Association of serum retinol binding protein 4 with atherogenic dyslipidemia in morbid obese patients.

Retinol binding protein 4 (RBP4) is an adipokine that may contribute to the development of insulin resistance. However, how this adipokine is affected and its possible involvement in lipid metabolism in obese patients with varying degrees of insulin resistance is yet to be determined. A total of 299 middle-aged morbid obese patients (BMI>40 kg/m(2)) were divided in euglycemic, metabolic syndrome or type 2 diabetic. Anthropometric measurements, biochemical variables and systemic RBP4 levels were determined. RBP4 levels were significantly higher in patients with metabolic syndrome and type 2 diabetes than in euglycemic subjects (42.9±14.6; 42.3±17.0 and 37.4±11.7 µg/ml, respectively) and correlated with triglycerides but not with those of HOMA-IR in the whole population. The multivariate regression model revealed that triglycerides were the strongest predictor of systemic RBP4 levels. Analysis of lipoprotein subfractions in a subpopulation of 80 subjects showed an altered profile of insulin resistant states characterized by higher VLDL, sdLDL and small HDL percentages and lower large HDL percentage. Although RBP4 levels correlated significantly with LDL particle size and small HDL percentage, the latter parameter was independently associated only with RBP4. Our study reveals that systemic RBP4 levels could play an important role in lipid metabolism in morbid obesity, increasing triglyceride levels and contributing to the formation of small HDL.

A single acute dose of pinitol from a naturally-occurring food ingredient decreases hyperglycaemia and circulating insulin levels in healthy subjects.

A limited amount of research suggests that oral ingestion of pinitol (3-O-methyl-d-chiro-inositol) positively influences glucose tolerance in humans. This study assessed the effects of different doses of pinitol supplementation on glucose tolerance, insulin sensitivity and plasma pinitol concentrations. Thirty healthy subjects underwent two one-day trials in which they consumed a nutritive beverage (Fruit Up®) containing 2.5, 4.0 or 6.0g of pinitol and a corresponding placebo equivalent in both energy and carbohydrates. Blood samples were collected frequently over the 240-min test period. The pinitol-enriched beverage reduced serum glucose and insulin at 45 and 60min, but only at a dose of 6.0g. Plasma pinitol concentrations, maximum concentration and AUC increased according to the dose administered. The results show that a single dose of pinitol from a naturally-occurring food ingredient at the highest dose administered acutely influences indices of whole-body glucose tolerance and insulin sensitivity in healthy subjects.

Mitochondrial dysfunction and oxidative stress in insulin resistance.

Evidence is mounting of the involvement of mitochondrial dysfunction in insulin resistance, diabetes and associated complications. This review aims to provide an overview of the effects of insulin resistance on mitochondrial function in several tissues. We consider the pathogenesis of insulin resistance from a mitochondrial perspective and contemplate potential beneficial effects of strategies aimed at modulating mitochondrial function in insulin resistance, including insulin and insulin-sensitizing drugs, antioxidants, and selectively targeting antioxidants to mitochondria.

Human leukocyte/endothelial cell interactions and mitochondrial dysfunction in type 2 diabetic patients and their association with silent myocardial ischemia.

OBJECTIVE: Diabetes is associated with oxidative stress and increased mortality, but a possible correlation between leukocyte-endothelium interactions, oxidative stress, and silent myocardial ischemia (SMI) is yet to be confirmed. RESEARCH DESIGN AND METHODS: Mitochondrial dysfunction and interactions between leukocytes and human umbilical vein endothelial cells were evaluated in 200 type 2 diabetic patients (25 with SMI) and 60 body composition- and age-matched control subjects. A possible correlation between these parameters and the onset of SMI was explored, and anthropometric and metabolic parameters were also analyzed. RESULTS: Waist, levels of triglycerides, proinflammatory cytokines (interleukin-6 and tumor necrosis factor-α), HbA1c, high-sensitivity C-reactive protein (hs-CRP), glucose, and insulin, and homeostasis model assessment of insulin resistance were higher in diabetic patients than in control subjects. However, no statistical differences in hs-CRP and insulin levels were detected when the data were adjusted for waist. None of these parameters varied between SMI and non-SMI patients. Mitochondrial function was impaired and leukocyte-endothelium interactions were more frequent among diabetic patients, which was evident in the lower mitochondrial O2 consumption, membrane potential, polymorphonuclear cell rolling velocity, and GSH/GSSG ratio, and in the higher mitochondrial reactive oxygen species production and rolling flux, adhesion, and vascular cell adhesion molecule-1 (VCAM-1) and E-selectin molecules observed in these subjects. Moreover, these differences correlated with SMI. Statistical differences were maintained after adjusting the data for BMI and waist, with the exception of VCAM-1 levels when adjusted for waist. CONCLUSIONS: Oxidative stress, mitochondrial dysfunction, and endothelium-inducing leukocyte-endothelium interactions are features of type 2 diabetes and correlate with SMI.

Estudio de las subfracciones lipoproteicas tras el tratamiento de simvastatina y ezetimiba, en monoterapia o combinado, en pacientes hiperlipidémicos / Study of lipoprotein subfractions following treatment with simvastatin and ezetimibe administred alone and in combination in hyperlipidemic patients

Introducción: La combinación de fármacos es habitual en el tratamiento de las dislipidemias, siendo las estatinas y la ezetimiba la asociación más utilizada. Al actuar a distinto nivel, con esta combinación se facilita la consecución de los objetivos terapéuticos. Sin embargo, poco se sabe sobre cómo estos fármacos -en monoterapia o asociados- podrían afectar cualitativamente la composición de las subfracciones lipoproteicas, las cuales difieren en tamaño y potencial aterogénico, así como su efecto antiinflamatorio. Métodos Se incluyeron 39 pacientes con hiperlipidemia, los cuales fueron aleatoriamente distribuidos en 2 grupos: a uno se le administró simvastatina (40mg/día) y al otro ezetimiba (10mg/día) durante 4 semanas, transcurridas las cuales se les adminsitró de forma conjunta ambos fármacos durante 4 semanas más. Se valoró el perfil lipídico, subfracciones lipoproteicas de LDL y HDL, así como parámetros inflamatorios. Resultados El tratamiento farmacológico en monoterapia (simvastatina vs ezetimiba) redujo el cLDL (..) (AU)

Introduction: Coadministration of drugs is common in the pharmacologic treatment of dyslipidemia, with statins and ezetimibe generally constituting the medication of choice. By acting at different levels, the combination of these drugs allows the therapeutic objective to be achieved. However, it is not known how these drugs qualitatively affect the composition of lipoproteinsubfractions, which differ in size and atherogenic potential. We set out to evaluate this effect as well as their (..) (AU)

Comparability of two different polyacrylamide gel electrophoresis methods for the classification of LDL pattern type.

BACKGROUND: The measurement of small dense low-density lipoprotein (sdLDL) particles is relevant when assessing cardiovascular risk. However, there is as yet no referenced method for the determination of LDL subfractions or a standardized comparison of the methods currently available. Therefore, the aim of this study was to compare the pattern of LDL particles measured by polyacrylamide tube gel electrophoresis (PTGE) and polyacrylamide gradient gel electrophoresis (PGGE) and to correlate the results with triglyceride concentration. MATERIALS AND METHODS: Serum samples were collected from 177 patients. Lipid profile and LDL particle size were assessed using PTGE and PGGE. RESULTS: Pearson correlation and kappa index revealed a very good agreement between the methods. There was 81.3% concordance for classification of sdLDL particles and 97.2% concordance for classification of large LDL when PTGE and PGGE were compared. LDL size correlated with triglyceride in subjects with triglyceride levels >116 mg/dl, pointing to a high CAD risk, as reflected by their higher prevalence of pattern B. CONCLUSIONS: PTGE correlates favourably and is in very good agreement with PGGE. The determination of LDL particle size may be an appropriate analytical procedure to estimate CAD risk in patients with high triglyceride levels.

Effect of weight loss on C3 and C4 components of complement in obese patients.

BACKGROUND: Circulating C3 levels are elevated in obese patients, but how this factor is affected after weight loss through diet is a question that is yet unanswered. Therefore, the aim of this study was to evaluate the effects of weight loss on lipid and hydrocarbonated metabolism parameters and on the levels of C3 and C4 components of complement in obese patients. DESIGN: This is a longitudinal intervention study based on a 6-week very low-calorie diet (VLCD), a liquid formula of 603 kcal/day. A total of 131 middle-aged patients were distributed among grades II, III and IV of obesity. Anthropometric parameters, total cholesterol, triglycerides, high-density lipoprotein cholesterol, LDLc, apolipoproteins A-I and B-100, glucose, insulin, HOMA-IR and C3 and C4 levels were evaluated at baseline and after 6 weeks of intervention. RESULTS: After VLCD, the moderate weight loss was accompanied by a significant reduction in C3 levels in grade III and grade IV patients (10.2% and 15.4%, respectively; P < 0.001). C4 levels were not altered. Adherence to the diet improved anthropometric parameters and was accompanied by a significant decrease in all lipid profile parameters (P < 0.001). In addition, weight loss was associated with an improvement in hydrocarbonated metabolism as shown by the decrease in glucose levels and HOMA-IR (P < 0.01). CONCLUSIONS: Our findings show that in severely obese patients following a VLCD for 6 weeks produces reductions in factor C3, a biomarker of cardiovascular disease, and a significant improvement in some features of metabolic syndrome. In this way, the abovementioned diet may represent an effective strategy for treating obesity and related cardiovascular risk factors.

A review on the role of phytosterols: new insights into cardiovascular risk.

Phytosterols, which are structurally related to cholesterol, are found in all plant foods with highest concentration occurring in vegetable oils and nuts. Phytosterols are known to reduce serum low-density lipoprotein cholesterol level without changing high-density lipoprotein cholesterol or triglyceride levels. Daily consumption of phytosterols-enriched foods is widely used as a therapeutic option to lower plasma cholesterol and atherosclerotic disease risk. The cholesterol-lowering action of phytosterols is thought to occur, at least in part, through competitive replacement of dietary and biliary cholesterol in mixed micelles, which undermines the absorption of cholesterol. The aim of this review is to provide a general overview of available evidence regarding the effects of phytosterols on cholesterol metabolism and addressing issues related to efficacy as dose, length, frequency of consumption, type of phytosterol (sterols versus stanols) or food matrix. Furthermore, we will explore the factors that influence the response of individuals to phytosterol therapy and evaluate their safety and the possibility that elevated plasma phytosterol concentrations contribute to the development of premature coronary artery disease.

Mitochondrial dysfunction and targeted drugs: a focus on diabetes.

Diabetes is a severe, heterogeneous, multifactorial, chronic disease. Diabetes and oxidative stress are related to continuous and acute overproduction of reactive oxygen species (ROS). These ROS are released principally from mitochondria, but also have other sources. Oxidative stress seems to play an important role in mitochondria-mediated disease processes, though the exact molecular mechanisms responsible remain elusive. ROS are necessary for the proper functioning of the cell, but their excessive production can be harmful, making antioxidant defenses essential. Some substances with antioxidant properties, such as vitamins C and E, have been used to eradicate the oxidative stress associated with diabetes. The results of clinical trials employing anti-oxidative stress reagents in patients with diabetes are contradictory, perhaps due to inadequate study design or the specific targets selected. This review considers the process of diabetes from a mitochondrial perspective and evaluates strategies currently under development for the targeted delivery of antioxidants or other molecules to mitochondria. The evidence compiled herein endorses the selective targeting of specific molecules to mitochondria as an effective strategy for modulating mitochondrial respiration and ROS production and protecting mitochondria against oxidative stress.

Low intestinal cholesterol absorption is associated with a reduced efficacy of phytosterol esters as hypolipemic agents in patients with metabolic syndrome.

BACKGROUND & AIMS: Phytosterols (PS) lower LDLc, but their effect on metabolic syndrome (MetS) remains unknown. We evaluated whether low-fat milk enriched with PS improves cardiovascular risk factors in these patients. METHODS: A randomised parallel trial employing 24 moderate-hypercholesterolaemic MetS patients and consisting of two 3-month intervention phases. After a 3-month healthy diet, patients were divided into two intervention groups: diet (n = 10) and diet + PS (n = 14) (2 g/day). A control group of 24 moderate-hypercholesterolaemic patients without MetS (matched in age and BMI) underwent the same procedure. RESULTS: Neither dietary intervention nor enrichment of PS induced any improvement in the serum lipoprotein profile of MetS patients. By contrast, in the non-MetS population, a healthy diet effectively reduced TC, LDLc, non-HDLc and Apo B-100, with further decreases in TC (6.9%), LDLc (10.5%), non-HDLc (10.3%), Apo B-100 (6.2%) and Apo B-100/ApoA-I ratio (11.6%) being observed when PS were administered. No differences in LDL diameter, hsCRP or homocysteine were detected in any of the groups after consuming PS. This supplementation produced a significant increase in PS levels only in the non-MetS population. CONCLUSIONS: PS therapy appears to be of little value to MetS patients, likely due to its reduced intestinal cholesterol absorption. The efficacy of PS as hypocholesterolaemic agents is thus limited.

Mitochondria-targeted antioxidant peptides.

Overproduction of reactive oxygen species (ROS) under pathophysiologic conditions is part of the disease process. These ROS are released from different sources, and in particular from mitochondria. Although the molecular mechanisms responsible for mitochondria-mediated disease processes are unclear, oxidative stress seems to play an important role. ROS are essential to cell function, but adequate levels of antioxidant defenses are required in order to avoid the harmful effects that excessive ROS production can produce. Mitochondrial oxidative stress damage and dysfunction contribute to a number of cell pathologies that manifest themselves through a range of conditions. The antioxidants available until now have not proved to be particularly effective against many of these disorders. It is possible that these antioxidants do not reach the sites of free radical generation, especially when mitochondria are the primary source of ROS. Recent developments in mitochondria-targeted antioxidants have moved closer to providing protection against mitochondrial oxidative damage. The SS (Szeto-Schiller) peptide antioxidants represent a novel approach that employs the targeted delivery of antioxidants to the inner mitochondrial membrane. These SS peptides scavenge hydrogen peroxide and peroxynitrite and inhibit lipid peroxidation. By reducing mitochondrial ROS, they inhibit mitochondrial permeability transition and cytochrome c release, thus preventing oxidant-induced cell death. Preclinical studies support the use of these peptides for ischemia-reperfusion injury and neurodegenerative disorders. Although peptides have often been considered to be poor drug candidates, the few that have been studied are promising agents for the treatment of diseases.