RESUMEN
AIMS/HYPOTHESIS: Diabetic peripheral neuropathy (DPN) is a highly prevalent cause of physical disability. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are used to treat type 2 diabetes and animal studies have shown that glucagon-like peptide-1 (GLP-1) receptors are present in the central and peripheral nervous systems. This study investigated whether GLP-1 RAs can improve nerve structure. METHODS: Nerve structure was assessed using peripheral nerve ultrasonography and measurement of tibial nerve cross-sectional area, in conjunction with validated neuropathy symptom scores and nerve conduction studies. A total of 22 consecutively recruited participants with type 2 diabetes were assessed before and 1 month after commencing GLP-1 RA therapy (semaglutide or dulaglutide). RESULTS: There was a pathological increase in nerve size before treatment in 81.8% of the cohort (n=22). At 1 month of follow-up, there was an improvement in nerve size in 86% of participants (p<0.05), with 32% returning to normal nerve morphology. A 3 month follow-up study (n=14) demonstrated further improvement in nerve size in 93% of participants, accompanied by reduced severity of neuropathy (p<0.05) and improved sural sensory nerve conduction amplitude (p<0.05). CONCLUSIONS/INTERPRETATION: This study demonstrates the efficacy of GLP-1 RAs in improving neuropathy outcomes, evidenced by improvements in mainly structural and morphological measures and supported by electrophysiological and clinical endpoints. Future studies, incorporating quantitative sensory testing and measurement of intraepidermal nerve fibre density, are needed to investigate the benefits for small fibre function and structure.
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Diabetes Mellitus Tipo 2 , Neuropatías Diabéticas , Animales , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Neuropatías Diabéticas/tratamiento farmacológico , Agonistas Receptor de Péptidos Similares al Glucagón , Estudios de Seguimiento , Péptido 1 Similar al Glucagón , Receptor del Péptido 1 Similar al Glucagón/agonistas , Hipoglucemiantes/uso terapéuticoRESUMEN
Ocular surface neuropeptides are vital molecules primarily involved in maintaining ocular surface integrity and homeostasis. They also serve as communication channels between the nervous system and the immune system, maintaining the homeostasis of the ocular surface. Tear film and ocular surface neuropeptides have a role in disease often due to abnormalities in their synthesis (either high or low production), signaling through defective receptors, or both. This creates imbalances in otherwise normal physiological processes. They have been observed to be altered in many ocular surface and systemic diseases including dry eye disease, ocular allergy, keratoconus, LASIK-induced dry eye, pterygium, neurotrophic keratitis, corneal graft rejection, microbial keratitis, headaches and diabetes. This review examines the characteristics of neuropeptides, their synthesis and their signaling through G-protein coupled receptors. The review also explores the types of neuropeptides within the tears and ocular surface, and how they change in ocular and systemic diseases.
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Síndromes de Ojo Seco , Queratitis , Neuropéptidos , Pterigion , Humanos , LágrimasRESUMEN
AIM: The effectiveness of continuous glucose monitoring (CGM) in maintaining glycaemic control in type 1 diabetes mellitus and type 2 diabetes mellitus has been well demonstrated. However, the degree of glycaemic variability (GV) in people with type 3c diabetes mellitus has not been fully explored using CGM. This study aims to evaluate GV in type 3c diabetes mellitus participants and compare it to type 1 diabetes mellitus and type 2 diabetes mellitus. METHODS: Participants were grouped according to type of diabetes. GV, defined as percentage coefficient of variation (%CV), and other glycaemic indices were obtained using CGM (FreeStyle Libre, Abbott, Australia) from 82 participants across all three cohorts over a 14-day period. Comparison of baseline characteristics and GV were performed across all groups. Correlation of GV with C-peptide values, and whether pancreatic supplementation had an effect on GV were also assessed in the type 3c diabetes mellitus cohort. RESULTS: GV of type 3c diabetes mellitus participants was within the recommended target of less than %CV 36% (p = 0.004). Type 3c diabetes mellitus participants had the lowest GV among the three groups (p = 0.001). There was a trend for lower C-peptide levels to be associated with higher GV in type 3c diabetes mellitus participants (p = 0.22). Pancreatic enzyme supplementation in type 3c diabetes mellitus participants did not have an effect on GV (p = 0.664). CONCLUSIONS: Although type 3c diabetes mellitus participants were the least variable, they had the highest mean glucose levels and estimated HbA1c , which suggests that the concept of 'brittle' diabetes in type 3c diabetes mellitus is not supported by the results of CGM in this study and may be leading to poorer glycaemic control.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Hiperglucemia , Glucemia , Automonitorización de la Glucosa Sanguínea/métodos , Péptido C , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucosa , Hemoglobina Glucada/análisis , Humanos , Hiperglucemia/complicacionesRESUMEN
INTRODUCTION/AIMS: Sonographic alterations of peripheral nerves in pre-dialytic kidney disease are yet to be determined. We aimed to assess peripheral nerve cross-sectional area (CSA) and intraneural blood flow in patients with pre-dialytic chronic kidney disease (CKD) and diabetic kidney disease (DKD). METHODS: Subjects with CKD (n = 20) or DKD (n = 20) underwent ultrasound to assess CSA of the median and tibial nerves as well as intraneural blood flow of the median nerve. Blood flow was quantified using maximum perfusion intensity. Neuropathy was assessed using the Total Neuropathy Score. A 6-m timed walk test was also performed. Healthy controls (n = 28) were recruited for comparison. RESULTS: The DKD group had more severe neuropathy (p = .024), larger tibial nerve CSA (p = .002) and greater median nerve blood flow than the CKD group (p = .023). Blood flow correlated with serum potassium in disease groups (r = 0.652, p = .022). Disease groups had larger tibial nerve CSA than controls (p < .05). No blood flow was detected in controls. Tibial nerve enlargement was associated with slower maximal walking speeds in disease groups (r = -0.389, p = .021). DISCUSSION: Subjects with DKD demonstrated enlarged tibial nerve CSA and increased median nerve blood flow compared to those with CKD. Elevations in serum potassium were associated with increased blood flow. Sonographic alterations were detectable in pre-dialytic kidney disease compared to controls, highlighting the utility of ultrasound in the assessment of nerve pathology in these patient groups.
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Diabetes Mellitus , Insuficiencia Renal Crónica , Femenino , Humanos , Masculino , Nervios Periféricos/diagnóstico por imagen , Potasio , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/diagnóstico por imagen , Nervio Tibial/diagnóstico por imagen , UltrasonografíaRESUMEN
BACKGROUND AND PURPOSE: Nerve conduction studies (NCS) are the current objective measure for diagnosis of peripheral neuropathy in type 2 diabetes but do not assess nerve structure. This study investigated the utility of peripheral nerve ultrasound as a marker of the presence and severity of peripheral neuropathy in type 2 diabetes. METHODS: A total of 156 patients were recruited, and nerve ultrasound was undertaken on distal tibial and distal median nerves. Neuropathy severity was graded using the modified Toronto Clinical Neuropathy Scale (mTCNS) and Total Neuropathy Score (TNS). Studies were undertaken by a single ultrasonographer blinded to nerve conduction results. RESULTS: A stepwise increase in tibial nerve cross-sectional area (CSA) was noted with increasing TNS grade (p < 0.001) and each mTCNS quartile (p < 0.001). Regression analysis demonstrated a correlation between tibial nerve CSA and neuropathy severity (p < 0.001). Using receiver operator curve analysis, tibial nerve CSA of >12.88 mm yielded a sensitivity of 70.5% and specificity of 85.7% for neuropathy detection. Binary logistic regression revealed that tibial nerve CSA was a predictor of abnormal sural sensory nerve action potential amplitude (odds ratio = 1.239, 95% confidence interval [CI] = 1.142-1.345) and abnormal neuropathy score (odds ratio = 1.537, 95% confidence interval [CI] = 1.286-1.838). CONCLUSIONS: Tibial nerve ultrasound has good specificity and sensitivity for neuropathy diagnosis in type 2 diabetes. The study demonstrates that tibial nerve CSA correlates with neuropathy severity. Future serial studies using both ultrasound and NCS may be useful in determining whether changes in ultrasound occur prior to development of nerve conduction abnormalities and neuropathic symptoms.
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Diabetes Mellitus Tipo 2 , Neuropatías Diabéticas , Humanos , Neuropatías Diabéticas/diagnóstico , Conducción Nerviosa/fisiología , Nervios Periféricos/diagnóstico por imagen , Nervio Tibial , UltrasonografíaRESUMEN
SIGNIFICANCE: There is a reduction in corneal nerve fiber density and length in type 2 diabetes mellitus with chronic kidney disease compared with type 2 diabetes mellitus alone; however, this difference does not result in worse ocular surface discomfort or dry eye disease. PURPOSE: This study aimed to determine the clinical impact of corneal nerve loss on ocular surface discomfort and markers of ocular surface homeostasis in people with type 2 diabetes mellitus without chronic kidney disease (T2DM-no CKD) and those with type 2 diabetes mellitus with concurrent chronic kidney disease (T2DM-CKD). METHODS: Participants were classified based on estimated glomerular filtration rates into two groups: T2DM-CKD (n = 27) and T2DM-no CKD (n = 28). RESULTS: There was a significant difference between the T2DM-CKD and T2DM-no CKD groups in corneal nerve fiber density (14.9 ± 8.6 and 21.1 ± 7.1 no./mm 2 , respectively; P = .005) and corneal nerve fiber length (10.0 ± 4.6 and 12.3 ± 3.7 mm/mm 2 , respectively; P = .04). Fluorescein tear breakup time was significantly reduced in T2DM-CKD compared with T2DM-no CKD (8.1 ± 4.4 and 10.7 ± 3.8 seconds, respectively; P = .01), whereas ocular surface staining was not significantly different (3.5 ± 1.7 and 2.7 ± 2.3 scores, respectively; P = .12). In terms of ocular surface discomfort, there were no significant differences in the ocular discomfort score scores (12.5 ± 11.1 and 13.6 ± 12.1, respectively; P = .81) and Ocular Pain Assessment Survey scores (3.3 ± 5.4 and 4.3 ± 6.1, respectively; P = .37) between the T2DM-CKD and T2DM-no CKD. CONCLUSIONS: The current study demonstrated that corneal nerve loss is greater in T2DM-CKD than in T2DM-no CKD. However, these changes do not impact ocular surface discomfort or markers of ocular surface homeostasis.
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Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Insuficiencia Renal Crónica , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Córnea , Insuficiencia Renal Crónica/complicaciones , Fibras NerviosasRESUMEN
BACKGROUND AND PURPOSE: There is a strong association between the metabolic syndrome in diabetes and the development of peripheral neuropathy; however, the pathophysiological mechanisms remain unknown. METHODS: Participants with type 2 diabetes and metabolic syndrome (T2DM/MetS, n = 89) and type 2 diabetes alone (T2DM; n = 59) underwent median nerve ultrasound and excitability studies to assess peripheral nerve structure and function. A subset of T2DM/MetS (n = 24) and T2DM (n = 22) participants underwent confocal microscopy to assess central and inferior whorl corneal nerve structure. Neuropathy severity was assessed using the modified Toronto Clinical Neuropathy Score (mTCNS). Diabetes groups were similar for age, sex distribution, diabetes duration, hemoglobin A1c , insulin treatment, and renal function. Sixty healthy controls similar for age and sex distribution were recruited for comparison. RESULTS: Participants with T2DM/MetS manifested with a greater mTCNS compared to T2DM (p < 0.05). Median nerve cross-sectional area was larger in the T2DM/MetS group compared to the T2DM cohort (p < 0.05). Participants with T2DM/MetS had reductions in central (all p < 0.01) and inferior whorl (all p < 0.05) nerve measures. Compared to T2DM, the T2DM/MetS group demonstrated more severe changes in nerve excitability measures, which was due to reduced sodium channel permeability and sodium-potassium pump function. In comparison, only sodium channel permeability was reduced in the T2DM group. CONCLUSIONS: Compared to participants with type 2 diabetes alone, those with diabetes and metabolic syndrome manifested greater alterations in peripheral nerve structure and function, which may be due to reduced function of the sodium-potassium pump.
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Diabetes Mellitus Tipo 2 , Síndrome Metabólico , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/complicaciones , Hemoglobina Glucada , Humanos , Síndrome Metabólico/complicaciones , Nervios PeriféricosRESUMEN
AIM: The present study was undertaken to investigate mechanisms of peripheral nerve dysfunction in latent autoimmune diabetes in adults (LADA). MATERIALS AND METHODS: Participants with LADA (n = 15) underwent median nerve ultrasonography and nerve excitability to examine axonal structure and function, in comparison to cohorts of type 1 diabetes (n = 15), type 2 diabetes (n = 23) and healthy controls (n = 26). The LADA group was matched for diabetes duration, glycaemic control, and neuropathy severity with the type 1 and type 2 diabetes groups. A validated mathematical model of the human axon was utilized to investigate the pathophysiological basis of nerve dysfunction. RESULTS: The most severe changes in nerve structure and function were noted in the LADA group. The LADA cohort demonstrated a significant increase in nerve cross-sectional area compared to type 1 participants and controls. Compared to type 1 and 2 diabetes, measures of threshold electrotonus, which assesses nodal and internodal conductances, were significantly worse in LADA in response to both depolarising currents and hyperpolarising currents. In the recovery cycle, participants with LADA had a significant increase in the relative refractory period. Mathematical modelling of excitability recordings indicated the basis of nerve dysfunction in LADA was different to type 1 and 2 diabetes. CONCLUSIONS: Participants with LADA exhibited more severe changes in nerve function and different underlying pathophysiological mechanisms compared to participants with type 1 or 2 diabetes. Intensive management of risk factors to delay the progression of neuropathy in LADA may be required.
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Neuropatías Diabéticas/fisiopatología , Diabetes Autoinmune Latente del Adulto/fisiopatología , Nervio Mediano/fisiopatología , Conducción Nerviosa/fisiología , Adulto , Anciano , Estudios de Casos y Controles , Diabetes Mellitus Tipo 1/diagnóstico por imagen , Diabetes Mellitus Tipo 1/fisiopatología , Neuropatías Diabéticas/diagnóstico por imagen , Progresión de la Enfermedad , Femenino , Humanos , Diabetes Autoinmune Latente del Adulto/diagnóstico por imagen , Masculino , Nervio Mediano/diagnóstico por imagen , Persona de Mediana Edad , Factores de Riesgo , UltrasonografíaRESUMEN
OBJECTIVE: To determine whether routine blood glucose assessment of patients admitted to hospital from emergency departments (EDs) results in higher rates of new diagnoses of diabetes and documentation of follow-up plans. DESIGN, SETTING: Cluster randomised trial in 18 New South Wales public district and tertiary hospitals, 31 May 2011 - 31 December 2012; outcomes follow-up to 31 March 2016. PARTICIPANTS: Patients aged 18 years or more admitted to hospital from EDs. INTERVENTION: Routine blood glucose assessment at control and intervention hospitals; automatic requests for glycated haemoglobin (HbA1c ) assessment and notification of diabetes services about patients at intervention hospitals with blood glucose levels of 14 mmol/L or more. MAIN OUTCOME MEASURE: New diagnoses of diabetes and documented follow-up plans for patients with admission blood glucose levels of 14 mmol/L or more. RESULTS: Blood glucose was measured in 133 837 patients admitted to hospital from an ED. The numbers of new diabetes diagnoses with documented follow-up plans for patients with blood glucose levels of 14 mmol/L or more were similar in intervention (83/506 patients, 16%) and control hospitals (73/278, 26%; adjusted odds ratio [aOR], 0.83; 95% CI 0.42-1.7; P = 0.61), as were new diabetes diagnoses with or without plans (intervention, 157/506, 31%; control, 86/278, 31%; aOR, 1.51; 95% CI, 0.83-2.80; P = 0.18). 30-day re-admission (31% v 22%; aOR, 1.34; 95% CI, 0.86-2.09; P = 0.21) and post-hospital mortality rates (24% v 22%; aOR, 1.07; 95% CI, 0.74-1.55; P = 0.72) were also similar for patients in intervention and control hospitals. CONCLUSION: Glucose and HbA1c screening of patients admitted to hospital from EDs does not alone increase detection of previously unidentified diabetes. Adequate resourcing and effective management pathways for patients with newly detected hyperglycaemia and diabetes are needed. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12611001007921.
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Glucemia/análisis , Diabetes Mellitus/diagnóstico , Pruebas Diagnósticas de Rutina/estadística & datos numéricos , Servicios Médicos de Urgencia/métodos , Adulto , Anciano , Anciano de 80 o más Años , Diabetes Mellitus/epidemiología , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Hiperglucemia/diagnóstico , Hiperglucemia/epidemiología , Masculino , Persona de Mediana Edad , Nueva Gales del SurRESUMEN
BACKGROUND: Clinical and experimental studies in patients with type 1 and type 2 diabetes have demonstrated changes in ion channel function and nerve structure. In this study, we investigated the relationship between axonal dysfunction and morphological change in diabetic polyneuropathy by using neuromuscular ultrasound and nerve excitability techniques. We also explored possible differences in this relationship between type 1 and type 2 diabetes. METHODS: Nerve ultrasound and corresponding motor excitability studies were undertaken in 110 diabetes patients (50 type 1; 60 type 2) and 60 age-matched controls (30 for each group). Neuropathy severity was assessed by using total neuropathy score. Median and tibial nerve cross-sectional areas were measured at nonentrapment sites by using high-resolution linear probe. RESULTS: Median and tibial nerve cross-sectional areas were significantly higher in diabetes patients compared with controls: type 1 (median = 7.6 ± 0.2 mm2 vs 6.3 ± 0.1 mm2 ; tibial = 14.5 ± 0.7 mm2 vs 10.8 ± 0.3 mm2 , P < .05) and type 2 (median = 9.1 ± 0.3 mm2 vs 7.2 ± 0.1 mm2 ; tibial = 18.5 ± 1.0 mm2 vs 12.8 ± 0.5 mm2 , P < .05). In the type 1 cohort, significant correlations were found between nerve cross-sectional area and excitability parameters including resting current-threshold slope (median: r = 0.523, P < .0001; tibial: r = -0.571, P = .004) and depolarizing threshold electrotonus at 90 to 100 ms (median: 0.424, P < .01; tibial: r = 0.435, P = .030). In contrast, there was no relationship between excitability values and nerve cross-sectional area in the type 2 cohort. CONCLUSIONS: This study has identified correlation between markers of axonal membrane function and structural abnormalities in peripheral nerves of type 1 diabetes patients. The differential relationship in nerve function and structure between type 1 and type 2 diabetes provides clinical evidence that different pathophysiological mechanisms underlie the development of neuropathy in these patient groups.
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Biomarcadores , Diabetes Mellitus Tipo 1/patología , Diabetes Mellitus Tipo 1/fisiopatología , Conducción Nerviosa/fisiología , Nervios Periféricos/patología , Nervios Periféricos/fisiología , Adulto , Axones/patología , Axones/fisiología , Biomarcadores/análisis , Estudios de Casos y Controles , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/patología , Diabetes Mellitus Tipo 2/fisiopatología , Neuropatías Diabéticas/diagnóstico , Neuropatías Diabéticas/patología , Neuropatías Diabéticas/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nervios Periféricos/diagnóstico por imagen , UltrasonografíaRESUMEN
INTRODUCTION: Glycemic variability (GV) may be a novel factor in the pathogenesis of diabetic complications. However, the effect of GV on peripheral nerve function has not been explored systematically. METHODS: The relationship between GV and acute glucose levels on motor and sensory nerve function in 17 patients with type 1 diabetes mellitus (T1DM) was assessed using continuous glucose monitoring and nerve excitability techniques to provide insight into the behavior of axonal voltage-gated ion channels. The mean amplitude of glycemic excursions (MAGE) was calculated to quantify GV. RESULTS: MAGE strongly correlated with excitability markers of altered motor and sensory axonal function, including superexcitability (r = 0.54), S2 accommodation (r = -0.76), minimum current threshold (I/V) slope (r = 0.71), strength duration time constant (r = 0.66), and latency (r = 0.65; P < 0.05). Acute glucose levels did not correlate with markers of axonal function. CONCLUSIONS: These findings suggest that GV may be an important mediator of axonal dysfunction in T1DM and a contributing factor in development of diabetic neuropathy. Muscle Nerve, 2016 Muscle Nerve 54: 967-969, 2016.
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Glucemia/metabolismo , Diabetes Mellitus Tipo 1/complicaciones , Índice Glucémico/fisiología , Enfermedades del Sistema Nervioso Periférico/etiología , Adulto , Femenino , Humanos , Masculino , Valor Predictivo de las PruebasRESUMEN
BACKGROUND: Diabetic peripheral neuropathy is a common and debilitating complication of diabetes mellitus. Although strict glycaemic control may reduce the risk of developing diabetic peripheral neuropathy, the neurological benefits of different insulin regimens remain relatively unknown. METHODS: In the present study, 55 consecutive patients with type 1 diabetes mellitus underwent clinical neurological assessment. Subsequently, 41 non-neuropathic patients, 24 of whom were receiving multiple daily insulin injections (MDII) and 17 receiving continuous subcutaneous insulin infusion (CSII), underwent nerve excitability testing, a technique that assesses axonal ion channel function and membrane potential in human nerves. Treatment groups were matched for glycaemic control, body mass index, disease duration and gender. Neurophysiological parameters were compared between treatment groups and those taken from age and sex-matched normal controls. RESULTS: Prominent differences in axonal function were noted between MDII-treated and CSII-treated patients. Specifically, MDII patients manifested prominent abnormalities when compared with normal controls in threshold electrotonus (TE) parameters including depolarizing TE(10-20ms), undershoot and hyperpolarizing TE (90-100 ms) (P < 0.05). Additionally, recovery cycle parameters superexcitability and subexcitability were also abnormal (P < 0.05). In contrast, axonal function in CSII-treated patients was within normal limits when compared with age-matched controls. The differences between the groups were noted in cross-sectional analysis and remained at longitudinal follow-up. CONCLUSIONS: Axonal function in type 1 diabetes is maintained within normal limits in patients treated with continuous subcutaneous insulin infusion and not with multiple daily insulin injections. This raises the possibility that CSII therapy may have neuroprotective potential in patients with type 1 diabetes.
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Axones/efectos de los fármacos , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Neuropatías Diabéticas/prevención & control , Hipoglucemiantes/administración & dosificación , Sistemas de Infusión de Insulina , Insulina/administración & dosificación , Fármacos Neuroprotectores/administración & dosificación , Adulto , Axones/metabolismo , Estudios de Cohortes , Estudios Transversales , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/fisiopatología , Femenino , Humanos , Hipoglucemiantes/uso terapéutico , Infusiones Subcutáneas , Insulina/uso terapéutico , Insulina Regular Humana/administración & dosificación , Estudios Longitudinales , Masculino , Examen Neurológico , Fármacos Neuroprotectores/uso terapéutico , Nueva Gales del Sur , Sistema Nervioso Periférico/efectos de los fármacos , Sistema Nervioso Periférico/fisiopatologíaRESUMEN
OBJECTIVE: Diabetic peripheral neuropathy (DPN) is a frequent complication for persons with type 2 diabetes. Previous studies have failed to demonstrate any significant impact of treatment for DPN. The present study assessed the role of axonal ion channel dysfunction in DPN and explored the hypothesis that there may be a progressive change in ion channel abnormalities that varied with disease stage. METHODS: Neurophysiological studies were conducted using axonal excitability techniques, a clinical method of assessing ion channel dysfunction. Studies were conducted in 178 persons with type 2 diabetes, with participants allocated into four groups according to clinical severity of neuropathy, assessed using the Total Neuropathy Grade. RESULTS: Analysis of excitability data demonstrated a progressive and stepwise reduction in two parameters that are related to the activity of Kv1.1 channels, namely superexcitability and depolarizing threshold electrotonus at 10-20 ms (p < 0.001), and mathematical modelling of axonal excitability findings supported progressive upregulation of Kv1.1 conductances with increasing greater disease severity. CONCLUSION: The findings are consistent with a progressive upregulation of juxtaparanodal Kv1.1 conductances with increasing clinical severity of diabetic peripheral neuropathy. SIGNIFICANCE: From a translational perspective, the study suggests that blockade of Kv1.1 channels using 4-aminopyridine derivatives such as fampridine may be a potential treatment for DPN.
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Diabetes Mellitus Tipo 2 , Neuropatías Diabéticas , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Axones/fisiología , 4-Aminopiridina , Canales IónicosRESUMEN
PURPOSE: This study aims to determine the effects of SGLT2 inhibitors on corneal dendritic cell density and corneal nerve measures in type 2 diabetes. METHODS: Corneal dendritic cell densities and nerve parameters were measured in people with type 2 diabetes treated with SGLT2 inhibitors (T2DM-SGLT2i) [n = 23] and those not treated with SGLT2 inhibitors (T2DM-no SGLT2i) [n = 23], along with 24 age and sex-matched healthy controls. RESULTS: There was a reduction in all corneal nerve parameters in type 2 diabetes groups compared to healthy controls (All parameters: p < 0.05). No significant differences in corneal nerve parameters were observed between T2DM-SGLT2i and T2DM-no SGLT2i groups (All parameters: p > 0.05). Central corneal dendritic cells were significantly reduced [mature (p = 0.03), immature (p = 0.06) and total (p = 0.002)] in the T2DM-SGLT2i group compared to the T2DM-no SGLT2i group. Significantly, higher mature (p = 0.04), immature (p = 0.004), total (p = 0.002) dendritic cell densities in the T2DM-no SGLT2i group were observed compared to the healthy controls. In the inferior whorl, no significant difference in immature (p = 0.27) and total dendritic cell densities (p = 0.16) between T2DM-SGLT2i and T2DM-no SGLT2i were observed except mature dendritic cell density (p = 0.018). No differences in total dendritic cell density were observed in the central (p > 0.09) and inferior whorl (p = 0.88) between T2DM-SGLT2i and healthy controls. CONCLUSION: The present study showed a reduced dendritic cell density in people with type 2 diabetes taking SGLT2 inhibitors compared to those not taking these medications.
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Diabetes Mellitus Tipo 2 , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Córnea , Recuento de Células , Células DendríticasRESUMEN
Diabetic peripheral neuropathy (DPN) affects around 50% of the 500 million people with type 2 diabetes worldwide and is considered disabling and irreversible. The present study was undertaken to assess the effect of metformin on peripheral neuropathy outcomes in type 2 diabetes. 69 type 2 diabetes participants receiving metformin were recruited and underwent clinical assessment, peripheral nerve ultrasound, nerve conduction studies and axonal excitability studies. 318 participants who were not on metformin were also concurrently screened, and 69 were selected as disease controls and matched to the metformin participants for age, sex, diabetes duration, BMI, HbA1c and use of other diabetes therapies. Medical record data over the previous 20 years were analysed for previous metformin use. Mean tibial nerve cross-sectional area (CSA) was lower in the metformin group (metformin 14.1 ∓ 0.7 mm2, non-metformin 16.2 ∓ 0.9mm2, p=0.038), accompanied by reduction in neuropathy symptom severity (p=0.021). Axonal excitability studies demonstrated superior axonal function in the metformin group and mathematical modelling demonstrated that these improvements were mediated by changes in nodal Na+ and K+ conductances. Metformin treatment is associated with superior nerve structure, clinical and neurophysiological measures. Treatment with metformin may be neuroprotective in DPN.
RESUMEN
BACKGROUND: The present study was undertaken to determine whether there were changes evident in axonal membrane function prior to the onset of neuropathy in patients with type 1 and type 2 diabetes. METHODS: From a cohort of 110 consecutive referrals, nerve excitability was investigated in 40 diabetic patients without clinical evidence of neuropathy (20 type 1 diabetic patients and 20 type 2 diabetic patients). Groups were matched for gender, disease duration and HbA(1c). Studies were also undertaken in two control groups, younger controls and older controls, matched for age and gender with the diabetic cohorts. RESULTS: Subjects with type 1 diabetes demonstrated significant nerve excitability abnormalities when compared with younger normal controls. Specifically, type 1 subjects showed a significant reduction at multiple time points in both depolarising and hyperpolarising threshold electrotonus. Additionally, the relative refractory period was prolonged (type 1, 3.19 ms; younger normal controls, 3.0 ms; p < 0.05) and superexcitability was reduced (type 1, -23.12%; younger normal controls, -26.37%; p < 0.05), consistent with axonal membrane depolarisation. Correlations were identified in type 1 patients between disease duration and nerve excitability parameters, including the relative refractory period (r = -0.533, p < 0.05). In contrast, only minor non-specific changes were noted in the type 2 group. DISCUSSION: This study provides clear evidence of altered axonal function in patients with type 1 diabetes in the absence of clinical neuropathy. These findings suggest that altered axonal membrane potential may precede neuropathy onset in type 1 diabetes and as such may indicate a window of opportunity to intervene and potentially reverse axonal membrane dysfunction before the development of irreversible neuropathy.
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Axones/fisiología , Diabetes Mellitus Tipo 1/fisiopatología , Neuropatías Diabéticas/fisiopatología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Potenciales de Acción/fisiología , Adulto , Anciano , Diabetes Mellitus Tipo 2/fisiopatología , Estimulación Eléctrica , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The conjunctival microcirculation is an accessible complex network of micro vessels whose quantitative assessment can reveal microvascular haemodynamic properties. Currently, algorithms for the measurement of conjunctival haemodynamics use either manual or semi-automated systems, which may provide insight into overall conjunctival health, as well as in ocular and systemic disease. These algorithms include functional slit-lamp biomicroscopy, laser doppler flowmetry, optical coherence tomography angiography, orthogonal polarized spectral imaging, computer-assisted intravitral microscopy, diffuse reflectance spectroscopy and corneal confocal microscopy. Furthermore, several studies have demonstrated a relationship between conjunctival microcirculatory haemodynamics and many diseases such as dry eye disease, Alzheimer's disease, diabetes, hypertension, sepsis, coronary microvascular disease, and sickle cell anaemia. This review aims to describe conjunctival microcirculation, its characteristics, and techniques for its measurement, as well as the association between conjunctival microcirculation and microvascular abnormalities in disease states.
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Conjuntiva , Hemodinámica , Humanos , Velocidad del Flujo Sanguíneo , Microcirculación , Conjuntiva/irrigación sanguínea , Microscopía con Lámpara de HendiduraRESUMEN
PURPOSE: The study aimed to ascertain the potential effects of chronic kidney disease (CKD) on substance P concentration in the tear film of people with type 2 diabetes. METHODS: Participants were classified into two groups: type 2 diabetes with concurrent chronic kidney disease (T2DM-CKD (n = 25)) and type 2 diabetes without chronic kidney disease (T2DM-no CKD (n = 25)). Ocular surface discomfort assessment, flush tear collection, in-vivo corneal confocal microscopy, and peripheral neuropathy assessment were conducted. Enzyme-linked immunosorbent assays were utilized to ascertain the levels of tear film substance P in collected flush tears. Correlation analysis, hierarchical multiple linear regression analysis, and t-tests or Mann-Whitney U tests were used in the analysis of data for two-group comparisons. RESULTS: There was no substantial difference between the T2DM-CKD and T2DM-no CKD groups for tear film substance P concentration (4.4 (0.2-50.4) and 5.9 (0.2-47.2) ng/mL, respectively; p = 0.54). No difference was observed in tear film substance P concentration between the low-severity peripheral neuropathy and high-severity peripheral neuropathy groups (4.4 (0.2-50.4) and 3.3 (0.3-40.7) ng/mL, respectively; p = 0.80). Corneal nerve fiber length (9.8 ± 4.6 and 12.4 ± 3.8 mm/mm2, respectively; p = 0.04) and corneal nerve fiber density (14.7 ± 8.5 and 21.1 ± 7.0 no/mm2, respectively; p < 0.01) were reduced significantly in the T2DM-CKD group compared to the T2DM-no CKD group. There were significant differences in corneal nerve fiber density (21.0 ± 8.1 and 15.8 ± 7.7 no/mm2, respectively; p = 0.04) and corneal nerve fiber length (12.9 ± 4.2 and 9.7 ± 3.8 mm/mm2, respectively; p = 0.03) between the low- and high-severity peripheral neuropathy groups. CONCLUSION: In conclusion, no significant difference in tear film substance P concentration was observed between type 2 diabetes with and without CKD. Corneal nerve loss, however, was more significant in type 2 diabetes with chronic kidney disease compared to type 2 diabetes alone, indicating that corneal nerve morphological measures could serve greater utility as a tool to detect neuropathy and nephropathy-related corneal nerve changes.
RESUMEN
BACKGROUND: Continuous glucose monitors (CGM) can provide detailed information on glucose excursions. There is little information on safe transitioning from hospital back to the community for patients who have had diabetes therapies adjusted in hospital and it is unclear whether newer technologies may facilitate this process. OBJECTIVE: Our aim was to determine whether offering CGM on discharge would be acceptable and if CGM initiated on hospital discharge in people with type 2 diabetes (T2DM) would reduce hospital re-presentations at 1 month. METHODS: This was an open-label study. Adult inpatients with T2DM, who were to be discharged home and required postdischarge glycemic stabilization, were offered usual care consisting of clinic review at 2 weeks and at 3 months. In addition to usual care, participants in the intervention arm were provided with a Libre flash glucose monitoring system (Abbott Australia). An initial run-in phase for the first 20 participants was planned, where all consenting participants were enrolled in an active arm. Subsequently, all participants were to be randomized to the active arm or usual care control group. RESULTS: Of 237 patients screened during their hospital admission, 34 had comorbidities affecting cognition that prevented informed consent and affected their ability to learn to use the CGM device. In addition, 21 were not able to be approached as the material was only in English. Of 101 potential participants who fulfilled eligibility criteria, 19 provided consent and were enrolled. Of the 82 patients who declined to participate, 31 advised that the learning of a new task toward discharge was overwhelming or too stressful and 26 were not interested, with no other details. Due to poor recruitment, the study was terminated without entering the randomization phase to determine whether CGM could reduce readmission rate. CONCLUSIONS: These results suggest successful and equitable implementation of telemedicine programs requires that any human factors such as language, cognition, and possible disengagement be addressed. Recovery from acute illness may not be the ideal time for introduction of newer technologies or may require more novel implementation frameworks.
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Aim: To determine the impact of chronic kidney disease on corneal nerve measures and dendritic cell counts in type 2 diabetes. Methods: In vivo corneal confocal microscopy images were used to estimate corneal nerve parameters and compared in people with type 2 diabetes with chronic kidney disease (T2DM-CKD) (n = 29) and those with type 2 diabetes without chronic kidney disease (T2DM-no CKD) (n = 29), along with 30 healthy controls. Corneal dendritic cell densities were compared between people with T2DM-CKD and those with T2DM-no CKD. The groups were matched for neuropathy status. Results: There was a significant difference in corneal nerve fiber density (p < 0.01) and corneal nerve fiber length (p = 0.04) between T2DM-CKD and T2DM-no CKD groups. The two diabetes groups had reduced corneal nerve parameters compared to healthy controls (all parameters: p < 0.01). Immature central dendritic cell density was significantly higher in the T2DM-CKD group compared to the T2DM-no CKD group ((7.0 (3.8−12.8) and 3.5 (1.4−13.4) cells/mm2, respectively, p < 0.05). Likewise, central mature dendritic cell density was significantly higher in the T2DM-CKD group compared to the T2DM-no CKD group (0.8 (0.4−2.2) and 0.4 (0.6−1.1) cells/mm2, respectively, p = 0.02). Additionally, total central dendritic cell density was increased in the T2DM-CKD group compared to T2DM-no CKD group (10.4 (4.3−16.1) and 3.9 (2.1−21.0) cells/mm2, respectively, p = 0.03). Conclusion: The study showed that central corneal dendritic cell density is increased in T2DM-CKD compared to T2DM-no CKD, with groups matched for peripheral neuropathy severity. This is accompanied by a loss of central corneal nerve fibers. The findings raise the possibility of additional local factors exacerbating central corneal nerve injury in people with diabetic chronic kidney disease.