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BACKGROUND: Diabetes mellitus has emerged as a pressing global concern, with a notable increase in recent years. Despite advancements in treatment, existing medications struggle to halt the progression of diabetes and its associated complications. Increasing evidence underscores inflammation as a significant driver in the onset of diabetes mellitus. Therefore, perspectives on new therapies must consider shifting focus from metabolic stress to inflammation. High mobility group box (HMGB-1), a nuclear protein regulating gene expression, gained attention as an endogenous danger signal capable of sparking inflammatory responses upon release into the extracellular environment in the late 1990s. PURPOSE: Given the parallels between inflammatory responses and type 2 diabetes (T2D) development, this review paper explores HMGB-1's potential involvement in onset and progression of diabetes complications. Specifically, we will review and update the understanding of HMGB-1 and its inflammatory pathways in insulin resistance, diabetic nephropathy, diabetic neuropathy, and diabetic retinopathy. CONCLUSIONS: HMGB-1 and its receptors i.e. receptor for advanced glycation end-products (RAGE) and toll-like receptors (TLRs) present promising targets for antidiabetic interventions. Ongoing and future projects in this realm hold promise for innovative approaches targeting HMGB-1-mediated inflammation to ameliorate diabetes and its complications.
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Proteína HMGB1 , Hipoglucemiantes , Receptor para Productos Finales de Glicación Avanzada , Transducción de Señal , Humanos , Proteína HMGB1/metabolismo , Proteína HMGB1/antagonistas & inhibidores , Animales , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Receptor para Productos Finales de Glicación Avanzada/antagonistas & inhibidores , Hipoglucemiantes/uso terapéutico , Mediadores de Inflamación/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Antiinflamatorios/uso terapéutico , Terapia Molecular Dirigida , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/tratamiento farmacológico , Resistencia a la Insulina , Receptores Toll-Like/metabolismo , Retinopatía Diabética/metabolismo , Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/etiología , Retinopatía Diabética/prevención & control , Neuropatías Diabéticas/metabolismo , Neuropatías Diabéticas/etiología , Neuropatías Diabéticas/tratamiento farmacológico , Complicaciones de la Diabetes/metabolismo , Complicaciones de la Diabetes/tratamiento farmacológicoRESUMEN
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.
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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
BACKGROUND: Symptoms of autonomic neuropathy (AN) are common in patients with diabetes and advanced renal disease. As yet different domains of autonomic neuropathy cannot be detected by a singular laboratory or invasive test. COMPASS 31, a new self-assessment test, has shown reliable results not only in cardiac autonomic neuropathy but also in different sub-domains when judging manifestation of AN by scores. METHODS: One hundred eighty-three patients with or without diabetes were enrolled, one hundred nineteen of them were treated with permanent dialysis therapy (HD), sixty-four patients served as controls (eGFR > 60 ml/min.) Using COMPASS 31 different symptoms of AN were assessed (orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, pupillomotor changes) and transferred into AN-scores. RESULTS: AN was more pronounced in dialysis patients compared with controls (AN-score 27,5 vs. 10,0; p < 0,01). These differences were present also in every sub-domain of AN (orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, pupillomotor changes; p < 0,05 for all sub-domains). In diabetic patients there was a strong correlation between symptoms of AN and diabetes duration (correlation coefficient r = 0,45, p < 0,001). Current glycemic control (HbA1c), body mass index (BMI), sex, and height had no influence on AN when comparing dialysis patients and controls. C-reactive protein (CRP) showed a positive linear correlation with AN-scores (correlation coefficient r = 0,21; p < 0,05). CONCLUSION: Symptoms of AN are more pronounced in dialysis patients not only in total but also in all different domains of neuropathic changes. Longlasting diabetic disease promotes development of AN, as duration of diabetes was positively correlated with AN. Future longitudinal studies might help to identify the high cardiovascular and mortality risk in dialysis patients by the easy-to-use COMPASS 31 without need of invasive and time-spending methods for diagnosing AN.
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Enfermedades del Sistema Nervioso Autónomo , Diálisis Renal , Humanos , Masculino , Femenino , Diálisis Renal/efectos adversos , Persona de Mediana Edad , Enfermedades del Sistema Nervioso Autónomo/etiología , Enfermedades del Sistema Nervioso Autónomo/diagnóstico , Anciano , Neuropatías Diabéticas/diagnóstico , Neuropatías Diabéticas/etiologíaRESUMEN
INTRODUCTION: Diabetic peripheral neuropathy (DPN), a widely prevalent complication in patients with type 2 diabetes, exerts a significant influence on patients' overall health and financial circumstances. Photobiomodulation therapy is one of the means of physical therapy for DPN. Although preliminary findings suggest the efficacy of photobiomodulation therapy in alleviating peripheral neuropathy, the existing literature lacks substantial evidence regarding its safety and effectiveness specifically in the context of diabetes-related peripheral neuropathy. Therefore, we plan to arrive at more distinct findings through systematic evaluation and meta-analysis. METHODS: We will conduct a comprehensive search for studies published from the beginning until October 1, 2023, using various databases including Web of Science, Embase, Cochrane Library, PubMed, AMED, Wanfang database, VIP database, China National Knowledge Infrastructure, and the Chinese Biomedical Literature database. Simultaneously, we will also search for the WHO International Clinical Trial Registration Platform, China Clinical Trial Registration Platform, and Clinical Trials.gov. Gray literature will be retrieved using Google Scholar and opengrey.edu. Only randomized controlled trials in Chinese and English were included, with no restrictions on publication status. The primary outcomes will include change of symptom scores, change of nerve conduction velocity. Additional outcomes will encompass quality of life, change in pain, blood glucose levels after fasting and 2 hours after eating, levels of glycosylated hemoglobin, and any adverse events associated with photobiomodulation therapy. Reman V.5.4 and R language will be used for the meta-analysis. Assessment of potential bias will be conducted through Cochrane risk of bias 2 tool (RoB 2.0) and Physiotherapy Evidence Database (PEDro) scale. Registration: PROSPERO (registration number: CRD42023466586). DISCUSSION: This meta-analysis aims to assess the efficacy and safety of photobiomodulation therapy as a potential treatment for diabetic peripheral neuropathy (DPN), and providing a straightforward and convenient therapeutic for patients. Additionally, it expands the range of treatment alternatives available to healthcare professionals managing DPN.
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Neuropatías Diabéticas , Terapia por Luz de Baja Intensidad , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/radioterapia , Neuropatías Diabéticas/etiología , Neuropatías Diabéticas/radioterapia , Terapia por Luz de Baja Intensidad/efectos adversos , Terapia por Luz de Baja Intensidad/métodos , Metaanálisis como Asunto , Calidad de Vida , Revisiones Sistemáticas como Asunto , Resultado del TratamientoRESUMEN
BACKGROUND: Cardiac autonomic neuropathy (CAN) in diabetes mellitus (DM) is independently associated with cardiovascular (CV) events and CV death. Diagnosis of this complication of DM is time-consuming and not routinely performed in the clinical practice, in contrast to fundus retinal imaging which is accessible and routinely performed. Whether artificial intelligence (AI) utilizing retinal images collected through diabetic eye screening can provide an efficient diagnostic method for CAN is unknown. METHODS: This was a single center, observational study in a cohort of patients with DM as a part of the Cardiovascular Disease in Patients with Diabetes: The Silesia Diabetes-Heart Project (NCT05626413). To diagnose CAN, we used standard CV autonomic reflex tests. In this analysis we implemented AI-based deep learning techniques with non-mydriatic 5-field color fundus imaging to identify patients with CAN. Two experiments have been developed utilizing Multiple Instance Learning and primarily ResNet 18 as the backbone network. Models underwent training and validation prior to testing on an unseen image set. RESULTS: In an analysis of 2275 retinal images from 229 patients, the ResNet 18 backbone model demonstrated robust diagnostic capabilities in the binary classification of CAN, correctly identifying 93% of CAN cases and 89% of non-CAN cases within the test set. The model achieved an area under the receiver operating characteristic curve (AUCROC) of 0.87 (95% CI 0.74-0.97). For distinguishing between definite or severe stages of CAN (dsCAN), the ResNet 18 model accurately classified 78% of dsCAN cases and 93% of cases without dsCAN, with an AUCROC of 0.94 (95% CI 0.86-1.00). An alternate backbone model, ResWide 50, showed enhanced sensitivity at 89% for dsCAN, but with a marginally lower AUCROC of 0.91 (95% CI 0.73-1.00). CONCLUSIONS: AI-based algorithms utilising retinal images can differentiate with high accuracy patients with CAN. AI analysis of fundus images to detect CAN may be implemented in routine clinical practice to identify patients at the highest CV risk. TRIAL REGISTRATION: This is a part of the Silesia Diabetes-Heart Project (Clinical-Trials.gov Identifier: NCT05626413).
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Aprendizaje Profundo , Neuropatías Diabéticas , Valor Predictivo de las Pruebas , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Neuropatías Diabéticas/diagnóstico , Neuropatías Diabéticas/fisiopatología , Neuropatías Diabéticas/diagnóstico por imagen , Neuropatías Diabéticas/etiología , Reproducibilidad de los Resultados , Retinopatía Diabética/diagnóstico , Retinopatía Diabética/diagnóstico por imagen , Retinopatía Diabética/epidemiología , Interpretación de Imagen Asistida por Computador , Sistema Nervioso Autónomo/fisiopatología , Sistema Nervioso Autónomo/diagnóstico por imagen , Fondo de Ojo , Cardiopatías/diagnóstico por imagen , Cardiopatías/diagnóstico , Adulto , Inteligencia ArtificialRESUMEN
Background: Gut microbiota (GM) homeostasis in the human body is closely associated with health, which can be used as a regulator for preventing the onset and progression of disease. Diabetic microvascular complications bring about not only a huge economic burden to society, but also miserable mental and physical pain. Thus, alteration of the GM may be a method to delay diabetic microvascular complications. Objective: A two-sample Mendelian randomization (MR) analysis was conducted to reveal the causal inference between GM and three core diabetic microvascular complications, namely, diabetic kidney disease (DKD), diabetic retinopathy (DR), and diabetic neuropathy (DNP). Methods: First, genome-wide association study (GWAS) summary statistics for GM from the MiBioGen consortium and three main diabetic microvascular complications acquired from the FinnGen research project were assessed. Second, a forward MR analysis was conducted to assess the causality of GM on the risk of DKD, DR, and DNP. Third, a series of sensitivity studies, such as heterogeneity tests, pleiotropy evaluations, and leave-one-out analyses, were further conducted to assess the accuracy of MR analysis. Finally, Steiger tests and reverse MR analyses were performed to appraise the possibility of reverse causation. Results: A total of 2,092 single-nucleotide polymorphisms related to 196 bacterial traits were selected as instrumental variables. This two-sample MR analysis provided strongly reasonable evidence that 28 genetically predicted abundance of specific GM that played non-negligible roles in the occurrence of DKD, DR, and DNP complications were causally associated with 23 GM, the odds ratio of which generally ranged from 0.9 to 1.1. Further sensitivity analysis indicated low heterogeneity, low pleiotropy, and high reliability of the causal estimates. Conclusion: The study raised the possibility that GM may be a potential target to prevent and delay the progression of diabetic microvascular complications. Further experiments of GM therapy on diabetic microvascular complications are warranted to clarify their effects and specific mechanisms.
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Angiopatías Diabéticas , Microbioma Gastrointestinal , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Humanos , Microbioma Gastrointestinal/genética , Angiopatías Diabéticas/genética , Angiopatías Diabéticas/microbiología , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/microbiología , Polimorfismo de Nucleótido Simple , Neuropatías Diabéticas/genética , Neuropatías Diabéticas/microbiología , Neuropatías Diabéticas/etiología , Retinopatía Diabética/genética , Retinopatía Diabética/microbiología , Retinopatía Diabética/etiologíaRESUMEN
Objectives: To determine how plasma fibrinogen levels impact the severity of microvascular complications in people with type 2 diabetes while focussing on the molecular mechanisms of fibrinogen's role in such complications. METHODS: The analytical, cross-sectional study was conducted from September 2022 to March 2023 at the Department of Medicine, Mardan Medical Complex and Teaching Hospital, Khyber Pakhtunkhwa, Pakistan, and comprised adult patients of either gender who had been diagnosed with type 2 diabetes and microvascular complications. Each patient was subjected to an evaluation of microvascular complications, including diabetic retinopathy, nephropathy and neuropathy, using validated diagnostic criteria and clinical examinations. Data was analysed using SPSS 26. RESULTS: Of the 174 patients 97(%) were males and 77(%) were females. Retinopathy was found in 57(32.7) patients with median age 53 years (interquartile range: 46-63 years). Nephropathy was found in 55(31.6%) subjects with median age 54 years (interquartile range: 50-61 years). Neuropathy was found in 62(35.6%) patients with median age 53 years (interquartile range: 48-58 years). Diabetic neuropathy was significantly associated with elevated plasma fibrinogen levels and various biomarkers, such as creatinine, urea, fasting blood glucose, glycated haemoglobin and estimated average glucose (p<0.05). Diabetic retinopathy was significantly linked with higher levels of fibrinogen, which manifested through symptoms, like floaters or dark spots, impaired colour vision, difficulty seeing at night, blurred or fluctuating vision and vision loss (p<0.05). Diabetic nephropathy and the progression of its severity was significantly associated with increased fibrinogen levels, as well as markers, like albuminuria, creatinine, urea, fasting blood glucose, glycated haemoglobin and estimated average glucose (p<0.05). CONCLUSIONS: Elevated plasma fibrinogen levels in patients with type 2 diabetes significantly correlated with increased microvascular complications, underscoring the importance of monitoring and managing fibrinogen levels to mitigate diabetes-associated vascular pathologies.
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Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Neuropatías Diabéticas , Retinopatía Diabética , Fibrinógeno , Humanos , Masculino , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/sangre , Femenino , Persona de Mediana Edad , Fibrinógeno/análisis , Fibrinógeno/metabolismo , Retinopatía Diabética/sangre , Retinopatía Diabética/epidemiología , Retinopatía Diabética/etiología , Estudios Transversales , Neuropatías Diabéticas/sangre , Neuropatías Diabéticas/epidemiología , Neuropatías Diabéticas/etiología , Nefropatías Diabéticas/sangre , Nefropatías Diabéticas/epidemiología , Nefropatías Diabéticas/etiología , Pakistán/epidemiología , Angiopatías Diabéticas/sangre , Angiopatías Diabéticas/epidemiología , Angiopatías Diabéticas/etiología , Hemoglobina Glucada/metabolismo , Hemoglobina Glucada/análisis , Biomarcadores/sangre , Glucemia/análisis , Glucemia/metabolismo , Creatinina/sangreRESUMEN
Previous studies have revealed that thyroid hormone (TH) levels are associated with the risk of diabetic peripheral neuropathy (DPN) in euthyroid patients with type 2 diabetes mellitus (T2DM). However, the relationship between TH sensitivity, a complementary method for assessing thyroid function, and DPN remains unclear. This study aimed to investigate the correlation between DPN and TH sensitivity in euthyroid patients with T2DM. Exactly 708 euthyroid adults with T2DM were retrospectively enrolled. The FT3/FT4 ratio was used to estimate peripheral TH sensitivity. Central TH sensitivity was assessed using the Thyrotroph T4 Resistance Index (TT4RI), Thyroid-Stimulating Hormone Index (TSHI), Thyroid Feedback Quantile-based Index (TFQI), and Parametric TFQI (PTFQI). DPN was assessed using neurologic symptoms, signs, and nerve conduction velocity tests. The relationship between DPN and TH sensitivity was examined using logistic regression analysis. We observed that an elevated FT3/FT4 ratio was associated with DPN (OR = 1.36, 95%CI: 1.13-1.63, p = 0.0012). For each standard deviation (SD) increase in the TT4RI, TSHI, TFQI, and PTFQI, the OR of DPN was 0.80 (95%CI: 0.68-0.94, p = 0.0078), 0.72 (95%CI: 0.60-0.86, p = 0.0002), 0.69 (95%CI: 0.58-0.83, p < 0.0001), and 0.69 (95%CI: 0.58-0.82, p < 0.0001), respectively. These results suggested that reduced central and peripheral TH sensitivity is associated with a decreased risk of developing DPN.
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Diabetes Mellitus Tipo 2 , Neuropatías Diabéticas , Hormonas Tiroideas , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/sangre , Masculino , Neuropatías Diabéticas/sangre , Neuropatías Diabéticas/etiología , Femenino , Persona de Mediana Edad , Hormonas Tiroideas/sangre , Anciano , Estudios Retrospectivos , Tirotropina/sangre , Adulto , Pruebas de Función de la Tiroides , Tiroxina/sangre , Triyodotironina/sangre , Glándula Tiroides/fisiopatología , Glándula Tiroides/metabolismoRESUMEN
Background: Observational studies and clinical trials have implicated polyunsaturated fatty acids (PUFAs) in potentially safeguarding against diabetic microvascular complication. Nonetheless, the causal nature of these relationships remains ambiguous due to conflicting findings across studies. This research employs Mendelian randomization (MR) to assess the causal impact of PUFAs on diabetic microvascular complications. Methods: We identified instrumental variables for PUFAs, specifically omega-3 and omega-6 fatty acids, using the UK Biobank data. Outcome data regarding diabetic microvascular complications were sourced from the FinnGen Study. Our analysis covered microvascular outcomes in both type 1 and type 2 diabetes, namely diabetic neuropathy (DN), diabetic retinopathy (DR), and diabetic kidney disease (DKD). An inverse MR analysis was conducted to examine the effect of diabetic microvascular complications on PUFAs. Sensitivity analyses were performed to validate the robustness of the results. Finally, a multivariable MR (MVMR) analysis was conducted to determine whether PUFAs have a direct influence on diabetic microvascular complications. Results: The study indicates that elevated levels of genetically predicted omega-6 fatty acids substantially reduce the risk of DN in type 2 diabetes (odds ratio (OR): 0.62, 95% confidence interval (CI): 0.47-0.82, p = 0.001). A protective effect against DR in type 2 diabetes is also suggested (OR: 0.75, 95% CI: 0.62-0.92, p = 0.005). MVMR analysis confirmed the stability of these results after adjusting for potential confounding factors. No significant effects of omega-6 fatty acids were observed on DKD in type 2 diabetes or on any complications in type 1 diabetes. By contrast, omega-3 fatty acids showed no significant causal links with any of the diabetic microvascular complications assessed. Conclusions: Our MR analysis reveals a causal link between omega-6 fatty acids and certain diabetic microvascular complications in type 2 diabetes, potentially providing novel insights for further mechanistic and clinical investigations into diabetic microvascular complications.
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Diabetes Mellitus Tipo 2 , Angiopatías Diabéticas , Análisis de la Aleatorización Mendeliana , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Angiopatías Diabéticas/genética , Angiopatías Diabéticas/epidemiología , Masculino , Ácidos Grasos Insaturados , Ácidos Grasos Omega-3 , Ácidos Grasos Omega-6 , Retinopatía Diabética/genética , Retinopatía Diabética/epidemiología , Femenino , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/genética , Nefropatías Diabéticas/genética , Neuropatías Diabéticas/etiología , Neuropatías Diabéticas/genética , Persona de Mediana EdadRESUMEN
About 20% of patients with diabetes suffer from chronic pain with neuropathic characteristics. We investigated the multivariate associations between 92 neurology-related proteins measured in serum from 190 patients with painful and painless diabetic neuropathy. Participants were recruited from the Pain in Neuropathy Study, an observational cross-sectional multicentre study in which participants underwent deep phenotyping. In the exploration cohort, two groups were defined by hierarchical cluster analyses of protein data. The proportion of painless vs painful neuropathy did not differ between the two groups, but one group had a significantly higher grade of neuropathy as measured by the Toronto Clinical Scoring System (TCSS). This finding was replicated in the replication cohort. Analyzing both groups together, we found that a group of 11 inter-correlated proteins (TNFRSF12A, SCARB2, N2DL-2, SKR3, EFNA4, LAYN, CLM-1, CD38, UNC5C, GFR-alpha-1, and JAM-B) were positively associated with TCSS values. Notably, EFNA4 and UNC5C are known to be part of axon guidance pathways. To conclude, although cluster analysis of 92 neurology-related proteins did not distinguish painful from painless diabetic neuropathy, we identified 11 proteins which positively correlated to neuropathy severity and warrant further investigation as potential biomarkers.
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Neuropatías Diabéticas , Humanos , Neuropatías Diabéticas/sangre , Neuropatías Diabéticas/diagnóstico , Neuropatías Diabéticas/etiología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estudios Transversales , Índice de Severidad de la Enfermedad , Biomarcadores/sangre , Análisis por ConglomeradosRESUMEN
BACKGROUND: Oxidative stress is a risk factor for distal sensorimotor polyneuropathy (DSPN). Selenoprotein P is a protein with antioxidant properties but has not been investigated in the context of DSPN. This study aimed to assess the associations between selenoprotein P and DSPN in people without and with type 2 diabetes (T2D). METHODS: Cross-sectional and prospective analyses were based on 1053 (including 217 with T2D) and 513 participants (including 79 with T2D), respectively, aged 61-82 years from the population-based KORA F4 survey. DSPN at baseline (KORA F4) and in the follow-up survey KORA FF4 was defined based on the Michigan Neuropathy Screening Instrument. Serum levels of full-length selenoprotein P were quantified by ELISA. Associations between selenoprotein P and prevalent or incident DSPN were estimated using logistic regression analysis adjusting for multiple confounders. RESULTS: Selenoprotein P levels were not associated with prevalent DSPN in the total sample. However, there was a significant interaction by diabetes status. Higher levels of selenoprotein P were associated with lower odds of prevalent DSPN in individuals without T2D (fully adjusted model: OR 0.825 [95 % CI 0.682, 0.998], p = 0.0476), but not in those with T2D (OR [95 % CI] 1.098 [0.829, 1.454], p = 0.5132; pinteraction = 0.0488). Selenoprotein P levels were not associated with incident DSPN over a follow-up of 6.5 years. CONCLUSION: In individuals without T2D from the older general population, lower selenoprotein P levels were associated with a higher prevalence of DSPN. Whether the antioxidant properties of selenoprotein P are responsible for the observed associations remains to be elucidated in future research.
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Diabetes Mellitus Tipo 2 , Selenoproteína P , Humanos , Selenoproteína P/sangre , Masculino , Anciano , Femenino , Persona de Mediana Edad , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/epidemiología , Estudios Transversales , Estudios Prospectivos , Anciano de 80 o más Años , Estrés Oxidativo , Factores de Riesgo , Polineuropatías/epidemiología , Polineuropatías/sangre , Neuropatías Diabéticas/epidemiología , Neuropatías Diabéticas/sangre , Neuropatías Diabéticas/etiología , PrevalenciaRESUMEN
Diabetes, commonly known for its metabolic effects, also critically affects the enteric nervous system (ENS), which is essential in regulating gastrointestinal (GI) motility, secretion, and absorption. The development of diabetes-induced enteric neuropathy can lead to various GI dysfunctions, such as gastroparesis and irregular bowel habits, primarily due to disruptions in the function of neuronal and glial cells within the ENS, as well as oxidative stress and inflammation. This editorial explores the pathophysiological mechanisms underlying the development of enteric neuropathy in diabetic patients. Additionally, it discusses the latest advances in diagnostic approaches, emphasizing the need for early detection and intervention to mitigate GI complications in diabetic individuals. The editorial also reviews current and emerging therapeutic strategies, focusing on pharmacological treatments, dietary management, and potential neuromodulatory interventions. Ultimately, this editorial highlights the necessity of a multidisciplinary approach in managing enteric neuropathy in diabetes, aiming to enhance patient quality of life and address a frequently overlooked complication of this widespread disease.
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Neuropatías Diabéticas , Sistema Nervioso Entérico , Motilidad Gastrointestinal , Humanos , Neuropatías Diabéticas/etiología , Neuropatías Diabéticas/terapia , Neuropatías Diabéticas/diagnóstico , Neuropatías Diabéticas/fisiopatología , Sistema Nervioso Entérico/fisiopatología , Enfermedades Gastrointestinales/fisiopatología , Enfermedades Gastrointestinales/terapia , Enfermedades Gastrointestinales/diagnóstico , Enfermedades Gastrointestinales/etiología , Tracto Gastrointestinal/inervación , Tracto Gastrointestinal/fisiopatología , Gastroparesia/terapia , Gastroparesia/fisiopatología , Gastroparesia/diagnóstico , Gastroparesia/etiología , Estrés Oxidativo , Calidad de VidaRESUMEN
Distal sensorimotor polyneuropathy (DSPN) is the earliest detectable and the most frequent microvascular complication in diabetes mellitus. Several studies have previously demonstrated correlations between cardiovascular risk factors in diabetic patients and independent risk factors for diabetic neuropathy. Our objective was to retrospectively analyze data from diabetic patients in the North-East region of Hungary who underwent neuropathy screening at the Diabetic Neuropathy Center, University of Debrecen, between 2017 and 2021. We aimed to investigate the correlations between cardiovascular risk factors and microvascular complications among patients with DSPN. The median age of the patients was 67 years, 59,6% were female, and 91,1% had type 2 diabetes. The prevalence of DSPN among the study subjects was 71.7%. A significantly longer duration of diabetes (p<0.01) was noted in patients with DSPN. Those with DSPN demonstrated a significantly higher HbA1c level (p<0.001) and a greater frequency of insulin use (p = 0.001). We observed a significantly elevated albumin/creatinine ratio (p<0.001) and a significantly lower eGFR (p<0.001) in patients with DSPN. Diabetic retinopathy exhibited a significantly higher prevalence in patients with DSPN (p<0.001). A higher prevalence of myocardial infarction (p<0.05), ischemic heart disease (p<0.001), peripheral arterial disease (p<0.05) and a history of atherosclerosis (p<0.05) was observed in patients with DSPN. In a multivariate logistic regression analysis, the following factors were independently associated with the presence of DSPN: higher HbA1c (OR:2.58, 95% CI:1.89-3.52, p<0.001), age (OR:1.03, 95% CI:1.01-1.05, p = 0.006), albumin/creatinine ratio above 3 mg/mmol (OR:1.23, 95% CI:1.06-1.45, p = 0.008), retinopathy (OR:6.06, 95% CI:1.33-27.53, p = 0.02), and composite cardiovascular endpoint (OR:1.95, 95% CI:1.19-3.19, p = 0.008). Our study revealed that age, elevated HbA1c levels, significant albuminuria, retinopathy, and cardiovascular complications may increase the risk of DSPN. Further investigation of these associations is necessary to understand the impact of patient characteristics during the treatment of diabetic neuropathy.
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Diabetes Mellitus Tipo 2 , Neuropatías Diabéticas , Humanos , Femenino , Masculino , Hungría/epidemiología , Anciano , Neuropatías Diabéticas/epidemiología , Neuropatías Diabéticas/etiología , Persona de Mediana Edad , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Estudios Retrospectivos , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/complicaciones , Factores de Riesgo , Prevalencia , Hemoglobina Glucada/análisis , Hemoglobina Glucada/metabolismo , Retinopatía Diabética/epidemiología , Retinopatía Diabética/complicacionesRESUMEN
Diabetic neuropathy and nephropathy are common complications of type 1 diabetes (T1D). The symptoms are often elusive in the early stages, and available diagnostic methods can be improved using biomarkers. Matrix metalloproteinase 3 (MMP-3) has been identified in the kidneys and is thought to be involved in diabetic nephropathy. Growth differentiation factor 15 (GDF-15) has been suggested to have positive effects in diabetes, but is otherwise associated with adverse effects such as cardiovascular risk, declined kidney function, and neurodegeneration. This study aims to investigate plasma MMP-3 and GDF-15 as systemic biomarkers for diabetic neuropathy and nephropathy in T1D. The study involves patients with childhood-onset T1D (n = 48, age 38 ± 4 years) and a healthy control group (n = 30, age 38 ± 5 years). Neurophysiology tests, evaluations of albuminuria, and measurements of routine biochemical markers were conducted. The neuropathy impairment assessment (NIA) scoring system, where factors such as loss of sensation and weakened reflexes are evaluated, was used to screen for symptoms of neuropathy. MMP-3 and GDF-15 concentrations were determined in heparinized plasma using ELISA kits. In total, 9 patients (19%) had albuminuria, and 25 (52%) had diabetic neuropathy. No significant differences were found in MMP-3 concentrations between the groups. GDF-15 levels were higher in T1D, with median and interquartile range (IQR) of 358 (242) pg/mL in T1D and 295 (59) in controls (p < 0.001). In the merged patient group, a positive correlation was found between MMP-3 and plasma creatinine, a negative correlation was found between MMP-3 and estimated glomerular filtration rate (eGFR; rho = -0.358, p = 0.012), and there was a positive correlation between GDF-15 and NIA (rho = 0.723, p < 0.001) and high-sensitive C-reactive protein (rho = 0.395, p = 0.005). MMP-3 was increased in macroalbuminuria and correlated positively with NIA only in the nine T1D patients with albuminuria (rho = 0.836, p = 0.005). The present study indicates that high MMP-3 is associated with low eGFR, high plasma creatinine, and macroalbuminuria, and that GDF-15 can be a biomarker for diabetic neuropathy in T1D. MMP-3 may be useful as biomarker for neuropathy in T1D with albuminuria.
Asunto(s)
Biomarcadores , Diabetes Mellitus Tipo 1 , Nefropatías Diabéticas , Neuropatías Diabéticas , Factor 15 de Diferenciación de Crecimiento , Metaloproteinasa 3 de la Matriz , Humanos , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/sangre , Factor 15 de Diferenciación de Crecimiento/sangre , Biomarcadores/sangre , Metaloproteinasa 3 de la Matriz/sangre , Masculino , Neuropatías Diabéticas/sangre , Neuropatías Diabéticas/diagnóstico , Neuropatías Diabéticas/etiología , Femenino , Nefropatías Diabéticas/sangre , Nefropatías Diabéticas/diagnóstico , Adulto , Estudios de Casos y Controles , Persona de Mediana EdadRESUMEN
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
The prevalence of overactive bladder (OAB) is known to be higher in patients with type 2 diabetes (T2DM). However, few studies have examined specific risk factors contributing to its progression among diabetes mellitus (DM) patients, so this study aimed to investigate the risk factors specific to diabetes mellitus that influence overactive bladder in the Syrian population. This cross-sectional study was conducted at four endocrinology centers in four Syrian provinces: Damascus, Aleppo, Homs, Hama, and Latakia. The study was comprised of patients who had been diagnosed with both T2DM and OAB and had visited these centers from February 2020 to January 2023. The Arabic version of the Overactive Bladder Symptom Score (OABSS) scale was used to categorize the participants based on the severity score into two groups: the mild OAB group and the moderate-severe OAB group. A logistic analysis was conducted to assess the risk factors associated with the OAB among patients with diabetes. Among the 153 patients diagnosed with both DM and OAB, significant distinctions were found between the two groups concerning the severity of overactive bladder, age, duration of diabetes, symptomatic diabetic peripheral neuropathy (DPN), and ankle reflex (P < 0.05). Furthermore, a multivariate analysis revealed that age (OR 1.48, 95% CI 0.89-2.19), duration of diabetes (OR 1.94, 95% CI 0.53-2.23), and symptomatic DPN (OR 2.74, 95% CI 1.39-4.13) independently acted as risk factors for the advancement of OAB. The severity of OAB in Syrian patients with diabetes is closely associated with the severity of DM. Factors such as age, duration of diabetes, and symptomatic DPN are independent predictors of the severity of OAB. Patients who experience symptomatic DPN are at an increased risk of developing OAB.
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Diabetes Mellitus Tipo 2 , Índice de Severidad de la Enfermedad , Vejiga Urinaria Hiperactiva , Humanos , Vejiga Urinaria Hiperactiva/epidemiología , Vejiga Urinaria Hiperactiva/etiología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Siria/epidemiología , Femenino , Masculino , Persona de Mediana Edad , Factores de Riesgo , Estudios Transversales , Anciano , Adulto , Prevalencia , Neuropatías Diabéticas/epidemiología , Neuropatías Diabéticas/etiologíaRESUMEN
PURPOSE: Few studies have investigated the association between smoking and microvascular complications in the Asian population with type 2 diabetes mellitus (T2DM). We aimed to investigate the relationship between smoking status and microvascular complications in Korean patients with T2DM. MATERIALS AND METHODS: From the Korean National Diabetes Program cohort, we included 2316 Korean male with T2DM who had baseline clinical information available, including their smoking status, and underwent diabetic complication studies. RESULTS: Compared to non-smokers, current smokers had higher odds of any-microvascular complications [adjusted odds ratio (aOR) 1.45, 95% confidence interval (CI) 1.07-1.97, p=0.016]. The odds of neuropathy were significantly higher; however, the odds of retinopathy were significantly lower in current smokers than in nonsmokers (all p<0.05). Among those who underwent repeated complication tests after 3 years, the risk of newly developed retinopathy was significantly increased in ex-smokers [aOR 3.77 (95% CI 1.61-8.87), p=0.002]. Within ex-smokers, long smoking duration and smoking cessation within the recent 5 years were associated with an increased risk of newly developed retinopathy (all p<0.05). CONCLUSION: Male smokers had higher odds of having overall diabetic microvascular complications, including neuropathy. However, the odds of having retinopathy were significantly lower among current smokers. More attention and research are needed regarding the increased risk of retinopathy development in ex-smokers who have recently stopped smoking after a long history of smoking.
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Diabetes Mellitus Tipo 2 , Retinopatía Diabética , Fumar , Humanos , Masculino , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Persona de Mediana Edad , República de Corea/epidemiología , Fumar/efectos adversos , Retinopatía Diabética/epidemiología , Retinopatía Diabética/etiología , Anciano , Angiopatías Diabéticas/epidemiología , Factores de Riesgo , Oportunidad Relativa , Neuropatías Diabéticas/epidemiología , Neuropatías Diabéticas/etiología , AdultoRESUMEN
Background: The evidence supporting a connection between elevated serum uric acid (SUA) levels and diabetic peripheral neuropathy (DPN) is controversial. The present study performed a comprehensive evaluation of this correlation by conducting a systematic review and meta-analysis of relevant research. Method: PubMed, Web of Science (WOS), Embase, and the Cochrane Library were searched for published literature from the establishment of each database to January 8, 2024. In total, 5 cohort studies and 15 cross-sectional studies were included, and 2 researchers independently screened and extracted relevant data. R 4.3.0 was used to evaluate the included literature. The present meta-analysis evaluated the relationship between SUA levels and the risk of DPN in type 2 diabetes (T2DM) by calculating the ratio of means (RoM) and 95% confidence intervals (CIs) using the method reported by JO Friedrich, and it also analyzed continuous outcome measures using standardized mean differences (SMDs) and 95% CIs to compare SUA levels between DPN and non-DPN groups. Funnel plot and Egger's test were used to assess publication bias. Sensitivity analysis was conducted by sequentially removing each study one-by-one. Results: The meta-analysis included 20 studies, with 12,952 T2DM patients with DPN and 16,246 T2DM patients without DPN. There was a significant correlation between SUA levels and the risk of developing DPN [odds ratio (OR) = 1.23; 95% CI: 1.07-1.41; p = 0.001]. Additionally, individuals with DPN had higher levels of SUA compared to those without DPN (SMD = 0.4; 95% CI: -0.11-0.91; p < 0.01). Conclusion: T2DM patients with DPN have significantly elevated SUA levels, which correlate with a heightened risk of peripheral neuropathy. Hyperuricemia (HUA) may be a risk indicator for assessing the risk of developing DPN in T2DM patients. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO, identifier CRD42024500373.
Asunto(s)
Diabetes Mellitus Tipo 2 , Neuropatías Diabéticas , Ácido Úrico , Humanos , Neuropatías Diabéticas/sangre , Neuropatías Diabéticas/etiología , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Ácido Úrico/sangre , Estudios Transversales , Factores de Riesgo , Biomarcadores/sangreRESUMEN
Background: Microvascular complications are long-term complications that affect small blood vessels, usually developed in diabetes, and are primary causes of end-stage renal disease, several painful neuropathies, and blindness. Thus, this study aimed to determine diabetic microvascular complications and factors associated with them among patients with type 2 diabetes. Methods: An institution-based cross-sectional study was conducted among 378 type 2 diabetes patients. The presence of at least one diabetic microvascular complications diagnosed by physicians and found on the record was considered to have microvascular complications. The data was collected by reviewing the medical records of T2DM patients who were on follow-up from January 1, 2012, to December 31, 2021. The collected data was entered into EpiData version 3.1 and analyzed by Stata version 14. Bivariate and multivariable logistic regression were used to identify statistically significant risk factors for diabetic microvascular complications at p-value < 0.05. Results: Patients with type 2 diabetes mellitus had a prevalence of diabetic microvascular complications of 26.5% (95% CI: 22.0%, 30.9%). Diabetic neuropathy was the highest (13.2%), followed by diabetic nephropathy (12.4%), and diabetic retinopathy (6.4%). Increasing age, poor glycemic control, hypertension comorbidity, anemia, positive proteinuria, a longer duration of type 2 diabetes mellitus, and hypercholesterolemia were significantly associated factors with diabetic microvascular complications. Conclusion: Diabetic microvascular complications were highly prevalent. Therefore, the study suggests that interventional strategies should be taken for poor glycemic control, hypertension comorbidity, anemia, positive proteinuria, and hypercholesterolemia to control the development of diabetic microvascular complications in patients with type 2 diabetes.