ABSTRACT
Recent epidemiologic studies clearly showed that early intensive glucose control has a legacy effect for preventing diabetic macrovascular complications. However, the cellular and molecular processes by which high glucose leads to macrovascular complications are poorly understood. Vascular smooth muscle cell (VSMC) dysfunction due to high glucose is a characteristic of diabetic vascular complications. Activation of nuclear factor-kappaB (NF-kappaB) may play a key role in the regulation of inflammation and proliferation of VSMCs. We examined whether VSMC proliferation and plasminogen activator inhibitor-1 (PAI-1) expression induced by high glucose were mediated by NF-kappaB activation. Also, we determined whether selective inhibition of NF-kappaB would inhibit proliferation and PAI-1 expression in VSMCs. VSMCs of the aorta of male SD rats were treated with various concentrations of glucose (5.6, 11.1, 16.7, and 22.2 mM) with or without an inhibitor of NF-kappaB or expression of a recombinant adenovirus vector encoding an IkappaB-alpha mutant (Ad-IkappaBalphaM). VSMC proliferation was examined using an MTT assay. PAI-1 expression was assayed by real-time PCR and PAI-1 protein in the media was measured by ELISA. NF-kappaB activation was determined by immunohistochemical staining, NF-kappaB reporter assay, and immunoblotting. We found that glucose stimulated VSMC proliferation and PAI-1 expression in a dose-dependent manner up to 22.2 mM. High glucose (22.2 mM) alone induced an increase in NF-kappaB activity. Treatment with inhibitors of NF-kappaB such as MG132, PDTC or expression of Ad-IkappaB-alphaM in VSMCs prevented VSMC proliferation and PAI-1 expression induced by high glucose. In conclusion, inhibition of NF-kappaB activity prevented high glucose-induced VSMC proliferation and PAI-1 expression.
Subject(s)
Animals , Male , Rats , Aorta/cytology , Cardiovascular Diseases/prevention & control , Cell Proliferation/drug effects , Cells, Cultured , Diabetes Complications/prevention & control , Gene Expression Regulation/drug effects , Glucose/immunology , Leupeptins/pharmacology , Muscle, Smooth, Vascular/cytology , Myocytes, Smooth Muscle/cytology , NF-kappa B/antagonists & inhibitors , Plasminogen Activator Inhibitor 1/genetics , Proline/analogs & derivatives , Rats, Sprague-Dawley , Thiocarbamates/pharmacologyABSTRACT
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Subject(s)
Humans , Male , Female , Child , Adolescent , Adult , Middle Aged , Aged , Exercise/physiology , Exercise/psychology , Diabetes Mellitus/prevention & control , Diabetes Mellitus/rehabilitation , Diabetes Mellitus/therapy , Diabetes Mellitus/epidemiology , Life Style , Obesity/complications , Obesity/diagnosis , Obesity/rehabilitation , Mental Health/classification , Glucose/immunology , Glucose/metabolismABSTRACT
El objetivo de este trabajo es revisar los diferentes aspectos en torno a la prevención y el tratamiento de la diabetes mellitus tipo 1. Desde el punto de vista preventivo, ninguno de los ensayos llevados a cabo hasta la actualidad (DPT-l y 2, ENDIT) ha sido capaz de detener la enfermedad en individuos de riesgo. En este sentido, vacunas con diferentes péptidos, tratamientos con anticuerpos monoclonales o inmunomoduladores son las alternativas futuras. En el aspecto terapéutico, las técnicas de determinación de glucemia capilar suponen un reto para el día a día de nuestros pacientes, dado el número de veces que realizan esta técnica cruenta. Así, la monitorización continua de glucosa (CGMS) aporta datos importantes durante las 24 horas del día, siendo posible ajustar mejor la pauta de insulina, sobre todo en aquellos pacientes con grandes irregularidades en los autocontroles. Por otro lado, los nuevos análogos de insulina, tanto de acción corta como larga, han mejorado el control metabólico y sobre todo las hipoglucemias y la calidad de vida. Recientemente, las bombas de insulina, hoy ya ofertadas por el Sistema Nacional de Salud, permiten que aquellos pacientes con un difícil control metabólico puedan beneficiarse de este tipo de terapia, que constituye una oferta más dentro del arsenal terapéutico en esta enfermedad, y para cuyo empleo, hoy por hoy, es necesario cumplir unos requisitos. Además, la incorporación, en un futuro próximo, de la insulina inhalada supondrá, presumiblemente, un avance importante sobre todo en la calidad de vida del paciente. Por último, la biología celular y molecular han permitido dar forma a distintas líneas terapéuticas, como el trasplante o la terapia génica, que plantean un cambio importante en la evolución de la enfermedad, aunque este reto, posiblemente, no sea a corto plazo
Aim: a review of the different aspects concerning prevention and treatment of type 1 diabetes at this moment. Up to now, none of all the different preventions trials (DPT1 and 2, ENDIT) have been able to stop the disease in high risk individuals. Vaccination strategies with different peptides, monoclonal autoantibodies or inmunomodulators could be alternative therapies. From the therapeutic point of view, blood glucose monitoring is a routine as well as a limitation for diabetic patients due to the high number of times their glucose should be checked. Continuous blood glucose monitoring system (CGMS) is a subcutaneous device that gives us important information during the whole day, so that we can improve insulin treatment mainly in those patients with uncontrolled diabetes. However insulin analogs (short and long acting-insulin) have lately improved diabetes control. and specially quality of life. Insulin pumps, which recently have been covered by the National health system, are a new option of treatment for those patients with poor metabolic control. In addition, inhaled insulin will presumably be a new useful tool to work with. Finally cell and molecular biology will help to come true new therapeutic lines as islets transplantation and gene therapy, which will probably change the natural course of the disease