Progression Of Diabetic Peripheral Neuropathy Research Articles

Whether coagulation dysfunction influences the onset and progression of diabetic peripheral neuropathy: A multicenter study in middle-aged and aged patients with type 2 diabetes.

Nearly half of patients with diabetes experience diabetic peripheral neuropathy (DPN), resulting in a mere 53% survival rate within 3 years. Aberrations in coagulation function have been implicated in the pathogenesis of microvascular complications, prompting the need for a thorough investigation into its role as a contributing factor in the development and progression of DPN. Data were gathered from 1211 type 2 diabetes patients admitted to five centers from September 2018 to October 2022 in China. DPN was evaluated by symptoms and electromyography. Motor and sensory nerve conduction velocity (NCV) was appraised and the NCV sum score was calculated for the median, ulnar, and peroneal motor or sensory nerves. Patients with DPN exhibited alterations in coagulation function. (i) Specifically, they exhibited prolonged thrombin time (p = 0.012), elevated fibrinogen (p < 0.001), and shortened activated partial thromboplastin time (APTT; p = 0.026) when compared to the control group. (ii) After accounting for potential confounders in linear regression, fibrinogen, and D-dimer were negatively related to the motor NCV, motor amplitude values, and mean velocity and amplitude. Also, fibrinogen was associated with higher Michigan neuropathy screening instrument (MNSI) scores (β 0.140; p = 0.001). This result of fibrinogen can be validated in the validation cohort with 317 diabetic patients. (iii) Fibrinogen was independently associated with the risk of DPN (OR 1.172; p = 0.035). In the total age group, DPN occurred at a slower rate until the predicted fibrinogen level reached around 3.75 g/L, after which the risk sharply escalated. Coagulation function is warranted to be concerned in patients with type 2 diabetes to predict and prevent the occurrence of DPN in clinical practice.

Antioxidant Effect in Diabetic Peripheral Neuropathy in Rat Model: A Systematic Review.

Oxidative stress is a contributing factor that leads to the vascular complications of diabetes mellitus. Diabetic peripheral neuropathy (DPN) is one of the microvascular complications with rising concern as the disease progresses despite strict glucose control and monitoring. Thus, there is an ongoing need for an early intervention that is effective in halting or slowing the progression of DPN where antioxidants have been proposed as potential therapeutic agents. This systematic review aims to evaluate the existing evidence on the antioxidant effect in DPN and provide insight on the role of antioxidants in the progression of DPN in a rat model. A comprehensive literature search was conducted on Web of Science, EBSCOhost, and Scopus to identify the effects and role of antioxidants in DPN. Data extraction was performed and SYRCLE's risk of bias (RoB) tool was used for risk assessment. This systematic review was written following the PRISMA 2020 statements. From the literature search, 1268 articles were screened, and a total of 101 full-text articles were further screened before 33 were analyzed. These findings collectively suggest that antioxidants can play a crucial role in managing and potentially reversing the effects of diabetic neuropathy by targeting oxidative stress and improving nerve function.

Single-cell transcriptome analysis reveals distinct cell populations in dorsal root ganglia and their potential roles in diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) is a common complication associated with diabetes, and can affect quality of life considerably. Dorsal root ganglion (DRG) plays an important role in the development of DPN. However, the relationship between DRG and the pathogenesis of DPN still lacks a thorough exploration. Besides, a more in-depth understanding of the cell type composition of DRG, and the roles of different cell types in mediating DPN are needed. Here we conducted single-cell RNA-seq (scRNA-seq) for DRG tissues isolated from healthy control and DPN rats. Our results demonstrated DRG includes eight cell-type populations (e.g., neurons, satellite glial cells (SGCs), Schwann cells (SCs), endothelial cells, fibroblasts). In the heterogeneity analyses of cells, six neuron sub-types, three SGC sub-types and three SC sub-types were identified, additionally, biological functions related to cell sub-types were further revealed. Cell communication analysis showed dynamic interactions between neurons, SGCs and SCs. We also found that the aberrantly expressed transcripts in sub-types of neurons, SGCs and SCs with DPN were associated with diabetic neuropathic pain, cell apoptosis, oxidative stress, etc. In conclusion, this study provides a systematic perspective of the cellular composition and interactions of DRG tissues, and suggests that neurons, SGCs and SCs play vital roles in the progression of DPN. Our data may provide a valuable resource for future studies regarding the pathophysiological effect of particular cell type in 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.

Prevention of Chronic Diabetic Neuropathy and Diabetes-Associated Cognitive Impairment Using Medicinal Herbs (Cassia Angustifolia and Nigella Sativa).

Nodal regions, areas of intensive contact between Schwann cells and axons, may be exceptionally vulnerable to diabetes-induced changes because they are exposed to and impacted by the metabolic implications of diabetes. Insulin receptors, glucose transporters, Na+ and K+ channels, and mitochondria are abundant in nodes, all of which have been linked to the development and progression of Diabetic Peripheral Neuropathy (DPN) and Type 1 Diabetes Mellitus (T1DM)-associated cognitive impairment. Our study aimed to evaluate if the administration of Nigella sativa (NS) and Cassia angustifolia (CA) prevented diabetes-associated nervous system deficits in hyperglycemic mice. We developed T1DM mice through Streptozotocin (STZ) injections and validated the elevations in blood glucose levels. NS and CA were administered immediately upon the induction of diabetes. Behavioral analysis, histopathological evaluations, and assessment of molecular biomarkers (NR2A, MPZ, NfL) were performed to assess neuropathy and cognitive impairment. Improvements in memory, myelin loss, and the expression of synaptic proteins, even with the retention of hyperglycemia, were evident in the mice who were given a dose of herbal products upon the detection of hyperglycemia. NS was more beneficial in preventing memory impairments, demyelination, and synaptic dysfunction. The findings indicate that including these herbs in the diets of diabetic as well as pre-diabetic patients can reduce complications associated with T1DM, notably diabetic peripheral neuropathy and cognitive deficits associated with T1DM.

Long-term sensorimotor changes after a sciatic nerve block with bupivacaine and liposomal bupivacaine in a high-fat diet/low-dose streptozotocin rodent model of diabetes

IntroductionIt is unclear whether patients with diabetes are more susceptible to nerve toxicity of local anesthetics or whether nerve blocks can accelerate the progression of diabetic peripheral neuropathy. Bupivacaine is one of the most widely used local anesthetics for regional anesthesia despite many pre-clinical studies demonstrating neurotoxicity. Herein, we report the long-term functional consequences of sciatic nerve block with bupivacaine and liposomal bupivacaine (Exparel®) in an animal model of diabetes.MethodsMale Sprague Dawley rats were subject to standard chow/vehicle or high-fat diet/low-dose streptozotocin to induce a diabetic phenotype. Animals were then subdivided into groups that received repeated sciatic nerve blocks of saline, bupivacaine, or liposomal bupivacaine. Mechanical allodynia and thermal hyperalgesia were assessed prior to and 12 weeks following nerve blocks utilizing the von Frey and Hargreaves tests, respectively. Exploratory and locomotor activity were assessed with open field testing, and nerve conduction velocity testing was conducted prior to the termination of the study at 28 weeks.ResultsAnimals in the diabetic group developed sustained hyperglycemia &amp;gt;200 mg/dl and signs of peripheral neuropathy six weeks after treatment with streptozotocin, which persisted until the end of the study. Twelve weeks after a repeated sciatic nerve block with saline, bupivacaine, or liposomal bupivacaine, results indicate significant interaction effects of the disease group (control vs. diabetic) and local anesthetic treatment. Overall, diabetic status resulted in worse sensorimotor function compared to control animals. Treatment with perineural bupivacaine resulted in worse sensorimotor functions in both control and diabetic animals. Furthermore, bupivacaine treatment in diabetic animals with pre-existing neuropathy exacerbated sensorimotor function in some measures. In contrast, liposomal bupivacaine did not appear to cause any negative effects on functional outcomes for control or diabetic animals.ConclusionOur data indicate that bupivacaine, and not liposomal bupivacaine, causes long-term changes in tactile allodynia, thermal hyperalgesia, locomotor behaviors, and nerve conduction velocity in control as well as a high-fat diet/low-dose streptozotocin rodent model of diabetes. These results highlight the necessity to investigate safe peripheral nerve block strategies to preserve long-term functional independence in patients with or at risk for diabetic peripheral neuropathy.

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 Peripheral Neuropathy by Assessment of Sudomotor Function

Chronic hyperglycemia in both type 1 and type 2 diabetes commonly lead to diabetic peripheral neuropathy (DPN) which commonly affects small nerve fibers, including autonomic sudomotor nerves, of the lower limbs. DPN results from nerve damage leading to gradual onset of foot pain, tingling, numbness, muscle weakness, extreme sensitivity to touch, and heat intolerance. Peripheral neuropathy is associated with increased all-cause mortality and morbidities such as foot ulcers, poor wound healing, local and systemic infection, limb amputation, and painful neuropathic symptoms. DPN is also typically diagnosed during later stages when disease progression has already led to irreversible nerve damage and associated severe symptoms. As such, early detection of peripheral neuropathy is important in implementing early interventions and can help preserve nerve function and prevent serious complications of DPN. Non-invasive methods of testing for early DPN rely on assessment of sudomotor nerve function. One method includes quantitative sudomotor axon reflex test (QSART) which measures postganglionic sympathetic function via iontophoresis which allows quantification of sweat production, and by extension, autonomic function. In general, QSART provides a non-invasive, reproducible, and precise evaluation of autonomic function in both controls and diabetics. It can be used to evaluate a large number of autonomic diseases, and the quantitative data it generates provides a measure of the extent and location of the peripheral neuropathy in each individual. Another assessment method includes the sympathetic skin response (SSR) test which measures the change in electrical potential of the skin which itself comes from activated eccrine sweat glands. The SSR test has a well-established protocol, and the results are easily-measured, and the results are quantifiable. It can be used reliably in the diagnosis of numerous autonomic disorders including DPN where a diminished or absent response correlate with sudomotor nerve damage. SudoCheck by VitalScan is an FDA-cleared, non-invasive autonomic sdomotor assessment tool that combines QSART, SSR, BIA, and EIS to provide rapid results with a specificity of 95% and a sensitivity of 80%. It was created to enable a precise evaluation of sweat gland function, and by extension, the presence and progression of diabetic peripheral neuropathy including early sub-clinical disease

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.

The Role of Nonspecific Inflammation in the Development of Diabetic Polyneuropathy

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes mellitus type 2 (DM2) and is associated with significant morbidity and mortality. The pathophysiological mechanisms leading to the development of DPN have not been fully studied and are still debatable. Currently, immune-mediated mechanisms of its development are being discussed. The aim of this study was to estimate the content of TNF-α in the blood serum of patients with DM2 complicated by DPN and to assess the significance of this factor in the development and progression of DPN. An open comparative study was conducted with the participation of 83 patients with DM2 of different duration. In patients with clinical manifestations of DPN and long-term course of DM2 (group 2), the level of TNF-α was significantly higher compared to patients with DM2 and duration of DPN less than 2 years, and both studied groups of patients with DM2 and DPN had a high level of TNF-α in comparison with the control group. The results obtained indicate a more aggressive immune-mediated process that develops with a longer duration of DM2 and makes a negative contribution to the functioning of the peripheral nerve fiber.

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.

Investigating the prevalence of diabetic peripheral neuropathy in patients diagnosed with type 2 diabetes mellitus

Abstract Background: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder affecting millions of individuals reaching epidemic proportions globally. diabetic peripheral neuropathy (DPN) is one of the most prevalent and debilitating complications of T2DM, affecting the lower limbs and increasing the risk of foot ulcers, infections, and lower limb amputations. The current study aims to assess the prevalence and severity of DPN using monofilament and MNSI tests in patients diagnosed with T2DM and examine factors associated with the onset and progression of DPN. Objective: To study the prevalence of diabetic peripheral neuropathy in patients with type 2 diabetes mellitus. Materials and Methods: A cross-sectional study was conducted at the Department of Medicine &amp; Diabetology, Marwari Hospital Assam. A total of 226 patients with type 2 diabetes were assessed for DPN using the Michigan Neuropathy Screening Instrument (MNSI). Results: The study assessed the prevalence of DPN among patients with diabetes mellitus. among the 226 participants, 32% had moderate neuropathy and 11% had severe neuropathy. Symptoms such as numbness, burning pain, and muscle cramps were reported by a significant proportion of participants. Examination findings showed foot-related complications and reduced nerve function in a considerable number of participants. The prevalence of neuropathy varied among different duration groups of patients with diabetes. The severity of neuropathy was higher among patients with longstanding diabetes. These findings emphasize the significant burden of DPN and the importance of diabetes management in managing and preventing diabetic neuropathy. Conclusion: This study revealed a considerable prevalence of DPN among patients with diabetes mellitus. The prevalence of neuropathy varied with the duration of diabetes, suggesting an increased risk with a longer disease duration. Timely intervention and appropriate diabetes management strategies are crucial in reducing the burden of DPN and improving patient outcomes.

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.