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INTRODUCTION: Patients with type 1 diabetes have high risk of developing microvascular complications, and microangiopathy contributes to premature cardiovascular disease in this population. The role that microvesicles (MVs) may play in the development of microangiopathy in type 1 diabetes remains unclear. MATERIALS AND METHODS: Plasma levels of endothelial MVs (EMVs) and platelet MVs (PMVs) in 130 patients with type 1 diabetes without microangiopathy, 106 patients with microangiopathy and 100 matched healthy controls were analyzed using flow cytometry. MV expression of procoagulant phosphatidylserine (PS) and proinflammatory high mobility group box-1 protein (HMGB1) was also assessed. RESULTS: Patients with type 1 diabetes had markedly elevated levels of EMVs and PS+ EMVs as well as PMVs and PS+ PMVs compared to healthy controls (p < .001 for all). Furthermore, HMGB1+ EMVs and HMGB1+ PMVs were significantly increased in patients (p < .001 for all). After adjusting for potential confounders, there were no clear differences between patients with or without microvascular complications for any of the MV parameters. CONCLUSION: Type 1 diabetes is a prothrombotic and proinflammatory disease state that, regardless of the presence of clinical microangiopathy, is associated with elevated levels of plasma MVs, in particular those of an endothelial origin. We have for the first time demonstrated that patients with type 1 diabetes have higher levels of HMGB1+ MVs. HMGB1 is an alarmin with potent proinflammatory effects that drive endothelial dysfunction, and it would therefore be of interest to further study the role of HMGB1+ MVs in the development of macrovascular complications in type 1 diabetes.
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Micropartículas Derivadas de Células , Diabetes Mellitus Tipo 1 , Proteína HMGB1 , Plaquetas , Diabetes Mellitus Tipo 1/complicaciones , Humanos , FosfatidilserinasRESUMEN
AIM: The aim of this study was to investigate the correlation between skin microvascular reactivity and clinical microangiopathy in patients with type 1 diabetes. METHODS: We included 61 patients with type 1 diabetes, that is, 31 patients with and 30 without clinical microangiopathy, and 31 healthy controls. A microangiopathy scoring system was introduced for comparison of data between patients with microangiopathy. Responses to iontophoresis of acetylcholine and sodium nitroprusside were assessed by laser Doppler imaging. RESULTS: Patients with microangiopathy had reduced acetylcholine- and sodium nitroprusside-mediated flux in forearm skin microcirculation compared to healthy controls (p = 0.03 and p < 0.001, respectively, repeated measures analysis of variance), whereas no significant differences were found between patients without microangiopathy and controls. Skin reactivity was reduced in patients with microangiopathy compared to patients without microangiopathy: 1.43 ± 0.38 versus 1.59 ± 0.39 arbitrary units for acetylcholine-mediated peak flux and 1.44 ± 0.46 versus 1.74 ± 0.34 arbitrary units for sodium nitroprusside-mediated peak flux (p < 0.05 for both). A tendency of gradual decrease in acetylcholine and sodium nitroprusside responses was found in patients with increasing microangiopathy scores. CONCLUSION: We conclude that skin microvascular reactivity is associated with clinical microangiopathy in patients with type 1 diabetes. Impaired skin microvascular function in type 1 diabetes seems to be multifactorial and involves both endothelial-dependent and endothelial-independent pathways. We introduce a novel microangiopathy score that could easily be used in a clinical setting for comparison of patients with various degrees of microangiopathy.
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Diabetes Mellitus Tipo 1/complicaciones , Angiopatías Diabéticas/etiología , Microcirculación , Piel/irrigación sanguínea , Vasodilatación , Administración Cutánea , Adulto , Anciano , Velocidad del Flujo Sanguíneo , Estudios de Casos y Controles , Estudios Transversales , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/fisiopatología , Angiopatías Diabéticas/diagnóstico , Angiopatías Diabéticas/fisiopatología , Femenino , Antebrazo , Humanos , Iontoforesis , Flujometría por Láser-Doppler , Masculino , Microcirculación/efectos de los fármacos , Angioscopía Microscópica , Persona de Mediana Edad , Proyectos Piloto , Valor Predictivo de las Pruebas , Factores de Riesgo , Vasodilatación/efectos de los fármacos , Vasodilatadores/administración & dosificaciónRESUMEN
INTRODUCTION: Type 1 diabetes is a prothrombotic state strongly linked to vascular complications. The role of microvesicles (MVs) as mediators and potential biomarkers in microangiopathy in type 1 diabetes remains unclear. MATERIALS AND METHODS: MV levels in plasma samples from 106 patients with type 1 diabetes with microangiopathy, 130 patients without microangiopathy and 100 healthy controls were analysed using flow cytometry. Phosphatidylserine (PS) expression in MVs was assessed by lactadherin, and the ability of MVs to induce thrombin generation was investigated in vitro. Endogenous plasma lactadherin levels were measured using ELISA. RESULTS: Patients with type 1 diabetes had higher MV levels compared to healthy controls, with no significant differences between patients with and without microangiopathy. MV-induced thrombin generation in normal-pooled plasma was blocked by addition of lactadherin. Endogenous lactadherin levels were higher in patients compared to controls, and the highest levels were found in patients with microangiopathy. Plasma lactadherin levels did not correlate with levels of PS positive/negative MVs. CONCLUSION: Patients with type 1 diabetes with and without microangiopathy have higher levels of circulating MVs than healthy controls, probably reflecting higher cellular activation and turnover. However, we found no associations between clinical microangiopathy and levels of MVs in total or PS-expressing MVs. Plasma levels of lactadherin, which is a glycoprotein important in the clearance of cells and MVs, are increased in patients with type 1 diabetes and correlate with microangiopathy.
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Micropartículas Derivadas de Células/patología , Diabetes Mellitus Tipo 1/complicaciones , Microvasos/patología , Fosfatidilserinas/análisis , Adulto , Antígenos de Superficie/análisis , Antígenos de Superficie/sangre , Coagulación Sanguínea , Micropartículas Derivadas de Células/metabolismo , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patología , Femenino , Humanos , Masculino , Microvasos/metabolismo , Persona de Mediana Edad , Proteínas de la Leche/análisis , Proteínas de la Leche/sangre , Fosfatidilserinas/metabolismo , Trombina/metabolismoRESUMEN
INTRODUCTION: Insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 1 (IGFBP-1) play an important role in vascular health. Many patients with type 1 diabetes are medicated with HMG-CoA reductase inhibitors, statins, in order to prevent vascular complications. Yet little is known about the effect of statins on the IGF-1/IGFBP-1 axis in these patients. OBJECTIVES: The aim of this study was to evaluate the effect of atorvastatin treatment on IGF-1 and IGFBP-1 with regards to microvascular function. DESIGN: Twenty patients with type 1 diabetes received either placebo or 80mg atorvastatin for two months in a double-blinded cross-over study. IGF-1 and IGFBP-1 levels were assessed before and after each treatment period. Skin microcirculation was studied using Doppler perfusion imaging during iontophoresis of acetylcholine and sodium nitroprusside to assess endothelium-dependent and endothelium-independent microvascular reactivity, respectively. RESULTS: Treatment with high-dose atorvastatin was associated with a significant decrease in IGF-1 levels compared to placebo (p<0.05, ANOVA repeated measures), whereas no effect was seen on IGFBP-1 or the IGF-1/IGFBP-1 ratio. These variables did not correlate with measurements of skin microvascular reactivity. CONCLUSIONS: The study found that treatment with high-dose atorvastatin was associated with reduced IGF-1 levels, which may indicate a potential negative effect on microvascular function and long-term risk of microangiopathy development.