RESUMEN
Diabetic peripheral neuropathy (DPN) is a complication of diabetes mellitus that lacks specific treatment, its high prevalence and disabling neuropathic pain greatly affects patients' physical and mental health. Schwann cells (SCs) are the major glial cells of the peripheral nervous system, which play an important role in various inflammatory and metabolic neuropathies by providing nutritional support, wrapping axons and promoting repair and regeneration. Increasingly, high glucose (HG) has been found to promote the progression of DPN pathogenesis by targeting SCs death regulation, thus revealing the specific molecular process of programmed cell death (PCD) in which SCs are disrupted is an important link to gain insight into the pathogenesis of DPN. This paper is the first to review the recent progress of HG studies on apoptosis, autophagy, pyroptosis, ferroptosis and necroptosis pathways in SCs, and points out the crosstalk between various PCDs and the related therapeutic perspectives, with the aim of providing new perspectives for a deeper understanding of the mechanisms of DPN and the exploration of effective therapeutic targets.
Asunto(s)
Neuropatías Diabéticas , Células de Schwann , Células de Schwann/metabolismo , Células de Schwann/patología , Humanos , Neuropatías Diabéticas/terapia , Neuropatías Diabéticas/patología , Neuropatías Diabéticas/metabolismo , Neuropatías Diabéticas/etiología , Animales , Apoptosis , Muerte Celular , Autofagia/fisiología , Necroptosis/fisiologíaRESUMEN
Diabetic neuropathy (DN) is a common complication of diabetes, affecting over 50% of patients, leading to significant pain and a burden. Currently, there are no effective treatments available. Cell death is considered a key factor in promoting the progression of DN. This article reviews how cell death is initiated in DN, emphasizing the critical roles of oxidative stress, mitochondrial dysfunction, inflammation, endoplasmic reticulum stress, and autophagy. Additionally, we thoroughly summarize the mechanisms of cell death that may be involved in the pathogenesis of DN, including apoptosis, autophagy, pyroptosis, and ferroptosis, among others, as well as potential therapeutic targets offered by these death mechanisms. This provides potential pathways for the prevention and treatment of diabetic neuropathy in the future.
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Muerte Celular , Neuropatías Diabéticas , Estrés Oxidativo , Humanos , Neuropatías Diabéticas/patología , Neuropatías Diabéticas/terapia , Neuropatías Diabéticas/metabolismo , Neuropatías Diabéticas/etiología , Animales , Autofagia , Estrés del Retículo Endoplásmico , Apoptosis , Ferroptosis , Mitocondrias/metabolismo , Mitocondrias/patologíaRESUMEN
Introdução:O diabetes mellitus é uma doença metabólica caracterizada pelo controle inadequado dos níveis de glicose no sangue, principalmente um estado crônico de hiperglicemia, causado por diferentes processos patogênicos, levando a complicaçõesdosistema nervoso do diabético queincluem axonopatias, doenças neurodegenerativas, doenças neurovasculares e comprometimento cognitivo geral.Objetivo:Avaliar as complicações clínicas da diabetes tipo 2 em mulheres. Metodologia:Tratou-se de um transversal, do tipo prevalência. Foram usados dois grupos de mulheres, onde todas as mulheres estavam com diagnóstico de diabetes Tipo 2 e idade de 40 e 60 anos, comotratamentooral -G1e com tratamentocominsulinoterapia G2,ambosfornecidospelarede pública Para comparação das variáveis estudadas foi utilizado o método de Mann-Whitney, adotando-se o nível de significância menor que 5% (p, valor ,0,05). Resultados:Aproporçãode pessoas com diabetes no Piauí, com consulta e hemoglobina glicada solicitada no primeiro quadrimestre de 2021, 2022, 2023, foi de18, 16 e 34 percentuais,respectivamenteeem Boa Hora nos mesmos quadrimestres foi 36, 39, 56 percentuais, respectivamente.Osprocedimentoshospitalares-por local de residência -Piauí foi de um total de 1.193e em Boa Hora 24. O grupo de mulheres estudadas mostrou uma diferença significativa para a glicemia em jejum e a Hemoglobina glicada quando comparados os grupos G1 e G2. Quase 100% da amostra estava obesa (IMC > 25), não fumava e não praticava atividade física.Conclusões:Concluiu-se que a as pacientes tiveram um agravamento do adoecimento ao longo dos anos com aumento de medicação. A ausência das boas práticas de promoção de saúde, atividade física e alimentação, podem ter contribuídocom o agravamento. Outrossim há necessidade urgente de uma intervenção para mudança de hábitos na população para que a medicalização seja diminuída para a promoção da saúde (AU).
Introduction: Diabetes mellitus is a metabolic disease characterized by inadequate control of blood glucose levels, mainly a chronic state of hyperglycemia, caused by different pathogenic processes, leading to complications of the nervous system including axonopathies, neurodegenerative diseases,neurovascular diseases and general cognitive impairment.Objective: To evaluate the clinical complications of type 2 diabetes in women.Methodology: This was a cross-sectional, prevalence study.Two groupsof women were used, where all women were diagnosed with Type 2 diabetes and aged between 40 and 60 years, with oral treatment -G1 and treatment with insulin therapy -G2, both provided by the public network .To compare the variables studied, the Mann-Whitney method was used, adopting a significance level of less than 5% (p, value 0.05).Results:The proportion of people with diabetes in Piauí, with consultation and glycated hemoglobin requested in the first four months of 2021, 2022, 2023, was 18, 16 and34 percentages, respectively and in Boa Hora in the same four months it was 36, 39, 56percentages, respectively.SUS hospital procedures -by place of residence -Piauí was a total of 1,193 and in Boa Hora 24. The group of women studied showed a significant difference in fasting blood glucose and glycated hemoglobin when comparing groups G1 and G2.Almost 100% of the sample was obese (BMI > 25), did not smoke and did not practice physical activity.Conclusions: It was concluded that the patients' illness worsened over the years with increased medication.The absence of good health promotion practices, physical activity and nutrition may have contributed to the worsening.Furthermore, there is an urgent need for intervention to change habits in the population so that medicalization is reduced to promote health (AU).
Introducción: La diabetes mellitus ecaracterizada por un control inadecuado de los niveles de glucosa en sangre, principalmente un estado crónico de hiperglucemia, causado por diferentes procesos patogénicos, derivando en complicaciones del sistema nervioso incluyendo axonopatías, enfermedades neurodegenerativas, enfermedades neurovasculares y deterioro cognitivo general.Objetivo: Evaluar las complicaciones clínicas de la diabetes tipo 2 en mujeres.Metodología: Se trata de un estudio transversal de prevalencia.Se utilizaron dos grupos de mujeres, donde todas fueron diagnosticadas con diabetes tipo 2 y con edades entre 40 y 60 años, con tratamiento oral -G1 y tratamiento con insulinoterapia -G2, ambos prestados por la red pública.Para comparar las variables estudiadas se utilizó el método de Mann-Whitney, adoptando un nivel de significancia inferior al 5% (p, valor 0,05).Resultados:La proporción de personas con diabetes en Piauí, con consulta y hemoglobina glucosilada solicitada en los primeros cuatro meses de 2021, 2022, 2023, fuede 18, 16 y 34 porcentajes, respectivamente y en Boa Hora en los mismos cuatro meses fue de 36 , 39, 56 porcentajes, respectivamente.Los procedimientos hospitalarios del SUS -por lugar de residencia -en Piauí fueron en total 1.193 y en Boa Hora 24. El grupo de mujeres estudiado presentó diferencia significativa en la glucemia en ayunas y en la hemoglobina glucosilada al comparar los grupos G1 y G2.Casi el 100% de la muestra era obesa (IMC > 25), no fumaba y no practicaba actividad física.Conclusiones:Se concluyó que la enfermedad de los pacientes empeoró con el paso de los años con el aumento de la medicación.La ausencia de buenas prácticas de promoción de la salud, actividad física y nutrición puede haber contribuido al empeoramiento.Además, es urgente intervenir para cambiar los hábitos de la población para promover la salud (AU).
Asunto(s)
Humanos , Femenino , Adulto , Persona de Mediana Edad , Enfermedades Neurodegenerativas/patología , Diabetes Mellitus Tipo 2/patología , Neuropatías Diabéticas/patología , Hiperglucemia , Hiperglucemia/inducido químicamente , Estudios Transversales/métodos , Estadísticas no Paramétricas , Diabetes Mellitus/patologíaRESUMEN
Complications of diabetes are often attributed to glucose and reactive dicarbonyl metabolites derived from glycolysis or gluconeogenesis, such as methylglyoxal. However, in the CNS, neurons and endothelial cells use lactate as energy source in addition to glucose, which does not lead to the formation of methylglyoxal and has previously been considered a safer route of energy consumption than glycolysis. Nevertheless, neurons and endothelial cells are hotspots for the cellular pathology underlying neurological complications in diabetes, suggesting a cause that is distinct from other diabetes complications and independent of methylglyoxal. Here, we show that in clinical and experimental diabetes plasma concentrations of dimethylglyoxal are increased. In a mouse model of diabetes, ilvb acetolactate-synthase-like (ILVBL, HACL2) is the enzyme involved in formation of increased amounts of dimethylglyoxal from lactate-derived pyruvate. Dimethylglyoxal reacts with lysine residues, forms Nε-3-hydroxy-2-butanonelysine (HBL) as an adduct, induces oxidative stress more strongly than other dicarbonyls, causes blood-brain barrier disruption, and can mimic mild cognitive impairment in experimental diabetes. These data suggest dimethylglyoxal formation as a pathway leading to neurological complications in diabetes that is distinct from other complications. Importantly, dimethylglyoxal formation can be reduced using genetic, pharmacological and dietary interventions, offering new strategies for preventing CNS dysfunction in diabetes.
Asunto(s)
Neuropatías Diabéticas , Glioxal , Ácido Pirúvico , Complicaciones de la Diabetes/metabolismo , Complicaciones de la Diabetes/patología , Animales , Ratones , Glioxal/análogos & derivados , Neuropatías Diabéticas/metabolismo , Neuropatías Diabéticas/patología , Glucosa/metabolismo , Ácido Pirúvico/metabolismo , Acetolactato Sintasa/metabolismo , Encéfalo/metabolismo , Liasas de Carbono-Carbono/metabolismo , Humanos , Ratones Endogámicos C57BLRESUMEN
Diabetic peripheral neuropathy (DPN) is caused by several factors, including reactive free oxygen radicals (ROS)-induced excessive Ca2+ influx. Transient receptor potential (TRP) vanilloid 4 (TRPV4) is a member of the Ca2+-permeable TRP superfamily. Resveratrol (RESV) has been extensively utilized in TRP channel regulation due to its pharmacological properties, which include antioxidant and TRP inhibitory effects. The protective function of RESV and the contribution of TRPV4 to streptozotocin (STZ)-induced neuropathic pain in mice are still unclear. Here, we evaluated the effects of RESV through the modulation of TRPV4 on Ca2+ influx, ROS-mediated pain, apoptosis, and oxidative damage in the mouse dorsal root ganglion (DRGs). From the 32 mice, four groups were induced: control, RESV, STZ, and STZ + RESV. We found that the injection of RESV reduced the changes caused by the STZ-induced stimulation of TRPV4, which in turn increased mechanical/thermal neuropathic pain, cytosolic Ca2+ influx, TRPV4 current density, oxidants (lipid peroxidation, mitochondrial ROS, and cytosolic ROS), and apoptotic markers (caspase-3, -8, and -9). The RESV injection also increased the STZ-mediated reduction of viability of DRG and the amounts of glutathione, glutathione peroxidase, vitamin A, ß-carotene, and vitamin E in the brain, erythrocytes, plasma, liver, and kidney. All of these findings suggest that TRPV4 stimulation generates oxidative neurotoxicity, neuropathic pain, and apoptosis in the STZ-induced diabetic mice. On the other hand, neurotoxicity and apoptosis were reduced due to the downregulation of TRPV4 carried out through the RESV injection.
Asunto(s)
Apoptosis , Diabetes Mellitus Experimental , Ganglios Espinales , Neuralgia , Estrés Oxidativo , Resveratrol , Canales Catiónicos TRPV , Animales , Canales Catiónicos TRPV/metabolismo , Apoptosis/efectos de los fármacos , Resveratrol/farmacología , Resveratrol/uso terapéutico , Masculino , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Estrés Oxidativo/efectos de los fármacos , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Neuralgia/patología , Ganglios Espinales/metabolismo , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/patología , Ratones , Calcio/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Estreptozocina/toxicidad , Neuropatías Diabéticas/metabolismo , Neuropatías Diabéticas/tratamiento farmacológico , Neuropatías Diabéticas/patologíaRESUMEN
BACKGROUND AND OBJECTIVES: There is a need for knowledge regarding the natural course of diabetic polyneuropathy (DPN), a complication in type 2 diabetes (T2D). The aim of this study was to examine the development of DPN over time. METHODS: Patients with newly diagnosed T2D, recruited from a national cohort, and controls without diabetes of similar age and sex, underwent sensory phenotyping in 2016-2018. The Toronto consensus criteria were used to classify patients into possible, probable, and confirmed DPN. For this 5-year, observational, follow-up, cohort study, all participants were invited to a reexamination combining bedside sensory examination, quantitative sensory testing (QST), nerve conduction studies (NCSs), and skin biopsies measuring intraepidermal nerve fiber density (IENFD) in order to compare phenotypic and diagnostic changes over time. RESULTS: Of the baseline 389 patients and 97 controls, 184 patients (median [interquartile range] diabetes duration 5.9 [4.1-7.4] years, mean hemoglobin A1c [HbA1c] 51 ± 11 mmol/mol at baseline) and 43 controls completed follow-up (46.9%). Confirmed DPN was present in 35.8% and 50.3%, probable DPN in 27.2% and 14.6%, possible DPN in 17.2% and 16.6%, and no DPN in 15.2% and 17.9% at baseline and follow-up, respectively. The estimated prevalence (95% CI) of confirmed DPN was 33.5% (24.9-42.1) compared with 22.7% (17.5-28.0) at baseline. During the follow-up period, 43.9% of patients with probable DPN developed confirmed DPN. Progression of neuropathy occurred in 16.5% and 24.7% and regression in 5.9% and 18.6% of patients based on NCS and IENFD, respectively. Progression based on NCS and/or IENFD was associated with higher baseline waist circumference and triglycerides, and regression with lower baseline HbA1c. Patients with at least probable DPN at baseline but neither patients without DPN nor controls developed increased spread of hyposensitivity, more hyposensitivity on QST and lower NCS z-scores at follow-up, and worsening of nerve parameters at follow-up correlated with higher baseline triglycerides. DISCUSSION: In patients with well-regulated T2D, the proportion of patients with confirmed DPN increased over 5 years driven by progression from probable DPN. A large proportion of patients progressed, and a smaller proportion regressed on nerve parameters. Higher triglycerides correlated with this progression and may constitute a risk factor.
Asunto(s)
Diabetes Mellitus Tipo 2 , Neuropatías Diabéticas , Progresión de la Enfermedad , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Masculino , Femenino , Persona de Mediana Edad , Neuropatías Diabéticas/epidemiología , Neuropatías Diabéticas/patología , Anciano , Estudios de Seguimiento , Conducción Nerviosa/fisiología , Estudios de Cohortes , Hemoglobina Glucada/metabolismoRESUMEN
INTRODUCTION: Diabetic polyneuropathy (DPN), a common complication of diabetes, can manifest as small, large, or mixed fiber neuropathy (SFN, LFN, and MFN, respectively), depending on the type of fibers involved. Despite evidence indicating small fiber involvement prior to large fiber involvement in type 1 diabetes mellitus (T1DM)-associated DPN, no evidence has been produced to determine the more prevalent subtype. We aim to determine the more prevalent type of nerve fiber damage-SFN, LFN, and MFN-in T1DM-associated DPN, both with and without pain. RESEARCH DESIGN AND METHODS: In this cross-sectional study, participants (n=216) were divided into controls; T1DM; T1DM with non-painful DPN (NP-DPN); and T1DM with painful DPN (P-DPN). DPN was further subgrouped based on neuropathy severity. The more prevalent type of fiber damage was determined applying small and large fiber-specific tests and three diagnostic models: model 1 (≥1 abnormal test); model 2 (≥2 abnormal tests); and model 3 (≥3 abnormal tests). RESULTS: MFN showed the highest prevalence in T1DM-associated DPN. No differences in neuropathy subtype were found between NP-DPN and P-DPN. DPN, with prevalent SFN plateaus between models 2 and 3. All models showed increased prevalence of MFN according to DPN severity. Model 3 showed increased DPN with prevalent LFN in early neuropathy. DPN with prevalent SFN demonstrated a similar, but non-significant pattern. CONCLUSIONS: DPN primarily manifests as MFN in T1DM, with no differentiation between NP-DPN and P-DPN. Additionally, we propose model 2 as an initial criterion for diagnosing DPN with a more prevalent SFN subtype in T1DM. Lastly, the study suggests that in mild stages of DPN, one type of nerve fiber (either small or large) is more susceptible to damage.
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Diabetes Mellitus Tipo 1 , Neuropatías Diabéticas , Humanos , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/epidemiología , Neuropatías Diabéticas/epidemiología , Neuropatías Diabéticas/patología , Neuropatías Diabéticas/diagnóstico , Neuropatías Diabéticas/etiología , Masculino , Estudios Transversales , Femenino , Adulto , Persona de Mediana Edad , Fibras Nerviosas/patología , Prevalencia , Estudios de Casos y Controles , Estudios de Seguimiento , Conducción Nerviosa/fisiología , Pronóstico , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Painful diabetic neuropathy (PDN) is closely linked to inflammation, which has been demonstrated to be associated with pyroptosis. Emerging evidence has implicated TANK-binding kinase 1 (TBK1) in various inflammatory diseases. However, it remains unknown whether activated TBK1 causes hyperalgesia via pyroptosis. METHODS: PDN mice model of type 1 or type 2 diabetic was induced by C57BL/6J or BKS-DB mice with Lepr gene mutation. For type 2 diabetes PDN model, TBK1-siRNA, Caspase-1 inhibitor Ac-YVAD-cmk or TBK1 inhibitor amlexanox (AMX) were delivered by intrathecal injection or intragastric administration. The pain threshold and plantar skin blood perfusion were evaluated through animal experiments. The assessments of spinal cord, dorsal root ganglion, sciatic nerve, plantar skin and serum included western blotting, immunofluorescence, ELISA, and transmission electron microscopy. RESULTS: In the PDN mouse model, we found that TBK1 was significantly activated in the spinal dorsal horn (SDH) and mainly located in microglia, and intrathecal injection of chemically modified TBK1-siRNA could improve hyperalgesia. Herein, we described the mechanism that TBK1 could activate the noncanonical nuclear factor κB (NF-κB) pathway, mediate the activation of NLRP3 inflammasome, trigger microglia pyroptosis, and ultimately induce PDN, which could be reversed following TBK1-siRNA injection. We also found that systemic administration of AMX, a TBK1 inhibitor, could effectively improve peripheral nerve injury. These results revealed the key role of TBK1 in PDN and that TBK1 inhibitor AMX could be a potential strategy for treating PDN. CONCLUSIONS: Our findings revealed a novel causal role of TBK1 in pathogenesis of PDN, which raises the possibility of applying amlexanox to selectively target TBK1 as a potential therapeutic strategy for PDN.
Asunto(s)
Neuropatías Diabéticas , Microglía , Proteínas Serina-Treonina Quinasas , Piroptosis , Animales , Masculino , Ratones , Aminopiridinas/farmacología , Aminopiridinas/uso terapéutico , Neuropatías Diabéticas/patología , Modelos Animales de Enfermedad , Hiperalgesia/patología , Ratones Endogámicos C57BL , Microglía/metabolismo , Microglía/patología , Microglía/efectos de los fármacos , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/genética , Piroptosis/efectos de los fármacos , ARN Interferente Pequeño/metabolismo , ARN Interferente Pequeño/genéticaRESUMEN
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.
Asunto(s)
Neuropatías Diabéticas , Ganglios Espinales , Perfilación de la Expresión Génica , Células de Schwann , Análisis de la Célula Individual , Animales , Ganglios Espinales/metabolismo , Ganglios Espinales/patología , Neuropatías Diabéticas/patología , Neuropatías Diabéticas/genética , Neuropatías Diabéticas/metabolismo , Ratas , Células de Schwann/metabolismo , Células de Schwann/patología , Masculino , Transcriptoma , Neuronas/metabolismo , Neuronas/patología , Ratas Sprague-Dawley , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patología , Análisis de Expresión Génica de una Sola CélulaRESUMEN
BACKGROUND: The white blood cell count to mean platelet volume ratio (WMR) is considered a promising inflammatory marker, and its recognition is increasing. Inflammation is closely related to metabolic diseases such as diabetes and its complications. However, there are currently no reports on the correlation between WMR and type 2 diabetic peripheral neuropathy (DPN). This study aims to explore the correlation between WMR and DPN in type 2 diabetes patients. By understanding this association, we hope to provide a theoretical basis for preventing DPN through the improvement of inflammatory responses. METHODS: This was a cross-sectional study involving 2515 patients with T2DM. Logistic regression analysis was conducted to assess the associations between WMR and DPN. Finally, the receiver operating characteristic curve (ROC curve) was employed to evaluate the predictive efficacy of WMR for DPN. RESULTS: Patients in higher WMR quartiles exhibited increased presence of DPN. Additionally, WMR remained significantly associated with a higher odds ratio (OR) of DPN (OR 4.777, 95% confidence interval [CI] 1.296-17.610, P < 0.05) after multivariate adjustment. Moreover, receiver operating characteristic curve analysis indicated that the optimal cutoff value for WMR in predicting DPN presence was 0.5395 (sensitivity: 65.40%; specificity: 41.80%; and area under the curve [AUC]: 0.540). CONCLUSIONS: In patients with T2DM, WMR was significantly increased in DPN and independently associated with an increased risk of DPN presence in Chinese patients. This suggests that WMR may serve as a useful and reliable biomarker of DPN, highlighting the importance of paying more attention to T2DM patients with high WMR to further prevent and reduce the development of DPN and related unfavorable health outcomes.
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Diabetes Mellitus Tipo 2 , Neuropatías Diabéticas , Volúmen Plaquetario Medio , Humanos , Estudios Transversales , Neuropatías Diabéticas/sangre , Neuropatías Diabéticas/patología , Neuropatías Diabéticas/etiología , Neuropatías Diabéticas/epidemiología , Masculino , Femenino , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/patología , Persona de Mediana Edad , Recuento de Leucocitos , China/epidemiología , Anciano , Biomarcadores/sangre , Pronóstico , Curva ROC , Pueblos del Este de AsiaRESUMEN
Currently, there are more than 10 million patients with diabetes mellitus in Japan. Therefore, the need to explore the pathogenesis of diabetes and the complications leading to its cure is becoming increasingly urgent. Pathological examination of pancreatic tissues from patients with type 2 diabetes reveals a decrease in the volume of beta cells because of a combination of various stresses. In human type 2 diabetes, islet amyloid deposition is a unique pathological change characterized by proinflammatory macrophage (M1) infiltration into the islets. The pathological changes in the pancreas with islet amyloid were different according to clinical factors, which suggests that type 2 diabetes can be further subclassified based on islet pathology. On the other hand, diabetic peripheral neuropathy is the most frequent diabetic complication. In early diabetic peripheral neuropathy, M1 infiltration in the sciatic nerve evokes oxidative stress or attenuates retrograde axonal transport, as clearly demonstrated by in vitro live imaging. Furthermore, islet parasympathetic nerve density and beta cell volume were inversely correlated in type 2 diabetic Goto-Kakizaki rats, suggesting that diabetic peripheral neuropathy itself may contribute to the decrease in beta cell volume. These findings suggest that the pathogenesis of diabetes mellitus and diabetic peripheral neuropathy may be interrelated.
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Diabetes Mellitus Tipo 2 , Neuropatías Diabéticas , Neuropatías Diabéticas/patología , Neuropatías Diabéticas/etiología , Humanos , Animales , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/patología , Ratas , Células Secretoras de Insulina/patología , Células Secretoras de Insulina/metabolismo , Islotes Pancreáticos/patología , Estrés Oxidativo , Páncreas/patologíaRESUMEN
OBJECTIVE: Meteorin-like (Metrnl), a secreted myokine, is a newly discovered neurotrophic factor. The aim of this study was to determine if there is a correlation between the Metrnl level and diabetic peripheral neuropathy (DPN). METHODS: The investigation was conducted on a sample of 80 patients with type 2 diabetes mellitus (T2DM) and 60 healthy controls. The T2DM patients were categorized into two subgroups based on skin biopsy: the DPN subgroup (n = 20) and the diabetes without neuropathy subgroup (n = 60). RESULTS: The T2DM groups had higher serum Metrnl concentrations compared with the controls. The serum Metrnl concentration was significantly lower in the DPN group than in T2DM patients without neuropathy. Logistic regression analysis demonstrated a notable correlation between serum Metrnl and DPN (OR: 0.997, 95% CI: 0.995-1.000, P < 0.05). Serum Metrnl level was negatively correlated with age and SBP after a simple logistic regression analysis. CONCLUSION: Serum Metrnl concentration is independently correlated with DPN.
Asunto(s)
Diabetes Mellitus Tipo 2 , Neuropatías Diabéticas , Humanos , Neuropatías Diabéticas/sangre , Neuropatías Diabéticas/diagnóstico , Neuropatías Diabéticas/patología , Neuropatías Diabéticas/etiología , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Masculino , Femenino , Persona de Mediana Edad , Estudios de Casos y Controles , Anciano , Biomarcadores/sangre , AdipoquinasRESUMEN
BACKGROUND: Diabetic neuropathic pain (DNP) is a complication of diabetes mellitus (DM). Hyperbaric lidocaine (HL), a local anesthetics drug, has neurotoxicity. The present study aims to study the effect and molecular mechanisms of HL on spinal nerve injury in DNP. METHODS: The DNP rat model was established through a high-fat-glucose diet in combination with Streptozotocin (STZ) administration. SB203580 and PD98059 were utilized to inhibit p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal-regulated kinase (ERK). The mechanical paw withdrawal threshold (PWT) and the thermal paw withdrawal latency (PWL) were tested to evaluate rats' mechanical allodynia and thermal hyperalgesia. Hematoxylin-eosin (H&E) and terminal deoxynucleotidyltransferase-mediated dUTP nick-end Labeling (TUNEL) staining were performed to evaluate the pathological changes and neuron apoptosis in spinal cord tissues of L4-5. Western blotting analysis and reverse transcription-polymerase chain reaction (RT-qPCR) assay were used to measure the levels of proteins and mRNAs, respectively. RESULTS: PWT and PWL were decreased in DNP rats with serious spinal nerve injury. HL administration downregulated the PWT and PWL and aggravated spinal nerve injury in DNP rats, but isobaric lidocaine had no effects on these changes. Meanwhile, p38 MAPK/ERK signaling and PTEN-induced kinase 1 (PINK1)-mediated mitophagy were activated in DNP, which was enhanced by HL but not isobaric lidocaine. Blocking p38 MAPK/ERK signaling could effectively attenuate HL-induced spinal nerve injury and inhibit mitophagy. CONCLUSION: In summary, HL can aggravate spinal cord tissue damage in DNP rats by inducing PINK1-mediated mitophagy via activating p38 MAPK/ERK signaling. Our data provide a novel insight that supports the potential role of p38 MAPK/ERK signaling in acting as a therapeutic target for HL-induced neurotoxicity.
Asunto(s)
Neuropatías Diabéticas , Lidocaína , Mitofagia , Proteínas Quinasas , Ratas Sprague-Dawley , Ubiquitina-Proteína Ligasas , Proteínas Quinasas p38 Activadas por Mitógenos , Animales , Lidocaína/farmacología , Ratas , Neuropatías Diabéticas/patología , Neuropatías Diabéticas/metabolismo , Neuropatías Diabéticas/etiología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Mitofagia/efectos de los fármacos , Masculino , Proteínas Quinasas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
Peripheral and central neuropathies frequently complicate worldwide diabetes. Compared to peripheral neuropathy, central neuropathy didn`t gain a major research interest. Angiotensin II is reported to be involved in diabetic neuropathic pain but its role in the central pathological changes in the spinal cord is not clear. Here, we study the role of Losartan; an Angiotensin II receptor 1 (AT1) antagonist in suppression of the diabetes-induced changes in the spinal cord. Three groups of rats were applied; a negative control group, a streptozotocin (STZ) diabetic group, and a group receiving STZ and Losartan. After two months, the pathological alteration in the spinal cord was investigated, and an immunohistochemical study was performed for neuronal, astrocytic, and microglial markers; nuclear protein (NeuN), Glial fibrillary acidic protein (GFAP), and Ionized calcium-binding adaptor molecule 1 (Iba1), respectively, and for an apoptosis marker; caspase-3, and the inflammatory marker; nuclear factor kappa B (NF-kB) signaling, heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2); physiological antioxidant system. The results showed that Losartan caused recovery of spinal cord changes, by inhibiting the microglial and astrocytic activation, suppressing neuronal apoptosis and NF-kB expression with activation of Nrf2/HO-1 (P<0.0005). It is suggested, herein, that Losartan can suppress diabetes-induced glial activation, inflammation, neuronal apoptosis, and oxidative stress in the spinal cord; the mechanisms that may underlie the role of AT1 antagonism in suppressing diabetic neuropathic pain.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II , Diabetes Mellitus Experimental , Losartán , Factor 2 Relacionado con NF-E2 , Médula Espinal , Animales , Médula Espinal/patología , Médula Espinal/metabolismo , Médula Espinal/efectos de los fármacos , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/complicaciones , Factor 2 Relacionado con NF-E2/metabolismo , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Ratas , Masculino , Losartán/farmacología , Hemo-Oxigenasa 1/metabolismo , Neuropatías Diabéticas/patología , Neuropatías Diabéticas/metabolismo , Neuropatías Diabéticas/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Ratas Wistar , Apoptosis/efectos de los fármacos , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacosRESUMEN
AIMS/INTRODUCTION: Deficiency of neurotropic factors is implicated in diabetic neuropathy (DN). Netrin-1 is a neurotropic factor, but its association with DN has not been explored. We have assessed the association between serum netrin-1 levels and early diabetic neuropathy assessed by quantifying corneal nerve fiber loss using corneal confocal microscopy. MATERIALS AND METHODS: A total of 72 participants with type 2 diabetes, without and with corneal nerve fiber loss (DN- n = 42, DN+ n = 30), and 45 healthy controls were studied. Serum netrin-1 levels were measured by enzyme-linked immunosorbent assay, and corneal nerve morphology was assessed using corneal confocal microscopy. RESULTS: Corneal nerve fiber density, branch density, fiber length and serum netrin-1 levels were significantly lower in the DN- and DN+ groups compared with controls (P < 0.001). Netrin-1 levels correlated with corneal nerve fiber length in the DN+ group (r = 0.51; P < 0.01). A receiver operating characteristic curve analysis showed that a netrin-1 cut-off value of 599.6 (pg/mL) had an area under the curve of 0.85, with a sensitivity of 76% and specificity of 74% (P < 0.001; 95% confidence interval 0.76-0.94) for differentiating patients with and without corneal nerve loss. CONCLUSIONS: Serum netrin-1 levels show a progressive decline with increasing severity of small nerve fiber damage in patients with diabetes. Netrin-1 could act as a biomarker for small nerve fiber damage in DN.
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Córnea , Diabetes Mellitus Tipo 2 , Neuropatías Diabéticas , Fibras Nerviosas , Netrina-1 , Humanos , Netrina-1/sangre , Masculino , Femenino , Persona de Mediana Edad , Neuropatías Diabéticas/sangre , Neuropatías Diabéticas/patología , Neuropatías Diabéticas/etiología , Fibras Nerviosas/patología , Córnea/inervación , Córnea/patología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/patología , Anciano , Biomarcadores/sangre , Estudios de Casos y Controles , Microscopía ConfocalRESUMEN
Painful Diabetic Neuropathy (PDN) is a common diabetes complication that frequently causes severe hyperalgesia and allodynia and presents treatment challenges. Mitochondrial-derived peptide (MOTS-c), a novel mitochondrial-derived peptide, has been shown to regulate glucose metabolism, insulin sensitivity, and inflammatory responses. This study aimed to evaluate the effects of MOTS-c in streptozocin (STZ)-induced PDN model and investigate the putative underlying mechanisms. We found that endogenous MOTS-c levels in plasma and spinal dorsal horn were significantly lower in STZ-treated mice than in control animals. Accordingly, MOTS-c treatment significantly improves STZ-induced weight loss, elevation of blood glucose, mechanical allodynia, and thermal hyperalgesia; however, these effects were blocked by dorsomorphin, an adenosine monophosphate-activated protein kinase (AMPK) inhibitor. In addition, MOTS-c treatment significantly enhanced AMPKα1/2 phosphorylation and PGC-1α expression in the lumbar spinal cord of PDN mice. Mechanistic studies indicated that MOTS-c significantly restored mitochondrial biogenesis, inhibited microglia activation, and decreased the production of pro-inflammatory factors, which contributed to the alleviation of pain. Moreover, MOTS-c decreased STZ-induced pain hypersensitivity in PDN mice by activating AMPK/PGC-1α signaling pathway. This provides the pharmacological and biological evidence for developing mitochondrial peptide-based therapeutic agents for PDN.
Asunto(s)
Neuropatías Diabéticas , Hiperalgesia , Mitocondrias , Biogénesis de Organelos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Estreptozocina , Animales , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Neuropatías Diabéticas/tratamiento farmacológico , Neuropatías Diabéticas/metabolismo , Neuropatías Diabéticas/patología , Masculino , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismo , Ratones Endogámicos C57BL , Proteínas Quinasas Activadas por AMP/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Péptidos/farmacología , Ratones , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Médula Espinal/patología , Microglía/efectos de los fármacos , Microglía/metabolismoRESUMEN
PURPOSE: Diabetic neuropathy (DN) is a notable complication of diabetes mellitus. The potential involvement of miR-146a in DN regulation is presently under investigation. Metformin, a commonly prescribed medication for diabetes, is the primary therapeutic intervention. This study aimed to unveil the potential protective effects of metformin on diabetic neuropathy and explore the mechanisms underlying its action. METHOD: Six-weeks male Sprague Dawley rats (n = 40) were randomly divided into 5 groups. The rat model of diabetic neuropathy (DN) was established by administering streptozotocin (STZ). To investigate the effects on the sciatic nerve and resident Schwann cells (RSCs), metformin and miR-146a mimics were administered, and our research explored the potential underlying mechanism. RESULT: The sciatic nerve samples obtained from diabetic rats exhibited noticeable morphological damage, accompanied by decreased miR-146a expression (2.61 ± 0.11 vs 5.0 ± 0.3, p < 0.01) and increased inflammation levels (p65: 1.89 ± 0.04 vs 0.82 ± 0.05, p < 0.01; TNF-α: 0.93 ± 0.03 vs 0.33 ± 0.03, p < 0.01). Notably, the administration of metformin effectively ameliorated the structural alterations in the sciatic nerve by suppressing the inflammatory pathway (p65: 1.15 ± 0.05 vs 1.89 ± 0.04, p < 0.01; TNF-α: 0.67 ± 0.04 vs 0.93 ± 0.03, p < 0.01) and reducing oxidative stress (NO: 0.062 ± 0.004 vs 0.154 ± 0.004umol/mg, p < 0.01; SOD: 3.08 ± 0.09 vs 2.46 ± 0.09 U/mg, p < 0.01). The miR-146a mimics intervention group exhibited comparable findings. CONCLUSION: This study's findings implied that metformin can potentially mitigate diabetic neuropathy in rats through the modulation of miR-146a expression.
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Diabetes Mellitus Experimental , Neuropatías Diabéticas , Metformina , MicroARNs , Estrés Oxidativo , Ratas Sprague-Dawley , Regulación hacia Arriba , Animales , Metformina/farmacología , MicroARNs/genética , MicroARNs/metabolismo , Neuropatías Diabéticas/patología , Neuropatías Diabéticas/metabolismo , Neuropatías Diabéticas/tratamiento farmacológico , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Nervio Ciático/efectos de los fármacos , Nervio Ciático/patología , Nervio Ciático/metabolismo , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Inflamación/tratamiento farmacológico , Células de Schwann/efectos de los fármacos , Células de Schwann/metabolismo , Células de Schwann/patologíaRESUMEN
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.
Asunto(s)
Plaquetas , Diabetes Mellitus Tipo 2 , Angiopatías Diabéticas , Linfocitos , Neutrófilos , Humanos , Masculino , Femenino , Persona de Mediana Edad , Neutrófilos/patología , Estudios Retrospectivos , Estudios Transversales , Linfocitos/patología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/sangre , Angiopatías Diabéticas/sangre , Angiopatías Diabéticas/diagnóstico , Angiopatías Diabéticas/inmunología , Angiopatías Diabéticas/patología , Plaquetas/patología , Anciano , Inflamación/sangre , Inflamación/patología , Neuropatías Diabéticas/sangre , Neuropatías Diabéticas/patología , Neuropatías Diabéticas/etiología , Neuropatías Diabéticas/diagnóstico , Retinopatía Diabética/sangre , Retinopatía Diabética/diagnóstico , Retinopatía Diabética/inmunología , Nefropatías Diabéticas/sangre , Nefropatías Diabéticas/patología , Nefropatías Diabéticas/diagnóstico , Recuento de Linfocitos , Recuento de Plaquetas , AdultoRESUMEN
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.
Asunto(s)
Neuropatías Diabéticas , Antagonistas Muscarínicos , Animales , Humanos , Ratones , Ratas , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Neuropatías Diabéticas/tratamiento farmacológico , Neuropatías Diabéticas/complicaciones , Neuropatías Diabéticas/patología , Ácidos Mandélicos , Antagonistas Muscarínicos/farmacología , Antagonistas Muscarínicos/uso terapéutico , Calidad de Vida , Receptores Muscarínicos , Diabetes Mellitus Tipo 1RESUMEN
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.