Frailty Is Associated with Oxidative Stress in Older Patients with Type 2 Diabetes

Aging has increased the prevalence of frailty, and type 2 diabetes (T2D) has also increased in prevalence. Diabetes and oxidative stress (OS) have been shown to be related to frailty. However, the exact mechanism by which it occurs is not fully known. Our aim was to analyze body composition in community-dwelling older diabetic people treated in our center and to evaluate the possible relation between OS, frailty, and body composition. We included 100 adults older than 65 years with T2D. We found that 15% were frail and 57% were prefrail. The patients included in the nonrobust group showed increased levels of OS. Our study shows that the presence of T2D in the geriatric population is associa…

Anti-inflammatory Therapies for Cardiovascular Disease: Signaling Pathways and Mechanisms

Cardiovascular diseases (CVD) are the clinical manifestation of atherosclerosis, a chronic inflammatory disease promoted by several risk factors such as dyslipidemia, type 2 diabetes mellitus, hypertension, and smoking. Acute CVD events are the result of an unresolved inflammatory chronic state that promotes the rupture of unstable plaque lesions. Of note, the existing intensive therapies modify risk factors but do not prevent life-threatening recurrent ischemic events in high-risk patients, who have a residual inflammatory risk displayed by increased C-reactive protein (CRP) levels. Better understanding of the role of innate and adaptive immunity in plaque development and rupture has led t…

MOESM1 of Type 1 diabetic mellitus patients with increased atherosclerosis risk display decreased CDKN2A/2B/2BAS gene expression in leukocytes

Additional file 1. Tables for correlation studies: Table S1 and Table S2.

Classical cardiovascular risk factors according to fasting plasma glucose levels

To compare the prevalence of classical cardiovascular risk factors (CVRF) and metabolic syndrome (MetS) in our population according to fasting plasma glucose levels (FPG).We have studied 344 subjects between 20-70 years of age, recruited in a Primary Care Clinic. Subjects were divided into four groups according to their fasting plasma glucose (FPG) values: normal plasma glucose (NG) when FPG5.6 mmol/L; FPG between 5.6 and 6.0 mmol/L (FPG1); FPG between 6.1-6.9 mmol/L (FPG2); and diabetes (DM) FPGor = 7 mmol/L or previous diagnosis of diabetes. Cardiovascular risk factors (hypertension, TC/HDL-C index and Apo B values), presence of the MetS and indirect measure of insulin resistance (HOMA) w…

Gender differences on oxidative stress markers and complement component C3 plasma values after an oral unsaturated fat load test

Abstract Objective Post-prandial lipaemia (PL), oxidative stress (OS), and complement component C3 (C3) values are related to the atherosclerosis process. The post-prandial response of C3 after an oral fat load test (OFLT) using unsaturated fat is poorly addressed. The aim of this study was to analyze and compare the post-prandial response of OS markers and C3 values in men and women after an OFLT using unsaturated fat. Methods The study included a total of 22 healthy subjects with normal lipids and normal blood glucose (11 men and 11 pre-menopausal women). An oral unsaturated fat load test (OFLT: 50 g fat per m2 body surface) was performed using a commercial liquid preparation of long chai…

Insulin resistance aggravates atherosclerosis by reducing vascular smooth muscle cell survival and increasing CX3CL1/CX3CR1 axis.

Aims Insulin resistance (IR) is a major risk factor for cardiovascular disease and atherosclerosis. Life-threatening acute events are mainly due to rupture of unstable plaques, and the role of vascular smooth muscle cells (VSMCs) in this process in IR, Type 2 diabetes mellitus, and metabolic syndrome (T2DM/MetS) has not been fully addressed. Therefore, the role of VSMC survival in the generation of unstable plaques in T2DM/MetS and the involvement of inflammatory mediators was investigated. Methods and results Defective insulin receptor substrate 2 (IRS2)-mediated signalling produced insulin-resistant VSMCs with reduced survival, migration, and higher apoptosis than control cells. Silencing…

Síndrome de McCune-Albright: otra forma de neoplasias endocrinas múltiples

Presentamos el caso de una mujer con sindrome de McCune-Albright como paradigma de afeccion tumoral en multiples glandulas endocrinas. El diagnostico de la enfermedad se baso en la presencia de la triada clasica (lesiones hiperpigmentadas cutaneas de color cafe con leche, pubertad precoz y displasia fibrosa). Durante su seguimiento presento hipertiroidismo secundario a bocio multinodular toxico, hiperparatiroidismo, probablemente secundario a hiperplasia paratiroidea, y acromegalia secundaria a adenoma hipofisario productor de hormona de crecimiento. Se comenta la base molecular de la enfermedad y su amplia expresion fenotipica.

Analysis of sequence variations in the LDL receptor gene in Spain: general gene screening or search for specific alterations?

Abstract Background: Familial hypercholesterolemia (FH) is a frequent form of autosomal-dominant hypercholesterolemia that predisposes to premature coronary atherosclerosis. FH is caused by sequence variations in the gene coding for the LDL receptor (LDLR). This gene has a wide spectrum of sequence variations, and genetic diagnosis can be performed by 2 strategies. Methods: Point variations and large rearrangements were screened along all the LDLR gene (promoter, exons, and flanking intron sequences). Results: We screened a sample of 129 FH probands from the Valencian Community, Spain, and identified 54 different LDLR sequence variations. The most frequent (10% of cases) was 111insA, and 60…

Enhanced levels of the light/lymphotoxin-beta receptor inflammatory axis in metabolic syndrome patients

Oxidative stress and antioxidant enzyme values in lymphomonocytes after an oral unsaturated fat load test in familial hypercholesterolemic subjects

Oxidative stress (OS) has been observed in conditions affecting the cardiovascular system. Familial hypercholesterolemia (FH) is associated with an increased risk of premature coronary heart disease. In the postprandial state, circulating lipids and lipoproteins can modulate OS status. Our aim was to study the response of lymphomonocyte OS status and reactive oxygen species by-products after an oral unsaturated fat load test (OFLT) in those with FH and to compare this response with that obtained in normolipidemic, normoglycemic subjects. We studied 12 patients with FH and 20 healthy controls. In both groups, lymphomonocyte, oxidized/reduced glutathione ratio, and malondialdehyde were determ…

Peripheral blood levels of CXCL10 are a useful marker for diabetic polyneuropathy in subjects with type 2 diabetes.

BACKGROUND Diabetic peripheral neuropathy (DPN) is a chronic complication of diabetes mellitus associated with high morbidity and mortality. Major risk factors for DPN include metabolic changes, duration of diabetes, nerve ischaemia and derangements in regeneration and nerve repair programmes. Chemokines have been previously implicated in the pathogenesis of various neuropathies and neuropathic pain processes. The aim of this pilot study was to evaluate the association between the plasma levels of chemokines (CXCL9, CXCL10 and CXCL11) in the presence of DPN in a cohort of type 2 diabetes (T2D) patients. MATERIALS AND METHODS We studied 73 patients with T2D: 36 with DPN and 37 without DPN. D…

Increased thioredoxin levels are related to insulin resistance in familial combined hyperlipidaemia

BACKGROUND Thioredoxins (TRX) are major cellular protein disulphide reductases that are critical for redox regulation. Oxidative stress and inflammation play promoting roles in the genesis and progression of atherosclerosis, but until now scarce data are available considering the influence of TRX activity in familial combined hyperlipidaemia (FCH). Since FCH is associated with high risk of cardiovascular disease, the objective of the present study was to assess oxidative stress status in FCH patients, and evaluate the influence of insulin resistance (IR). MATERIALS AND METHODS A cohort of 35 control subjects and 35 non-related FCH patients were included, all of them nondiabetic, normotensiv…

Efficacy and safety of lomitapide in homozygous familial hypercholesterolaemia: the pan-European retrospective observational study

Abstract Aims Lomitapide is a lipid-lowering agent indicated as an adjunct therapy for adult homozygous familial hypercholesterolaemia (HoFH). This study evaluated the medium-term effectiveness and safety of lomitapide in a large cohort of HoFH patients in Europe. Methods and results In a multicentre retrospective, observational study including 75 HoFH patients treated with lomitapide in a real-world clinical setting from 9 European countries, low-density lipoprotein cholesterol (LDL-C) changes, adverse events (AEs), and major adverse cardiovascular events (MACE) were assessed. After a median 19 months (interquartile range 11–41 months) of treatment with a mean dosage of 20 mg of lomitapide…

Altered glutathione system is associated with the presence of distal symmetric peripheral polyneuropathy in type 2 diabetic subjects.

Abstract Distal symmetric peripheral polyneuropathy (DSPN) is a highly prevalent complication of diabetes. However, underlying pathophysiological mechanisms are multiple and not well understood. The aim of our study was to analyze the oxidative stress levels in circulating mononuclear cells by measuring the glutathione system, malondialdehyde and oxidized-LDL, in 60 type 2 diabetic patients from a well-characterized cohort of 196 type 2 diabetic patients. Using a nested case–control design, we studied 30 type 2 diabetic patients with distal symmetric polyneuropathy and 30 diabetic controls without this complication, according to the Neuropathy Disability Score. We have found that diabetic p…

Homocisteína plasmática, Lp(a) y marcadores de estrés oxidativo en la vasculopatía periférica del paciente con diabetes tipo 2

Resumen Objetivo Buscar nuevos factores biologicos como el estres oxidativo (EO) y su interaccion con los clasicos, edad, HbA1c, Lp(a) y homocisteina plasmatica asociados con la vasculopatia periferica (VP) del paciente con diabetes tipo 2 (DMT2). Sujetos y metodos Estudiamos 204 diabeticos tipo 2 seleccionados de forma consecutiva de un hospital de referencia y un hospital comarcal de nuestra comunidad autonoma en el periodo comprendido entre enero de 2009 a mayo de 2010. Se trato de un estudio transversal de caso (ITB   1,2. Los parametros clinicobiologicos fueron medidos por procedimientos estandarizados. Resultados Los sujetos fueron divididos en 2 grupos: con VP (ITB > 0,89) o sin VP (…

Supresión del eje hipotálamohipofisario-suprarrenal por la exposición crónica a glucocorticoides de uso tópico. Presentación de dos casos clínicos

Presentamos 2 casos clinicos con psoriasis extensa en los que el mal uso prolongado de corticoides topicos indujo la supresion del eje hipotalamohipofisario- suprarrenal y, como consecuencia, una insuficiencia suprarrenal secundaria. Se comentan los mecanismos y los factores que pueden dar lugar a dicha supresion.

Semiquantitative multiplex PCR: a useful tool for large rearrangement screening and characterization

Methods presently employed for detection of large rearrangements have several drawbacks, such as the amount of sample and time required, technical difficulty, or the probability of false-negative carriers. Using the low-density-lipoprotein receptor (LDLR) gene, whose mutations are responsible for familial hypercholesterolemia (FH), we have developed a procedure to detect large rearrangements in this gene based on semiquantitative PCR, with important improvements as compared to previous methods. Our method covers the complete LDLR gene and introduces an internal control in the reaction. The procedure discriminates the four different large rearrangements (two deletions and two insertions) tha…

Prevalence of plasma lipid abnormalities and its association with glucose metabolism in Spain: The di@bet.es study

Abstract Introduction Dyslipidemia is a significant contributor to the elevated CVD risk observed in type 2 diabetes mellitus. We assessed the prevalence of dyslipidemia and its association with glucose metabolism status in a representative sample of the adult population in Spain and the percentage of subjects at guideline-recommended LDL-C goals. Material and methods The di@bet.es study is a national, cross-sectional population-based survey of 5728 adults. Results A total of 4776 subjects were studied. Dyslipidemia was diagnosed in 56.8% of subjects; only 13.2% of subjects were treated with lipid lowering drugs. Lipid abnormalities were found in 56.8% of Spanish adults: 23.3% with high LDL…

Impact of Cholesterol Metabolism in Immune Cell Function and Atherosclerosis

Cholesterol, the most important sterol in mammals, helps maintain plasma membrane fluidity and is a precursor of bile acids, oxysterols, and steroid hormones. Cholesterol in the body is obtained from the diet or can be de novo synthetized. Cholesterol homeostasis is mainly regulated by the liver, where cholesterol is packed in lipoproteins for transport through a tightly regulated process. Changes in circulating lipoprotein cholesterol levels lead to atherosclerosis development, which is initiated by an accumulation of modified lipoproteins in the subendothelial space; this induces significant changes in immune cell differentiation and function. Beyond lesions, cholesterol levels also play …

Postprandial triglyceridaemia is modulated by insulin resistance but not by grade of obesity in abdominal and morbid obese subjects

Background Obesity is associated with high cardiovascular risk. Postprandial lipidaemia has been associated with cardiovascular disease risk. Our aim was to identify whether anthropometric parameters, insulin resistance (IR) and/or fasting plasma triglycerides may determine postprandial changes in lipoprotein concentrations in abdominal and morbid obese subjects. Methods We have studied 20 non-diabetic, normolipidaemic subjects with abdominal obesity, 20 morbid obese subjects and 20 healthy individuals, that have similar age and gender. In all of them a standardised oral fat load test (OFLT) with unsaturated fat was performed. Results During the OFLT, the postprandial triglycerides response…

Estudio de receptor anómalo suprarrenal en sujetos con síndrome de Cushing ACTH-independiente e hiperplasia nodular suprarrenal

Resumen Introduccion El sindrome de Cushing ACTH-independiente (SCAI) supone el 15-20% de los casos de sindrome de Cushing, de los cuales Material y metodos Estudio descriptivo multicentrico de una serie de 15 casos de SCAI con hiperplasia nodular suprarrenal (periodo de estudio: 2002-2016). En ellos se hizo el despistaje de receptor anomalo, mediante pruebas de estimulacion, considerando patologico un aumento de cortisol plasmatico ≥ del 25% respecto al valor basal. Resultados De los 15 casos, 13 fueron mujeres, con una edad media al diagnostico de 56,8 anos. En 12 de los 15 casos estudiados se detecto positividad de las pruebas de estimulacion. De ellos, fueron positivos para comida de pr…

Oxidative Stress and Chronic Inflammatory State Present in Familial Hypercholesterolemia is Reduced After a Fat Overload Rich in Unsaturated Fatty Acids

Increased plasma xanthine oxidase activity is related to nuclear factor kappa beta activation and inflammatory markers in familial combined hyperlipidemia

Abstract Background and aims Xanthine oxidase (XO) has been described as one of the major enzymes producing free radicals in blood. Oxidative stress and inflammatory processes have been implicated in the pathogenesis of endothelial dysfunction and the progression of atherosclerosis but until now, there is little data about the influence of vascular prooxidant systems and inflammation in familial combined hyperlipidemia (FCH). Our goal was to evaluate whether XO activity was altered in FCH and if it was related to the inflammatory process represented by NFkB, IL-6 and hsCRP, and assessing the correlation between XO activity and insulin resistance (IR). Method and results 40 Non-related subje…

Reduced penetrance of autosomal dominant hypercholesterolemia in a high percentage of families: importance of genetic testing in the entire family.

Abstract Background Autosomal dominant hypercholesterolemias (ADHs) are characterised by increased plasma levels of total and LDL cholesterol, predisposing to premature atherosclerosis. ADHs comprise several diseases with undistinguishable phenotype, caused by mutations in different genes: LDLR, APOB and PCSK9. Genetic studies are usually performed in patients with altered cholesterol levels. However, some persons carrying pathogenic mutations are normocholesterolemic and there are no further studies about this subject. We have studied the frequency of families and individuals carrying ADH mutations who do not present the disease in Spanish population. Methods We have analysed genes known t…

Terapias antiinflamatorias para la enfermedad cardiovascular: vías de señalización y mecanismos

Resumen Las enfermedades cardiovasculares (ECV) son una manifestacion clinica de la ateroesclerosis, una enfermedad inflamatoria que se agrava en presencia de diferentes factores de riesgo como la dislipemia o la diabetes mellitus tipo 2. Los eventos cardiovasculares agudos son resultado de un proceso inflamatorio cronico no resuelto que facilita la rotura de placas inestables. Los tratamientos existentes reducen los factores de riesgo, pero no previenen los eventos isquemicos recurrentes en pacientes con riesgo residual inflamatorio caracterizado por altas concentraciones de proteina C reactiva. Una mejor comprension del papel de la inmunidad innata y adaptativa en la ateroesclerosis ha ll…

Misclassification of subjects with insulin resistance and associated cardiovascular risk factors by homeostasis model assessment index. Utility of a postprandial method based on oral glucose tolerance test

Different methods are available for assessing insulin sensitivity in the fasting state. However, insulin resistance (IR) is initially a postprandial disturbance; and usually, when basal (fasting) disturbance appears, the process has been in progress for some time. Our aim was to investigate if a postprandial measurement, performing an oral glucose tolerance test (OGTT), is more sensitive than fasting values. We wished to identify early IR states in healthy, nonobese individuals and ascertain if this situation was associated with other cardiovascular risk factors. A total of 90 nonobese, nondiabetic, and nonsmoker individuals were studied. They were divided into 3 groups according to IR stat…

Association of C677T polymorphism in MTHFR gene, high homocysteine and low HDL cholesterol plasma values in heterozygous familial hypercholesterolemia.

Aim: to investigate the association of C677T polymorphism in the methylene tetrahydrofolate reductase (MTHFR) gene, homocysteine plasma values (Hcy), and plasma HDL cholesterol in heterozy-gous familial hypercholesterolemia (hFH).Methods: One hundred and twenty-five hFH subjects were studied. Plasma lipid, lipoprotein, vitamin B12, folic acid and Hcy values were determined. C677T polymorphism in the MTHFR gene was detected by SSCP-PCR. Genetic diagnosis of FH was determined by a three-step protocol using SSCP-PCR, Southern blot, long PCR and automatic sequencing.Results: We found significant differences in plasma HDL-C (CC 1.39±0.34, CT 1.33±0.39 and TT 1.14±0.26 mmol/L, p=0.028) between th…

Estudio de los valores de 8-oxo-7,8-dihidro-2’-desoxiguanosina como marcador de estrés oxidativo del ADN en pacientes con hiperlipemia familiar combinada

Fundamento y objetivo: Comparar los valores de 8-oxo-7,8-dihidro-2'-desoxiguanosina (8-oxo-dG) como marcador de estres oxidativo entre personas sanas y pacientes con hiperlipemia familiar combinada (HFC), modelo de dislipemia mixta con resistencia a la insulina y cardiopatia isquemica precoz, y estudiar su relacion con parametros clinicobiologicos de resistencia a la insulina. Sujetos y metodo: Se ha analizado a 40 pacientes (15 mujeres) no relacionados entre si y diagnosticados de HFC y a 20 sujetos sanos (8 mujeres) normolipemicos y no diabeticos. Se recogieron de forma estandarizada parametros clinicos, antropometricos y bioquimicos: perfil lipidico, glucemia e insulinemia basales y dete…

Familial Combined Hyperlipidemia, Metabolic Syndrome and Cardiovascular Disease

Our aim was to investigate the relationship between metabolic syndrome and cardiovascular disease (i.e., survivors of myocardial infarction) in patients with familial combined hyperlipidemia (FCH). We compared a group of 20 male patients with FCH who had survived a myocardial infarction with two other groups matched for age and body mass index, comprising 20 individuals with FCH who had not had a myocardial infraction and 20 control subjects. Plasma lipid, glucose, and insulin levels were determined. Metabolic syndrome was judged to present on the basis of World Health Organization (WHO) and National Cholesterol Education Program-Adult treatment panel (NCEP-ATPIII) criteria. Differences bet…

Gender differences on oxidative stress markers and complement component C3 plasma values after an oral unsaturated fat load test

Los niveles plasmáticos de IL-18 se relacionan con la insulinemia y están modulados por polimorfismos del gen de IL-18

INTRODUCTION Atherosclerosis is an inflammatory chronic disease influenced by multiple factors. Different prospective studies have shown that plasmatic levels of inflammatory markers were related to atherosclerosis and cardiovascular disease. OBJECTIVE To evaluate whether plasmatic levels of interleukin 18 (IL-18) are modulated by SNPs (single nucleotide polymorphisms) of the IL 18 gene and its possible association with insulin levels and other cardiovascular risk factors. METHODS 746 individuals were studied for a period of two years by opportunistic selection in the metropolitan area of Valencia. Parameters of lipid and glucose metabolism were analyzed by standard methodology. IL-18 was m…

Efficacy of Long-Term Treatment of Autosomal Recessive Hypercholesterolemia With Lomitapide: A Subanalysis of the Pan-European Lomitapide Study

Backgroundand aim: Autosomal recessive hypercholesterolemia (ARH) is a rare autosomal recessive disorder of low-density lipoprotein (LDL) metabolism caused by pathogenic variants in the LDLRAP1 gene. Like homozygous familial hypercholesterolemia, ARH is resistant to conventional LDL-lowering medications and causes a high risk of atherosclerotic cardiovascular diseases (ASCVDs) and aortic valve stenosis. Lomitapide is emerging as an efficacious therapy in classical HoFH, but few data are available for ARH.Results: This is a subanalysis carried out on nine ARH patients included in the Pan-European Lomitapide Study. The age at starting lomitapide was 46 (interquartile range (IQR), 39.0–65.5) y…

Plasma homocysteine levels are associated with ulceration of the foot in patients with type 2 diabetes mellitus.

Background To examine the association of biochemical markers of risk (plasma Hcy, microalbuminuria, lipoprotein (a)(Lp(a)) and diabetic dyslipidaemia) with the prevalence of diabetic foot ulceration in type 2 diabetic patients. Methods Case/control study conducted in 198 type 2 diabetic patients. 89 patients have foot ulcers and 109 have no foot ulcers (control group), in order to establish ORs for diabetic foot ulceration. In all subjects plasma Hcy, Lp(a), total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, apolipoprotein B, HbA1c and microalbuminuria were measured using standard procedures. Results Plasma Hcy, microalbuminuria, HbA…

Circulating mononuclear cells nuclear factor-kappa B activity, plasma xanthine oxidase, and low grade inflammatory markers in adult patients with familial hypercholesterolaemia.

Eur J Clin Invest 2010; 40 (2): 89–94 Abstract Background  Few data are available on circulating mononuclear cells nuclear factor-kappa B (NF-kB) activity and plasma xanthine oxidase (XO) activity in heterozygous familial hypercholesterolaemia (FH). The goal of the study was to analyse circulating mononuclear cells NF-kB and plasma XO activities in FH patients. Materials and methods  Thirty FH index patients and 30 normoglycaemic normocholesterolaemic controls matched by age, gender, body mass index, abdominal circumference and homeostasis model assessment index were studied. Plasma XO and inflammatory markers were measured by standard methods. NF-kB was assayed in circulating mononuclear c…

Differences in clinical and biological characteristics and prevalence of chronic complications related to aging in patients with type 2 diabetes

Type 2 diabetes mellitus (T2DM) is a chronic, highly prevalent disease that increases with age. Because of this, and due to its chronic complications, T2DM causes high human, social, and financial costs. In addition, the elderly population with T2DM has a marked clinical heterogeneity. Therefore, our main objective was to analyze the relationship of age with the clinical and biological manifestations of the disease and the prevalence of chronic complications in patients with T2DM.A cross-sectional study of a large population with T2DM (n=405) randomly selected from a Diabetes Unit and 2 health care centers (60%). The clinical, anthropometric, and biochemical variables of the subjects were c…

Oxidative stress and mrna expression after an oral unsaturated fat load test in subjects with abdominal obesity

Erythrocyte-associated apolipoprotein B and its relationship with clinical and subclinical atherosclerosis

Eur J Clin Invest 2012; 42 (4): 365–370 Abstract Background  Apolipoprotein (apo) B-containing lipoproteins are closely linked to atherogenesis. These lipoproteins are transported in plasma and are also associated with blood leucocytes. Our aim was to investigate whether apoB-containing lipoproteins are also present on the surface of erythrocytes and investigate the relationship with the presence of atherosclerosis in a cross-sectional study. Materials and methods  Erythrocyte-bound apoB (ery-apoB) was measured by flowcytometry in subjects with (CAD+) and without coronary artery disease (CAD−), based on coronary angiography or on a history of cardiovascular disease. Intima media thickness (…

Establishing cut-off values for apolipoprotein B and non-HDL-C according to LDL-C values in a South European population

SUMMARY Background: Low-density lipoprotein cholesterol (LDL-C) remains the primary target of therapy in most strategies of dyslipidaemia management focused on cardiovascular disease prevention. Different guidelines have identified specific LDL-C cut-off points as targets for therapeutic intervention. Many clinical situations characterised by dyslipidaemia and elevated triglycerides are common in our environment and in overall industrialised countries. Thus, lipid goals based only on LDL-C could misclassify an important percentage of subjects. The objective of the present study was to establish cut-off point values for apoB and non-HDL-C in relation to the identified LDL-C cut-off points fo…

Evaluation of clinical diagnosis criteria of familial ligand defective apoB 100 and lipoprotein phenotype comparison between LDL receptor gene mutations affecting ligand-binding domain and the R3500Q mutation of the apoB gene in patients from a South European population

Familial hypercholesterolemia (FH) and familial defective apoB 100 (FDB) are characterized by increased plasma low-density lipoprotein cholesterol (LDLc) levels and risk of coronary heart disease (CHD). FDB is clinically indistinguishable from FH. The aims of this study were to evaluate clinical diagnosis criteria for FDB and to compare the lipoprotein phenotype between carriers of LDL receptor (LDLR) gene mutations that affect the ligand-binding domain and subjects with the R3500Q mutation in apoB gene. We studied 213 subjects (113 probands) with FH and 19 heterozygous FDB subjects. Genetic diagnosis was determined by following a protocol based on Southern blot and polymerase chain reactio…

Oral Unsaturated Fat Load Impairs Postprandial Systemic Inflammation in Primary Hypercholesterolemia Patients.

Context: Primary hypercholesterolemia (PH) is a lipid disorder characterized by elevated levels of cholesterol and low-density lipoprotein (LDL). Low-grade systemic inflammation is associated with PH, which might explain the higher incidence of cardiovascular diseases in this setting.Objective: To evaluate the effect of an oral unsaturated fat load (OUFL) on different immune parameters and functional consequences in patients with PH in postprandial state.Design: A commercial liquid preparation of long-chain triglycerides (Supracal®; ω6/ω3 ratio >20/1, OUFL) was administered to 20 patients and 10 age-matched controls. Whole blood was collected before (fasting state) and 4 h after admi…

Polymorphisms in endothelin system genes, arsenic levels and obesity risk.

Background/objectivesObesity has been linked to morbidity and mortality through increased risk for many chronic diseases. Endothelin (EDN) system has been related to endothelial function but it can be involved in lipid metabolism regulation: Receptor type A (EDNRA) activates lipolysis in adipocytes, the two endothelin receptors mediate arsenic-stimulated adipocyte dysfunction, and endothelin system can regulate adiposity by modulating adiponectin activity in different situations and, therefore, influence obesity development. The aim of the present study was to analyze if single nucleotide polymorphisms (SNPs) in the EDN system could be associated with human obesity.Subjects/methodsWe analyz…

Enhanced reduction in oxidative stress and altered glutathione and thioredoxin system response to unsaturated fatty acid load in familial hypercholesterolemia.

Abstract Objectives Familial hypercholesterolemia (FH) is characterized by increased oxidative stress (OS) levels. In the postprandial state, lipids and lipoproteins modulate OS status through their impact on pro-oxidant and antioxidant mechanisms. The objective of this study was to evaluate in patients with FH the response to an unsaturated oral fat load test (OFLT) by analyzing the mRNA levels of genes involved in the glutathione and thioredoxin antioxidant systems. Design and Methods We analyzed 14 FH patients and 20 normolipidemic and normoglycemic controls. In both groups, mRNA values of antioxidant enzyme genes (glutathione and thioredoxin systems) were determined at baseline and at 2…

Utilidad de la ultrasonografía endoscópica para el diagnóstico de localización de tumores neuroendocrinos pancreáticos: presentación de 2 insulinomas benignos

Los insulinomas son tumores neuroendocrinos que se manifiestan por episodios de hipoglucemia de ayuno. El diagnostico se basa en la sospecha clinica, que debe ir seguida de la demostracion de hiperinsulinismo y la localizacion tumoral. Sin embargo, la localizacion no siempre es posible con las tecnicas de imagen habituales, por lo que se debe recurrir a otras mas complejas. Presentamos 2 casos de insulinomas cuya localizacion tumoral no fue posible con tecnicas de imagen convencionales, pero si con ultrasonografia endoscopica.

Association of chemokines IP-10/CXCL10 and I-TAC/CXCL11 with insulin resistance and enhance leukocyte endothelial arrest in obesity

Abstract Background and aims Obesity is a key contributing factor to incidental type 2 diabetes and cardiovascular disease. CXCR3 receptor and its ligands CXCL 10 and 11 are associated with atherosclerosis and cardiovascular disease. The aim of our study was to analyse the role of the CXCR3 ligands on insulin resistance (IR) and endothelial dysfunction in human obesity. Methods and results We have studied 45 obese patients (mean age 44 ± 6 years, body mass index 45 ± 9 kg/m2) who were selected for Roux-Y-gastric bypass surgery and 21 non obese control subjects with similar age and gender distribution. We measured by ELISA the circulating levels of the CXCR3 ligands interferon-γ inducible pr…

Polymorphisms of the UCP2 gene are associated with body fat distribution and risk of abdominal obesity in Spanish population

Eur J Clin Invest 2011 Abstract Background  Increased accumulation of fat results from an imbalance between energy expenditure and intake, being modulated by different environmental and genetic factors. Uncoupling proteins (UCPs) are mitochondrial carrier proteins able to spend energy generating heat. Therefore, variations in these genes are good candidates as potential modulators of body fat accumulation. Our aim was to investigate the possible association of genetic variations of the gene codifying the UCP2 protein with obesity and fat distribution. Design  We performed a cross-sectional study in 2367 individuals from two population-based studies from different regions of Spain. The Horte…

Different impacts of cardiovascular risk factors on oxidative stress.

The objective of the study was to evaluate oxidative stress (OS) status in subjects with different cardiovascular risk factors. With this in mind, we have studied three models of high cardiovascular risk: hypertension (HT) with and without metabolic syndrome, familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCH) with and without insulin resistance. Oxidative stress markers (oxidized/reduced glutathione ratio, 8-oxo-deoxyguanosine and malondialdehide) together with the activity of antioxidant enzyme triad (superoxide dismutase, catalase, glutathione peroxidase) and activation of both pro-oxidant enzyme (NAPDH oxidase components) and AGTR1 genes, as well as antioxidant…

Insulin resistance and oxidative stress in familial combined hyperlipidemia.

Oxidative stress is associated with atherosclerosis. Familial combined hyperlipidemia (FCH) is considered as a human model of primary dyslipidemia and atherosclerosis frequently associated with insulin resistance (IR), but there are few data on its possible relation to oxidative stress. The objective of this study was to evaluate oxidative stress status using different markers in subjects with FCH assessing its possible correlation with anthropometric parameters and IR. This was a cross-sectional study. A cohort of 40 FCH patients (20 with IR (HOMAor=3.2) and 20 without IR (HOMA3.2)), and 20 healthy volunteers were included, all of them non-diabetic, normotensive and non-smokers. We measure…

Lipoprotein hydrophobic core lipids are partially extruded to surface in smaller HDL: "Herniated" HDL, a common feature in diabetes

AbstractRecent studies have shown that pharmacological increases in HDL cholesterol concentrations do not necessarily translate into clinical benefits for patients, raising concerns about its predictive value for cardiovascular events. Here we hypothesize that the size-modulated lipid distribution within HDL particles is compromised in metabolic disorders that have abnormal HDL particle sizes, such as type 2 diabetes mellitus (DM2). By using NMR spectroscopy combined with a biochemical volumetric model we determined the size and spatial lipid distribution of HDL subclasses in a cohort of 26 controls and 29 DM2 patients before and after two drug treatments, one with niacin plus laropiprant a…

Urinary- and Plasma-Derived Exosomes Reveal a Distinct MicroRNA Signature Associated With Albuminuria in Hypertension.

Urinary albumin excretion (UAE) is a marker of cardiovascular risk and renal damage in hypertension. MicroRNAs (miRNAs) packaged into exosomes function as paracrine effectors in cell communication and the kidney is not exempt. This study aimed to state an exosomal miRNA profile/signature associated to hypertension with increased UAE and the impact of profibrotic TGF-β1 (transforming growth factor β1) on exosomes miRNA release. Therefore, exosomes samples from patients with hypertension with/without UAE were isolated and characterized. Three individual and unique small RNA libraries from each subject were prepared (total plasma, urinary, and plasma-derived exosomes) for next-generation sequ…

Síndrome de apnea-hipopnea del sueño como causa de seudofeocromocitoma

Los feocromocitomas son tumores neuroendocrinos poco frecuentes cuya manifestacion mas caracteristica es la hipertension arterial. Su diagnostico se basa en la demostracion de un exceso de produccion de catecolaminas o de sus metabolitos, seguido de tecnicas de imagen para la localizacion tumoral. Sin embargo, hay situaciones en las que estas hormonas pueden estar elevadas sin que haya un feocromocitoma; por tanto, esto se trata de falsos positivos. En esos casos hablamos de seudofeocromocitoma. Presentamos el caso de un paciente con un nodulo suprarrenal y catecolaminas elevadas de forma repetida en orina de 24 h. Fue intervenido quirurgicamente, pero a pesar de ello persistian las alterac…

PAI-1 Levels are Related to Insulin Resistance and Carotid Atherosclerosis in Subjects with Familial Combined Hyperlipidemia

Familial combined hyperlipidemia (FCH) is a primary atherogenic dyslipidemia with insulin resistance and increased cardiovascular risk. Plasminogen activator inhibitor type 1 (PAI-1) and myeloperoxidase (MPO) activity are associated with proinflammatory and atherothrombotic risk. Our aim was to study the role played by PAI-1 and MPO activity in the carotid atherosclerosis prevalence in FCH subjects. 36 FCH unrelated subjects (17 women) were matched by age and body weight with 36 healthy normolipidemic subjects (19 female). Blood lipids, glucose, insulin, insulin resistance (homeostasis model assessment (HOMA)), MPO, and PAI-1 were determined in both groups. Carotid intima media thickness (…

Dificultad en el tratamiento del hipertiroidismo por amiodarona: Presentación de un caso

La amiodarona puede alterar la función tiroidea en un 15-20% de los pacientes que la toman, dando lugar a hipotiroidismo o hipertiroidismo. La sobrecarga de yodo y la toxicidad directa sobre el tiroides inducida por amiodarona pueden provocar hipertiroidismo. Describimos un caso de tirotoxicosis grave por amiodarona que se diagnosticó buscando la causa que descompensó la cardiopatía de base del paciente, condicionando ésta el pronóstico y el manejo terapéutico. El tratamiento precisó un estrecho seguimiento y se basó en dosis elevadas de propiltiouracilo y dexametasona que no controlaron las consecuencias del hipertiroidismo a nivel cardiaco necesitando la tiroidectomia total. Creemos, con …

Study of abnormal adrenal receptors in subjects with ACTH-independent Cushing's syndrome and nodular adrenal hyperplasia

ACTH-independent Cushing's Syndrome (AICS) accounts for 15-20% of cases of Cushing's syndrome, with1% due to abnormal receptors. Our aim is to study the presence of abnormal receptors in subjects diagnosed with AICS with nodular adrenal hyperplasia in a 14-year period (2002-2016), as well as its clinical-biological and evolutive characteristics.A multicentre descriptive study of a 15-case series of AICS with nodular adrenal hyperplasia (study period: 2002-2016). In these cases, abnormal receptor screening was performed by means of stimulation tests, with a plasma cortisol increase of ≥ 25% from baseline being considered pathologic.Of the 15 cases, 13 were female, with a mean age at diagnosi…

Plasma homocysteine levels are independently associated with the severity of peripheral polyneuropathy in type 2 diabetic subjects.

Peripheral polyneuropathy (PN) is a frequent complication of diabetes. However, mechanisms underlying the development of PN are multifactorial and not well understood. Our aim was to examine the association of plasma homocysteine (Hcy) with the prevalence and grade of peripheral PN in patients with type 2 diabetes (T2DM). We studied a cohort of 196 subjects with T2DM classified according to the grade of PN (Neuropathy Disability Score, NDS). Subjects with the highest grade of PN were older and had significantly increased levels of creatinine, microalbuminuria, HbA1c, and plasma Hcy compared to the other two groups. The differences in plasma Hcy values were maintained after correcting for co…

A new PCSK9 gene promoter variant affects gene expression and causes autosomal dominant hypercholesterolemia.

Autosomal dominant hypercholesterolemia (ADH) is a genetic disorder characterized by increased low-density lipoprotein (LDL)-cholesterol levels, leading to high risk of premature cardiovascular disease. More than 900 mutations in LDL receptor, six in APOB and 10 in PCSK9 have been identified as a cause of the disease in different populations. All known mutations in PCSK9 causing hypercholesterolemia produce an increase in the enzymatic activity of this protease. Up to now, there are data about the implication of PCSK9 in ADH in a low number of populations, not including a Spanish population.The objective of the study was to study the prevalence of PCSK9 mutations in ADH Spanish population.W…

Unsaturated Oral Fat Load Test Improves Glycemia, Insulinemia and Oxidative Stress Status in Nondiabetic Subjects with Abdominal Obesity.

Aims To evaluate the changes in glycemia, insulinemia, and oxidative stress markers during an oral fat load test in nondiabetic subjects with abdominal obesity and to analyze the association between postprandial oxidative stress markers and postprandial glucose and insulin responses. Methods We included 20 subjects with abdominal obesity (waist circumference > 102 cm for men and > 88 cm for women) and 20 healthy lean controls (waist circumference < 102 cm for men and < 88 cm for women). After 12 hours of fasting we performed a standardized fat load test (0–8 hours) with supracal® (50 g/m2). We determined metabolic parameters, oxidized and reduced glutathione, and malondialdehyde. Results In…