Progression Of Diabetic Peripheral Neuropathy Research Articles

Xiaoke Bitong capsule alleviates inflammatory impairment via inhibition of the TNF signaling pathway to against diabetic peripheral neuropathy

BackgroundXiaoke Bitong capsule (XBC) is a crude herbal compound believed to tonify qi, improve blood circulation, and alleviate blood stasis. It has been used as an herbal formula for the prevention and treatment of diabetic peripheral neuropathy (DPN) under the guidance of traditional Chinese medicine (TCM). However, the pharmacological mechanisms by which XBC ameliorates DPN remain poorly understood. The interaction between pro-inflammatory factors and the activation of tumor necrosis factor (TNF) plays a critical role in the underlying mechanisms of DPN. XBC may protect against DPN through the regulation of the TNF pathway. PurposeMany studies show the association between DPN and nerve dysfunction, however, treatment options are limited. To identify specific therapeutic targets and active components of XBC that contribute to its anti-DPN effects, our study aimed to investigate the potential mechanism of action of XBC during the progression of DPN using a system pharmacology approach. MethodsAn approach involving UPLC-Q-TOF/MS and network pharmacology was used to analyze the compositions, potential targets, and active pathways of XBC. Further, models of streptozocin (STZ) induced mouse and glucose induced RSC96 cells were established to explore the therapeutic effects of XBC. High glucose induced RSC96 cells were pretreated with small interfering RNA (siRNA) to identify potential therapeutic targets of DPN. ResultsSeventy-one active compositions of XBC and five potential targets, including mitogen-activated protein kinase 8 (MAPK), interleukin-6 (IL-6), poly-ADP-ribose polymerase-1 (PARP1), vascular endothelial growth factor A (VEGFA), and transcription factor p65 (NF-κB), were considered as the potential regulators of DPN. In addition, the results revealed that the TNF signaling pathway was closely related to DPN. Moreover, DPN contributed to the decreased expressions of PI3K and AKT, increased TNF-α and IL-1β in RSC96 cells, which were both reversed by XBC or TNF-α siRNA. ConclusionXBC could protect against DPN by inhibiting the release of pro-inflammatory cytokines and regulating the activation of the TNF signaling pathway, further accelerating neurogenesis, and alleviating peripheral nerve lesions. Therefore, this study highlights the therapeutic value of XBC for DPN.

Xiaoke Bitong capsule alleviates inflammatory impairment via inhibition of the TNF signaling pathway to against diabetic peripheral neuropathy

BackgroundXiaoke Bitong capsule (XBC) is a crude herbal compound believed to tonify qi, improve blood circulation, and alleviate blood stasis. It has been used as an herbal formula for the prevention and treatment of diabetic peripheral neuropathy (DPN) under the guidance of traditional Chinese medicine (TCM). However, the pharmacological mechanisms by which XBC ameliorates DPN remain poorly understood. The interaction between pro-inflammatory factors and the activation of tumor necrosis factor (TNF) plays a critical role in the underlying mechanisms of DPN. XBC may protect against DPN through the regulation of the TNF pathway. PurposeMany studies show the association between DPN and nerve dysfunction, however, treatment options are limited. To identify specific therapeutic targets and active components of XBC that contribute to its anti-DPN effects, our study aimed to investigate the potential mechanism of action of XBC during the progression of DPN using a system pharmacology approach. MethodsAn approach involving UPLC-Q-TOF/MS and network pharmacology was used to analyze the compositions, potential targets, and active pathways of XBC. Further, models of streptozocin (STZ) induced mouse and glucose induced RSC96 cells were established to explore the therapeutic effects of XBC. High glucose induced RSC96 cells were pretreated with small interfering RNA (siRNA) to identify potential therapeutic targets of DPN. ResultsSeventy-one active compositions of XBC and five potential targets, including mitogen-activated protein kinase 8 (MAPK), interleukin-6 (IL-6), poly-ADP-ribose polymerase-1 (PARP1), vascular endothelial growth factor A (VEGFA), and transcription factor p65 (NF-κB), were considered as the potential regulators of DPN. In addition, the results revealed that the TNF signaling pathway was closely related to DPN. Moreover, DPN contributed to the decreased expressions of PI3K and AKT, increased TNF-α and IL-1β in RSC96 cells, which were both reversed by XBC or TNF-α siRNA. ConclusionXBC could protect against DPN by inhibiting the release of pro-inflammatory cytokines and regulating the activation of the TNF signaling pathway, further accelerating neurogenesis, and alleviating peripheral nerve lesions. Therefore, this study highlights the therapeutic value of XBC for DPN.

Relationship of lncRNA FTX and miR-186-5p levels with diabetic peripheral neuropathy in type 2 diabetes and its bioinformatics analysis.

Diabetic peripheral neuropathy (DPN) frequently occurs as a secondary condition in individuals with type 2 diabetes mellitus (T2DM). To explore the relationship of lncRNA FTX and miR-186-5p levels with DPN in T2DM. The study enrolled 50 patients withT2DM and 45 patients with DPN. Expression levels of FTX and miR-186-5p were measured by RT-qPCR. The levels of MDA, GSH, and SOD in the serum were measured to assess the patients' oxidative stress levels. In addition, the target genes of miR-186-5p were analyzed by bioinformatics. Serum FTX levels were increased and miR-186-5p levels were decreased in patients with T2DM and DPN. Both of them had high diagnostic value for T2DM and DPN. In addition, FTX and miR-186-5p were risk factors for the onset of DPN in people with T2DMand were significantly correlated with oxidative stress indicators in patients. FTX and miR-186-5p are closely related to the disease progression of DPN in people with T2DM and may become therapeutic targets for DPN in people with T2DM.

Combination therapy is it in the future for successfully treating peripheral diabetic neuropathy?

In 2022, the Center for Disease Control and Prevention reported that 11.3% of the United States population, 37.3 million people, had diabetes and 38% of the population had prediabetes. A large American study conducted in 2021 and supported by many other studies, concluded that about 47% of diabetes patients have peripheral neuropathy and that diabetic neuropathy was present in 7.5% of patients at the time of diabetes diagnosis. In subjects deemed to be pre-diabetes and impaired glucose tolerance there was a wide range of prevalence estimates (interquartile range (IQR): 6%-34%), but most studies (72%) reported a prevalence of peripheral neuropathy ≥10%. There is no recognized treatment for diabetic peripheral neuropathy (DPN) other than good blood glucose control. Good glycemic control slows progression of DPN in patients with type 1 diabetes but for patients with type 2 diabetes it is less effective. With obesity and type 2 diabetes at epidemic levels the need of a treatment for DPN could not be more important. In this article I will first present background information on the "primary" mechanisms shown from pre-clinical studies to contribute to DPN and then discuss mono- and combination therapies that have demonstrated efficacy in animal studies and may have success when translated to human subjects. I like to compare the challenge of finding an effective treatment for DPN to the ongoing work being done to treat hypertension. Combination therapy is the recognized approach used to normalize blood pressure often requiring two, three or more drugs in addition to lifestyle modification to achieve the desired outcome. Hypertension, like DPN, is a progressive disease caused by multiple mechanisms. Therefore, it seems likely as well as logical that combination therapy combined with lifestyle adjustments will be required to successfully treat DPN.

Early Detection of Diabetic Peripheral Neuropathy in Diabetic Patients: A Cross-Sectional Study.

Diabetic Peripheral Neuropathy (DPN) is a chronic complication in Type 2 Diabetes Mellitus (T2DM) patients and is characterized by paresthesia, pain, and hypoesthesia of the extremities. The Diabetic Neuropathy Symptom-Score (DNS) is a quick, inexpensive, and easy-to-perform tool to detect DPN in clinical practice. Biochemical markers like Nitric Oxide (NO) and Vascular Endothelial Growth Factor (VEGF) play a role in the early detection of DPN. This study aims to investigate the relationship between risk factors and these biomarkers. So, it is expected to improve the prevention and treatment of diabetic neuropathy more effectively. A cross-sectional method was used for this study. The sample size was 85 patients with T2DM who visited several primary healthcare in Medan, selected by consecutive sampling method based on eligibility criteria. Data collected included DNS, assessment of NO, VEGF, Glycated Hemoglobin (HbA1C), plasma blood glucose (PBG), and lipid profile. The collected data were analyzed using an independent T-test. The results showed that most T2DM patients, namely 73 people (85.9%), experienced DPN. From the bivariate analysis results, the risk factors associated with the prevalence of DPN in T2DM patients were found to be increased levels of total cholesterol, HbA1c, NO, and VEGF (p < 0.05). Meanwhile, blood pressure, fasting BGL, HDL-C, LDL-C, and triglycerides were not related to the occurrence of DPN in this study (p> 0.05). DNS can be used as a quick and easy initial screening tool implemented in clinical practice for screening DPN. Diabetic patients with DPN tend to have lower NO and increased VEGF; besides, NO levels are also associated with the progression of DPN. Furthermore, education, blood sugar control, and physical exercise, especially leg exercises, can prevent progressive DPN.

Association of serum NF-κB levels with peripheral neuropathy in type 2 diabetes mellitus patients: a pilot study.

Hyperglycaemia-induced inflammation plays a vital role in the development of diabetic peripheral neuropathy (DPN). Recent evidences had reported the involvement of the transcription factor nuclear factor kappa-light-chain-enhancer of activated Bcell (NF-κB) in diabetic experimental models. So, this pilot study aimed to evaluate serum NF-κB levels in DPN patients. We recruited 50 T2DM patients, of which 25 were T2DM with neuropathy and 25 were T2DM without neuropathy. In all the participants peripheral neuropathy was diagnosed based on Total neuropathy score (TNS). Serum NF-κB levels were measured by ELISA. We observed that the serum NF-κB levels were higher in DPN patients in comparison to T2DM patients without neuropathy. On spearman correlation, a positive correlation was found between serum NF-κB levels and TNS in the DPN group (r=0.741, p<0.001). The regression model shows the TNS to be an independent determinant of serum NF-κB levels after adjustment for potential confounders like age, duration of diabetes, and HbA1C (B=81.34; p<0.001). NF-κB activation plays a key role in promoting inflammation which is associated with the progression of DPN. In this respect, the study of NF-κB levels in serum may be an additional diagnostic marker for DPN.

Glucagon-like peptide-1 receptor agonists for the management of diabetic peripheral neuropathy.

Diabetes mellitus is a prevalent chronic disease characterized by hyperglycemia. Diabetic peripheral neuropathy (DPN) is one of the complications of diabetes mellitus and is caused by neuron injury induced by hyperglycemic circumstances. The incidence of DPN varies among different countries and regions, ranging from nearly 20% to over 70%. Patients with DPN may encounter symmetric pain or discomfort of the extremes, leading to reduced quality of life and even amputation. The pharmacological management for painful DPN mainly includes antidepressants due to their analgesic effects. Nevertheless, effective therapies to impact the pathogenesis and progression of DPN are lacking. Glucagon-like peptide-1 receptor (GLP-1R) agonists show efficacy in controlling blood glucose and serve as a treatment modality for diabetes mellitus. In recent years, evidence has been proposed that GLP-1R agonists exert neuroprotective effects through modulating inflammation, oxidative stress, and mitochondrial dysfunction. On the other hand, clinical evidence on the potential of GLP-1R agonists for treating DPN is still controversial and limited. This narrative review summarizes the preclinical and clinical studies investigating the capacity of GLP-1R agonists as therapeutic agents for DPN.

Association between Angiotensin-converting Enzyme Gene Insertion/Deletion Polymorphism with Diabetic Peripheral Neuropathy and Its Importance as a Genetic Biomarker

Background: Diabetic peripheral neuropathy (DPN) is the most common microvascular complication of type 2 diabetes mellitus (T2DM) with a prevalence ranging from 18.8% to 61.9% in India. For patients with T2DM, identifying those who are at risk of developing DPN is crucial for planning and implementing secondary preventive interventions, as well as for stepping up efforts to address risk factors. Very few studies have discovered a connection between angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphisms and the onset and progression of DPN in T2DM. Objectives: The current study intends to investigate the relationship between ACE gene I/D polymorphism with T2DM and DPN subjects among the South Tamil Nadu regional population. Materials and Methods: Thirty T2DM patients with DPN, 30 T2DM patients without DPN, and 30 control (nondiabetic) subjects were enrolled in this study. DPN was diagnosed using clinical and neurophysiological evaluation. Blood samples were collected and subjected to relevant investigations including blood glucose, glycated hemoglobin, serum creatinine, and serum lipids. Polymerase chain reaction amplification was performed to genotype the DNA for ACE I/D polymorphism using specific primers. Results: The ACE genotypes were distributed as II, 17 (57%); DD, 3 (10%); and ID, 10 (33%) in control group; II, 7 (23%); DD, 11 (37%); and ID, 12 (40%) in T2DM without DPN group, II, 3 (10%); DD, 16 (53%); and ID, 11 (37%) in T2DM with DPN group. The frequency of DD genotype was significantly higher in T2DM (P = 0.03) and T2DM patients with DPN (P = 0.001) compared to controls. The DD genotype versus II genotype was found to be associated with an increased risk of DPN (odds ratio [OR] = 10.28; 95% confidence interval [CI] =2.55–41.37). The D allele was more frequent among T2DM patients with DPN (71.6%) followed by T2DM patients (56.6%) compared to controls (26.6%). The D allele (vs. the I allele) is associated with an increased risk of T2DM (OR = 3.59, 95% CI = 1.670–7.742) and DPN (OR = 6.95, 95% CI = 3.120–15.507). Conclusion: The D allele and DD genotype of the ACE gene may both be risk factors for T2DM; in fact, the D allele of this polymorphism may potentially be linked to the development of DPN in T2DM patients. This finding implies that it may be possible to prevent DPN by early detection by identifying defects in ACE I/D polymorphisms in the south Indian regional population.

Reliability of a novel point of care device for monitoring diabetic peripheral neuropathy

We aimed to assess DPNCheck’s reliability for repeated sural nerve conduction (NC) parameters. This post hoc analysis used data from the randomized controlled ACUDPN trial assessing NC of the N. Suralis every eight weeks over a 6-month period in 62 patients receiving acupuncture against diabetic peripheral neuropathy (DPN) symptoms. The reliability of DPNCheck for nerve conduction velocity and amplitude was assessed using intraclass correlation coefficients (ICC) and was calculated using data from single time points and repeated measures design. The results of the NC measurements were correlated with the Total Neuropathy Score clinical (TNSc). Overall, for both nerve velocity and amplitude, the reliability at each measurement time point can be described as moderate to good and the reliability using repeated measures design can be described as moderate. Nerve velocity and amplitude showed weak correlation with TNSc. DPNCheck’s reliability results question its suitability for monitoring DPN’s progression. Given the limitation of our analysis, a long-term, pre-specified, fully crossed study should be carried out among patients with DPN to fully determine the suitability of the device for DPN progression monitoring. This was the first analysis assessing the reliability of the DPNCheck for DPN progression monitoring using data from multiple collection time points.

SUMOylation Modulates Reactive Oxygen Species (ROS) Levels and Acts as a Protective Mechanism in the Type 2 Model of Diabetic Peripheral Neuropathy.

Diabetic peripheral neuropathy (DPN) is the prevalent type of peripheral neuropathy; it primarily impacts extremity nerves. Its multifaceted nature makes the molecular mechanisms of diabetic neuropathy intricate and incompletely elucidated. Several types of post-translational modifications (PTMs) have been implicated in the development and progression of DPN, including phosphorylation, glycation, acetylation and SUMOylation. SUMOylation involves the covalent attachment of small ubiquitin-like modifier (SUMO) proteins to target proteins, and it plays a role in various cellular processes, including protein localization, stability, and function. While the specific relationship between high blood glucose and SUMOylation is not extensively studied, recent evidence implies its involvement in the development of DPN in type 1 diabetes. In this study, we investigated the impact of SUMOylation on the onset and progression of DPN in a type 2 diabetes model using genetically modified mutant mice lacking SUMOylation, specifically in peripheral sensory neurons (SNS-Ubc9-/-). Behavioural measurement for evoked pain, morphological analyses of nerve fibre loss in the epidermis, measurement of reactive oxygen species (ROS) levels, and antioxidant molecules were analysed over several months in SUMOylation-deficient and control mice. Our longitudinal analysis at 30 weeks post-high-fat diet revealed that SNS-Ubc9-/- mice exhibited earlier and more pronounced thermal and mechanical sensation loss and accelerated intraepidermal nerve fibre loss compared to control mice. Mechanistically, these changes are associated with increased levels of ROS both in sensory neuronal soma and in peripheral axonal nerve endings in SNS-Ubc9-/- mice. In addition, we observed compromised detoxifying potential, impaired respiratory chain complexes, and reduced levels of protective lipids in sensory neurons upon deletion of SUMOylation in diabetic mice. Importantly, we also identified mitochondrial malate dehydrogenase (MDH2) as a SUMOylation target, the activity of which is negatively regulated by SUMOylation. Our results indicate that SUMOylation is an essential neuroprotective mechanism in sensory neurons in type 2 diabetes, the deletion of which causes oxidative stress and an impaired respiratory chain, resulting in energy depletion and subsequent damage to sensory neurons.

Tauroursodeoxycholic acid protects Schwann cells from high glucose-induced cytotoxicity by targeting NLRP3 to regulate cell migration and pyroptosis.

Diabetic peripheral neuropathy (DPN) is the most prevalent complication of type 2 diabetes mellitus (T2DM), and it seriously affects the quality of life of patients. Tauroursodeoxycholic acid (TUDCA) is a bile acid that plays a protective role against various diseases. However, the function of TUDCA in DPN progression needs to be elucidated. Hence, this study clarified the action of TUDCA on DPN development and explored its mechanism of action. Fecal samples were collected from 50 patients with T2DM or DPN. Schwann cells induced by high levels were constructed to simulate an uncontrolled diabetic state. Cell viability and migration were measured using the CCK-8 and wound-healing assays, respectively. Reactive oxygen species and pyroptosis were detected using flow cytometry. Parabacteroides goldsteinii and Parabacteroides distasonis levels were decreased in the feces of patients with DPN. TUDCA enhanced the viability and migration ability of high glucose-stimulated Schwann cells. In addition, Schwann cell pyroptosis stimulated by high glucose levels was inhibited by TUDCA. Furthermore, the protective roles of TUDCA in cell viability, migration ability, and pyroptosis of Schwann cells stimulated by high glucose were suppressed by the overexpression of NLRP3. TUDCA enhanced cell viability and migration and suppressed pyroptosis in Schwann cells stimulated by high glucose levels by modulating NLRP3 expression. Thus, TUDCA may be a promising drug for DPN therapy.

Advances in cardiovascular-related biomarkers to predict diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) is a common chronic complication of diabetes mellitus. One of the most common types is distal symmetric poly-neuropathy, which begins as bilateral symmetry pain and hyperesthesia and gradually progresses into hypoesthesia with nerve fibre disorder and is frequently accompanied by depression and anxiety. Notably, more than half of patients with DPN can be asymptomatic, which tends to delay early detection. Furthermore, the study of adverse outcomes showed that DPN is a prominent risk factor for foot ulceration, gangrene and nontraumatic amputation, which decreases quality of life. Thus, it is essential to develop convenient diagnostic biomarkers with high sensitivity for screening and early intervention. It has been reported that there may be common pathways for microvascular and macrovascular complications of diabetes. The pathogenesis of both disorders involves vascular endothelial dys-function. Emerging evidence indicates that traditional and novel cardiovascular-related biomarkers have the potential to characterize patients by subclinical disease status and improve risk prediction. Additionally, beyond traditional cardiovascular-related biomarkers, novel cardiovascular-related biomarkers have been linked to diabetes and its complications. In this review, we evaluate the association between major traditional and nontraditional car-diovascular-related biomarkers of DPN, such as cardiac troponin T, B-type natriuretic peptide, C-reactive protein, myeloperoxidase, and homocysteine, and assess the evidence for early risk factor-based management strategies to reduce the incidence and slow the progression of DPN.

Ablation of Argonaute 2 in Schwann cells accelerates the progression of diabetic peripheral neuropathy.

Schwann cells (SCs) form myelin and provide metabolic support for axons, and are essential for normal nerve function. Identification of key molecules specific to SCs and nerve fibers may provide new therapeutic targets for diabetic peripheral neuropathy (DPN). Argonaute2 (Ago2) is a key molecular player that mediates the activity of miRNA-guided mRNA cleavage and miRNA stability. Our study found that Ago2 knockout (Ago2-KO) in proteolipid protein (PLP) lineage SCs in mice resulted in a significant reduction of nerve conduction velocities and impairments of thermal and mechanical sensitivities. Histopathological data revealed that Ago2-KO significantly induced demyelination and neurodegeneration. When DPN was induced in both wild-type and Ago2-KO mice, Ago2-KO mice exhibited further decreased myelin thickness and exacerbated neurological outcomes compared with wild-type mice. Deep sequencing analysis of Ago2 immunoprecipitated complexes showed that deregulated miR-206 in Ago2-KO mice is highly related to mitochondrial function. In vitro data showed that knockdown of miR-200 induced mitochondrial dysfunction and apoptosis in SCs. Together, our data suggest that Ago2 in SCs is essential to maintain peripheral nerve function while ablation of Ago2 in SCs exacerbates SC dysfunction and neuronal degeneration in DPN. These findings provide new insight into the molecular mechanisms of DPN.

Axonal transport deficits in the pathogenesis of diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) is a chronic and prevalent metabolic disease that gravely endangers human health and seriously affects the quality of life of hyperglycemic patients. More seriously, it can lead to amputation and neuropathic pain, imposing a severe financial burden on patients and the healthcare system. Even with strict glycemic control or pancreas transplantation, peripheral nerve damage is difficult to reverse. Most current treatment options for DPN can only treat the symptoms but not the underlying mechanism. Patients with long-term diabetes mellitus (DM) develop axonal transport dysfunction, which could be an important factor in causing or exacerbating DPN. This review explores the underlying mechanisms that may be related to axonal transport impairment and cytoskeletal changes caused by DM, and the relevance of the latter with the occurrence and progression of DPN, including nerve fiber loss, diminished nerve conduction velocity, and impaired nerve regeneration, and also predicts possible therapeutic strategies. Understanding the mechanisms of diabetic neuronal injury is essential to prevent the deterioration of DPN and to develop new therapeutic strategies. Timely and effective improvement of axonal transport impairment is particularly critical for the treatment of peripheral neuropathies.

The m6A reader YTHDC2 promotes SIRT3 expression by reducing the stabilization of KDM5B to improve mitochondrial metabolic reprogramming in diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) is a common diabetic complication. Aberrant mitochondrial function causes neurodegeneration under hyperglycemia-induced metabolic stress, which in turn results in DPN progression. m6A and m6A reader (YTHDC2) are closely related to diabetes and diabetes complications, while the role of YTHDC2 in regulating mitochondrial metabolism in DPN needs to be further probed. For HG treatment, Schwann cells (RSC96) were subjected to D-glucose for 72h. db/db mice were used as the diabetic mouse model. Me-RIP assay was performed to evaluate KDM5B m6A level. RNA degradation assay was conducted to examine KDM5B mRNA stability. In addition, OCR and ECAR were examined by XF96 Analyzer. Moreover, the content of ATP and PDH activity in RSC96 cells were detected using kits, and the level of ROS was detected using MitoSOX staining. RIP, RNA pull-down and dual-luciferase reporter gene assays were carried out to verify the binding relationships between YTHDC2, KDM5B and SIRT3. We first observed that KDM5B expression and KDM5B mRNA stabilization were significantly increased in DPN. The m6A reader YTHDC2 was lowly expressed in DPN. Meanwhile, YTHDC2 over expression decreased KDM5B mRNA stability in an m6A-dependent manner. Our results also revealed that YTHDC2 overexpression resulted in reduced ROS level and increased ATP level, PDH activity, OCR and ECAR in HG-treated Schwann cells, while these effects were reversed by KDM5B overexpression. Additionally, SIRT3 served as the target of YTHDC2/KDM5B axis in regulating mitochondrial metabolism in DPN. Taken together, YTHDC2 promoted SIRT3 expression by reducing the stabilization of KDM5B to improve mitochondrial metabolic reprogramming in DPN.

Identification of Immune Infiltration and the Potential Biomarkers in Diabetic Peripheral Neuropathy through Bioinformatics and Machine Learning Methods.

Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications in diabetes. Previous studies have shown that chronic neuroinflammation was associated with DPN. However, further research is needed to investigate the exact immune molecular mechanism underlying the pathogenesis of DPN. Expression profiles were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were screened by R software. After functional enrichment analysis of DEGs, a protein-protein interaction (PPI) network analysis was performed. The CIBERSORT algorithm was used to evaluate the infiltration of immune cells in DPN. Next, the least absolute shrinkage and selection operator (LASSO) logistic regression and support vector machine-recursive feature elimination (SVM-RFE) algorithms were applied to identify potential DPN diagnostic markers. Finally, the results were further validated by qRT-PCR. A total of 1308 DEGs were screened in this study. Enrichment analysis identified that DEGs were significantly enriched in immune-related biological functions and pathways. Immune cell infiltration analysis found that M1 and M2 macrophages, monocytes, resting mast cells, resting CD4 memory T cells and follicular helper T cells were involved in the development of DPN. LTBP2 and GPNMB were identified as diagnostic markers of DPN. qRT-PCR results showed that 15 mRNAs, including LTBP2 and GPNMB, were differentially expressed, consistent with the microarray results. In conclusion, LTBP2 and GPNMB can be used as novel candidate molecular diagnostic markers for DPN. Furthermore, the infiltration of immune cells plays an important role in the progression of DPN.

Hedysarum polysaccharide alleviates oxidative stress to protect against diabetic peripheral neuropathy via modulation of the keap1/Nrf2 signaling pathway

Diabetic peripheral neuropathy (DPN) is a chronic complication of diabetes mellitus. Oxidative stress is implicated in DPN progression, suggesting that antioxidant therapy could be a viable anti-DPN method. Hedysarum polysaccharide (HPS) is an active component of Radix Hedysari, a plant that has been widely used as food and a herb for treating multiple diseases. Here, we evaluated the mechanisms of action of anti-DPN effects of HPS in genetically obese (ob/ob) mice. Schwann cells (SCs) were exposed to glucose (100 mM) in vitro and then treated with HPS at concentrations of 30, 60, 120, and 240 mg/L. Notably, HPS significantly inhibited high glucose-mediated cytotoxicity and oxidative stress by reducing malondialdehyde (MDA) levels and upregulating the expression of antioxidant enzymes (γ-glutamate-cysteine ligase catalytic subunit (GCLC) and glutathione reductase (GR)) in SCs. Moreover, HPS increased the expression of nerve growth factor, stimulated Nrf2 signaling, and decreased Keap1 expression levels. Analysis of DPN mice models gavaged with HPS at 50, 100, and 200 mg/kg/d or lipoic acid (LA) at 30 mg/kg/d (positive control) for 8 weeks revealed that HPS markedly increased motor nerve conduction velocity (MNCV), shortened thermal withdrawal latency (TWL), and inhibited oxidative stress in serum and sciatic nerves of DPN mice models. Mechanistically, HPS suppressed Keap1 signaling and enhanced Nrf2 signaling in sciatic nerves. These findings imply that HPS ameliorates DPN via antioxidant mechanisms and by activating Keap1/Nrf2 signaling, suggesting that HPS is a potential treatment option for DPN.

Reversing painful and non-painful diabetic neuropathy with the capsaicin 8% patch: Clinical evidence for pain relief and restoration of function via nerve fiber regeneration.

Current oral treatments for pain in diabetic peripheral neuropathy (DPN) do not affect the progression of DPN i.e., "disease modification." We assessed whether Capsaicin 8% patch treatment can provide pain relief and also restore nerve density and function via nerve regeneration, in both painful (PDPN) and non-painful (NPDPN) diabetic peripheral neuropathy. 50 participants with PDPN were randomized to receive Capsaicin 8% patch Qutenza with Standard of Care (SOC) (PDPN Q+SOC group), or SOC alone (PDPN SOC group). Pain symptoms were assessed with a diary (Numerical Pain Rating Scale, NRPS) and questionnaires. Investigations included quantitative sensory testing (QST) and distal calf skin biopsies, at baseline and 3 months after baseline visit; subsequent options were 3-monthly visits over 1 year. 25 participants with NPDPN had tests at baseline, and 3 months after all received Capsaicin 8% patch treatment. At 3 months after baseline, PDPN Q+SOC group had reduction in NPRS score (p = 0.0001), but not PDPN SOC group. Short-Form McGill Pain Questionnaire (SF-MPQ) showed significant reductions in scores for overall and other pain descriptors only in the PDPN Q+SOC group. Warm perception thresholds were significantly improved only in the PDPN Q+SOC group (p = 0.02), and correlated with reduction in SF-MPQ overall pain score (p = 0.04). NPDPN Q+SOC group did not report pain during the entire study. Density of intra-epidermal nerve fibers (IENF) with PGP9.5 was increased at 3 months in PDPN Q+SOC (p = 0.0002) and NPDPN Q+SOC (p = 0.002) groups, but not in the PDPN SOC group. Increased sub-epidermal nerve fibers (SENF) were observed with GAP43 (marker of regenerating nerve fibers) only in PDPN Q+SOC (p = 0.003) and NPDPN Q+SOC (p = 0.0005) groups. Pain relief in the PDPN Q+SOC group was correlated with the increased PGP9.5 IENF (p = 0.0008) and GAP43 (p = 0.004), whereas those with lack of pain relief showed no such increase; in some subjects pain relief and increased nerve fibers persisted over months. PGP9.5 IENF increase correlated with axon-reflex vasodilatation in a NPDPN Q+SOC subset (p = 0.006). Capsaicin 8% patch can provide pain relief via nerve regeneration and restoration of function in DPN (disease modification). It may thereby potentially prevent diabetic foot complications, including ulcers.

Morphological and Mechanical Properties of Lower-Limb Muscles in Type 2 Diabetes: New Potential Imaging Indicators for Monitoring the Progress of DPN.

The aim of this study was to explore changes in morphological and mechanical properties of lower-limb skeletal muscles in patients with diabetes with and without diabetic peripheral neuropathy (DPN) and seek to find a potential image indicator for monitoring the progress of DPN in patients with type 2 diabetes mellitus (T2DM). A total of 203 patients with T2DM, with and without DPN, were included in this study. Ultrasonography and ultrasound shear wave imaging (USWI) of the abductor hallux (AbH), tibialis anterior (TA), and peroneal longus (PER) muscles were performed for each subject, and the shear wave velocity (SWV) and cross-sectional area (CSA) of each AbH, TA, and PER were measured. The clinical factors influencing AbH_CSA and AbH_SWV were analyzed, and the risk factors for DPN complications were investigated. AbH_CSA and AbH_SWV in the T2DM group with DPN decreased significantly (P < 0.05), but no significant differences were found in the SWV and CSA of the TA and PER between the two groups. Toronto Clinical Scoring System (CSS) score and glycosylated hemoglobin (HbA1c) were independent predictors of AbH_CSA and AbH_SWV. As AbH_SWV and AbH_CSA decreased, Toronto CSS score and HbA1c increased and incidence of DPN increased significantly. In conclusion, the AbH muscle of T2DM patients with DPN became smaller and softer, while its morphological and mechanical properties were associated with the clinical indicators related to the progression of DPN. Thus, they could be potential imaging indicators for monitoring the progress of DPN in T2DM patients.

Peripheral neuropathy and impaired sensation of feet among patients with type 2 diabetes mellitus: a descriptive cross-sectional study

Background: Diabetic peripheral neuropathy (DPN) is the most prevalent consequence of type 2 diabetes mellitus (T2DM). Impaired sensation of feet due to DPN increases the risk of foot injury. Therefore, the objectives of this study were to assess the level of glycemic control, the prevalence of DPN and the impaired sensation of feet among the T2DM patients attending community clinics.Methods: A descriptive cross-sectional study was conducted on 386 T2DM patients attending community clinics in Sri Lanka. The baseline data were collected by an interviewer-administered questionnaire. DPN was diagnosed by Michigan neuropathy screening instrument (MNSI) and monofilament test. Glycemic control was assessed by serum glycated hemoglobin (HbA1c) and fasting blood glucose (FBS).Results: Among 386 T2DM patients, 265 (68.7%) were females, 179 (46.4%) had 1-5 years duration of disease. Poor long-term glycemic control (HbA1c) was observed in 292 (75.6%), while poor short-term glycemic control (FBS) was observed in 202 (52.4%). DPN was diagnosed in 68 (17.6%). Monofilament test assessed the touch sensation in 10 points of each foot. The ninth point (plantar central heel) of each foot was the commonest point with absent sensation. It was observed in 99 (25.6%) right feet and 94 (24.4%) left feet respectively.Conclusions: High prevalence of DPN and impaired sensation in specific sites of foot indicate high risk for foot disease. Most patients with DPN had poor glycemic control. Urgent interventions to attain glycemic control and testing for impaired sensation regularly are essential to decrease progression of DPN and foot disease.