RESUMEN
Diabetes mellitus and arterial hypertension are among the five risk factors that increase mortality in the world. Both are chronic, non-communicable diseases (NCDs), that have a pathophysiological association. Advanced glycation end products (AGEs), produced by the lack of glycemic control in diabetic patients, interact with their AGE receptors (AGER) resulting in increased arterial stiffness, inflammation and endothelial changes - which increases the risk of developing hypertension and other complications. We ran a systematic review in Pubmed, SciELO, Cochrane Library and Web of Science databases using keywords and Boolean operators to optimize the search, with the objective of assessing the mechanism of non-enzymatic glycation of proteins present in patients with diabetes and its correlation with the onset of hypertension, exposing all the endothelial and cellular damage caused by AGEs. We found 719 papers, of which 99 were read in full, and 26 met the eligibility criteria and were included in the present review. AGEs should be considered one of the main cardiometabolic risk factors. Reducing the AGE-AGER interaction will result in cardiovascular protection and increased life expectancy.
Asunto(s)
Angiopatías Diabéticas , Productos Finales de Glicación Avanzada , Hipertensión , Receptor para Productos Finales de Glicación Avanzada , Humanos , Diabetes Mellitus/metabolismo , Productos Finales de Glicación Avanzada/metabolismo , Hipertensión/etiología , Hipertensión/metabolismo , Reacción de Maillard , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Angiopatías Diabéticas/complicaciones , Angiopatías Diabéticas/metabolismoRESUMEN
BACKGROUND: Rubeosis faciei diabeticorum is a persistent facial erythema in patients with diabetes mellitus. The actual pathogenesis has not been studied. However, it is speculated to be a cutaneous diabetic microangiopathy. OBJECTIVE: Examine the correlation between the severity of facial erythema and the possible causes of microvascular diabetic complications, namely oxidative stress, hyperglycemia, and cutaneous accumulation of advanced glycation end-products . METHODS: Patients diagnosed with Type 2 diabetes mellitus (n=32) were enrolled in the study. The facial erythema index was measured using the Mexameter MX18; cutaneous accumulation of advanced glycation end-products was estimated by measuring skin auto fluorescence with the AGE Reader (DiagnOptics Technologies B.V. - Groningen, Netherlands). Glycated haemoglobin, total antioxidant status, and malondialdehyde were measured in blood by TBARS assay. The correlation between the selected variables was assessed by Spearman's rank test; p≤0.05 was considered statistically significant. RESULTS: There was a statistically significant correlation between total antioxidant status and the facial erythema index (ρ=0.398, p=0.024). Malondialdehyde, skin autofluorescence, glycated haemoglobin, body mass index, duration of diabetes, and age did not demonstrate statistically significant correlation with the facial erythema index. STUDY LIMITATIONS: This is an observational study. Elevation of total antioxidant status could have been caused by several factors that might have also influenced the development of rubeosis faciei, including hyperbilirubinemia and hyperuricemia. CONCLUSIONS: The results contradicted expectations. Total antioxidant status correlated positively with facial erythema index; however, there was no correlation with oxidative stress and skin autofluorescence. Further investigations should be conducted to reveal the cause of total antioxidant status elevation in patients with rubeosis faciei.
Asunto(s)
Angiopatías Diabéticas/metabolismo , Eritema/metabolismo , Dermatosis Facial/metabolismo , Estrés Oxidativo , Adulto , Anciano , Antioxidantes/análisis , Índice de Masa Corporal , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Angiopatías Diabéticas/complicaciones , Eritema/etiología , Dermatosis Facial/etiología , Femenino , Fluorescencia , Hemoglobina Glucada/análisis , Humanos , Masculino , Malondialdehído/sangre , Persona de Mediana Edad , Valores de Referencia , Espectrofotometría , Estadísticas no ParamétricasRESUMEN
Abstract Background Rubeosis faciei diabeticorum is a persistent facial erythema in patients with diabetes mellitus. The actual pathogenesis has not been studied. However, it is speculated to be a cutaneous diabetic microangiopathy. Objective Examine the correlation between the severity of facial erythema and the possible causes of microvascular diabetic complications, namely oxidative stress, hyperglycemia, and cutaneous accumulation of advanced glycation end-products . Methods Patients diagnosed with Type 2 diabetes mellitus (n = 32) were enrolled in the study. The facial erythema index was measured using the Mexameter MX18; cutaneous accumulation of advanced glycation end-products was estimated by measuring skin auto fluorescence with the AGE Reader (DiagnOptics Technologies B.V. - Groningen, Netherlands). Glycated haemoglobin, total antioxidant status, and malondialdehyde were measured in blood by TBARS assay. The correlation between the selected variables was assessed by Spearman's rank test; p ≤ 0.05 was considered statistically significant. Results There was a statistically significant correlation between total antioxidant status and the facial erythema index (ρ = 0.398, p = 0.024). Malondialdehyde, skin autofluorescence, glycated haemoglobin, body mass index, duration of diabetes, and age did not demonstrate statistically significant correlation with the facial erythema index. Study limitations This is an observational study. Elevation of total antioxidant status could have been caused by several factors that might have also influenced the development of rubeosis faciei, including hyperbilirubinemia and hyperuricemia. Conclusions The results contradicted expectations. Total antioxidant status correlated positively with facial erythema index; however, there was no correlation with oxidative stress and skin autofluorescence. Further investigations should be conducted to reveal the cause of total antioxidant status elevation in patients with rubeosis faciei.
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Estrés Oxidativo , Angiopatías Diabéticas/metabolismo , Eritema/metabolismo , Dermatosis Facial/metabolismo , Valores de Referencia , Espectrofotometría , Hemoglobina Glucada/análisis , Índice de Masa Corporal , Estadísticas no Paramétricas , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Angiopatías Diabéticas/complicaciones , Eritema/etiología , Dermatosis Facial/etiología , Fluorescencia , Malondialdehído/sangre , Antioxidantes/análisisRESUMEN
Impaired wound healing is a debilitating complication of diabetes that leads to significant morbidity, particularly foot ulcers. Natural products have shown to be effective in treating skin wounds. Lupeol is known to stimulate angiogenesis, fibroblast proliferation, and expressions of cytokines and growth factors involved in wound healing. The study is performed to evaluate the wound healing activity of lupeol in streptozotocin-induced hyperglycemic rats by macroscopical, histological, immunohistochemical, immunoenzymatic, and molecular methods. Percentage of wound closure and contraction was increased in the lupeol-treated group when compared to the Lanette group. Histopathological observation revealed decreased inflammatory cell infiltration and increased proliferation of fibroblasts, vascularization, and deposition of collagen fibers after lupeol treatment. Immunohistochemical analyses showed decreased intensity of NF-κB and increased intensity of FGF-2, TGF-ß1, and collagen III. ELISA results revealed downregulated IL-6 levels and upregulated IL-10 levels in response to lupeol. The mRNA expression levels of Hif-1α, Sod-2, and Ho-1 were significantly increased in response to lupeol as compared to Lanette whereas Nf-κb and Vegf-A levels were decreased in relation to insulin and lupeol treatment. These findings indicate that lupeol possesses wound healing potential in hyperglycemic conditions and may be useful as a treatment for chronic wounds in diabetic patients.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Angiopatías Diabéticas/tratamiento farmacológico , Hiperglucemia/tratamiento farmacológico , Neovascularización Fisiológica/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Triterpenos Pentacíclicos/farmacología , Cicatrización de Heridas/efectos de los fármacos , Animales , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Angiopatías Diabéticas/metabolismo , Angiopatías Diabéticas/patología , Hiperglucemia/inducido químicamente , Hiperglucemia/metabolismo , Hiperglucemia/patología , Masculino , Ratas , Ratas WistarRESUMEN
The maintenance of the pH homeostasis is maintained by several mechanisms including the efflux of protons (H+) via membrane transporters expressed in almost all mammalian cells. Along these membrane transporters the sodium/H+ exchangers (NHEs), mainly NHE isoform 1 (NHE1), plays a key role in this phenomenon. NHE1 is under modulation by several environmental conditions (e.g. hyperglycaemia, protein kinase C activity) as well as hormones, including insulin. NHE1 activation causes intracellular alkalization in human endothelial cells leading to activation of the endothelial Nitric Oxide Synthase (eNOS) to generate NO. Intracellular alkalization is a phenomenon that also results in upregulation of the glucose transporter GLUT4 in cells that are responsive to insulin. A reduction in the removal of the extracellular D-glucose is seen in states of insulin resistance, such as in diabetes mellitus and obesity. Since insulin is a potent activator of eNOS in human endothelium, therefore causing vasodilation, and its vascular effect is reduced in insulin resistance it is likely that a defective signal to activate NHE1 in insulin target cells is expected. This phenomenon results in lower redistribution and activation of GLUT4 leading to reduced uptake of D-glucose and hyperglycaemia. The general concept of a role for NHE1, and perhaps other NHEs isoforms, in insulin resistance in the human vasculature is proposed.
Asunto(s)
Equilibrio Ácido-Base , Glucemia/metabolismo , Vasos Sanguíneos/metabolismo , Diabetes Mellitus/metabolismo , Angiopatías Diabéticas/metabolismo , Hiperglucemia/metabolismo , Resistencia a la Insulina , Insulina/sangre , Animales , Biomarcadores/sangre , Vasos Sanguíneos/fisiopatología , Diabetes Mellitus/fisiopatología , Angiopatías Diabéticas/etiología , Angiopatías Diabéticas/fisiopatología , Transportador de Glucosa de Tipo 4/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Hiperglucemia/complicaciones , Hiperglucemia/fisiopatología , Factores de Riesgo , Intercambiador 1 de Sodio-Hidrógeno/metabolismoRESUMEN
Diabetes currently affects more than 400 million people worldwide. This metabolic disorder causes various micro- and macrovascular complications that accelerate atherosclerosis and yet trigger other cardiovascular diseases. The characteristic frame of hyperglycaemia, hyperinsulinaemia and hyperlipidaemia in diabetes increases several inflammatory mediators leading to endothelial dysfunction and pro-atherosclerotic processes. This MiniReview summarizes evidence that antidiabetic drugs have effects beyond lowering glycaemic levels. In experimental studies, antidiabetic drugs reduce the vascular production and release of pro-inflammatory cytokines, the recruitment, infiltration and activation of immune cells and pro-inflammatory mediators, thus decreasing vascular inflammatory responses; they also re-establish vascular redox homeostasis by reducing oxidative stress and balancing the release of vasoconstrictor and vasodilator factors, hence contributing to the improvement of endothelial function. These effects are associated with a reduction in vascular remodelling due to decreased matrix metalloproteinases expression/activity, reduced inflammatory processes and vascular wall fibrosis. In clinical studies, antidiabetic drugs also reduce the production and release of pro-inflammatory, pro-atherosclerotic and pro-oxidative mediators and improve flow-mediated dilatation, indicating beneficial effects on endothelial function. These bonus effects of antidiabetic drugs may delay and/or reduce the installation and development of the atherosclerotic disease, decrease cardiovascular risk and possibly impact mortality risk, life expectancy and quality.
Asunto(s)
Enfermedades Cardiovasculares/prevención & control , Angiopatías Diabéticas , Hipoglucemiantes/farmacología , Angiopatías Diabéticas/tratamiento farmacológico , Angiopatías Diabéticas/inmunología , Angiopatías Diabéticas/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Resultado del Tratamiento , Resistencia Vascular/efectos de los fármacosRESUMEN
AIMS/HYPOTHESES: We hypothesized that there is decreased synthesis of glutathione (GSH) in type 2 diabetes (T2DM) especially in the presence of microvascular complications, and this is dependent on the degree of hyperglycemia. METHODS: In this case-control study, we recruited 16 patients with T2DM (7 without and 9 with microvascular complications), and 8 age- and sex-matched non-diabetic controls. We measured GSH synthesis rate using an infusion of [2H2]-glycine as isotopic tracer and collection of blood samples for liquid chromatography mass spectrometric analysis. RESULTS: Compared to the controls, T2DM patients had lower erythrocyte GSH concentrations (0.90 ± 0.42 vs. 0.35 ± 0.30 mmol/L; P = 0.001) and absolute synthesis rates (1.03 ± 0.55 vs. 0.50 ± 0.69 mmol/L/day; P = 0.01), but not fractional synthesis rates (114 ± 45 vs. 143 ± 82%/day; P = 0.07). The magnitudes of changes in patients with complications were greater for both GSH concentrations and absolute synthesis rates (P-values ≤ 0.01) compared to controls. There were no differences in GSH concentrations and synthesis rates between T2DM patients with and without complications (P-values > 0.1). Fasting glucose and HbA1c did not correlate with GSH concentration or synthesis rates (P-values > 0.17). CONCLUSIONS: Compared to non-diabetic controls, patients with T2DM have glutathione deficiency, especially if they have microvascular complications. This is probably due to reduced synthesis and increased irreversible utilization by non-glycemic mechanisms.
Asunto(s)
Glucemia , Diabetes Mellitus Tipo 2/metabolismo , Angiopatías Diabéticas/metabolismo , Glutatión/metabolismo , Microvasos/patología , Adulto , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Angiopatías Diabéticas/sangre , Angiopatías Diabéticas/etiología , Angiopatías Diabéticas/patología , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: Prolonged sedentary time (ST) might be contributing to the diabetes epidemic, but most studies have been cross-sectional and few have objectively measured ST. The purpose of this study was to evaluate cross-sectional and 5-year longitudinal relationships between ST and metabolic parameters and outcomes. RESEARCH DESIGN AND METHODS: This was an analysis of 2,027 Coronary Artery Risk Development in Young Adults (CARDIA) study participants (aged 38-50 years, 57% female, and mean BMI of 29.0 ± 7.0 kg/m(2)) with accelerometry data (≥4 days with ≥10 h/day) measured at the year 20 follow-up exam (2005-2006). Metabolic variables (fasting glucose, fasting insulin, 2-h postchallenge glucose, HOMA of insulin resistance [HOMA-IR], and HbA1c) and outcomes (impaired fasting glucose [IFG], impaired glucose tolerance [IGT], prediabetes by HbA1c, and diabetes) were assessed concurrently and 5 years later. RESULTS: Average ST was 8.1 ± 1.7 h/day or 55 ± 10% of wear time. Each additional hour per day of ST was cross-sectionally associated with a 3% higher fasting insulin and HOMA-IR (both P < 0.01) but not 5-year changes in metabolic parameters. Having ≥10 h/day vs. <6 h/day of ST was associated with an odds ratio (OR) = 2.74 (95% CI 1.13, 6.62) for IGT and an OR = 3.80 (95% CI 1.39, 10.35) for diabetes. ST was not associated with prevalent IFG, prevalent prediabetes by HbA1c, or 5-year incidence of any metabolic outcomes (all P > 0.05). CONCLUSIONS: ST was independently related to insulin, HOMA-IR, and prevalent diabetes and IGT but did not predict 5-year changes in metabolic parameters or incidence of metabolic outcomes. These results suggest that higher ST may not be a risk factor for future metabolic outcomes, but more research with repeated ST measurement and longer follow-up is needed.
Asunto(s)
Enfermedad de la Arteria Coronaria/etiología , Enfermedades Metabólicas/etiología , Conducta Sedentaria , Adolescente , Adulto , Glucemia/metabolismo , Enfermedad de la Arteria Coronaria/metabolismo , Estudios Transversales , Angiopatías Diabéticas/etiología , Angiopatías Diabéticas/metabolismo , Ejercicio Físico/fisiología , Ayuno/sangre , Femenino , Intolerancia a la Glucosa/metabolismo , Hemoglobina Glucada/metabolismo , Humanos , Insulina/metabolismo , Resistencia a la Insulina/fisiología , Masculino , Enfermedades Metabólicas/metabolismo , Estado Prediabético/metabolismo , Factores de Riesgo , Adulto JovenRESUMEN
OBJECTIVE: This study was carried out to determine high pressure and pulsatile flow perfusion effects on human saphenous vein (HSV) segments obtained from diabetic and non-diabetic patients. METHODS: The veins were perfused with oxygenated Krebs solution for 3 h, with a pulsatile flow rate of 100 mL/min and pressures of 250 × 200 or 300 × 250 mmHg. After perfusion, veins were studied by light microscopy; nitric oxide synthase (NOS) isoforms, CD34 and nitrotyrosine immunohistochemistry and tissue nitrite/nitrate (NO(x)) and malondialdehyde (MDA) quantification. RESULTS: Light microscopy revealed endothelial denuding areas in all HSV segments subjected to 300 × 250 mmHg perfusion pressure, but the luminal area was similar. The percentage of luminal perimeter covered by endothelium decreased as perfusion pressures increased, and significant differences were observed between groups. The endothelial nitric oxide synthase (eNOS) isoform immunostaining decreased significantly in diabetic patients' veins independent of the perfusion pressure levels. The inducible NOS (iNOS), neuronal NOS (nNOS) and nitrotyrosine immunostaining were similar. Significant CD34 differences were observed between the diabetic 300 × 250 mmHg perfusion pressure group and the non-diabetic control group. Tissue nitrite/nitrate and MDA were not different among groups. CONCLUSIONS: Pulsatile flow and elevated pressures for 3 h caused morphological changes and decreased the eNOS expression in the diabetic patients' veins.
Asunto(s)
Angiopatías Diabéticas/fisiopatología , Regulación hacia Abajo , Endotelio Vascular/fisiopatología , Hipertensión/complicaciones , Óxido Nítrico Sintasa de Tipo III/metabolismo , Venas/fisiopatología , Anciano , Antígenos CD34/metabolismo , Angiopatías Diabéticas/complicaciones , Angiopatías Diabéticas/metabolismo , Angiopatías Diabéticas/patología , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Femenino , Humanos , Inmunohistoquímica , Técnicas In Vitro , Masculino , Persona de Mediana Edad , Óxido Nítrico Sintasa de Tipo I/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Perfusión , Presión/efectos adversos , Flujo Pulsátil , Vena Safena/metabolismo , Vena Safena/patología , Vena Safena/fisiopatología , Fumar/efectos adversos , Venas/metabolismo , Venas/patologíaRESUMEN
Hypertension and diabetes have been related to noradrenergic system impairment, especially to the response mediated by alpha-1 receptors. The aim of this work was to investigate possible changes in the expression of alpha-1 adrenergic receptors in aorta and carotid arteries of Wistar Kyoto and spontaneously hypertensive rats after 4 weeks of the onset of diabetes. Our results suggest that early diabetes modifies the expression of alpha-1 adrenergic receptors in aorta and carotid arteries of both WKY and SHR strains in a different way.
Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Angiopatías Diabéticas/metabolismo , Hipertensión/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Animales , Aorta/metabolismo , Glucemia/metabolismo , Presión Sanguínea , Arterias Carótidas/metabolismo , Diabetes Mellitus Experimental/fisiopatología , Angiopatías Diabéticas/fisiopatología , Hipertensión/fisiopatología , Masculino , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Receptores Adrenérgicos alfa 1/clasificaciónRESUMEN
BACKGROUND: Advanced glycation end products (AGE) alter lipid metabolism and reduce the macrophage expression of ABCA-1 and ABCG-1 which impairs the reverse cholesterol transport, a system that drives cholesterol from arterial wall macrophages to the liver, allowing its excretion into the bile and feces. Oxysterols favors lipid homeostasis in macrophages and drive the reverse cholesterol transport, although the accumulation of 7-ketocholesterol, 7alpha- hydroxycholesterol and 7beta- hydroxycholesterol is related to atherogenesis and cell death. We evaluated the effect of glycolaldehyde treatment (GAD; oxoaldehyde that induces a fast formation of intracellular AGE) in macrophages overloaded with oxidized LDL and incubated with HDL alone or HDL plus LXR agonist (T0901317) in: 1) the intracellular content of oxysterols and total sterols and 2) the contents of ABCA-1 and ABCG-1. METHODS: Total cholesterol and oxysterol subspecies were determined by gas chromatography/mass spectrometry and HDL receptors content by immunoblot. RESULTS: In control macrophages (C), incubation with HDL or HDL + T0901317 reduced the intracellular content of total sterols (total cholesterol + oxysterols), cholesterol and 7-ketocholesterol, which was not observed in GAD macrophages. In all experimental conditions no changes were found in the intracellular content of other oxysterol subspecies comparing C and GAD macrophages. GAD macrophages presented a 45% reduction in ABCA-1 protein level as compared to C cells, even after the addition of HDL or HDL + T0901317. The content of ABCG-1 was 36.6% reduced in GAD macrophages in the presence of HDL as compared to C macrophages. CONCLUSION: In macrophages overloaded with oxidized LDL, glycolaldehyde treatment reduces the HDL-mediated cholesterol and 7-ketocholesterol efflux which is ascribed to the reduction in ABCA-1 and ABCG-1 protein level. This may contribute to atherosclerosis in diabetes mellitus.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Regulación hacia Abajo , Productos Finales de Glicación Avanzada/metabolismo , Cetocolesteroles/metabolismo , Lipoproteínas/metabolismo , Macrófagos/metabolismo , Esteroles/metabolismo , Transportador 1 de Casete de Unión a ATP , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1 , Acetaldehído/análogos & derivados , Acetaldehído/farmacología , Animales , Anticolesterolemiantes/farmacología , Línea Celular , Angiopatías Diabéticas/inmunología , Angiopatías Diabéticas/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Cromatografía de Gases y Espectrometría de Masas , Humanos , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/metabolismo , Receptores X del Hígado , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Ratones , Receptores Nucleares Huérfanos/agonistas , Oxidantes/farmacología , Estrés OxidativoRESUMEN
AIMS: Recent data identified uric acid as an independent risk factor for cardiovascular disease. The aim of the present study was to assess the association between uric acid and endothelial dysfunction in 57 patients with Type 1 diabetes and 53 healthy control subjects. METHODS: Microvascular endothelial function was evaluated using laser Doppler perfusion monitoring coupled with pharmacological (iontophoretic administration of acetylcholine and sodium nitroprusside) and physiological (post-occlusive reactive hyperaemia and thermal hyperaemia) stimuli. RESULTS: Uric acid was higher in subjects without diabetes than in those with diabetes (P = 0.03). Microvascular vasodilator response to acetylcholine was significantly reduced in Type 1 diabetes (P = 0.002) and was correlated to disease duration (r = -0.3, P = 0.01), triglyceride (r = -0.37, P = 0.005), insulin dose (r = -0.28, P = 0.03), fasting plasma glucose levels (r = -0.3, P = 0.02), HbA(1c) (r = -0.34, P = 0.001) and uric acid (r = -0.3, P = 0.005). On stepwise multivariate analysis, age, HbA(1c) and uric acid were the most important independent variables that were associated with the endothelium-dependent response in Type 1 diabetes (P = 0.02). CONCLUSIONS: Glycaemic control and uric acid in the normal range were the most important contributing factors to the decreasing endothelium-dependent responses associated with Type 1 diabetes. Consequently, uric acid could be a new potential marker of microvascular endothelial dysfunction in these patients. Further studies are required to explore the clinical relevance of the relationship between uric acid levels, oxidative stress and endothelial dysfunction in patients with Type 1 diabetes, as well as whether treatment with uric acid-lowering drugs for slight elevations in uric acid would benefit these patients.
Asunto(s)
Glucemia/metabolismo , Diabetes Mellitus Tipo 1/sangre , Angiopatías Diabéticas/metabolismo , Endotelio Vascular/metabolismo , Microcirculación , Ácido Úrico/sangre , Adulto , Análisis de Varianza , Biomarcadores/sangre , Enfermedad de la Arteria Coronaria/metabolismo , Estudios Transversales , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/fisiopatología , Angiopatías Diabéticas/sangre , Angiopatías Diabéticas/tratamiento farmacológico , Angiopatías Diabéticas/fisiopatología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiopatología , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Flujometría por Láser-Doppler , Masculino , Microcirculación/efectos de los fármacos , Adulto JovenRESUMEN
The vascular manifestations associated with diabetes mellitus (DM) result from the dysfunction of several vascular physiology components mainly involving the endothelium, vascular smooth muscle and platelets. It is also known that hyperglycemia-induced oxidative stress plays a role in the development of this dysfunction. This review considers the basic physiology of the endothelium, especially related to the synthesis and function of nitric oxide. We also discuss the pathophysiology of vascular disease associated with DM. This includes the role of hyperglycemia in the induction of oxidative stress and the role of advanced glycation end-products. We also consider therapeutic strategies.
Asunto(s)
Angiopatías Diabéticas/tratamiento farmacológico , Angiopatías Diabéticas/fisiopatología , Endotelio Vascular/fisiología , Endotelio Vascular/fisiopatología , Óxido Nítrico/fisiología , Estrés Oxidativo/fisiología , Animales , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Angiopatías Diabéticas/metabolismo , Endotelio Vascular/efectos de los fármacos , Productos Finales de Glicación Avanzada/fisiología , Humanos , Hiperglucemia/fisiopatología , Músculo Liso Vascular/fisiología , Músculo Liso Vascular/fisiopatología , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
The association between type 1 diabetes and coronary heart disease has become very clear since the late 1970. It has been demonstrated that there is an important increased risk in morbidity and mortality caused by coronary artery disease in young adults with type 1 diabetes compared with the non diabetic population. The underlying pathogeneses is still poorly understood. While the role of glycemic control in the development of microvascular disease complication is well established its role in CVD in patients with DM1 remains unclear with epidemiologic studies reporting conflicting data. Recent findings from the DCCT/EDIC showed that prior intensive diabetes treatment during the DCCT was associated with less atherosclerosis, largely because of reduced level of HbA1c during the DCCT. The improvement of glycemic control itself appeared to be particularly effective in younger patients with shorter duration of the disease. Other analyses suggested the glycemia may have a stronger effect on CAD in patients without than in those with albuminúria. Other major determinants of coronary artery disease are the components of metabolic syndrome and the surrogate measure of insulin resistence: eGDR. It is proposed that patients with DM1 should have aggressive medical therapy, risk factor modification and careful monitoring not only of his blood sugar but also of the other processes involved in the atherosclerotic process, mostly the ones with family history of type 2 diabetes.
Asunto(s)
Enfermedad de la Arteria Coronaria/etiología , Diabetes Mellitus Tipo 1/complicaciones , Angiopatías Diabéticas/etiología , Adolescente , Adulto , Anciano , Glucemia/análisis , Niño , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/metabolismo , Diabetes Mellitus Tipo 1/epidemiología , Angiopatías Diabéticas/epidemiología , Angiopatías Diabéticas/metabolismo , Femenino , Hemoglobina Glucada/análisis , Humanos , Hiperglucemia/complicaciones , Hiperglucemia/etiología , Hiperglucemia/metabolismo , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Resistencia a la Insulina , Masculino , Síndrome Metabólico/etiología , Síndrome Metabólico/metabolismo , Persona de Mediana Edad , Prevalencia , Adulto JovenRESUMEN
O risco de doença arterial coronariana (DAC) nos pacientes com diabetes melito tipo 1 (DM1) é conhecido desde o final dos anos 1970, sendo atualmente a principal causa de mortalidade na população adulta com diabetes tipo 1 de longa duração. A patogênese do processo aterosclerótico nesta doença ainda é obscura, acreditando-se que a hiperglicemia desenvolva aí um papel importante, entretanto vários estudos epidemiológicos mostraram que a associação entre doença coronariana e glicemia, em pacientes com DM1 seja fraca. Dados recentes do estudo DCCT/EDIC mostram que o grupo que recebeu tratamento insulínico intensificado durante o DCCT desenvolveu graus menores de aterosclerose, relacionado aos valores reduzidos de HbA1c durante a fase ativa do estudo, com melhor proteção nos pacientes mais jovens e com menor duração da doença. Há também evidências de que os benefícios são maiores nos pacientes sem nefropatia quando comparados aos com doença renal. Outros fatores de risco importante para o desenvolvimento de DAC em pacientes com DM1 são os mesmos descritos para DM2, incluindo os componentes da síndrome metabólica e marcadores de resistência insulínica. Sugere-se que pacientes com DM1 devam ter o melhor controle glicêmico possível, desde o início da sua doença acrescido de vigilância e tratamento rígido dos fatores de riscos clássicos para DAC, principalmente naqueles com história familiar de DM2.
The association between type 1 diabetes and coronary heart disease has become very clear since the late 1970. It has been demonstrated that there is an important increased risk in morbidity and mortality caused by coronary artery disease in young adults with type 1 diabetes compared with the non diabetic population. The underlying pathogeneses is still poorly understood. While the role of glycemic control in the development of microvascular disease complication is well established its role in CVD in patients with DM1 remains unclear with epidemiologic studies reporting conflicting data. Recent findings from the DCCT/EDIC showed that prior intensive diabetes treatment during the DCCT was associated with less atherosclerosis, largely because of reduced level of HbA1c during the DCCT. The improvement of glycemic control itself appeared to be particularly effective in younger patients with shorter duration of the disease. Other analyses suggested the glycemia may have a stronger effect on CAD in patients without than in those with albuminúria. Other major determinants of coronary artery disease are the components of metabolic syndrome and the surrogate measure of insulin resistence: eGDR. It is proposed that patients with DM1 should have aggressive medical therapy, risk factor modification and careful monitoring not only of his blood sugar but also of the other processes involved in the atherosclerotic process, mostly the ones with family history of type 2 diabetes.
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Adolescente , Adulto , Anciano , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Enfermedad de la Arteria Coronaria/etiología , Diabetes Mellitus Tipo 1/complicaciones , Angiopatías Diabéticas/etiología , Glucemia/análisis , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/metabolismo , Diabetes Mellitus Tipo 1/epidemiología , Angiopatías Diabéticas/epidemiología , Angiopatías Diabéticas/metabolismo , Hemoglobina Glucada/análisis , Hiperglucemia/complicaciones , Hiperglucemia/etiología , Hiperglucemia/metabolismo , Hipoglucemiantes/uso terapéutico , Resistencia a la Insulina , Insulina/uso terapéutico , Síndrome Metabólico/etiología , Síndrome Metabólico/metabolismo , Prevalencia , Adulto JovenRESUMEN
Diabetic patients have a 3-fold higher risk of developing atherosclerosis and its clinical complications as compared to non-diabetic individuals. Part of the cardiovascular risk associated with diabetes is probably due to genetic determinants influencing both glucose homeostasis and the development of atherosclerosis. However, type 2 diabetes frequently coexists with other cardiovascular risk factors like arterial hypertension, central obesity and dyslipidemia. Genetic variability affecting many areas such as lipid and energy metabolisms, hypertension and haemodynamic mechanisms, blood clotting homeostasis, inflammation, and matrix turnover in the vascular wall will have an impact on the development of macrovascular complications in diabetic patients. Adiponectin is abundantly secreted by adipocytes. It plays important roles in lipid and glucose metabolisms and has direct anti-inflammatory and anti-atherogenic effects. In this review, we summarize recent data from the literature suggesting an implication of allelic variations of the adiponectin gene (ADIPOQ) in the genetic determinants of cardiovascular disease in diabetic subjects.
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Adiponectina/genética , Alelos , Enfermedad de la Arteria Coronaria/genética , Diabetes Mellitus Tipo 2/complicaciones , Angiopatías Diabéticas/genética , Variación Genética , Enfermedad de la Arteria Coronaria/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Angiopatías Diabéticas/metabolismo , Metabolismo Energético , Predisposición Genética a la Enfermedad , Humanos , Metabolismo de los Lípidos , Lipoproteínas/metabolismo , Factores de RiesgoRESUMEN
Diabetic patients have a 3-fold higher risk of developing atherosclerosis and its clinical complications as compared to non-diabetic individuals. Part of the cardiovascular risk associated with diabetes is probably due to genetic determinants influencing both glucose homeostasis and the development of atherosclerosis. However, type 2 diabetes frequently coexists with other cardiovascular risk factors like arterial hypertension, central obesity and dyslipidemia. Genetic variability affecting many areas such as lipid and energy metabolisms, hypertension and haemodynamic mechanisms, blood clotting homeostasis, inflammation, and matrix turnover in the vascular wall will have an impact on the development of macrovascular complications in diabetic patients. Adiponectin is abundantly secreted by adipocytes. It plays important roles in lipid and glucose metabolisms and has direct anti-inflammatory and anti-atherogenic effects. In this review, we summarize recent data from the literature suggesting an implication of allelic variations of the adiponectin gene (ADIPOQ) in the genetic determinants of cardiovascular disease in diabetic subjects.
Os pacientes com diabetes apresentam risco três vezes maior de desenvolverem aterosclerose e suas complicações quando comparados a indivíduos sem hiperglicemia. Parte desse risco associado ao diabetes é provavelmente relacionado a determinantes genéticos que influenciam tanto a homeostase glicídica quanto o desenvolvimento da aterosclerose. Entretanto, o diabetes tipo 2 freqüentemente coexiste com outros fatores de risco cardiovascular, tais como hipertensão arterial, obesidade central e dislipidemia. A variabilidade genética interfere em várias áreas tais como o metabolismo lipídico, o metabolismo energético, hipertensão, mecanismos hemodinâmicos, mecanismos de coagulação, inflamação e na formação da matriz na parede vascular, que podem estar envolvidos nas complicações macrovasculares dos pacientes com diabetes. A adiponectina é secretada com abundância pelos adipócitos. Apresenta importante papel no metabolismo lipídico e glicídico, tendo ação direta tanto antiinflamatória quanto anti-aterogênica. Na atual revisão, nós resumimos os dados recentes da literatura que sugerem uma implicação de variantes alélicas do gene da adiponectina (ADIPOQ) que podem estar envolvidos na determinação genética da doença cardiovascular em indivíduos com diabetes.
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Humanos , Alelos , Adiponectina/genética , Enfermedad de la Arteria Coronaria/genética , /complicaciones , Angiopatías Diabéticas/genética , Variación Genética , Enfermedad de la Arteria Coronaria/metabolismo , /metabolismo , Angiopatías Diabéticas/metabolismo , Metabolismo Energético , Predisposición Genética a la Enfermedad , Metabolismo de los Lípidos , Lipoproteínas/metabolismo , Factores de RiesgoRESUMEN
Recent work has shown that high-density lipoprotein (HDL) isolated from human atherosclerotic lesions and the blood of patients with established coronary artery disease contains elevated levels of 3-nitrotyrosine and 3-chlorotyrosine. A higher nitrotyrosine content in lipoprotein is significantly associated with diminished cholesterol efflux capacity of the lipoprotein. Since accelerated atherogenesis is a key complication of diabetes mellitus, and nitrosative stress has recently been implicated in diabetic pathology, we set out to demonstrate an increase in the circulating levels of nitrated apolipoprotein A (apoA)-I in type 2 diabetic patients and its putative correlation with metabolic biomarkers. In this work we addressed this hypothesis in a case-control study with 30 type 2 diabetic patients and 30 age-matched control subjects. Nitrated apoA-I was 3280+/-1910 absorbance peak area/apoA-I (g/L) for diabetic patients and 2320+/-890 for control subjects (p<0.037). This represents a 50% increase in circulating nitrated apoA-I in diabetic patients to age-matched controls. Diabetic patients also showed increases of a similar magnitude in circulating advanced glycation endproducts measured as pentosidine fluorescence (44.16+/-16.26 vs. 30.84+/-12.86 AU; p<0.01) and in circulating lipoperoxides (46.0+/-18.0 vs. 37.2+/-18.0 nmol/L; p<0.03). No significant correlation was found between nitration of apoA-I and glycosylated hemoglobin or any of the other parameters measured. If proven in subsequent functional and in vivo studies, increased nitrated apoA-I would represent another mechanism by which nitrosative stress participates in diabetic macro-angiopathy.
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Apolipoproteína A-I/sangre , Diabetes Mellitus Tipo 2/sangre , Anciano , Apolipoproteína A-I/metabolismo , Arteriosclerosis/etiología , Arteriosclerosis/metabolismo , Biomarcadores/sangre , Estudios de Casos y Controles , Complicaciones de la Diabetes/etiología , Complicaciones de la Diabetes/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Angiopatías Diabéticas/etiología , Angiopatías Diabéticas/metabolismo , Femenino , Hemoglobina Glucada/análisis , Humanos , Masculino , Persona de Mediana Edad , Nitratos/sangre , Nitratos/metabolismoRESUMEN
The role of CETP expression and diabetes in atherogenesis was investigated in mice with heterozygous disruption of the LDL receptor gene (LDLR1). LDLR1 mice with and without CETP expression were treated with streptozotocin (STZ) and maintained on a standard diet for one month before switching to an atherogenic diet for an additional month. STZ-sensitive mice had approximately 2.5-fold higher glycemia and 7.5- to 8.0-fold higher cholesterolemia. Factorial analysis of variance showed no significant effect of diabetes, CETP or diabetes-CETP interaction on the size of the atherosclerotic lesions. CETP expression in non-diabetic mice resulted in a 50% reduction in the area of the atherosclerotic lesions. Multiple regression analysis showed a positive and independent atherogenic effect of triglyceridemia in LDLR1 mice and of cholesterolemia in diabetic mice. Logistic analysis showed that elevated plasma cholesterol level significantly increased the risk of developing large lesion size (>75th percentile). In conclusion, CETP expression did not alter the lesion formation in response to diabetes, although it may be protective in the euglycemic state; the triglyceride level was an independent risk factor for LDL receptor-deficient mice but not for CETP-expressing mice; and elevated plasma cholesterol levels increased the risk of developing large atherosclerotic lesions, independently of CETP and diabetes.
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Arteriosclerosis/metabolismo , Proteínas Portadoras/genética , Diabetes Mellitus Experimental/metabolismo , Angiopatías Diabéticas/metabolismo , Glicoproteínas/genética , Receptores de LDL/deficiencia , Animales , Glucemia/metabolismo , Proteínas Portadoras/metabolismo , Proteínas de Transferencia de Ésteres de Colesterol , Diabetes Mellitus Experimental/complicaciones , Angiopatías Diabéticas/etiología , Angiopatías Diabéticas/patología , Dieta Aterogénica , Glicoproteínas/metabolismo , Lípidos/sangre , Ratones , Análisis de RegresiónRESUMEN
The PPAR-gamma receptor agonists, as a relatively new and perhaps still not very widely used class of antidiabetic agent in the Caribbean and particularly the Trinidadian context, possess pharmacologic properties that certainly have been shown to have impact on many of the inflammatory, metabolic, biochemical and structural macrovascular aberrations that occur in the type 2 diabetic. Activation of PPAR(gamma) nuclear receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. PPAR(gamma)-responsive genes also participate in the regulation of fatty acid metabolism, an important contributory pathogenic factor in this subset of patients. The unique mode of action of this class of therapeutic agent addresses a range of anomalies occurring at the cellular and sub-cellular level that are injurious to the diabetic. My aim in addressing the issue of the potential impact of PPAR-gamma receptor agonists on cardiovascular disease (CVD) morbidity and mortality in the diabetic, is first, to seek to enhance both an awareness of, and greater familiarity among our own physicians, with this class of drug, and secondly, to effect a timely review of the recent literature as it relates to the tremendous possibilities for the potential clinical gains that might accrue from their use, in so far as this may serve to ameliorate the ravages of the CVD disease that all too tragically attends the type 2 diabetic, and more specifically those with the insulin resistance syndrome.