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Diabetic painful neuropathy (DPN) is one of the most detrimental complications of diabetes. Alterations in neuroinflammatory mediators play significant roles in the development of DPN. Infiltration of the neutrophils and monocyte/macrophages contributes substantial role in the degenerative process of the distal sciatic nerve by forming neutrophil extracellular traps (NETs) under diabetic condition. Citrullination of histones due to increase in protein arginine deiminase (PAD) enzyme activity under hyperglycemia may promote NET formation, which can further increase the cytokine production by activating macrophages and proliferation of neutrophils. This study reveals that the increase in histone deacetylases (HDAC) is crucial in DPN and inhibition of HDAC using HDAC inhibitor (HDACi) FK228 would suppress NETosis and alleviate diabetic nerve degeneration and pain. FK228, also known as romidepsin, is FDA approved for the treatment of cutaneous T-cell lymphoma yet the molecular mechanisms of this drug are not completely understood in DPN. In this study, type 2 diabetic (T2D) mice with pain were treated with HDACi, FK228 1 mg/kg; I.P. 2 × /week for 3 weeks. The results demonstrate that FK228 treatment can alleviate thermal hyperalgesia and mechanical allodynia significantly along with changes in the expression of HDACs in the dorsal root ganglia (DRG) and spinal cord dorsal horn neurons of diabetic animals. The results also indicate that FK228 treatment can alter the expression of neutrophil elastase (NE), extracellular or cell free DNA (cfDNA), citrullinated histone-3 (CitH3), PADI4, growth-associated protein (GAP)-43, and glucose transporter (GLUT)-4. Overall, this study suggests that FK228 could amend the expression of nerve regeneration markers and inflammatory mediators in diabetic animals and may offer an alternative treatment approach for DPN., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Diabetes is a global health concern characterized by chronic hyperglycemia resulting from insulinopenia and/or insulin resistance. The rising prevalence of diabetes and its associated complications (ulcers, periodontitis, healing of bone defect, neuropathy, retinopathy, cardiopathy and nephropathy) necessitate innovative therapeutic approaches. Photobiomodulation (PBM), involves exposing tissues and cells to low-energy light radiation, leading to biological effects, largely via mitochondrial activation., Methods: This review evaluates preclinical and clinical studies exploring the potential of PBM in diabetes and its complications, as well all clinical trials, both planned and completed, available on ClinicalTrials database., Results: This review highlights the variability in PBM parameters across studies, hindering consensus on optimal protocols. Standardization of treatment parameters and rigorous clinical trials are needed to unlock PBM's full therapeutic potential. 87 clinical trials were identified that investigated PBM in diabetes mellitus (with 5,837 patients planned to be treated with PBM). Clinical trials assessing PBM effects on diabetic neuropathy revealed pain reduction and potential quality of life improvement. Studies focusing on wound healing indicated encouraging results, with PBM enhancing angiogenesis, fibroblast proliferation, and collagen density. PBM's impact on diabetic retinopathy remains inconclusive however, requiring further investigation. In glycemic control, PBM exhibits positive effects on metabolic parameters, including glucose tolerance and insulin resistance., Conclusion: Clinical studies have reported PBM-induced reductions in fasting and postprandial glycemia without an increased hypoglycemic risk. This impact of PBM may be related to its effects on the beta cells and islets in the pancreas. Notwithstanding challenges, PBM emerges as a promising adjunctive therapy for managing diabetic neuropathy, wound healing, and glycemic control. Further investigation into its impact on diabetic retinopathy and muscle recovery is warranted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Perrier, Moro and Lablanche.)

The 1989 Saint Vincent Declaration established a goal of halving global diabetes-related amputation rates. A generation later, this goal has been achieved for major but not minor amputations. However, diabetic foot disease (DFD) is not only a leading cause of global amputation but also of hospitalisation, poor quality of life (QoL) and disability burdens. In this paper, we review latest estimates on the global disease burden of DFD and the next generation care of DFD that could reduce this burden. We found DFD causes 2% of the global disease burden. This makes DFD the 13 th largest of 350+ leading conditions causing the global disease burden, and much larger than dementia, breast cancer and type 1 diabetes. Neuropathy without ulcers and amputations makes up the largest portion of the global DFD burden yet receives the least DFD focus. Future care focussed on improving safe physical activity in people with DFD could considerably reduce the DFD burden, as this incorporates increasing physical fitness and QoL, while simultaneously decreasing ulceration and other risks. Charcot neuro-osteoarthropathy is more prevalent than previously thought. Most cases respond well to non-removable offloading devices, but surgical intervention may further reduce the considerable burden of these neuropathic fracture dislocations. Ischaemia is becoming more common and complex. Most cases respond well to revascularisation interventions, but novel revascularisation techniques, medical management and autologous cell therapies may hold the key to more cases responding in the future. We conclude that DFD causes a global disease burden larger than most conditions and existing guideline-based care and next generation treatments can reduce this burden. We suggest the World Health Organization and International Diabetes Federation declare a new goal: halving the global DFD burden from 2% to 1% within the next generation., (© 2023 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.)

Background: The assessment of the normative values of sensory nerve action potentials (SNAP) and their diagnostic accuracies using validated neuropathy-assessment tools to classify participants into groups with and without neuropathy was not previously described in the literature., Methods: The Utah Early Neuropathy Scale (UENS), Michigan neuropathy-screening instrument, and nerve conduction data were collected prospectively. We described and compared the values of the sural, superficial peroneal sensory (SPS), and superficial radial SNAP amplitude in different age groups for three groups. Group 1 (G1)-control participants (UENS <5), group 2 (G2)-participants with diabetes without clinical diabetic neuropathy (UENS <5), and group 3 (G3)-participants with clinical diabetic neuropathy (UENS ≥5). We also described the diagnostic accuracy of single-nerve amplitude and a combined sensory polyneuropathy index (CSPNI) that consists of four total points (one point for each of the following nerves if their amplitude was <25% lower limit of normal: right sural, left sural, right SPS, and left SPS potentials)., Results: We assessed 135 participants, including 41, 37, and 57 participants in G1, G2, and G3, respectively, with age median (interquartile ranges) of 51 (45-56), 47 (38-56), and 54 (51-61) years, respectively, whereas 19 (46.3%), 18 (48.7%), and 32 (56.14%) of them were males, respectively. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) scores were 68.4%, 92.3%, 86.7%, and 80% for the sural amplitude; 86%, 58.3%, 62%, and 84% for the SPS amplitude; 66.7%, 94.4%, 90.5%, and 78.2% for the CSPNI of 3; and 54.4%, 98.6%, 96.9%, and 73.2% for the CSPNI of 4, respectively., Conclusion: Sural nerve had a high specificity for neuropathy; however, the CSPNI had the highest specificity and PPV, whereas the SPS had the highest sensitivity and NPV., (© 2024 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

In today's culture, obesity and overweight are serious issues that have an impact on how quickly diabetes develops and how it causes complications. For the development of more effective therapies, it is crucial to understand the molecular mechanisms underlying the chronic problems of diabetes. The most prominent effects of diabetes are microvascular abnormalities such as retinopathy, nephropathy, and neuropathy, especially diabetes foot ulcers, as well as macrovascular abnormalities such as heart disease and atherosclerosis. MicroRNAs (miRNAs), which are highly conserved endogenous short non-coding RNA molecules, have been implicated in several physiological functions recently, including the earliest stages of the disease. By binding to particular messenger RNAs (mRNAs), which cause mRNA degradation, translation inhibition, or even gene activation, it primarily regulates posttranscriptional gene expression. These molecules exhibit considerable potential as diagnostic biomarkers for disease and are interesting treatment targets. This review will provide an overview of the latest findings on the key functions that miRNAs role in diabetes and its complications, with an emphasis on the various stages of diabetic wound healing., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Spinal cord stimulation (SCS) technology has been recently approved by the US Food and Drug Administration (FDA) for painful diabetic neuropathy (PDN). The treatment involves surgical implantation of electrodes and a power source that delivers electrical current to the spinal cord. This treatment decreases the perception of pain in many chronic pain conditions, such as PDN. The number of patients with PDN treated with SCS and the amount of data describing their outcomes is expected to increase given four factors: (1) the large number of patients with this diagnosis, (2) the poor results that have been obtained for pain relief with pharmacotherapy and noninvasive non-pharmacotherapy, (3) the results to date with investigational SCS technology, and (4) the recent FDA approval of systems that deliver this treatment. Whereas traditional SCS replaces pain with paresthesias, a new form of SCS, called high-frequency 10-kHz SCS, first used for pain in 2015, can relieve PDN pain without causing paresthesias, although not all patients experience pain relief by SCS. This article describes (1) an overview of SCS technology, (2) the use of SCS for diseases other than diabetes, (3) the use of SCS for PDN, (4) a comparison of high-frequency 10-kHz and traditional SCS for PDN, (5) other SCS technology for PDN, (6) deployment of SCS systems, (7) barriers to the use of SCS for PDN, (8) risks of SCS technology, (9) current recommendations for using SCS for PDN, and (10) future developments in SCS., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: KTN is a consultant to Abbott Diabetes Care. NYX s a consultant to Abbott Diabetes Care. DCK is a consultant for EOFlow, Fractyl Health, Integrity, Lifecare, Rockley Photonics, and Thirdwayv. AMY, JH, LTH, BKA, and NE have nothing relevant to disclose.

Painful diabetic neuropathy is a common vexing problem for people with diabetes and a costly problem for society. The pathophysiology is not well understood, and no safe and effective mechanistically-based treatment has been identified. Poor glycemic control is a risk factor for painful diabetic neuropathy. Excessive intraneuronal glucose in people with diabetes can be shunted away from physiological glycolysis into multiple pathological pathways associated with neuropathy and pain. The first three treatments that are traditionally offered consist of risk factor reduction, lifestyle modifications, and pharmacological therapy, which includes only three drugs that are approved for this indication by the United States Food and Drug Administration. All of these traditional treatments are often inadequate for relieving neuropathic pain, and thus, new approaches are needed. Modern devices based on neuromodulation technology, which act directly on the nervous system, have been recently cleared by the United States Food and Drug Administration for painful diabetic neuropathy and offer promise as next-in-line therapy when traditional therapies fail., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DCK is a consultant for EOFlow, Fractyl Health, Integrity, Lifecare, Rockley Photonics, and Thirdwayv. AMY, JH, KTN, NYX, LTH, BKA, and NE have nothing relevant to disclose.

Background: Diabetes mellitus leading to foot ulcer is a serious complication, and it is considered a global epidemic. Neuropathyand high blood glucose levels are the primary causes of foot ulcers. Fifteen percent of people with diabetes develop foot ulcers, and these foot disorders are the main cause of lower extremity amputation among such patients., Introduction: Complications of diabetic foot, affecting the lower extremities are common and quite complex and life-threatening. This review focuses on the life-threatening factors associated with diabetic foot ulcers and also the diagnosing and preventive measures. Neuropathy assessment and the range of foot ulcers were accurately examined., Conclusion: Novel therapies focusing on the vascularity of the lower limbs, infection control, and ischemic control are being developed to mainly treat nonhealing ulcers., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aims: To assess sensory neuropathy development after severe COVID-19., Methods: Patients with severe COVID-19 underwent assessment of neuropathic symptoms, tendon reflexes, and quantitative sensory testing to evaluate vibration (VPT), cold (CPT), warm (WPT) and heat perception thresholds (HPT) within 1-3 weeks of admission and after 1-year., Results: 32 participants with severe COVID-19 aged 68.6 ± 12.4 (18.8 % diabetes) were assessed. At baseline, numbness and neuropathic pain were present in 56.3 % and 43.8 % of participants, respectively. On the feet, VPT, WPT, and HPT were abnormal in 81.3 %, CPT was abnormal in 50.0 % and HPT on the face was abnormal in 12.5 % of patients. At 1-year follow-up, the prevalence of abnormal VPT (81.3 % vs 50.0 %, P < 0.01), WPT (81.3 % vs 43.8 %, P < 0.01), and HPT (81.3 % vs 50.0 %, P < 0.01) decreased, with no change in CPT (P = 0.21) on the feet or HPT on the face (P = 1.0). Only participants without diabetes recovered from an abnormal VPT, CPT, and WPT. Patients with long-COVID (37.5 %) had comparable baseline VPT, WPT and CPT with those without long-COVID (P = 0.07-0.69)., Conclusions: Severe COVID-19 is associated with abnormal vibration and thermal thresholds which are sustained for up to 1 year in patients with diabetes. Abnormal sensory thresholds have no association with long-COVID development., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Phi Med Europe S.L. provided the NerveCheck Master device and funded the study. M.N. Odriozola, S. Odriozola, M.B. Odriozola and A. Odriozola are the owners and inventors of the NerveCheck Master. We declare that we have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship and are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us., (Copyright © 2023. Published by Elsevier B.V.)

Introduction: the rising prevalence of diabetes mellitus (DM) around the world has dramatically increased the number of people bearing the complications of this potentially incapacitating disease. One of these complications is foot ulcers that may result in amputation. This study sets out to determine the profiles of the "foot-at-risk" for ulceration and the associated socio-medical factors in DM patients., Methods: this study was conducted at Bowen University Teaching Hospital, Ogbomoso, Southwest, Nigeria. This was a descriptive cross-sectional study comprising 299 outpatient adults aged 18 years and above with diabetes mellitus of at least 6 months in duration. Comprehensive Foot Examination and Risk Assessment tool was used to identify the foot-at-risk categories of the participants. Data analysis was done using Statistical Package for Social Sciences (SPSS) version 20., Results: the prevalence of foot-at-risk among the participants was 64.9% (194). Among the 194 participants with foot-at-risk, 35.1% (105) belonged to the foot-at-risk categories 0, 37.8% (113) in category 1, 16.1% (48) in category 2, and 11.0% (33) in category 3. Other factors that had a statistically significant association with foot-at-risk included; age, religion, level of education, duration of diabetes, history of smoking, and glycemic control., Conclusion: foot-at-risk was found to have an alarming prevalence among the participants. In addition, the level of glycemic control in this group was unacceptably poor. Clinicians need to intensify preventive measures like foot screening and health education to prevent foot ulcerations, which may result in limb amputation in DM patients., Competing Interests: The authors declare no competing interests., (Copyright: Adeola Ebenezer Idowu et al.)

Introduction: People with diabetic peripheral neuropathy (DPN) and limited joint mobility syndrome (LJMS) can experience increased forefoot peak plantar pressures (PPPs), a known risk factor for ulceration. The aim of this study was to investigate whether ankle and 1st metatarsophalangeal (MTP) joint mobilisations and home-based stretches in people with DPN improve joint range of motion (ROM) and reduce forefoot PPPs., Design and Methods: Sixty-one people with DPN (IWGDF risk 2), were randomly assigned to a 6-week programme of ankle and 1 st MTP joint mobilisations (n = 31) and home-based stretches or standard care only (n = 30). At baseline (T0); 6-week post intervention (T1) and at 3 months follow-up (T2), a blinded assessor recorded dynamic ankle dorsiflexion range using 3D (Codamotion) motion analysis and the weight bearing lunge test, static 1st MTP joint dorsiflexion ROM, dynamic plantar pressure and balance., Results: At T1 and T2 there was no difference between both groups in ankle dorsiflexion in stance phase, plantar pressure and balance. Compared to the control group, the intervention group showed a statistically significant increase in static ankle dorsiflexion range (Left 1.52 cm and 2.9cms, Right 1.62 cm and 2.7 cm) at 6 (T1) and 18 weeks (T2) respectively p < 0.01). Between group differences were also seen in left hallux dorsiflexion (2.75°, p < 0.05) at T1 and in right hallux dorsiflexion ROM (4.9°, p < 0.01) at T2 follow up. Further, functional reach showed a significant increase in the intervention group (T1 = 3.13 cm p < 0.05 and T2 = 3.9 cm p < 0.01). Intervention adherence was high (80%)., Conclusions: Combining ankle and 1 st MTP joint mobilisations with home-based stretches in a 6-week programme in people with DPN is effective in increasing static measures of range. This intervention may be useful for improving ankle, hallux joint mobility and anteroposterior stability limits in people with diabetes and neuropathy but not for reducing PPP or foot ulcer risk., Trial Registration: https://classic., Clinicaltrials: gov/ct2/show/NCT03195855 ., (© 2023. The Author(s).)

Introduction: Nepal is a developing country where diabetes is becoming a major health challenge due to its high prevalence of 8.5% affecting around 2 million people. Due to limited resources, there are many barriers to providing affordable and convenient diabetes care or regular screening for complications. There is no reliable data on incidence, prevalence, and complications of diabetic foot problems in Nepal., Methods: We conducted an online survey amongst senior physicians, who were members of 'Diabetes & Endocrine Association of Nepal' to assess their perception of diabetic foot problems in Nepal., Results: Thirty-Eight physicians responded to the survey who saw a total of 17597 patients in the preceding month. They recalled seeing 647 with 'Diabetic Foot Ulcers', giving a crude Diabetic Foot Ulcer prevalence rate of 3.7%. They recalled seeing 2522 patients with painful neuropathy that required medical treatment, giving a crude painful neuropathy prevalence rate of 14.3%. A history of foot ulcer was present in an additional 578 patients. Previous minor amputation had been performed in 215 patients (1.2%) and major amputation in 135 patients (0.8%)., Discussion: Despite having expertise in various fields there is no dedicated multi-disciplinary diabetic foot clinic in Nepal. This survey shows that diabetic foot problems are abundant in Nepal and there is a need for structured multi-disciplinary approach for screening and treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Baral and Rajbhandari.)

Diabetes mellitus is a chronic metabolic disease commonly associated with complications such as cardiovascular disease, nephropathy and neuropathy, the incidence of which is increasing yearly. Transcription factor forkhead box M1 (FOXM1) serves an important role in development of diabetes and its complications. The present study aimed to review the association between FOXM1 with pathogenesis of diabetes and its complications. FOXM1 may be involved in development and progression of diabetes and its complications by regulating cell biological processes such as cell cycle, DNA damage repair, cell differentiation and epithelial‑mesenchymal transition. FOXM1 is involved in regulation of insulin secretion and insulin resistance, and FOXM1 affects insulin secretion by regulating expression of insulin‑related genes and signaling pathways; FOXM1 is involved in the inflammatory response in diabetes, and FOXM1 can regulate key genes associated with inflammatory response and immune cells, which in turn affects occurrence and development of the inflammatory response; finally, FOXM1 is involved in the regulation of diabetic complications such as cardiovascular disease, nephropathy and neuropathy. In summary, the transcription factor FOXM1 serves an important role in development of diabetes and its complications. Future studies should explore the mechanism of FOXM1 in diabetes and find new targets of FOXM1 as a potential treatment for diabetes and its complications.

To update the literature on the effectiveness of photobiomodulation (PBM) therapy in relieving pain in patients with diabetic peripheral neuropathy (DPN) compared to the effects of post-intervention, control/placebo groups, and other therapies. Search on the following databases: PORTAL PERIODICOS CAPES, PUBMED, GOOGLE ACADEMIC/SCHOLAR, SCOPUS, SCIELO, CENTRAL, and MEDLINE. Manual search: 1) manually capture the references of relevant articles originally selected to be included in the eligible studies. Two independent researchers performed the screening and selection of studies, methods assessment, and data extraction with unblinded authors and impressions. Subsequently, the full text of the originally selected studies was screened. The screening form registered the criteria for excluding literature from the full-text screening. The screening resulted in a total of 1692 citations. Out of these, 1402 citations were examined for titles and abstracts, followed by the removal of duplicated studies; therefore, 68 articles remained for full-text evaluation. 54 articles were excluded after full-text screening. Fourteen articles met the selection criteria, hence being selected and included in this narrative review. PBM showed to be a promising modality in relieving painful symptoms in DPN, especially when implemented in combination with other therapies, by improving the quality of life of diabetic patients., (© 2023. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Appropriate animal models, mimicking conditions of both health and disease, are needed to understand not only the biology and the physiology of neurons and other cells under normal conditions but also under stress conditions, like nerve injuries and neuropathy. In such conditions, understanding how genes and different factors are activated through the well-orchestrated programs in neurons and other related cells is crucial. Knowledge about key players associated with nerve regeneration intended for axonal outgrowth, migration of Schwann cells with respect to suitable substrates, invasion of macrophages, appropriate conditioning of extracellular matrix, activation of fibroblasts, formation of endothelial cells and blood vessels, and activation of other players in healthy and diabetic conditions is relevant. Appropriate physical and chemical attractions and repulsions are needed for an optimal and directed regeneration and are investigated in various nerve injury and repair/reconstruction models using healthy and diabetic rat models with relevant blood glucose levels. Understanding dynamic processes constantly occurring in neuropathies, like diabetic neuropathy, with concomitant degeneration and regeneration, requires advanced technology and bioinformatics for an integrated view of the behavior of different cell types based on genomics, transcriptomics, proteomics, and imaging at different visualization levels. Single-cell-transcriptional profile analysis of different cells may reveal any heterogeneity among key players in peripheral nerves in health and disease.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs, incretin mimetics) and dipeptidyl peptidase-4 inhibitors (DPP-4is, incretin enhancers) are glucose-lowering therapies with proven cardiovascular safety, but their effect on microvascular disease is not fully understood. Both therapies increase GLP-1 receptor agonism, which is associated with attenuation of numerous pathological processes that may lead to microvascular benefits, including decreased reactive oxygen species (ROS) production, decreased inflammation and improved vascular function. DPP-4is also increase stromal cell-derived factor-1 (SDF-1), which is associated with neovascularisation and tissue repair. Rodent studies demonstrate several benefits of these agents in the prevention or reversal of nephropathy, retinopathy and neuropathy, but evidence from human populations is less clear. For nephropathy risk in human clinical trials, meta-analyses demonstrate that GLP-1RAs reduce the risk of a composite renal outcome (doubling of serum creatinine, eGFR reduction of 30%, end-stage renal disease or renal death), whereas the benefits of DPP-4is appear to be limited to reductions in the risk of albuminuria. The relationship between GLP-1RAs and retinopathy is less clear. Many large trials and meta-analyses show no effect, but an observed increase in the risk of retinopathy complications with semaglutide therapy (a GLP-1RA) in the SUSTAIN-6 trial warrants caution, particularly in individuals with baseline retinopathy. Similarly, DPP-4is are associated with increased retinopathy risk in both trials and meta-analysis. The association between GLP-1RAs and peripheral neuropathy is unclear due to little trial evidence. For DPP-4is, one trial and several observational studies show a reduced risk of peripheral neuropathy, with others reporting no effect. Evidence in other less-established microvascular outcomes, such as microvascular angina, cerebral small vessel disease, skeletal muscle microvascular disease and autonomic neuropathies (e.g. cardiac autonomic neuropathy, gastroparesis, erectile dysfunction), is sparse. In conclusion, GLP-1RAs are protective against nephropathy, whereas DPP-4is are protective against albuminuria and potentially peripheral neuropathy. Caution is advised with DPP-4is and semaglutide, particularly for patients with background retinopathy, due to increased risk of retinopathy. Well-designed trials powered for microvascular outcomes are needed to clarify associations of incretin therapies and microvascular diseases., (© 2023. The Author(s).)

Aims: To evaluate the long-term efficacy of high-frequency (10 kHz) spinal cord stimulation (SCS) for treating refractory painful diabetic neuropathy (PDN)., Methods: The SENZA-PDN study was a prospective, multicenter, randomized controlled trial that compared conventional medical management (CMM) alone with 10 kHz SCS plus CMM (10 kHz SCS+CMM) in 216 patients with refractory PDN. After 6 months, participants with insufficient pain relief could cross over to the other treatment. In total, 142 patients with a 10 kHz SCS system were followed for 24 months, including 84 initial 10 kHz SCS+CMM recipients and 58 crossovers from CMM alone. Assessments included pain intensity, health-related quality of life (HRQoL), sleep, and neurological function. Investigators assessed neurological function via sensory, reflex, and motor tests. They identified a clinically meaningful improvement relative to the baseline assessment if there was a significant persistent improvement in neurological function that impacted the participant's well-being and was attributable to a neurological finding., Results: At 24 months, 10 kHz SCS reduced pain by a mean of 79.9% compared to baseline, with 90.1% of participants experiencing ≥50% pain relief. Participants had significantly improved HRQoL and sleep, and 65.7% demonstrated clinically meaningful neurological improvement. Five (3.2%) SCS systems were explanted due to infection., Conclusions: Over 24 months, 10 kHz SCS provided durable pain relief and significant improvements in HRQoL and sleep. Furthermore, the majority of participants demonstrated neurological improvement. These long-term data support 10 kHz SCS as a safe and highly effective therapy for PDN., Trial Registration: ClincalTrials.gov Identifier, NCT03228420., Competing Interests: Declaration of competing interest Author Erika A. Petersen has received consulting fees from Abbott Laboratories, Biotronik, Boston Scientific, Medtronic Neuromodulation, Nalu Medical, Neuros Medical, Nevro Corp, Presidio Medical, Saluda, and Vertos Medical, research support from Mainstay, Medtronic Neuromodulation, Nalu Medical, Neuros Medical, Nevro Corp, ReNeuron, Saluda, and SPR, and stock options from neuro42 and SynerFuse. Author Thomas G. Stauss has received research support from Nevro Corp. Author James A. Scowcroft has received research support from Boston Scientific, Nevro Corp, Saluda Medical, and Vertiflex. Author Michael J. Jaasma is an employee of Nevro Corp. Author Elizabeth S. Brooks was an employee of Nevro Corp during her contributions to the work associated with this manuscript. Author Deborah R. Edgar received consulting fees from Nevro in her capacity as an independent medical writer. Author Judith L. White has received consulting fees from California Institute for Biomedical Research and Eli Lilly and research support from Nevro Corp. Author Shawn M. Sills has received research support from Nevro Corp. Author Kasra Amirdelfan has received consulting fees from Biotronik, Medtronic, Nalu Medical, Nevro Corp, and Saluda Medical, as well as research support from Biotronik, IPM Medical Group, Nevro Corp, Saluda Medical, SPR Therapeutics, and Vivex Biologics. Author Maged N. Guirguis has received consulting fees from Abbott Laboratories, Avanos Medical, Avertis Pharmacy, Boston Scientific, Nevro Corp, and Saluda Medical, as well as research support from Abbott Laboratories, Avanos Medical, Boston Scientific, Nalu Medical, Neuros Medical, Nevro Corp, and Saluda Medical. Author Jijun Xu has received research support from the Cleveland Clinic Velosano Program, the National Institutes of Health, the Steve and Melody Golding Foundation, and Nevro Corp. Author Cong Yu has received research support from Nevro Corp. Author Ali Nairizi has received consulting fees from Aurora Spine, Flowonix, and Nevro Corp as well as research support from Nevro Corp. Author Denis G. Patterson has received consulting fees from Abbott Laboratories, AIS Healthcare, Allergan, Amgen, Aurora Spine, CornerLoc, Flowonix, Lundbeck, Pajunk Medical, Saluda Medical, Spark Biomedical, and Vertos Medical, research support from Abbott Laboratories, Aurora Spine, Flowonix, Nevro Corp, and Saluda Medical, speakers’ bureau or honoraria from Abbott Laboratories, Allergan, Amgen, CornerLoc, Lundbeck, Saluda Medical, and Vertos Medical, and stock options from CornerLoc. Author Michael J. Creamer has received research support from Nevro Corp. Author Vincent Galan has received research support from Biotronik, Medtronic, Nevro Corp, PainTEQ, SPR Therapeutics, and St. Jude. Author Richard H. Bundschu has received research support from Nevro Corp. Author Neel D. Mehta has received consulting fees from Averitas, Nevro Corp, and Salix Pharmaceuticals, as well as research support from Boston Scientific and Nevro Corp. Author Dawood Sayed has received consulting fees from Abbott Laboratories, Boston Scientific, Flowonix, Medtronic, Nevro Corp, Vertiflex, and Vertos Medical, as well as research support from Abbott Laboratories, Biotronic, Nevro Corp, Vertiflex, and Vertos Medical. Author Shivanand P. Lad has received consulting fees from Nevro Corp and research support from Nevro Corp. Author David J. DiBenedetto has received research support from Nevro Corp, as well as funding for serving as principal investigator of a study supported by SPR Therapeutics paid to his institution. Author Khalid A. Sethi has received research support from Nevro Corp. Author Johnathan H. Goree has received consulting fees from Abbott Laboratories and Stratus Medical. Author Paul W. Wu has received research support from Nevro Corp. Author Charles E. Argoff has received consulting fees from AbbVie, Amgen, Biohaven, Clexio Biosciences, Collegium, Eli Lilly, Elsevier, Flowonix, Gene Pharma, Lundbeck, Nevro Corp, Novartis, Pfizer, SK Life Science, Teva Pharmaceutical, and Vertex as well as research support from AbbVie, Allergan, Amgen, Daiichi Sankyo, Eli Lilly, Novartis, Teva Pharmaceutical, and Vertex Pharmaceuticals. Author Christian E. Nasr has received consulting fees from Exelixis, Neurogastrx, and Nevro Corp as well as research support from Nevro Corp. Author Rod S. Taylor has received consulting fees from Nevro Corp, Medtronic, and Saluda Medical. Author David L. Caraway is an employee of Nevro Corp. Author Nagy A. Mekhail has received consulting fees from Nevro Corp, Relievant Medsystems, Saluda Medical, Sollis Therapeutics, and Vertos Medical, as well as research support from Avanos Medical, Mesoblast, Neuros Medical, and Nevro Corp., (Copyright © 2023. Published by Elsevier B.V.)

Cutaneous manifestations affect most patients with diabetes mellitus, clinically presenting with numerous dermatologic diseases from xerosis to diabetic foot ulcers (DFUs). Skin conditions not only impose a significantly impaired quality of life on individuals with diabetes but also predispose patients to further complications. Knowledge of cutaneous biology and the wound healing process under diabetic conditions is largely limited to animal models, and studies focusing on biology of the human condition of DFUs remain limited. In this review, we discuss the critical molecular, cellular, and structural changes to the skin in the hyperglycaemic and insulin-resistant environment of diabetes with a focus specifically on human-derived data. Elucidating the breadth of the cutaneous manifestations coupled with effective diabetes management is important for improving patient quality of life and averting future complications including wound healing disorders., (© 2023 The Wound Healing Society.)

Diabetic neuropathy is a neuro-degenerative disorder that encompasses numerous factors that impact peripheral nerves in the context of diabetes mellitus (DM). Diabetic peripheral neuropathy (DPN) is very prevalent and impacts 50% of diabetic patients. DPN is a length-dependent peripheral nerve lesion that primarily causes distal sensory loss, discomfort, and foot ulceration that may lead to amputation. The pathophysiology is yet to be fully understood, but current literature on the pathophysiology of DPN revolves around understanding various signaling cascades involving the polyol, hexosamine, protein-kinase C, AGE, oxidative stress, and poly (ADP ribose) polymerase pathways. The results of research have suggested that hyperglycemia target Schwann cells and in severe cases, demyelination resulting in central and peripheral sensitization is evident in diabetic patients. Various diagnostic approaches are available, but detection at an early stage remains a challenge. Traditional analgesics and opioids that can be used "as required" have not been the mainstay of treatment thus far. Instead, anticonvulsants and antidepressants that must be taken routinely over time have been the most common treatments. For now, prolonging life and preserving the quality of life are the ultimate goals of diabetes treatment. Furthermore, the rising prevalence of DPN has substantial consequences for occupational therapy because such therapy is necessary for supporting wellness, warding off other chronic-diseases, and avoiding the development of a disability; this is accomplished by engaging in fulfilling activities like yoga, meditation, and physical exercise. Therefore, occupational therapy, along with palliative therapy, may prove to be crucial in halting the onset of neuropathic-symptoms and in lessening those symptoms once they have occurred., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Chronic pruritus is common in patients with diabetes though its pathophysiology is unknown and difficult to pinpoint given the multi-system manifestations of diabetes. Herein, we aim to evaluate the severity of chronic itch in patients with diabetes and its association with glycaemic control, microvascular complications and quality of life., Methods: We conducted a retrospective study of 105 adults with diabetes evaluated by a dermatologist at a tertiary care centre in Mexico City. Degree of chronic pruritus and its impact on quality of life as well as laboratory, clinical and demographic data were collected. Patients without chronic pruritus (n = 62) were compared to those with chronic pruritus (n = 43). The latter cohort was further stratified by itch severity, and characteristics of their itch were quantified., Results: Neuropathy and loss of protective sensation were more common in patients with chronic pruritus, compared to those without chronic pruritus (p = 0.007 and p = 0.001, respectively). Anxiety and depression were more common in individuals with chronic pruritus (p = 0.009), and these group reported higher effect of pruritus on their quality of life (p < 0.0001). The most common sites of itch were the head, back and arms. Among patients with chronic itch, increasing itch severity was associated with decreasing eGFR (p = 0.080)., Conclusions: The underlying cause of chronic itch in patients with diabetes is likely multifactorial and owing to microvascular complications such as neuropathy and nephropathy. Better understanding of the causes of itch in these patients can allow for more targeted treatment, leading to improved quality of life., (© 2023 Australasian College of Dermatologists.)

Diabetes is a common metabolic disease characterized by loss of blood sugar control and a high rate of complications. γ-Aminobutyric acid (GABA) functions as the primary inhibitory neurotransmitter in the adult mammalian brain. The normal function of the GABAergic system is affected in diabetes. Herein, we summarize the role of the GABAergic system in diabetic cognitive dysfunction, diabetic blood sugar control disorders, diabetes-induced peripheral neuropathy, diabetic central nervous system damage, maintaining diabetic brain energy homeostasis, helping central control of blood sugar and attenuating neuronal oxidative stress damage. We show the key regulatory role of the GABAergic system in multiple comorbidities in patients with diabetes and hope that further studies elucidating the role of the GABAergic system will yield benefits for the treatment and prevention of comorbidities in patients with diabetes., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To compare the number of ulcer-free days during 24 months in persons with diabetes and a healed foot ulcer below the ankle provided with adjusted therapeutic shoes who were given standard information and participated in participant-driven group education compared with standard information alone. Methods: A randomized controlled trial was designed to evaluate the number of ulcer-free days after participant-driven group education in addition to standard information compared with standard information alone. The number needed to treat ( N  = 174) was not met, as only 138 persons with diabetes and previously healed foot ulcer were recruited (age median 63 years [34-79], 101 men/37 women). Results: A total of 138 persons were recruited, of whom 107 (77.5%) completed the study, 7 (5%) dropped out, and 12 (9%) deceased. No statistically significant difference was found between the intervention group compared with the control group after 6, 18, or 24 months. After 12 months, more patients in the intervention group had developed ulcers. Seventy-seven participants (56%) developed new foot ulcers, irrespective of side and site. Development of one ulcer appeared in 36 participants, two ulcers in 19, and 22 participants developed three ulcers. Forty-eight participants remained ulcer-free (35%) during the 24-month follow-up. Median ulcer-free days until first ulceration were 368 (4-720); until second ulceration, 404 (206-631); and until third ulceration, 660 (505-701). The participants wore prescribed therapeutic shoes during 88% of the follow-up visits. Conclusions: One-third of the participants remained ulcer-free for 24 months. Patient-driven education in groups did not give better results than standard information in this underpowered study. This study illustrates the challenges to perform comparative preventive studies in this group of patients with extensive comorbidity. Further studies are needed to evaluate interventions on ulceration in persons with a healed foot ulcer.

Background: Foot and ankle amputation is a feared complication of diabetic neuropathy and diabetes mellitus (DM) accounts for 80% of all in-hospital amputations. Magnetic resonance neurography is an effective tool in characterizing neuromuscular sequelae of the disease. However, conventional ankle MRI is more commonly performed and has not been studied to assess neuromuscular changes of DM., Objective: The objective is to characterize neuromuscular changes of diabetic patients in a case-control study using conventional ankle MRI., Methods: Between November 2019 and July 2021, 110 consecutive ankle MRI scans (n = 102 patients) at our county hospital were reviewed and met the inclusion criteria. Patients were divided into two cohorts, diabetic (N = 63) and non-diabetic (N = 39). Demographics, HgbA1c, and reason for MRI study were collected via retrospective chart review. The presence of intramuscular edema-like signal, pattern of the edema, muscle fatty infiltration, and measurements of the cross-sectional area of the posterior, medial, and lateral tibial nerves (PTN, MPN, and LPN) was recorded blinded to the clinical findings by two readers., Results: Muscle edema-like signal was much more likely to be found in DM (odds ratio 19.5, 95% CI 7.0-54.6, p < 0.001). DM also showed increase of 0.87 in the mean grade of muscle fatty infiltration (p < 0.001). There were higher rates of nerve T2 hyperintensity (odds ratio 14.0, 95% CI 3.1-62.7, p < 0.001) and the measured areas of the PTN, MPN, and LPN were also larger in DM compared to their non-diabetic counterparts (PTN: 0.16 cm 2 vs. 0.10 cm 2 , p < 0.01; MPN: 0.09 cm 2 vs. 0.05 cm 2 , p < 0.01; LPN: 0.07 cm 2 vs. 0.04 cm 2 , p < 0.05)., Conclusion: Conventional ankle MRIs can be used to detect DM-related neuromuscular changes., (© 2022. The Author(s), under exclusive licence to International Skeletal Society (ISS).)

Deoxysphingolipids (1-deoxySLs) are neurotoxic sphingolipids associated with obesity and diabetic neuropathy (DN) and have been linked to severity of functional peripheral neuropathies. While l-serine supplementation can reduce 1-deoxySL accumulation and improve insulin sensitivity and sensory nerve velocity, long-term outcomes have not yet been examined. To assess this, we treated 2 month old db/db mice, a model of DN, with 5-20 % oral l-serine for 6 months and longitudinally quantified the extent of functional neuropathy progression. We examined putative biomarkers of neuropathy in blood and tissue and quantified levels of small fiber neuropathy, looking for associations between lowered 1-deoxySL and phenotypes. Toxic 1-deoxySLs were suppressed long-term in plasma and various tissue including the sciatic nerve, which is particularly targeted in DN. Functional neuropathy and sensory modalities were significantly improved in the treatment group well into advanced stages of disease. However, structural assessments revealed prominent axonal degeneration, apoptosis and Schwann cell pathology, suggesting that neuropathy was ongoing. Hyperglycemia and dyslipidemia persisted during our study, and high levels of glutathione were seen in the spinal cord. Our results demonstrate that despite significant functional improvements, l-serine does not prevent chronic degenerative changes specifically at the structural level, pointing to other processes such as oxidative damage and hyperglycemia, that persist despite 1-deoxySL reduction., Competing Interests: Declaration of competing interest Authors declare no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Various nutraceuticals from different sources have various beneficial actions and have been reported for many years. The important findings from the research conducted using various nutraceuticals exhibiting significant physiological and pharmacological activities have been summarized., Methods: An extensive investigation of literature was done using several worldwide electronic scientific databases like PUBMED, SCOPUS, Science Direct, Google Scholar, etc. The entire manuscript is available in the English language that is used for our various compounds of interest. These databases were thoroughly reviewed and summarized., Results: Nutraceuticals obtained from various sources play a vital role in the management of peripheral neuropathy associated with diabetes. Treatment with nutraceuticals has been beneficial as an alternative in preventing the progression. In particular, in vitro and in vivo studies have revealed that a variety of nutraceuticals have significant antioxidant and anti-inflammatory properties that may inhibit the early diabetes-driven molecular mechanisms that induce DPN., Conclusion: Nutraceuticals obtained from different sources like a plant, an animal, and marine have been properly utilized for the safety of health. In our opinion, this review could be of great interest to clinicians, as it offers a complementary perspective on the management of DPN. Trials with a well-defined patient and symptom selection have shown robust pharmacological design as pivotal points to let these promising compounds become better accepted by the medical community., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

With the global prevalence of diabetes mellitus over recent decades, more patients suffered from various diabetic complications, including diabetic ocular surface diseases that may seriously affect the quality of life and even vision sight. The major diabetic ocular surface diseases include diabetic keratopathy and dry eye. Diabetic keratopathy is characterized with the delayed corneal epithelial wound healing, reduced corneal nerve density, decreased corneal sensation and feeling of burning or dryness. Diabetic dry eye is manifested as the reduction of tear secretion accompanied with the ocular discomfort. The early clinical symptoms include dry eye and corneal nerve degeneration, suggesting the early diagnosis should be focused on the examination of confocal microscopy and dry eye symptoms. The pathogenesis of diabetic keratopathy involves the accumulation of advanced glycation end-products, impaired neurotrophic innervations and limbal stem cell function, and dysregulated growth factor signaling, and inflammation alterations. Diabetic dry eye may be associated with the abnormal mitochondrial metabolism of lacrimal gland caused by the overactivation of sympathetic nervous system. Considering the important roles of the dense innervations in the homeostatic maintenance of cornea and lacrimal gland, further studies on the neuroepithelial and neuroimmune interactions will reveal the predominant pathogenic mechanisms and develop the targeting intervention strategies of diabetic ocular surface complications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhou, Yang, Wang, Li, Wei and Xie.)

Background: Painful diabetic neuropathy (PDN) is a progressive chronic pain condition that significantly affects the quality of life of patients with long-standing diabetes mellitus. Sensory deficits may result in falls, foot ulceration, and lower limb amputations. Recently, spinal cord stimulation (SCS) was studied for treatment of painful diabetic neuropathy. In addition to pain relief, we were surprised to discover that sensory improvements were also demonstrated. No mechanistic explanation has yet been offered to explain these findings., Objectives: Sensory improvements were observed in patients during the Senza-PDN clinical trial. Our objective was to offer a hypothesis to explain these results., Study Design: The randomized, prospective, multicenter, open-label Senza-PDN clinical trial was aimed at documenting the value of 10 kHz SCS in addition to conventional medical management alone. We formulated an hypothesis to explain the neurologic improvement observed while using SCS in these study patients., Setting: This work was conducted in a private clinical practice., Results: SCS resulted in an overall decrease in pain for the enrolled PDN patients. An unexpected improvement in neurologic outcomes was also noticed at up to 12 months, which had never been reported before. We hypothesized that stochastic resonance mechanism could explain these sensory improvements. We believe that waveforms delivered to the spinal cord may have had the unexpected effect of creating noise-enhanced signal processing., Limitations: Further research will have to be performed to confirm the plausibility of the stochastic resonance hypothesis formulated., Conclusions: SCS might have unexpected benefits in patients with PDN beyond pain reduction. The Senza-PDN trial is the first to describe improved sensation in association with SCS. While the mechanism of action are still unknown, we hypothesize that noise-enhanced signal processing via stochastic resonance may explain these results. Stochastic resonance, or the benefit of additional randomness, should be further studied in the context of spinal cord stimulation. Further, SCS programming that optimizes for stochastic resonance should also be investigated for restoration of sensory and possibly even motor function.

Background: A comprehensive insight into the effect of longstanding diabetes mellitus and neuropathy on foot joint kinetics during walking is lacking. Our goal was to assess the in-vivo kinetics of major foot joints in persons with diabetes., Methods: Three groups, matched for age, sex and walking speed were recruited in this study: 1) people with diabetic peripheral neuropathy, 2) people with diabetes without peripheral neuropathy, and 3) control subjects without diabetes. Participants were instrumented with retroreflective markers on both feet and lower limbs and underwent a barefoot gait analysis using a state-of-the-art multi-segment kinetic foot modelling approach in order to provide accurate joint loading measures at the ankle, midtarsal, tarso-metatarsal and hallux joints., Findings: The group with neuropathy showed reduced ankle peak plantarflexion angular velocity compared to the control group (P = 0.002). Both groups with diabetes showed a significantly reduced midtarsal peak plantarflexion angular velocity, peak power generation and positive work compared to the control group (p < 0.01). Groups showed significant differences with respect to the tarsometatarsal peak dorsiflexion (p = 0.006) and plantarflexion angular velocity (P < 0.05)., Interpretation: This study shows that both diabetes groups have similar joint loading and power absorption capacity but seem to lose their power generation capacity especially at the midtarsal joint. This loss of power generation capacity and the resulting decreased net mechanical work of the foot potentially embodies a foot that poorly supplements the body's mechanical energy during push-off. This phenomenon may cause excessive tissue stresses that contribute to foot deformity and joint-destruction mechanisms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Historically, diabetic retinopathy has been recognized as a vascular disease. Recent clinical evidence suggests the initiation of diabetic retinopathy with neuropathy rather than microangiopathy. However, the molecular mechanism that drives diabetic retinopathy-associated neuropathy remains mostly unexplored. Here, we reported progressive diabetic retinopathy defects in blood glucose levels, shortening of cone segments and uncoupled appearance of retinal vascular abnormalities from pdx1 +/- mutants zebrafish to glucose-treated pdx1 +/- mutants zebrafish of both sexes. Further single-cell transcriptomic analysis revealed cones as the most vulnerable retinal neuron type that underwent three developmentally progressive cell states (States 1-3), predominantly present in WT animals, pdx1 reduction in diabetic retinopathy-associated cone defects. Thus, our study provided a vertebrate retina model representing progressive diabetic retinopathy defects and further gained new mechanistic insights into the cone morphologic defects as an early neuropathy in diabetic retinopathy. +/- mutants , and glucose-treated pdx1 +/- mutants , respectively. Mechanistically, the expression of hcn1 was progressively decreased in cones during its transition from State 1 to State 3. Furthermore, genetic hcn1 disruption resulted in similar cone segment defects found in the diabetic retinopathy model, suggesting the involvement of progressive hcn1 reduction in diabetic retinopathy-associated cone defects. Thus, our study provided a vertebrate retina model representing progressive diabetic retinopathy defects and further gained new mechanistic insights into the cone morphologic defects as an early neuropathy in diabetic retinopathy. SIGNIFICANCE STATEMENT We create a vertebrate retina model representing the progressive diabetic retinopathy-associated defects using zebrafish. Further systematic single-cell transcriptome analysis reveals two novel cell states of cones in response to different levels of higher glucose and the progressive decrease of HCN1 channels as a mechanism underlying cone defects in diabetic retinopathy., (Copyright © 2022 the authors.)

Diabetes mellitus with the lack of glycemic control increases risks for developing comorbidities affecting organ systems responsible for critical function. The development of diabetic neuropathy predisposes patients to the onset of Charcot neuroarthropathy (CN). There is significant complexity with treatment of diabetic-induced CN, which can have an often delayed or missed diagnosis. Supervision and treatment from trained specialists are required to provide care for this multifaceted disease process. It is essential for patients to partner with glucose control, comorbidity prevention and care, as well as lower extremity management. Ultimately, CN can result in significant lower extremity deformity placing patients at risk of limb and life., Competing Interests: Disclosures The author has nothing to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The present study aimed to evaluate diabetes patients over a 10-year period that visited our outpatient clinic for prevention of diabetic foot ulcers and then investigate the incidence and aetiology of diabetic foot ulcers. The Department of Diabetes and Metabolic Diseases of a university hospital was in charge of the clinic that provided diabetes patients with individual education via the use of visualisation techniques. In this prospective cohort study, a total of 942 diabetes patients who visited the clinic were evaluated for neuropathy, angiopathy and medical history between November 2006 and March 2017. Using the patients' medical records, diabetic foot ulcer development was evaluated between the day of the first visit and December 31, 2018, with 20 out of 942 participants developing these ulcers. Over a period of 12, 60 and 120 months, the diabetic foot ulcer cumulative incidence was 0.2%, 2.4% and 5.8%, respectively. A history of diabetic foot ulcers and the male sex were shown by a Cox regression analysis to be correlated with diabetic foot ulcer development (Hazard Ratio [HR] 11.55, 95%CI 4.600-29.004, p < 0.001; and HR 3.55, 95%CI 1.031-12.196, p = 0.045, respectively). However, only five out of 20 participants with ulceration returned to the clinic for re-examination. In conclusion, a 12-month evaluation showed there was a low incidence of diabetic foot ulcers. These results might suggest that patients with a diabetic foot ulcer history need to undergo at least an annual follow-up in order to further reduce diabetic foot ulcer incidence, although studies involving control groups needs to be conducted, in presenting these as evidence., (© 2022 The Wound Healing Society.)

Objective: The lifetime risk of developing a diabetic foot ulcer (DFU) in people with diabetes is as high as 25%. A trio of factors constitute the diabetic foot syndrome that characterises DFUs, including neuropathy, vascular disease and infections. Vitamin C has important functions in the nervous, cardiovascular, and immune systems that are implicated in DFU development. Furthermore, vitamin C deficiency has been observed in individuals with DFUs, suggesting an important function of vitamin C in DFU management and treatment. Therefore, this literature review evaluates the role of vitamin C in the nervous, cardiovascular and immune systems in relation to wound healing and DFUs, as well as discussing vitamin C's lesser known role in depression, a condition that affects many individuals with a DFU., Method: A literature search was done using PubMed, Cochrane Library, Embase, Ovid, Computer Retrieval of Information on Scientific Projects, and NIH Clinical Center. Search terms included 'diabetic foot ulcer,' 'diabetic foot,' 'vitamin C,' and 'ascorbic acid.', Results: Of the 71 studies initially identified, seven studies met the inclusion criteria, and only three were human clinical trials. Overall, the literature on this subject is limited, with mainly observational and animal studies, and few human clinical trials., Conclusion: There is a need for additional human clinical trials on vitamin C supplementation in individuals with a DFU to fill the knowledge gap and guide clinical practice.

When diabetes neuropathy occurs, the oxidative stress caused by chronic hyperglycemia may result in chronic neuronal damage. To mitigate the effects of hyperglycemia-induced neuronal damage, it may be beneficial to address oxidative stress and inflammation in the body. The current study evaluated the neuroprotective efficacy of Thuja occidentalis in streptozotocin (STZ)-nicotinamide (NAD)-induced diabetic neuropathy in male Wistar rats. A single dose of STZ (65 mg/kg, i.p.) was used to induce diabetic neuropathy in Wistar rats. Serum insulin, glucose, hyperalgesia, oxidative stress, inflammatory markers, and histopathology of the sciatic nerve were evaluated for neuropathy. Wistar rats were treated with varying doses of hydroalcoholic extracts of Thuja occidentalis (HAETO) and gabapentin for 30 days. Thuja occidentalis considerably corrected the levels of inflammatory markers and oxidative stress caused by hyperglycemia; also, it led to the restoration of neuronal functions, indicating that it is effective in treating diabetic neuropathy. Furthermore, the molecular docking of thujone at the active pockets of various inflammatory mediators (IL-1β, IL-6, TGF-β1, and TNF-α) has shown good interactions with critical amino acid residues. These findings indicate that the hydroalcoholic extract of Thuja occidentalis effectively inhibits the development of diabetic neuropathy. The hypoglycemic, antioxidant, anti-hyperalgesia, and anti-inflammatory properties of Thuja occidentalis are thought to be responsible for the neuroprotective benefit., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: Diabetic foot ulceration can contribute to lowered life expectancy and quality of life for people with diabetes, and yet, scant attention has been given to improving preventive and educational measures. This article uses a phenomenological approach to explore individuals' lived experiences of diabetic foot ulcerations to explore factors that can be harnessed to achieve improved outcomes., Design: This was a qualitative study using semi-structured interviews grounded in a phenomenological framework to explore how patients perceive and understand their foot problems., Methods: Study participants were recruited from February 2020 to February 2021 from a tertiary referral centre that treats foot problems in persons with diabetes. A total of 15 Hispanic, Native American and White patients participated in the study. We conducted in-depth semi-structured interviews which were audio recorded with the participant's consent. Interview data were transcribed and analysed with Dedoose data management software., Results: Analysis revealed findings in two primary domains: (1) how patients perceive foot ulceration, with themes around limited understandings of foot ulceration, close sensory observation of foot problems and barriers to ulcer perception and (2) how patients experience the timing of foot ulceration, with themes on how time perceptions shifted as foot problems became more serious, which correlated closely to how patients responded to their foot problems., Conclusion: Despite the close sensory observation of their feet, people with diabetes face an array of barriers to recognizing and understanding the implications of diabetic foot ulceration, which can lead to delayed care seeking. Nurses can play a critical role in promoting patient education and improving patient self-management of foot ulcers., Impact: This phenomenological study offers important lessons to guide nurses and other providers in enhancing patient self-management of DFUs and improving care outcomes by expanding an understanding of DFU early warning signs, the imperative to seek medical care quickly, and addressing possible barriers., (© 2022 John Wiley & Sons Ltd.)

Background: Diabetic retinopathy is a principal cause of visual damage and blindness, in which laser treatment offers proven therapy. The progressive degeneration of the retina, secondary to diabetes, is believed to cause postural instability although this is not well documented. The aim of this research was to assess how optic flow stimuli contribute to the control of stance in people with impaired retinal functions., Research Question: Does the different retinal functionality correspond to different specific patterns of movements and muscles recruitment?, Methods: Postural mechanisms and motor strategies were measured by testing subjects in quiet stance on a force platform with surface electromyography under different optic flow stimulations. Root mean square values of the center of pressure time-varying signals and normalized EMG values were used to evaluate the postural sway., Results: People with diabetic retinopathy, and to a greater extent laser group, were more unstable than healthy subjects. The greater amplitude of the body sway observed in the retinopathy group, and especially in the laser group, could be an expression of the difficulty for this population in processing this kind of visual information., Significance: The increase in muscle activity indicates that there are musculoskeletal and postural changes in the lower limb musculature with increasing severity of diabetic retinopathy. An impaired retinal function might negatively affect postural control in a way that is dependent on the severity of retinal damage., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Several soft tissue and osseous substitutes have become widely available for consideration in diabetic foot and ankle reconstruction. Although autogenous skin and bone grafts remain the gold standard, the diabetic foot often presents with challenging clinical scenarios in which these options are limited or contraindicated. Selection of the appropriate substitute depends on the patient's medical status, type and extent of soft tissue and bone loss, and expected function of the given site. This article reviews several of the specific advanced orthobiologics and their clinical indications., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Diabetic foot wounds should be treated in a timely fashion to prevent infection and potential limb loss. When local wound care and traditional off-loading fails, surgeons may consider local random flaps for definitive closure. Wound size, location, and type are characteristics that should be considered for selection of the best flap. This article reviews the application of local random flaps in the treatment of diabetic foot wounds., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The development of painful diabetic neuropathy (PDN) is a common complication of chronic diabetes that can be associated with significant disability and healthcare costs. Prompt symptom identification and aggressive glycemic control is essential in controlling the development of neuropathic complications; however, adequate pain relief remains challenging and there are considerable unmet needs in this patient population. Although guidelines have been established regarding the pharmacological management of PDN, pain control is inadequate or refractory in a high proportion of patients. Pharmacotherapy with anticonvulsants (pregabalin, gabapentin) and antidepressants (duloxetine) are common first-line agents. The use of oral opioids is associated with considerable morbidity and mortality and can also lead to opioid-induced hyperalgesia. Their use is therefore discouraged. There is an emerging role for neuromodulation treatment modalities including intrathecal drug delivery, spinal cord stimulation, and dorsal root ganglion stimulation. Furthermore, consideration of holistic alternative therapies such as yoga and acupuncture may augment a multidisciplinary treatment approach. This aim of this review is to focus on the current management strategies for the treatment of PDN, with a discussion of treatment rationale and practical considerations for their implementation.

Background: Diabetes is one of the most prevalent chronic health conditions and diabetic neuropathy one of its most prevalent and debilitating complications. While there are treatments available for painful diabetic peripheral neuropathy (pDPN), their effectiveness is limited., Method: This retrospective, multi-center, real-world review assessed pain relief and functional improvements for consecutive patients with diabetic neuropathy aged ≥18 years of age who were permanently implanted with a high-frequency (10 kHz) spinal cord stimulation (SCS) device. Available data were extracted from a commercial database., Results: In total 89 patients consented to being included in the analysis. Sixty-one percent (54/89) of participants were male and the average age was 64.4 years (SD = 9.1). Most patients (78.7%, 70/89) identified pain primarily in their feet or legs bilaterally. At the last assessment, 79.5% (58/73) of patients were treatment responders, defined as having at least 50% patient-reported pain relief from baseline. The average time of follow-up was 21.8 months (range: 4.3 to 46.3 months). A majority of patients reported improvements in sleep and overall function relative to their baseline., Conclusions: This real-world study in typical clinical practices found 10 kHz SCS provided meaningful pain relief for a substantial proportion of patients refractory to current pDPN management, similar to published literature. This patient population has tremendous unmet needs and this study helps demonstrate the potential for 10 kHz SCS to provide an alternative pain management approach.

Diabetic painless and painful peripheral neuropathy remains the most frequent complication of diabetes mellitus, but the pathophysiology remains undescribed, there are no robust clinical endpoints and no efficient treatment exists. This hampers good clinical practice, fruitful clinical research and successful pharmacological trials, necessary for the development of early detection, prevention and treatment. This chapter supplies an update on background and treatment of diabetic peripheral neuropathy. Goals and perspectives for future clinical and scientific approaches are also described., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Significance: Diabetes is a major source of neuropathy and neuropathic pain that is set to continue growing in prevalence. Diabetic peripheral neuropathy (DPN) and pain associated with diabetes are not adequately managed by current treatment regimens. Perhaps the greatest difficulty in treating DPN is the complex pathophysiology, which involves aspects of metabolic disruption and neurotrophic deficits, along with neuroimmune interactions. There is, therefore, an urgent need to pursue novel therapeutic options targeting the key cellular and molecular players. Recent Advances: To that end, cellular targeting becomes an increasingly compelling drug delivery option as our knowledge of neuroimmune interactions continues to mount. These nanomedicine-based approaches afford a potentially unparalleled specificity and longevity of drug targeting, using novel or established compounds, all while minimizing off-target effects. Critical Issues: The DPN therapeutics directly targeted at the nervous system make up the bulk of currently available treatment options. However, there are significant opportunities based on the targeting of non-neuronal cells and neuroimmune interactions in DPN. Future Directions: Nanomedicine-based agents represent an exciting opportunity for the treatment of DPN with the goals of improving the efficacy and safety profile of analgesia, as well as restoring peripheral neuroregenerative capacity. Antioxid. Redox Signal. 36, 122-143.

The objective is to determine, by systematic review, the reliability of testing methods for diagnosis of diabetes-related peripheral neuropathy (DPN) as recommended by the most recent guidelines from the International Diabetes Foundation, International Working Group on the Diabetic Foot and American Diabetes Association. Electronic searches of Cochrane Library, EBSCO Megafile Ultimate and EMBASE were performed to May 2021. Articles were included if they reported on the reliability of recommended chairside tests in diabetes cohorts. Quality appraisal was performed using a Quality Appraisal of Reliability Studies checklist and where possible, meta-analyses, with reliability reported as estimated Cohen's kappa (95% CI). Seventeen studies were eligible for inclusion. Pooled analysis found acceptable inter-rater reliability of vibration perception threshold (VPT) (κ=0.61 (0.50 to 0.73)) and ankle reflex testing (κ=0.60 (0.55 to 0.64)), but weak inter-rater reliability for pinprick (κ=0.45 (0.22 to 0.69)) and 128 Hz tuning fork (κ=0.42 (0.15 to 0.70)), though intra-rater reliability of the 128 Hz tuning fork was moderate (κ=0.54 (0.37 to 0.73)). Inter-rater reliability of the four-site monofilament was acceptable (κ=0.61 (0.45 to 0.77)). These results support the clinical use of VPT, ankle reflexes and four-site monofilament for screening and ongoing monitoring of DPN as recommended by the latest guidelines. The reliability of temperature perception, pinprick, proprioception, three-site monofilament and Ipswich touch test when performed in people with diabetes remains unclear., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Neuropathy, or dysfunction of peripheral nerve, is one of the most common neurological manifestation in patients with diabetes mellitus (DM). DM is typically associated with a hyperglycaemic milieu, which promotes non-enzymatic glycation of proteins. Proteins with advanced glycation are known to engage a cell-surface receptor called the receptor for advanced glycation end products (RAGE). Thus, it is reasonable to assume that RAGE and its associated molecule-mediated cellular signalling may contribute to DM-induced symmetrical axonal (length-dependent) neuropathy. Of particular interest is diaphanous related formin 1 (DIAPH1), a cytoskeletal organizing molecule, which interacts with the cytosolic domain of RAGE and whose dysfunction may precipitate axonopathy/neuropathy. Indeed, it has been demonstrated that both RAGE and DIAPH1 are expressed in the motor and sensory fibres of nerve harvested from DM animal models. Although the detailed molecular role of RAGE and DIAPH1 in diabetic neurological complications remains unclear, here we will discuss available evidence of their involvement in peripheral diabetic neuropathy. Specifically, we will discuss how a hyperglycaemic environment is not only likely to elevate advanced glycation end products (ligands of RAGE) and induce a pro-inflammatory environment but also alter signalling via RAGE and DIAPH1. Further, hyperglycaemia may regulate epigenetic mechanisms that interacts with RAGE signalling. We suggest the cumulative effect of hyperglycaemia on RAGE-DIAPH1-mediated signalling may be disruptive to axonal cytoskeletal organization and transport and is therefore likely to play a key role in pathogenesis of diabetic symmetrical axonal neuropathy., (© 2021 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Objectives: This study aims to evaluate the impact of Microburst Insulin Infusion (MII) treatment on Type 1 and 2 diabetic patients' HbA1c, lipids, peripheral neuropathy, and patient-reported health status. Methods: We reviewed clinical charts, including lab results, for more than 80 diabetic and pre-diabetic patients treated at one U.S. outpatient clinic in St. Louis, Missouri between February 2017 and December 2019. Data included patient demographics, treatment data, lab and neuropathy tests, and self-reported patient health status questions. The explanatory variable was number of months of MII treatment. Treatments are 3-4 h in length, with two intensive infusions the first week and one treatment each week thereafter, usually for 12 weeks total. Lab tests were at 12-week intervals. Generalized linear modeling and t-tests assessed the significance of differences between patients' baseline lab values, neuropathy measures, and health status before treatment vs. after final treatment. Results: Number of MII treatments per patient ranged from 1 to 262, over 1-24 months. Time in MII treatment was significantly associated with reductions in HbA1c by nearly 0.04 points per month, and triglycerides declined 3 points per month. Neuropathy measures of large toe vibratory sensation (clanging tuning fork) improved significantly, as did patient-reported health and feelings of improvement since beginning treatment. Discussion: The MII therapy appears to be efficacious in treating diabetic patients, particularly those with complications like neuropathy. Our findings affirmed several other studies. We uniquely incorporated patient health questionnaires, and empirically studied MII treatment efficacy for diabetes in a population large enough to permit statistically valid inferences. With multiple waves of data for over 80 patients, this is one of the most extensive quantitative studies of microburst insulin infusion therapy conducted to date, with protocols more uniformly implemented and survey instruments more consistently administered by the same clinical team. Given the advances in insulin infusion therapy brought by MII, and early indications of its efficacy, the time is right for more in-depth studies of the outcomes patients can achieve, the physiological mechanisms by which they occur, MII's comparative effectiveness vis-à-vis traditional treatments, and cost-effectiveness., Competing Interests: SH previously consulted on a clinical improvement and strategic planning project with Mitokon Health Center, the St. Louis clinic from which the de-identified data were obtained. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Howard, Zhang, Linomaz, Lam, Qian, Thurman and BeLue.)

Objective: to determine massage lavender essential oil on neuropathic pain and quality of life in diabetic patients., Methods: A randomized three-group control trial with the pre-post design was performed from 2019 to 2020 on 75 diabetic neuropathic patients. The patients were randomly allocated into aromatherapy (n = 26), placebo (n = 26), and control (n = 26) groups. Patients in the intervention group used 2.5 cc of 3% lavender oil on their feet as a gentle massage for 10 min every night before bedtime for a month. Data collected using the Visual analog scale (VAS), Douleur Neuropathic 4 (DN4) and Quality of Life Questionnaire (SF36)., Results: The mean difference of pain scores in short-term and long-term in the aromatherapy group was significantly reduced compared to the placebo and control groups (P < 0.001). In addition, after four weeks, a significant increase was found in the QoL domains in the aromatherapy group (P < 0.001)., Conclusion: Aromatherapy massage with lavender oil helped reduce neuropathic pain two to four weeks after the intervention and improved the patients' QoL without causing any side effects. Thus, nurses are recommended to use it as a complementary method to reduce neuropathic pain and improve patients' QoL., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Patients with diabetic peripheral neuropathy (DPN) usually have reduced somatosensory information and altered perception in feet and ankles. Somatosensory information acts as feedback for movement control and loss of somatosensation leads to altered plantar pressure patterns during gait and stance. Offloading devices are used to reduce peak plantar pressure and prevent diabetic foot ulcers. However, offloading devices can unfortunately have negative effects on static and dynamic balance. It is important to investigate these unwanted effects, since patient with DPN already are at high risk of falling and offloading devices could potentially increase this risk. The aim of this systematic review is to investigate the effects of plantar offloading devices used for ulcer prevention on their role in static and dynamic balance control in patients with DPN. PubMed and Embase were systematically searched using relevant search terms. After title selection, abstract selection, and full-text selection only five articles could be included for further analysis. Two articles included static balance measurements, two articles included dynamic balance measurements, and one article included both. Results suggested that static balance control is reduced when rocker bottom shoes and different insole configurations are used, however, toe-only rockers showed less evidence for reduced static balance control. There was no evidence for reduced dynamic balance control in combination with offloading devices. However, these results should be interpreted with care, since the number of studies was very small and the quality of the studies was moderate. Future research should evaluate balance in combination with different offloading devices, so that clinicians subscribing them are more aware of their potential unwanted consequences.

This review discusses the evidence on diabetic retinopathy (DR) in patients with diabetic foot ulceration (DFU). A systematic literature review was performed on PubMed, Medline, Springer Nature, and Scopus, following the PRISMA guidelines, using the following terms, individually or in combination: "diabetic foot ulcer" OR "diabetic foot syndrome" OR "DFU" and "diabetic retinopathy." The initial search yielded 648 articles published between 1975 and 2020. After applying exclusion and inclusion criteria, a total of 9 articles were analyzed, assessing the correlations between DR and DFU. In all cases, DR and especially proliferative diabetic retinopathy were significantly higher in the presence of DFU, though the frequency of DR showed large variability (22.5% to 95.6%). There was a significant correlation between advanced stages of DFU and increased frequency of DR and proliferative diabetic retinopathy. On the other hand, there is a risk of accelerated progression of DR in nonhealing DFUs, possibly related to chronic inflammation and associated infection. Hence, patients with DFUs should be monitored by an ophthalmologist, and those with DR should be promptly referred to a specialized diabetic foot clinic.

Background: A toe-extension movement pattern may contribute to metatarsophalangeal joint deformity and ulceration in people with diabetes. We sought to quantify the relationship between toe extension magnitude and variability during three functional tasks (ankle range of motion, sit to stand, walking) with metatarsophalangeal joint deformity, and identify potential mechanisms associated with a toe-extension movement pattern., Methods: Individuals with diabetes and peripheral neuropathy were included (n = 60). Metatarsophalangeal joint deformity was assessed using computed tomography (CT). Toe-extension movement was quantified using 3-dimensional motion capture. Linear regression was used to investigate the role of toe-extension movement pattern on metatarsophalangeal joint deformity. Regression analysis was used to identify mechanisms (neuropathy severity, foot intrinsic muscle deterioration ratio, ankle dorsiflexion range of motion) contributing to toe-extension movement pattern., Findings: Toe extension with each functional task as well as the mean and coefficient of variation across all tasks were significantly related to metatarsophalangeal joint deformity (range of correlation coefficients = (-0.386, 0.692), p ≤ 0.001). Ankle dorsiflexion range of motion was associated with mean toe extension across all tasks (r sp  = -0.282, p = 0.029). Neuropathy severity and foot intrinsic muscle deterioration ratio were associated with toe extension variability (r sp  = -0.373, p = 0.003 and r sp  = -0.266, p = 0.043; respectively)., Interpretation: Greater magnitude and lower variability of a toe-extension movement pattern was found to be associated with metatarsophalangeal joint deformity. These findings may support clinical assessment and treatment of movement across more than one task., (Copyright © 2021. Published by Elsevier Ltd.)