpose: Neuropathy is one of the common complications of diabetes mellitus. This study aimed to determine the analgesic and antiapoptotic effects of the aqueous extract of Achillea millefolium L. (Ach) in rats with experimental painful diabetic neuropathy by behavioral and molecular procedures. Experimental approach: Thirty male Wistar rats were divided into 5 groups including control, diabetes + saline, and diabetes + Ach extract (doses of 150, 300, and 600 mg/kg/day for 3 weeks, orally). A tail-flick test was performed to assess the pain threshold in different groups. Western blotting test was used to evaluate the apoptotic (Bax, Bcl2, cleaved caspase-3, and cytochrome-c) and inflammatory (TNF-α and NF-kB) protein factors in the lumbar portion of the spinal cord tissue. Also, commercial assay kits were used to evaluate oxidative stress factors (MDA, GPx, and SOD enzyme activity) in the lumbar portion of the spinal cord tissue. Findings/Results: Results showed that administering Ach extract at the doses of 300 and 600 mg/kg/day significantly increased the nociception threshold in treated diabetic animals compared to untreated diabetic animals. Moreover, the treatment of diabetic animals with Ach extract (300 and 600 mg/kg/day) significantly reduced the oxidative stress, inflammation, and apoptosis biochemical indicators in the lumbar spinal cord tissue compared to the untreated diabetic group. Conclusion and implications: The findings showed that Ach extract has neuroprotective and anti-nociceptive effects in rats with diabetic neuropathy. The effects can be due to the inhibition of oxidative stress, inflammation, and apoptosis in the spinal cord tissue.

The Bruns-Garland syndrome (diabetic amyotrophy) is a rare disorder that affects fewer than 1% of patients with diabetes. It is manifested by unilateral or bilateral pain, weakness and muscle wasting in the proximal part of the lower limbs (proximal motor neuropathy). We present a 72-year-old patient with long-term type 2 diabetes mellitus and with the Bruns-Garland syndrome. All the symptoms, including neurological manifestations, were reversible and resolved after the implementation of intensive treatment. Optimizing diabetes treatment, rehabilitation, pain management and the use of benfotiamine and alpha-lipoic acid preparations were crucial to accelerate the treatment effects of diabetic amyotrophy.

Sandra Pebrianti,1,2 Indra Maulana,2 Iwan Shalahuddin,3 Theresia Eriyani,4 Bambang Aditya Nugraha1 1Medical Surgical Nursing Department, University of Padjadjaran, Bandung, West Java, Indonesia; 2Psychiatric Nursing Department, University of Padjadjaran, Bandung, West Java, Indonesia; 3Community Nursing Department, University of Padjadjaran, Bandung, West Java, Indonesia; 4Basic Nursing Department, University of Padjadjaran, Bandung, West Java, IndonesiaCorrespondence: Indra Maulana, Psychiatric Nursing Department, University of Padjadjaran, Jl. Raya Ir. Soekarno KM. 21, Hegarmanah, Jatinangor, Bandung, West Java, 45363, Indonesia, Tel +6281394665577, Fax +6202287793411, Email indra.maulana@unpad.ac.idPurpose: This study aims to identify physical activity that can reduce pain scales in diabetic neuropathy patients.Patients and Methods: The scoping review method was used in this research using three databases and one search engine, namely PubMed, CINAHL, Sage Journal, and Google Scholar. Inclusion criteria include full-text articles and publications in English and Indonesian between 2012– 2022 with a minimal quasi-experimental design. Critical Appraisal was used to assess the article’s bias.Results: Research found 12 articles discussing the effectiveness of activity training in reducing the pain scale in diabetic neuropathy patients from the results of a scoping review of 12 studies, articles were found that used pain scales such as the Visual Analog Scale (VAS), Numeric Rating Scale (NRS), Foot Health Status Questionnaire Pain Score (FHSQ), and Leeds Assessment of Neuropathic symptoms and signs Scale for pain assessment, in measuring pain intensity. Some variations of physical activity include aerobic exercise, resistance exercise, vibration, and a combination of aerobic and resistance training. 30 minutes each session for 8 weeks with a frequency of 6 days/week. These studies used various designs, namely RCT, Experiment, and Quasi-experimental Pre test-post test with control group design Physical activity improves blood circulation and minimizes peripheral nerve damage so that pain intensity can decrease.Conclusion: Conclusion: Physical activity intervention is effective in reducing pain scales in diabetic neuropathy patients and can be a supportive therapy for diabetic neuropathy patients who experience pain.Keywords: physical activity, pain, diabetes, diabetic neuropathy, review

ABSTRACT The world is experiencing an enormous rise in the prevalence of diabetes, which is associated with massive healthcare costs that threaten to overwhelm many healthcare systems. Most of the diabetes expenditure is attributed to the management of chronic diabetes complications, including diabetic peripheral neuropathy (DPN)/diabetic foot complications, chronic kidney disease, sight‐threatening retinopathy and cardiovascular diseases. Of these complications, the most overlooked is DPN. Most consultations around the world do not even involve taking off shoes and socks to carry out a foot examination, and even when carried out, the peripheral neurological examination using the 10‐g monofilament diagnoses DPN when it is already at an advanced stage. Thus, all too often diabetes complications are diagnosed late, resulting in devastating outcomes, particularly in low‐ to middle‐income countries. There is, therefore, an urgent need to instigate new strategies to improve microvascular screening uptake using a holistic protocol for annual diabetes health checks outside the busy diabetes clinic. One such approach, the Sheffield One‐Stop Microvascular Screening Service, which involves modern point of care devices to diagnose DPN, has been shown to be feasible and effective, resulting in high uptake and early management of diabetes complications. This article outlines the advantages of this One‐Stop Microvascular Screening Service and a plan to trial an adapted version of this service to a resource‐limited country, the Philippines. If successful, this model has the potential for implementation in other countries around the world.

ABSTRACT Aims/Introduction To investigate risk factors for diabetic peripheral neuropathy (DPN) and to explore the connection between insulin‐like growth factor‐1 (IGF‐1) and DPN in individuals with type 2 diabetes. Materials and Methods A total of 790 patients with type 2 diabetes participated in a cross‐sectional study, divided into two groups: those with DPN (DPN) and those without DPN (non‐DPN). Blood samples were taken to measure IGF‐1 levels and other biochemical markers. Participants underwent nerve conduction studies and quantitative sensory testing. Results Patients with DPN exhibited significantly lower levels of IGF‐1 compared with non‐DPN patients (P 0.05), or the temperature detection threshold (P > 0.05). Multivariate regression analysis identified diabetes duration, HbA1c, and the low levels of IGF‐1 as independent risk factors (P

Introduction This study investigated the effect of foot muscle energy technique (MET) on nerve conduction velocity (NCV) and isometric muscle strength in patients with type 2 diabetic neuropathy (DN). Methods Forty-four patients were randomly assigned to either the MET group (group A) or the conventional physical therapy program group (group B). Electrophysiological measurements, including peroneal and tibial motor NCV studies, and isometric muscle strength using a toe strength dynamometer, were conducted. The assessment period ranged from April to November 2022, with measurements taken before the first session and after 4 weeks of treatment. Results Significant improvements were observed in post-treatment peroneal motor NCV ( p < 0.001), tibial motor NCV ( p < 0.001), and isometric muscle strength ( p < 0.001) in group A, but not in group B. Conclusions MET enhances motor NCV and isometric muscle strength in patients with type 2 DN.

Background: Diabetic neuropathy (DN) is one of the common chronic complications, leading to limb disability and increased risks of hospitalization and mortality. Traditional Chinese medicine (TCM) has been commonly applied in Taiwan as an adjunctive treatment to ameliorate diabetes-associated chronic complications, including neuropathy. Aim: We aimed to investigate whether the clinical treatment of DN combined with TCM can reduce the associated hospitalization and mortality using the National Health Insurance Research Database (NHIRD) of Taiwan. Methods: We selected 1,152 patients with DN who received TCM treatment as the study cohort group, and 4,940 patients with DN who did not receive TCM treatment from Taiwan NHIRD were further matched 1:1 for sex, age, and index year as the comparison cohort group. Cox proportional hazards analysis was performed to compare hospitalization and mortality during a mean follow-up period of 15 years. Results: A total of 687/225 enrolled patients (29.82%/9.77%) had hospitalization/mortality, including 298/97 in the TCM group (25.87%/8.42%) and 389/128 in the comparison group (33.77%/11.11%). Cox proportional hazard regression analysis showed a lower rate of hospitalization and mortality for patients in the TCM group (adjusted hazard ratio [HR] of 0.434, 95 confidence interval [CI] =0.172–0.798, P < 0.001; adjusted HR of 0.689, 95 CI = 0.372–0.981, P = 0.039). The Kaplan–Meier analysis showed that the cumulative risk of hospitalization and mortality in the study and comparison cohort groups was significantly different (log-rank P < 0.001 and P = 0.007, respectively). Conclusion: Our results suggest that the application of TCM might be beneficial for patients with DN to lower the risks of hospitalization and mortality; however, further prospective cohort studies are still required to confirm our observations.

Yue Li,1,2,&ast; Yuhui Wang,2,3,&ast; Yonghong Cao,1,2 Xinxiu Zhang,1,2 Wu Dai,1,2 Yiran Zhao,1,2 Lei Zhang,1,2 Xiaofang Han1,2 1Department of Endocrinology, Hefei Hospital Affiliated to Anhui Medical University, Hefei, People’s Republic of China; 2The Fifth Clinical College of Anhui Medical University, Hefei, People’s Republic of China; 3Department of Cardiology, Hefei Hospital Affiliated to Anhui Medical University, Hefei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaofang Han, Email hxfanghf@sina.comPurpose: To inquire into the relationship between diabetic peripheral neuropathy (DPN) and serum levels of growth differentiation factor-15 (GDF-15) in individuals with type 2 diabetes mellitus (T2DM).Patients and Methods: Out of 162 T2DM patients classified according to the diagnostic criteria of DPN, 75 were allocated to the non-DPN group and 87 to the DPN group. In turn, based on serum GDF-15 quartiles, all patients were additionally divided (GDF-15 low to high) into group A (40 cases), group B (41 cases), group C (41 cases), and group D (40 cases). General data and laboratory indexes of patients were collected, and enzyme-linked immunosorbent assay (ELISA) was used to determine serum GDF-15 levels.Results: Compared to the non-DPN group, in the DPN group GDF-15 levels were noticeably greater (P < 0.001). Using serum GDF-15 as a grouping variable, DPN prevalence and body mass index were gradually increased, motor and sensory nerve latencies were gradually lengthened, and amplitude (Amp) and nerve conduction velocity (NCV) were gradually decreased with increasing GDF-15 levels (P < 0.05). Linear regression modeling revealed that GDF-15 levels correlated positively with the latencies of sensory and motor nerves, and negatively with their corresponding NCV (P < 0.05). Binary logistic regression results indicated GDF-15 as an independent predictor for DPN (P < 0.05), whereas restricted cubic spline analysis indicated a dose-response, nonlinear relationship between GDF-15 and DPN.Conclusion: Serum GDF-15 level strongly correlates with DPN, and may represent an independent predictor and a biological marker for the disease.Keywords: growth differentiation factor 15, diabetic neuropathy, nerve conduction study, type 2 diabetes mellitus

Abstract Aims/Introduction Deficiency of neurotropic factors is implicated in diabetic neuropathy (DN). Netrin‐1 is a neurotropic factor, but its association with DN has not been explored. We have assessed the association between serum netrin‐1 levels and early diabetic neuropathy assessed by quantifying corneal nerve fiber loss using corneal confocal microscopy. Materials and Methods A total of 72 participants with type 2 diabetes, without and with corneal nerve fiber loss (DN− n = 42, DN+ n = 30), and 45 healthy controls were studied. Serum netrin‐1 levels were measured by enzyme‐linked immunosorbent assay, and corneal nerve morphology was assessed using corneal confocal microscopy. Results Corneal nerve fiber density, branch density, fiber length and serum netrin‐1 levels were significantly lower in the DN− and DN+ groups compared with controls (P

Abstract Background Diabetic neuropathy (DN), a frequent complication in individuals with diabetes mellitus (DM), is hypothesized to have a correlation with systemic iron status, though the nature of this relationship remains unclear. This study employs two-sample Mendelian randomization (MR) analysis to explore this potential genetic association. Methods We used genetic instruments significant associated with iron status including serum iron, ferritin, transferrin, and transferrin saturation, derived from an extensive Genome-Wide Association Study (GWAS) undertaken by the Genetics of Iron Status Consortium, involving a cohort of 48,972 European ancestry individuals. Summary statistics for DN were collected from a public GWAS, including 1,415 patients and 162,201 controls of European descent. Our MR analysis used the inverse-variance-weighted (IVW) method, supplemented by MR-Egger, weighted-median (WM) methods, Cochran’s Q test, MR-Egger intercept analysis, MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO) method, and leave-one-out analysis to ensure robustness and consistency of the findings. Results No genetic causal relationship was found between iron status markers and DN (all IVW p value > 0.05). Interestingly, a causative effect of DN on ferritin (IVW: OR = 0.943, 95% CI = 0.892–0.996, p = 0.035) and transferrin saturation (IVW: OR = 0.941, 95% CI = 0.888–0.998, p = 0.044) emerged. Sensitivity analyses confirmed the absence of significant heterogeneity and horizontal pleiotropy. Conclusion While systemic iron status was not found to be causally related to DN, our findings suggest that DN may increase the risk of iron deficiency. These results provide further evidence supporting iron supplementation in patients with DN.