Association of the systemic immuno-inflammation index, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio with diabetic microvascular complications.

Background: The systemic immuno-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) are widely used and have been shown to be predictive indicators of various diseases. Diabetic nephropathy (DN), retinopathy (DR), and peripheral neuropathy (DPN) are the most prominent and common microvascular complications, which have seriously negative impacts on patients, families, and society. Exploring the associations with these three indicators and diabetic microvascular complications are the main purpose. Methods: There were 1058 individuals with type 2 diabetes mellitus (T2DM) in this retrospective cross-sectional study. SII, NLR, and PLR were calculated. The diseases were diagnosed by endocrinologists. Logistic regression and subgroup analysis were applied to evaluate the association between SII, NLP, and PLR and diabetic microvascular complications. Results: SII, NLR, and PLR were significantly associated with the risk of DN [odds ratios (ORs): 1.52, 1.71, and 1.60, respectively] and DR [ORs: 1.57, 1.79, and 1.55, respectively] by multivariate logistic regression. When NLR ≥2.66, the OR was significantly higher for the risk of DPN (OR: 1.985, 95% confidence interval: 1.29-3.05). Subgroup analysis showed no significant positive associations across different demographics and comorbidities, including sex, age, hypertension, HbA1c (glycated hemoglobin), and dyslipidemia. Conclusion: This study found a positive relationship between NLR and DN, DR, and DPN. In contrast, SII and PLR were found to be only associated with DN and DR. Therefore, for the diagnosis of diabetic microvascular complications, SII, NLR and PLR are highly valuable.

A muscarinic receptor antagonist reverses multiple indices of diabetic peripheral neuropathy: preclinical and clinical studies using oxybutynin.

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

Animal Models of Type 2 Diabetes Complications: A Review.

Diabetes mellitus is a multifactorial metabolic disease, of which type 2 diabetes (T2D) is one of the most common. The complications of diabetes are far more harmful than diabetes itself. Type 2 diabetes complications include diabetic nephropathy (DN), diabetic heart disease, diabetic foot ulcers (DFU), diabetic peripheral neuropathy (DPN), and diabetic retinopathy (DR) et al. Many animal models have been developed to study the pathogenesis of T2D and discover an effective strategy to treat its consequences. In this sense, it is crucial to choose the right animal model for the corresponding diabetic complication. This paper summarizes and classifies the animal modeling approaches to T2D complications and provides a comprehensive review of their advantages and disadvantages. It is hopeful that this paper will provide theoretical support for animal trials of diabetic complications.

Autophagy and anti-inflammation ameliorate diabetic neuropathy with Rilmenidine.

PURPOSE: To evaluate the neuroprotective effects of Rilmenidine on diabetic peripheral neuropathy (DPN) in a rat model of diabetes induced by streptozotocin (STZ). METHODS: STZ (60 mg/kg) was administered to adult Sprague-Dawley rats to induce diabetes. On the 30th day after STZ administration, electromyography (EMG) and motor function tests confirmed the presence of DPN. Group 1: Control (n = 10), Group 2: DM + 0.1 mg/kg Rilmenidine (n = 10), and Group 3: DM + 0.2 mg/kg Rilmenidine (n = 10) were administered via oral lavage for four weeks. EMG, motor function test, biochemical analysis, and histological and immunohistochemical analysis of sciatic nerves were then performed. RESULTS: The administration of Rilmenidine to diabetic rats substantially reduced sciatic nerve inflammation and fibrosis and prevented electrophysiological alterations. Immunohistochemistry of sciatic nerves from saline-treated rats revealed increased perineural thickness, HMGB-1, tumor necrosis factor-α, and a decrease in nerve growth factor (NGF), LC-3. In contrast, Rilmendine significantly inhibited inflammation markers and prevented the reduction in NGF expression. In addition, Rilmenidine significantly decreased malondialdehyde and increased diabetic rats' total antioxidative capacity. CONCLUSIONS: The findings of this study suggest that Rilmenidine may have therapeutic effects on DNP by modulating antioxidant and autophagic pathways.

[Research advances on the role of Schwann cells in diabetic peripheral neuropathy].

Diabetic peripheral neuropathy (DPN) is one of the common chronic complications of diabetes, resulting in neuropathy of spinal nerve, cranial nerve, and vegetative nerve. Diabetic distal symmetric multiple neuropathy is the most representative lesion of DPN, including symptoms of bilateral limbs pain, numbness, and paresthesia, etc. DPN is one of the main reasons causing diabetic foot ulcer (DFU). Schwann cells (SCs) are the primary glia cells of the peripheral nervous system, which play very important role in repairing after nerve injury. As the target cells of chronic hyperglycemia, SCs' functions, including the formation of myelin sheath, the secretion of neurotrophic factors, energy supplying for the axon, and the guidance of axon regeneration, etc., are damaged under the action of high glucose. The destroyed functions of SCs can inhibit the repair of damaged nerves and accelerate the progress of DPN. Therefore, if the damage of high glucose to SCs can be effectively reduced, it will provide a new way for the treatment of DPN and DFU and reduce the morbidity of DFU. This review focuses on the function of SCs and its relationship with DPN.

Vincamine as an agonist of G-protein-coupled receptor 40 effectively ameliorates diabetic peripheral neuropathy in mice.

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes, which has yet no curable medication. Neuroinflammation and mitochondrial dysfunction are tightly linked to DPN pathology. G-protein-coupled receptor 40 (GPR40) is predominantly expressed in pancreatic ß-cells, but also in spinal dorsal horn and dorsal root ganglion (DRG) neurons, regulating neuropathic pain. We previously have reported that vincamine (Vin), a monoterpenoid indole alkaloid extracted from Madagascar periwinkle, is a GPR40 agonist. In this study, we evaluated the therapeutic potential of Vin in ameliorating the DPN-like pathology in diabetic mice. Both STZ-induced type 1 (T1DM) and db/db type 2 diabetic (T2DM) mice were used to establish late-stage DPN model (DPN mice), which were administered Vin (30 mg·kg-1·d-1, i.p.) for 4 weeks. We showed that Vin administration did not lower blood glucose levels, but significantly ameliorated neurological dysfunctions in DPN mice. Vin administration improved the blood flow velocities and blood perfusion areas of foot pads and sciatic nerve tissues in DPN mice. We demonstrated that Vin administration protected against sciatic nerve myelin sheath injury and ameliorated foot skin intraepidermal nerve fiber (IENF) density impairment in DPN mice. Moreover, Vin suppressed NLRP3 inflammasome activation through either ß-Arrestin2 or ß-Arrestin2/IκBα/NF-κB signaling, improved mitochondrial dysfunction through CaMKKß/AMPK/SIRT1/PGC-1α signaling and alleviated oxidative stress through Nrf2 signaling in the sciatic nerve tissues of DPN mice and LPS/ATP-treated RSC96 cells. All the above-mentioned beneficial effects of Vin were abolished by GPR40-specific knockdown in dorsal root ganglia and sciatic nerve tissues. Together, these results support that pharmacological activation of GPR40 as a promising therapeutic strategy for DPN and highlight the potential of Vin in the treatment of this disease.

Compound Qiying Granules alleviates diabetic peripheral neuropathy by inhibiting endoplasmic reticulum stress and apoptosis.

BACKGROUND: Diabetic peripheral neuropathy (DPN) is a major complication of diabetes. This study aimed to investigate the therapeutic effects and molecular mechanisms of Compound Qiying Granules (CQYG) for DPN. METHODS: Rats and RSC96 cells of DPN models were established to evaluate the therapeutic effects of CQYG. Then the morphology and apoptotic changes of sciatic nerves were detected. Further, tandem mass tag based quantitative proteomics technology was used to identify differentially expressed proteins (DEPs) and the underlying molecular mechanisms. Protein expression of key signaling pathways was also detected. RESULTS: CQYG treatment significantly improved blood glucose and oxidative stress levels, and further reduced nerve fiber myelination lesions, denervation, and apoptosis in DPN rats. Further, 2176 DEPs were found in CQYG treated DPN rats. Enrichment analysis showed that protein processing in the endoplasmic reticulum (ER), and apoptosis were all inhibited after CQYG treatment. Next, CQYG treatment reduced inflammatory factor expression, mitochondrial damage, and apoptosis in RSC96 cells which induced by high glucose. Transmission electron microscopy results found that CQYG treatment improved the morphology of nerve myelin, mitochondria, and ER. CQYG treatment decreased ER stress and apoptosis pathway proteins that were highly expressed in DPN models. In addition, we also predicted the potential targets of CQYG in DEPs. CONCLUSIONS: CQYG exerts neuroprotective effects in experimental diabetic neuropathy through anti-ER stress and anti-apoptosis.

Gut microbiota modulate distal symmetric polyneuropathy in patients with diabetes.

The pathogenic mechanisms underlying distal symmetric polyneuropathy (DSPN), a common neuropathy in patients with diabetes mellitus (DM), are not fully understood. Here, we discover that the gut microbiota from patients with DSPN can induce a phenotype exhibiting more severe peripheral neuropathy in db/db mice. In a randomized, double-blind, and placebo-controlled trial (ChiCTR1800017257), compared to 10 patients who received placebo, DSPN was significantly alleviated in the 22 patients who received fecal microbiota transplants from healthy donors, independent of glycemic control. The gut bacterial genomes that correlated with the Toronto Clinical Scoring System (TCSS) score were organized in two competing guilds. Increased guild 1, which had higher capacity in butyrate production, and decreased guild 2, which harbored more genes in synthetic pathway of endotoxin, were associated with improved gut barrier integrity and decreased proinflammatory cytokine levels. Moreover, matched enterotype between transplants and recipients showed better therapeutic efficacy with more enriched guild 1 and suppressed guild 2. Thus, changes in these two competing guilds may play a causative role in DSPN and have the potential for therapeutic targeting.

Effect of Hesperidin on Sciatic Nerve Damage in STZ-Induced Diabetic Neuropathy: Modulation of TRPM2 Channel.

Diabetic neuropathy (DNP) is a severe complication of diabetes mellitus. In this study, we examined the potential of hesperidin (HES) to attenuate DNP and the involvement of the TRPM2 channel in this process. The rats were given a single dose of 45 mg/kg of streptozotocin (STZ) intraperitoneally to induce diabetic neuropathic pain. On the third day, we confirmed the development of diabetes in the DNP and DNP + HES groups. The HES groups were treated with 100 mg/kg and intragastric gavage daily for 14 days. The results showed that treatment with HES in diabetic rats decreased STZ-induced hyperglycemia and thermal hyperalgesia. Furthermore, in the histopathological examination of the sciatic nerve, HES treatment reduced STZ-induced damage. The immunohistochemical analysis also determined that STZ-induced increased TRPM2 channel, type-4 collagen, and fibrinogen immunoactivity decreased with HES treatment. In addition, we investigated the TRPM2 channel activation in the sciatic nerve damage mechanism of DNP model rats created by STZ application using the ELISA method. We determined the regulatory effect of HES on increased ROS, and PARP1 and TRPM2 channel activation in the sciatic nerves of DNP model rats. These findings indicated that hesperidin treatment could attenuate diabetes-induced DNP by reducing TRPM2 channel activation.

The potential of esculin in ameliorating Type-2 diabetes mellitus induced neuropathy in Wistar rats and probing its inhibitory mechanism of insulin aggregation.

Diabetic neuropathy encompasses multiple pathological disturbances, many of which coincide with the pathophysiological mechanisms of neurodegenerative disorders. In the present study, various biophysical techniques like Rayleigh light scattering assay, Thioflavin T assay, far-UV Circular Dichroism spectroscopy, Transmission electron microscopy have unveiled the anti-fibrillatory effect of esculin upon human insulin fibrillation. MTT cytotoxicity assay demonstrated the biocompatibility of esculin and in-vivo studies such as behavioral tests like hot plate test, tail immersion test, acetone drop test, plantar test were performed for validating diabetic neuropathy. Assessment of levels of serum biochemical parameters, oxidative stress parameters, pro-inflammatory cytokines as well as neuron specific markers was done in the current study. Rat brains were subjected to histopathology and their sciatic nerves were subjected to transmission electron microscopy to analyze myelin structure alterations. All these results reveal that esculin ameliorates diabetic neuropathy in experimental diabetic rats. Conclusively, our study demonstrates the anti-amyloidogenic potential of esculin in the form of inhibition of human insulin fibrillation, making it a promising candidate in combating neurodegenerative disorders in the near future and the results of various behavioral, biochemical, and molecular studies reveal that esculin possesses anti-lipidemic, anti-inflammatory, anti-oxidative and neuroprotective properties which help in ameliorating diabetic neuropathy in streptozotocin induced diabetic Wistar rats.

Genetic Profiling of Sodium Channels in Diabetic Painful and Painless and Idiopathic Painful and Painless Neuropathies.

Neuropathic pain is a frequent feature of diabetic peripheral neuropathy (DPN) and small fiber neuropathy (SFN). Resolving the genetic architecture of these painful neuropathies will lead to better disease management strategies, counselling and intervention. Our aims were to profile ten sodium channel genes (SCG) expressed in a nociceptive pathway in painful and painless DPN and painful and painless SFN patients, and to provide a perspective for clinicians who assess patients with painful peripheral neuropathy. Between June 2014 and September 2016, 1125 patients with painful-DPN (n = 237), painless-DPN (n = 309), painful-SFN (n = 547) and painless-SFN (n = 32), recruited in four different centers, were analyzed for SCN3A, SCN7A-SCN11A and SCN1B-SCN4B variants by single molecule Molecular inversion probes-Next Generation Sequence. Patients were grouped based on phenotype and the presence of SCG variants. Screening of SCN3A, SCN7A-SCN11A, and SCN1B-SCN4B revealed 125 different (potential) pathogenic variants in 194 patients (17.2%, n = 194/1125). A potential pathogenic variant was present in 18.1% (n = 142/784) of painful neuropathy patients vs. 15.2% (n = 52/341) of painless neuropathy patients (17.3% (n = 41/237) for painful-DPN patients, 14.9% (n = 46/309) for painless-DPN patients, 18.5% (n = 101/547) for painful-SFN patients, and 18.8% (n = 6/32) for painless-SFN patients). Of the variants detected, 70% were in SCN7A, SCN9A, SCN10A and SCN11A. The frequency of SCN9A and SCN11A variants was the highest in painful-SFN patients, SCN7A variants in painful-DPN patients, and SCN10A variants in painless-DPN patients. Our findings suggest that rare SCG genetic variants may contribute to the development of painful neuropathy. Genetic profiling and SCG variant identification should aid in a better understanding of the genetic variability in patients with painful and painless neuropathy, and may lead to better risk stratification and the development of more targeted and personalized pain treatments.

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.

Obstetric Neuropathy in Diabetic Patients: The "Double Hit Hypothesis".

The two-hit model has been proposed to explain the effects of diabetes on mothers who are already in a putative subclinical damaged state and then undergo neuronal damage during the delivery process. However, the anatomical and pathophysiological mechanisms are not well understood. Our overarching hypothesis in this review paper is that pregnant women who are diabetic have a damaged peripheral nervous system, constituting the "first hit" hypothesis. The delivery process itself-the "second hit"-can produce neurological damage to the mother. Women with diabetes mellitus (DM) are at risk for neurological damage during both hits, but the cumulative effects of both "hits" pose a greater risk of neurological damage and pathophysiological changes during delivery. In our analysis, we introduce the different steps of our concept paper. Subsequently, we describe each of the topics. First, we outline the mechanisms by which diabetes acts as a detrimental variable in neuropathy by focusing on the most common form of diabetic neuropathy, diabetic distal symmetrical polyneuropathy, also known as distal sensorimotor neuropathy. The possible role of macrosomia in causing diabetic neuropathy and obstetric neurological injury is discussed. Second, we describe how vaginal delivery can cause various obstetrical neurological syndromes and pathophysiological changes. Third, we highlight the risk of obstetric neuropathy and discuss anatomical sites at which lesions may occur, including lesions during delivery. Fourth, we characterize the pathophysiological pathways involved in the causation of diabetic neuropathy. Finally, we highlight diabetic damage to sensory vs. motor nerves, including how hyperglycemia causes different types of damage depending on the location of nerve cell bodies.

Human IAPP is a contributor to painful diabetic peripheral neuropathy.

Peripheral neuropathy is a frequent complication of type 2 diabetes mellitus (T2DM). We investigated whether human islet amyloid polypeptide (hIAPP), which forms pathogenic aggregates that damage pancreatic islet ß cells in T2DM, is involved in T2DM-associated peripheral neuropathy. In vitro, hIAPP incubation with sensory neurons reduced neurite outgrowth and increased levels of mitochondrial reactive oxygen species. hIAPP-transgenic mice, which have elevated plasma hIAPP levels without hyperglycemia, developed peripheral neuropathy as evidenced by pain-associated behavior and reduced intraepidermal nerve fiber (IENF) density. Similarly, hIAPP Ob/Ob mice, which have hyperglycemia in combination with elevated plasma hIAPP levels, had signs of neuropathy, although more aggravated. In wild-type mice, intraplantar and intravenous hIAPP injections induced long-lasting allodynia and decreased IENF density. Non-aggregating murine IAPP, mutated hIAPP (pramlintide), or hIAPP with pharmacologically inhibited aggregation did not induce these effects. T2DM patients had reduced IENF density and more hIAPP oligomers in the skin compared with non-T2DM controls. Thus, we provide evidence that hIAPP aggregation is neurotoxic and mediates peripheral neuropathy in mice. The increased abundance of hIAPP aggregates in the skin of T2DM patients supports the notion that hIAPP is a potential contributor to T2DM neuropathy in humans.

Neuronal-Hematopoietic Cell Fusion in Diabetic Neuropathy.

Diabetic neuropathy is a major complication of diabetes mellitus that occurs during the early stages of the disease. Many pathogenic mechanisms are related and induced by hyperglycemia. However, even if these factors improve, diabetic neuropathy cannot go into remission and progresses slowly. Furthermore, diabetic neuropathy often progresses even with proper glycemic control. Recently, bone marrow-derived cells (BMDCs) were reported to be involved in the pathogenesis of diabetic neuropathy. BMDCs expressing proinsulin and TNFα migrate to the dorsal root ganglion and fuse with neurons, and this neuronal-hematopoietic cell fusion induces neuronal dysfunction and apoptosis. The CD106-positive lineage-sca1+c-kit+ (LSK) stem cell fraction in the bone marrow is strongly involved in cell fusion with neurons, leading to diabetic neuropathy. Surprisingly, when CD106-positive LSK stem cells obtained from diabetic mice were transplanted into nondiabetic mice, they fused with dorsal root ganglion neurons and induced neuropathy in non-hyperglycemic normal mice. The transplanted CD106-positive LSK fraction inherited the trait even after transplantation; this "progeny effect" may explain the irreversibility of diabetic neuropathy and is a significant finding for determining the target of radical treatments and provides new directions for developing therapeutic methods for diabetic neuropathy.

Lumbosacral Radiculoplexus Neuropathy After COVID-19.

INTRODUCTION: Lumbosacral Radiculoplexus Neuropathy (LRPN) is a subacute, painful, paralytic, asymmetric immune-mediated lower-limb neuropathy associated with weight loss and diabetes mellitus (called DLRPN). Approximately one-third of LRPN cases have a trigger. Our purpose is to show that COVID-19 can trigger LRPN. CASE REPORT: We describe the clinical, neurophysiological, radiologic, and pathologic findings of a 55-year-old man who developed DLRPN after severe acute respiratory syndrome coronavirus-2 infection. Shortly after mild coronavirus disease 2019 (COVID-19), the patient developed severe neuropathic pain (allodynia), postural orthostasis, fatigue, weight loss, and weakness of bilateral lower extremities requiring wheelchair assistance. One month after COVID-19, he was diagnosed with type 2 diabetes mellitus. Neurological examination showed bilateral severe proximal and distal lower extremity weakness, absent tendon reflexes, and pan-modality sensation loss. Electrophysiology demonstrated an asymmetric axonal lumbosacral and thoracic radiculoplexus neuropathies. Magnetic resonance imaging showed enlargement and T2 hyperintensity of the lumbosacral plexus. Cerebral spinal fluid (CSF) showed an elevated protein (138 mg/dL). Right sural nerve biopsy was diagnostic of nerve microvasculitis. He was diagnosed with DLRPN and treated with intravenous methylprednisolone 1 g weekly for 12 weeks. The patient had marked improvement in pain, weakness, and lightheadedness and at the 3-month follow-up was walking unassisted. CONCLUSION: COVID-19 can trigger postinfectious inflammatory neuropathies including LRPN.

Corneal dendritic cells in diabetes mellitus: A narrative review.

Diabetes mellitus is a global public health problem with both macrovascular and microvascular complications, such as diabetic corneal neuropathy (DCN). Using in-vivo confocal microscopy, corneal nerve changes in DCN patients can be examined. Additionally, changes in the morphology and quantity of corneal dendritic cells (DCs) in diabetic corneas have also been observed. DCs are bone marrow-derived antigen-presenting cells that serve both immunological and non-immunological roles in human corneas. However, the role and pathogenesis of corneal DC in diabetic corneas have not been well understood. In this article, we provide a comprehensive review of both animal and clinical studies that report changes in DCs, including the DC density, maturation stages, as well as relationships between the corneal DCs, corneal nerves, and corneal epithelium, in diabetic corneas. We have also discussed the associations between the changes in corneal DCs and various clinical or imaging parameters, including age, corneal nerve status, and blood metabolic parameters. Such information would provide valuable insight into the development of diagnostic, preventive, and therapeutic strategies for DM-associated ocular surface complications.

MicroRNA-7a-5p ameliorates diabetic peripheral neuropathy by regulating VDAC1/JNK/c-JUN pathway.

AIMS: The pathogenesis of diabetic peripheral neuropathy (DPN) is complex, and its treatment is extremely challenging. MicroRNA-7a-5p (miR-7a-5p) has been widely reported to alleviate apoptosis and oxidative stress in various diseases. This study aimed to investigate the mechanism of miR-7a-5p in DPN. METHODS: DPN cell model was constructed with high-glucose-induced RSC96 cells. Cell apoptosis and viability were detected by flow cytometry analysis and cell counting kit-8 (CCK-8) assay respectively. The apoptosis and Jun N-terminal kinase (JNK)/c-JUN signalling pathway-related proteins expression were detected by Western blotting. The intracellular calcium content and oxidative stress levels were detected by flow cytometry and reagent kits. Mitochondrial membrane potential was evaluated by tetrechloro-tetraethylbenzimidazol carbocyanine iodide (JC-1) staining. The targeting relationship between miR-7a-5p and voltage-dependent anion-selective channel protein 1 (VDAC1) was determined by RNA pull-down assay and dual-luciferase reporter gene assay. The streptozotocin (STZ) rat model was constructed to simulate DPN in vivo. The paw withdrawal mechanical threshold (PTW) was measured by Frey capillary line, and the motor nerve conduction velocity (MNCV) was measured by electromyography. RESULTS: MiR-7a-5p expression was decreased, while VDAC1 expression was increased in HG-induced RSC96 cells and STZ rats. In HG-induced RSC96 cells, miR-7a-5p overexpression promoted cell proliferation, inhibited apoptosis, down-regulated calcium release, improved mitochondrial membrane potential and repressed oxidative stress response. MiR-7a-5p negatively regulated VDAC1 expression. VDAC1 knockdown improved cell proliferation activity, suppressed cell apoptosis and mitochondrial dysfunction by inhibiting JNK/c-JUN pathway activation. MiR-7a-5p overexpression raised PTW, restored MNCV and reduced oxidative stress levels and nerve cell apoptosis in STZ rats. CONCLUSION: MiR-7a-5p overexpression ameliorated mitochondrial dysfunction and inhibited apoptosis in DPN by regulating VDAC1/JNK/c-JUN pathway.

Histone deacetylase 5-induced deficiency of signal transducer and activator of transcription-3 acetylation contributes to spinal astrocytes degeneration in painful diabetic neuropathy.

Diabetes patients with painful diabetic neuropathy (PDN) show severe spinal atrophy, suggesting pathological changes of the spinal cord contributes to central sensitization. However, the cellular changes and underlying molecular mechanisms within the diabetic spinal cord are less clear. By using a rat model of type 1 diabetes (T1D), we noted an extensive and irreversible spinal astrocyte degeneration at an early stage of T1D, which is highly associated with the chronification of PDN. Molecularly, acetylation of astrocytic signal transducer and activator of transcription-3 (STAT3) that is essential for maintaining the homeostatic astrocytes population was significantly impaired in the T1D model, resulting in a dramatic loss of spinal astrocytes and consequently promoting pain hypersensitivity. Mechanistically, class IIa histone deacetylase, HDAC5 were aberrantly activated in spinal astrocytes of diabetic rats, which promoted STAT3 deacetylation by direct protein-protein interactions, leading to the PDN phenotypes. Restoration of STAT3 signaling or inhibition of HDAC5 rescued astrocyte deficiency and attenuated PDN in the T1D model. Our work identifies the inhibitory axis of HDAC5-STAT3 induced astrocyte deficiency as a key mechanism underlying the pathogenesis of the diabetic spinal cord that paves the way for potential therapy development for PDN.

The pathogenesis of painful diabetic neuropathy and clinical presentation.

Diabetic neuropathy is a common complication of diabetes that affects up to 50% of patients during the course of the disease; 20-30% of the patients also develop neuropathic pain. The mechanisms underlying neuropathy are not known in detail, but both metabolic and vascular factors may contribute to the development of neuropathy. The development of the most common type of neuropathy is insidious, often starting distally in the toes and feet and gradually ascending up the leg and later also involving fingers and hands. The symptoms are mainly sensory with either sensory loss or positive symptoms with different types of paresthesia or painful sensations. In more advanced cases motor dysfunction may occur, causing gait disturbances and falls. The diagnosis of neuropathy is based on history and a careful examination, which includes a sensory examination of both large and small sensory nerve fiber function, as well as an examination of motor function and deep tendon reflexes of the lower limbs. Attention needs to be paid to the feet including examination of the skin, joints, and vascular supply. Nerve conduction studies are rarely needed to make a diagnosis of neuropathy. In patients with clear motor deficit or with an asymmetrical presentation, additional electrophysiological examination may be necessary. Early detection of diabetic neuropathy is important to avoid further irreversible injury to the peripheral nerves.