Publications by authors named "José T Real"

71 Publications

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

Microvasc Res 2021 Sep 15;139:104254. Epub 2021 Sep 15.

INCLIVA Biomedical Research Institute, Valencia, Spain; Endocrinology and Nutrition Service, University Clinic Hospital of Valencia, Valencia, Spain; CIBERDEM: Diabetes and Associated Metabolic Diseases Networking Biomedical Research- ISCIII, Madrid, Spain; Department of Medicine, Faculty of Medicine, University of Valencia, Spain. Electronic address:

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/m) 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 protein 10 (IP-10/CXCL10) and interferon-γ-inducible T-cell alpha chemoattractant (I-TAC/CXCL11). Using an ex vivo procedure with the flow chamber assay, we have investigated the effect of such chemokines on endothelial leukocytes arrest under dynamic conditions. Peripheral blood levels of CXCL10 and CXCL11 were significantly higher in obese subjects than in controls (p < 0.001) and significantly correlated with BMI, waist circunference and HOMA-IR. Obese patients with HOMA-IR index above 75th percentile showed highest increase of circulating CXCL10 and CXCL11 values. Under dynamic flow conditions, the enhanced adhesion of patient leukocytes to TNFα-induced human arterial endothelial cells was partly dependent on CXCR3.

Conclusions: The study demonstrates that CXCL10 and CXCL11 are associated with IR and enhance leukocyte endothelial arrest in obese subjects. Blockade of CXCR3 signaling might be a new therapeutic approach for the prevention of obesity-associated cardiovascular co-morbidities.
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http://dx.doi.org/10.1016/j.mvr.2021.104254DOI Listing
September 2021

Activation of the Constitutive Androstane Receptor Inhibits Leukocyte Adhesiveness to Dysfunctional Endothelium.

Int J Mol Sci 2021 Aug 27;22(17). Epub 2021 Aug 27.

Institute of Health Research-INCLIVA, 46010 Valencia, Spain.

Leukocyte cell recruitment into the vascular subendothelium constitutes an early event in the atherogenic process. As the effect of the constitutive androstane receptor (CAR) on leukocyte recruitment and endothelial dysfunction is poorly understood, this study investigated whether the role of CAR activation can affect this response and the underlying mechanisms involved. Under physiological flow conditions, TNFα-induced endothelial adhesion of human leukocyte cells was concentration-dependently inhibited by preincubation of human umbilical arterial endothelial cells with the selective human CAR ligand CITCO. CAR agonism also prevented TNFα induced VCAM-1 expression, as well as MCP-1/CCL-2 and RANTES/CCL-5 release in endothelial cells. Suppression of CAR expression with a small interfering RNA abrogated the inhibitory effects of CITCO on these responses. Furthermore, CITCO increased interaction of CAR with Retinoid X Receptor (RXR) and reduced TNFα-induced p38-MAPK/NF-κB activation. In vivo, using intravital microscopy in the mouse cremasteric microcirculation treatment with the selective mouse CAR ligand TCPOBOP inhibited TNFα-induced leukocyte rolling flux, adhesion, and emigration and decreased VCAM-1 in endothelium. These results reveal that CAR agonists can inhibit the initial inflammatory response that precedes the atherogenic process by targeting different steps in the leukocyte recruitment cascade. Therefore, CAR agonists may constitute a new therapeutic tool in controlling cardiovascular disease-associated inflammatory processes.
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http://dx.doi.org/10.3390/ijms22179267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431649PMC
August 2021

Hypercholesterolemic patients have higher eryptosis and erythrocyte adhesion to human endothelium independently of statin therapy.

Int J Clin Pract 2021 Sep 2:e14771. Epub 2021 Sep 2.

Endocrinology and Nutrition Department, Hospital Clínico Universitario, Department of Medicine, University of Valencia, Valencia, Spain.

Background: Phosphatidylserine (PS) externalization out of the membrane facilitates the eryptotic erythrocytes (EE) binding to endothelial cells (EC), potentially leading to atherosclerosis. Thus, the levels of eryptosis and interactions of EE-EC in hypercholesterolemic patients, either non-medicated or medicated, compared with healthy subjects were studied.

Methods: A total of 56 subjects clustered into three groups: (control (n = 20), hypercholesterolemic non-treated (HCNT) (n = 15), and statin-treated (HCT) (n = 21)) were enrolled in this cross-sectional study. Biochemical parameters were determined with validated and standard methods. PS exposure was estimated from annexin-V-binding, cell volume from forward scatter (FSC), and GSH from CMFDA fluorescence by flow cytometry. The erythrocyte-EC adhesion assay was performed by using the parallel-plate flow chamber technique.

Results: Higher PS externalization and adhesion of erythrocytes to EC (P < .05) was found in hypercholesterolemic subjects, regardless of statin treatment, compared with the control group. Although no correlation between FSC and PS externalization with other parameters was found, GSH was inversely correlated with erythrocyte adhesion, which was significantly correlated with total cholesterol, LDL-c, and apolipoprotein B.

Conclusion: The link between hypercholesterolemia and eryptosis suggests a possible detrimental impact of this binomial on endothelial function with possible further development of atherosclerosis and microcirculation problems in hypercholesterolemic patients, independently of statin therapy.
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http://dx.doi.org/10.1111/ijcp.14771DOI Listing
September 2021

Anthropometric Indicators as a Tool for Diagnosis of Obesity and Other Health Risk Factors: A Literature Review.

Front Psychol 2021 9;12:631179. Epub 2021 Jul 9.

Service of Endocrinology and Nutrition, Hospital Clínico Universitario de Valencia, Valencia, Spain.

Obesity is characterized by the accumulation of an excessive amount of fat mass (FM) in the adipose tissue, subcutaneous, or inside certain organs. The risk does not lie so much in the amount of fat accumulated as in its distribution. Abdominal obesity (central or visceral) is an important risk factor for cardiovascular diseases, diabetes, and cancer, having an important role in the so-called metabolic syndrome. Therefore, it is necessary to prevent, detect, and appropriately treat obesity. The diagnosis is based on anthropometric indices that have been associated with adiposity and its distribution. Indices themselves, or a combination of some of them, conform to a big picture with different values to establish risk. Anthropometric indices can be used for risk identification, intervention, or impact evaluation on nutritional status or health; therefore, they will be called anthropometric health indicators (AHIs). We have found 17 AHIs that can be obtained or estimated from 3D human shapes, being a noninvasive alternative compared to X-ray-based systems, and more accessible than high-cost equipment. A literature review has been conducted to analyze the following information for each indicator: definition; main calculation or obtaining methods used; health aspects associated with the indicator (among others, obesity, metabolic syndrome, or diabetes); criteria to classify the population by means of percentiles or cutoff points, and based on variables such as sex, age, ethnicity, or geographic area, and limitations.
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http://dx.doi.org/10.3389/fpsyg.2021.631179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299753PMC
July 2021

Lipid metabolism and classification of hyperlipaemias.

Clin Investig Arterioscler 2021 May;33 Suppl 1:3-9

Departamento de Medicina, Universitat de València, Valencia, España; Instituto de Investigación Sanitaria INCLIVA, Valencia, España; CIBER de Diabetes y Enfermedades Metabólicas Asociadas - CIBERDEM, ISCIII, Madrid, España. Electronic address:

This chapter summarises, and updates, lipid metabolism. Both pathways, exogenous metabolisms route via the chylomicrons, and the endogenous pathway of very low-density lipoproteins (VLDL) and low-density lipoproteins (LDL). The reverse cholesterol metabolism will also be mentioned. It also includes the current classification of hyperlipidaemias or hyperlipoproteinaemias, with a reminder of the phenotype classification, and further developments of the aetiological classification. Both parts have updated references, with which knowledge of this vast subject can be expanded.
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http://dx.doi.org/10.1016/j.arteri.2020.12.008DOI Listing
May 2021

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

Front Pharmacol 2021 20;12:656244. Epub 2021 Apr 20.

Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain.

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. 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. A commercial liquid preparation of long-chain triglycerides (Supracal; 6/3 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 administration (postprandial state). Flow cytometry was employed to determine platelet and leukocyte activation, and the levels of circulating platelet-leukocyte aggregates. Soluble markers were determined by ELISA, and the parallel-plate flow chamber was employed to study leukocyte adhesion to the dysfunctional arterial endothelium. The PH group had a lower percentage of activated platelets and circulating type 1 monocytes, and blunted neutrophil activation after the OUFL, accompanied by a significant increase in the percentage of regulatory T lymphocytes. In this group, the OUFL led to a significant impairment of leukocyte adhesion to the dysfunctional [tumor necrosis factor α (TNFα)-stimulated] endothelium and reduced the plasma levels of soluble P-selectin, platelet factor-4 (PF-4)/CXCL4, CXCL8, CCL2, CCL5, and TNFα. The OUFL has a beneficial impact on the pro-thrombotic and pro-inflammatory state of PH patients and might be a promising macronutrient approach to dampen the systemic inflammation associated with PH and the development of further cardiovascular events.
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http://dx.doi.org/10.3389/fphar.2021.656244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093814PMC
April 2021

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

Int J Clin Pract 2021 Aug 24;75(8):e14302. Epub 2021 May 24.

Endocrinology and Nutrition Service, Hospital Clínico Universitario de Valencia, Valencia, Spain.

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. DPN was established through the Semmes-Weinstein test (SW). Plasma levels of circulating chemokines CXCL9, CXCL10 and CXCL11 were determined using DuoSet ELISA kits (Abingdon, UK).

Results: We found that levels of CXCL10 were significantly higher in patients with DPN than amongst patients without DPN (57.6 ± 38.3 vs 38.1 ± 33.4 pg/mL, respectively; P = .034). Serum levels of chemokine CXCL9 were also higher amongst patients with DPN but did not reach a statistical significance (188.1 ± 72.7 and 150.4 ± 83.6 pg/mL, respectively, P = .06).

Conclusions: Increased circulating levels of CXCL10 were associated with DPN in T2D patients, suggesting a role of this chemokine in the DPN. Determination of CXCL10 levels could be used as a marker for the early detection and implementation of therapeutic strategies in order to reverse and prevent the DPN.
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http://dx.doi.org/10.1111/ijcp.14302DOI Listing
August 2021

NT3/TrkC Pathway Modulates the Expression of UCP-1 and Adipocyte Size in Human and Rodent Adipose Tissue.

Front Endocrinol (Lausanne) 2021 18;12:630097. Epub 2021 Mar 18.

Departamento de Farmacología, Facultad de Farmacia, Universidad de Valencia, Valencia, Spain.

(NT3), through activation of its tropomyosin-related kinase receptor C (TrkC), modulates neuronal survival and neural stem cell differentiation. It is widely distributed in peripheral tissues (especially vessels and pancreas) and this ubiquitous pattern suggests a role for NT3, outside the nervous system and related to metabolic functions. The presence of the NT3/TrkC pathway in the adipose tissue (AT) has never been investigated. Present work studies in human and murine adipose tissue (AT) the presence of elements of the NT3/TrkC pathway and its role on lipolysis and adipocyte differentiation. qRT-PCR and immunoblot indicate that NT3 (encoded by ) was present in human retroperitoneal AT and decreases with age. NT3 was also present in rat isolated adipocytes and retroperitoneal, interscapular, perivascular, and perirenal AT. Histological analysis evidences that NT3 was mainly present in vessels irrigating AT close associated to sympathetic fibers. Similar mRNA levels of TrkC (encoded by ) and β-adrenoceptors were found in all ATs assayed and in isolated adipocytes. NT3, through TrkC activation, exert a mild effect in lipolysis. Addition of NT3 during the differentiation process of human pre-adipocytes resulted in smaller adipocytes and increased uncoupling protein-1 (UCP-1) without changes in β-adrenoceptors. Similarly, transgenic mice with reduced expression of NT3 (Ntf3 knock-in lacZ reporter mice) or lacking endothelial NT3 expression (Ntf3flox1/flox2;Tie2-Cre+/0) displayed enlarged white and brown adipocytes and lower UCP-1 expression.

Conclusions: NT3, mainly released by blood vessels, activates TrkC and regulates adipocyte differentiation and browning. Disruption of NT3/TrkC signaling conducts to hypertrophied white and brown adipocytes with reduced expression of the thermogenesis marker UCP-1.
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http://dx.doi.org/10.3389/fendo.2021.630097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015941PMC
March 2021

The nuclear retinoid-related orphan receptor RORα controls adipose tissue inflammation in patients with morbid obesity and diabetes.

Int J Obes (Lond) 2021 07 26;45(7):1369-1381. Epub 2021 Feb 26.

Institute of Health Research-INCLIVA, Valencia, Spain.

Background/aims: Inflammation governs adipose tissue (AT) dysfunction in obesity. Retinoic acid receptor-related orphan receptor alpha (RORα) is associated with inflammation and insulin resistance in animal studies, but its role in human obesity remains elusive. We investigated the expression and function of RORα on AT inflammation in patients with morbid obesity with/without diabetes.

Subjects/methods: We assessed RORα expression in paired biopsies of subcutaneous and omental AT from 41 patients (body mass index (BMI) 43.3 ± 0.8 kg/m) during Roux-en-Y-gastric surgery and explored the functional consequences of pharmacological RORα blockade in AT ex vivo.

Results: RORα expression was significantly higher in omental AT than in subcutaneous AT (p = 0.03) and was positively associated with BMI (r = 0.344, p = 0.027) and homeostasis model assessment of insulin resistance (r = 0.319, p = 0.041). In ex vivo assays, IL-8/CXCL8 and MCP-1/CCL2 chemokine release was significantly higher in omental fat explants from diabetic patients than from non-diabetics and was significantly diminished by RORα blockade (p < 0.05). Inhibition of RORα improved protein kinase B signaling and decreased NF-κB activity in omental AT from patients with diabetes (p < 0.05). Under dynamic flow conditions, RORα blockade prevented mononuclear cell attachment to human dysfunctional endothelial cells.

Conclusions: RORα blockade represents a potential therapy to prevent AT dysfunction and inflammation associated with insulin resistance in human obesity.
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http://dx.doi.org/10.1038/s41366-021-00787-5DOI Listing
July 2021

Therapeutic inertia in patients with type 2 diabetes treated with non-insulin agents.

J Diabetes Complications 2021 03 5;35(3):107828. Epub 2021 Jan 5.

Department of Endocrinology & Nutrition, Clinic University Hospital and INCLIVA, Valencia, Spain; Department of Medicine, Medicine Faculty, University of Valencia (UV), Valencia, Spain; CIBERDEM, CIBER de Diabetes y Enfermedades Metabólicas asociadas, Madrid, Spain.

Aims: To analyze therapeutic inertia in type 2 diabetes (T2D) subjects with suboptimal glycemic control and treated with ≥2 non-insulin antidiabetic agents in a primary care setting.

Methods: A retrospective study was conducted using electronic medical records from subjects with HbA1c ≥7.0% (≥53 mmol/mol). Therapeutic inertia was defined as the absence of treatment intensification despite suboptimal glycemic control where intensification should have been implemented (HbA1c ≥7.5% [≥58 mmol/mol]). Time to the first intensification with non-insulin antidiabetic agent or insulin and HbA1c values at the time of intensification were evaluated by competing risk analysis.

Results: 2652 adults with T2D and HbA1c ≥7.0% (≥53 mmol/mol) were included. During the 4-year follow-up, among 1628 individuals with HbA1c ≥7.5% [≥58 mmol/mol], therapeutic inertia was present in 42.9% of cases. Median time to intensification was 14.5 months (IQR, 4-24 months). In this subgroup, 72.7% of subjects initiated non-insulin agents whereas 27.3% initiated insulin. Mean HbA1c values at initiation of treatment intensification were 8.6% (70 mmol/mol) and 9.2% (77 mmol/mol), respectively.

Conclusions: Therapeutic inertia occurred in over 40% of subjects. Treatment intensification took longer and was performed at higher HbA1c than recommended in clinical guidelines. Reducing therapeutic inertia is a priority to achieve therapeutic goals and prevent chronic complications in T2D.
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http://dx.doi.org/10.1016/j.jdiacomp.2020.107828DOI Listing
March 2021

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

Int J Clin Pract 2021 Apr 9;75(4):e13776. Epub 2020 Nov 9.

Service of Endocrinology and Nutrition, Hospital Clínico Universitario de Valencia, Valencia, Spain.

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 was significantly higher in subjects with abdominal obesity compared with morbid obese subjects (4 hours triglycerides pick value and AUC of triglycerides). Both obese groups showed significantly higher postprandial triglycerides response compared with healthy subjects. Dividing the obesity group according to the presence of IR, we found that IR was an important factor related with postprandial lipaemia but not BMI or waist circumference. In addition, postprandial glycaemia and insulinaemia significantly decreased in all studied subjects, being the highest decrease in morbid obese subjects and in subjects with IR. Postprandial triglyceridaemia significantly correlated with IR parameters and not with anthropometric parameters in AO and MO subjects.

Conclusion: In subjects with AO and MO, postprandial triglycerides values are higher than healthy individuals and independently predicted by fasting IR parameters. Furthermore, unsaturated fat improved IR state.
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http://dx.doi.org/10.1111/ijcp.13776DOI Listing
April 2021

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

Clin Investig Arterioscler 2020 May - Jun;32(3):87-93. Epub 2020 Apr 11.

Service of Endocrinology and Nutrition, Hospital Clínico Universitario de Valencia, Valencia, Spain; Institute of Health Research of the Hospital Clinico Universitario de Valencia (INCLIVA), Valencia, Spain; Department of Medicine, University of Valencia, Valencia, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.

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: 50g fat per m body surface) was performed using a commercial liquid preparation of long chain triglycerides (Supracal®). OS markers and C3 were measured using standardized methods at fasting state and every 2h up to 8h after the OFLT.

Results: Men showed statistically significant higher C3, oxidized glutathione (GSSG), and oxidized-reduced glutathione (GSSG/GSH) ratio values at fasting state compared to that obtained in women. In addition, post-prandial C3 values and GSSG/GSH ratios were significantly higher in men compared to women. The GSSG value and GSSG/GSH ratio significantly decreased in men after the OFLT compared to fasting values. In contrast, the post-prandial OS markers decrease observed in women was not statistically significant.

Conclusions: In fasting state, men showed higher statistically significant C3 values and OS markers than women. The post-prandial OS markers (GSSG and GSSG/GSH ratio) significantly decrease after the OFLT with unsaturated fat in men compared to women.
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http://dx.doi.org/10.1016/j.arteri.2019.11.002DOI Listing
June 2021

Easy One-Step Amplification and Labeling Procedure for Copy Number Variation Detection.

Clin Chem 2020 03;66(3):463-473

I+D+I Department, Sequencing Multiplex SL (I+d+I, Seqplexing), Serra, Valencian Community, Spain.

Background: The specific characteristics of copy number variations (CNVs) require specific methods of detection and characterization. We developed the Easy One-Step Amplification and Labeling procedure for CNV detection (EOSAL-CNV), a new method based on proportional amplification and labeling of amplicons in 1 PCR.

Methods: We used tailed primers for specific amplification and a pair of labeling probes (only 1 labeled) for amplification and labeling of all amplicons in just 1 reaction. Products were loaded directly onto a capillary DNA sequencer for fragment sizing and quantification. Data obtained could be analyzed by Microsoft Excel spreadsheet or EOSAL-CNV analysis software. We developed the protocol using the LDLR (low density lipoprotein receptor) gene including 23 samples with 8 different CNVs. After optimizing the protocol, it was used for genes in the following multiplexes: BRCA1 (BRCA1 DNA repair associated), BRCA2 (BRCA2 DNA repair associated), CHEK2 (checkpoint kinase 2), MLH1 (mutL homolog 1) plus MSH6 (mutS homolog 6), MSH2 (mutS homolog 2) plus EPCAM (epithelial cell adhesion molecule) and chromosome 17 (especially the TP53 [tumor protein 53] gene). We compared our procedure with multiplex ligation-dependent probe amplification (MLPA).

Results: The simple procedure for CNV detection required 150 min, with <10 min of handwork. After analyzing >240 samples, EOSAL-CNV excluded the presence of CNVs in all controls, and in all cases, results were identical using MLPA and EOSAL-CNV. Analysis of the 17p region in tumor samples showed 100% similarity between fluorescent in situ hybridization and EOSAL-CNV.

Conclusions: EOSAL-CNV allowed reliable, fast, easy detection and characterization of CNVs. It provides an alternative to targeted analysis methods such as MLPA.
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http://dx.doi.org/10.1093/clinchem/hvaa002DOI Listing
March 2020

Diabetes as a paradigm of the impact of noncommunicable diseases.

Authors:
José T Real

Clin Investig Arterioscler 2020 Jan - Feb;32(1):27-29

Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valencia, Departamento de Medicina, Universitat de Valéncia, INCLIVA-CIBERDEM. Electronic address:

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http://dx.doi.org/10.1016/j.arteri.2019.12.001DOI Listing
November 2020

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

Endocrinol Diabetes Nutr (Engl Ed) 2020 Apr 28;67(4):245-252. Epub 2019 Oct 28.

Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valencia, INCLIVA, Valencia, España; Departamento de Medicina, Universidad de Valencia, Valencia, España; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM).

Introduction: ACTH-independent Cushing's Syndrome (AICS) accounts for 15-20% of cases of Cushing's syndrome, with <1% 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.

Material And Methods: 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.

Results: Of the 15 cases, 13 were female, with a mean age at diagnosis of 56.8 years. In 12 of the 15 cases studied, positivity was detected with stimulation tests, and, of them, 25% were positive for the meal test, 58.3% for posture walking test, 33.3% for desmopressin; 25% for terlipressin; 33.3% for GnRH; 25% for LH and 50% for metoclopramide. Regarding treatment, bilateral adrenalectomy was performed in 16.7% and unilateral adrenalectomy in 41.7%. The rest continue under observation with periodic follow-up (41.7%).

Conclusions: In most of the cases studied with AICS and nodular adrenal hyperplasia (80%), an abnormal cortisol response is detected due to the presence of abnormal receptors. The test with the highest percentage of positivity was the postural walking test (58.3%).
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http://dx.doi.org/10.1016/j.endinu.2019.07.005DOI Listing
April 2020

SGLT-2 (Sodium-Glucose Cotransporter 2) Inhibition Reduces Ang II (Angiotensin II)-Induced Dissecting Abdominal Aortic Aneurysm in ApoE (Apolipoprotein E) Knockout Mice.

Arterioscler Thromb Vasc Biol 2019 08 11;39(8):1614-1628. Epub 2019 Jul 11.

From the Institute of Health Research-INCLIVA, Valencia, Spain (R.O., A.C., F.S., H.G.-N., M.J.S., J.T.R., L.P.).

Objective: Abdominal aortic aneurysm (AAA) is a pathological condition of permanent vessel dilatation that predisposes to the potentially fatal consequence of aortic rupture. SGLT-2 (sodium-glucose cotransporter 2) inhibitors have emerged as powerful pharmacological tools for type 2 diabetes mellitus treatment. Beyond their glucose-lowering effects, recent studies have shown that SGLT-2 inhibitors reduce cardiovascular events and have beneficial effects on several vascular diseases such as atherosclerosis; however, the potential effects of SGLT-2 inhibition on AAA remain unknown. This study evaluates the effect of oral chronic treatment with empagliflozin-an SGLT-2 inhibitor-on dissecting AAA induced by Ang II (angiotensin II) infusion in apoE (apolipoprotein E) mice. Approach and Results: Empagliflozin treatment significantly reduced the Ang II-induced increase in maximal suprarenal aortic diameter in apoE mice independently of blood pressure effects. Immunohistochemistry analysis revealed that empagliflozin diminished Ang II-induced elastin degradation, neovessel formation, and macrophage infiltration at the AAA lesion. Furthermore, Ang II infusion resulted in a marked increase in the expression of chemokines (CCL-2 [chemokine (C-C motif) ligand 2] and CCL-5 [chemokine (C-C motif) ligand 5]), VEGF (vascular endothelial growth factor), and MMP (matrix metalloproteinase)-2 and MMP-9 in suprarenal aortic walls of apoE mice, and all were reduced by empagliflozin cotreatment. Western blot analysis revealed that p38 MAPK (p38 mitogen-activated protein kinase) and NF-κB (nuclear factor-κB) activation was also reduced in the suprarenal aortas of apoE mice cotreated with empagliflozin. Finally, in vitro studies in human aortic endothelial cells and macrophages showed that empagliflozin inhibited leukocyte-endothelial cell interactions and release of proinflammatory chemokines.

Conclusions: Pharmacological inhibition of SGLT-2 by empagliflozin inhibits AAA formation. SGLT-2 inhibition might represent a novel promising therapeutic strategy to prevent AAA progression.
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http://dx.doi.org/10.1161/ATVBAHA.119.312659DOI Listing
August 2019

Systemic Inflammation in Metabolic Syndrome: Increased Platelet and Leukocyte Activation, and Key Role of CXCL1/CXCR1 and CCL2/CCR2 Axes in Arterial Platelet-Proinflammatory Monocyte Adhesion.

J Clin Med 2019 May 18;8(5). Epub 2019 May 18.

Department of Pharmacology, University of Valencia, Av. Blasco Ibáñez 15, 46010 Valencia, Spain.

Background: Metabolic syndrome is associated with low-grade systemic inflammation, which is a key driver of premature atherosclerosis. We characterized immune cell behavior in metabolic syndrome, its consequences, and the potential involvement of the CXCL1/CXCR1 and CCL2/CCR2 chemokine axes.

Methods: Whole blood from 18 patients with metabolic syndrome and 21 age-matched controls was analyzed by flow cytometry to determine the leukocyte immunophenotypes, activation, platelet-leukocyte aggregates, and CXCR1 expression. ELISA determined the plasma marker levels. Platelet-leukocyte aggregates adhesion to tumor necrosis factor-α (TNFα)-stimulated arterial endothelium and the role of CXCL1/CXCR1 and CCL2/CCR2 axes was investigated with the parallel-plate flow chamber.

Results: When compared with the controls, the metabolic syndrome patients presented greater percentages of eosinophils, CD3 T lymphocytes, Mon2/Mon3 monocytes, platelet-eosinophil and -lymphocyte aggregates, activated platelets, neutrophils, eosinophils, monocytes, and CD8 T cells, but lower percentages of Mon1 monocytes. Patients had increased circulating interleukin-8 (IL-8) and TNFα levels and decreased IL-4. CXCR1 up-regulation in platelet-Mon1 monocyte aggregates in metabolic syndrome patients led to increased CXCR1/CCR2-dependent platelet-Mon1 monocyte adhesion to dysfunctional arterial endothelium.

Conclusion: We provide evidence of generalized immune activation in metabolic syndrome. Additionally, CXCL1/CXCR1 or CCL2/CCR2 axes are potential candidates for therapeutic intervention in cardiovascular disorders in metabolic syndrome patients, as their blockade impairs the augmented arterial platelet-Mon1 monocyte aggregate adhesiveness, which is a key event in atherogenesis.
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http://dx.doi.org/10.3390/jcm8050708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572270PMC
May 2019

Novel Immune Features of the Systemic Inflammation Associated with Primary Hypercholesterolemia: Changes in Cytokine/Chemokine Profile, Increased Platelet and Leukocyte Activation.

J Clin Med 2018 Dec 22;8(1). Epub 2018 Dec 22.

Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Av. Blasco Ibáñez 15, 46010 Valencia, Spain.

Primary hypercholesterolemia (PH) is associated with a low grade systemic inflammation that is likely the main driver of premature atherosclerosis. Accordingly, we characterized the immune cell behaviour in PH and its potential consequences. Whole blood from 22 PH patients and 21 age-matched controls was analysed by flow cytometry to determine the percentage of leukocyte immunophenotypes, activation, and platelet-leukocyte aggregates. Plasma markers were determined by Enzyme-Linked ImmunoSorbent Assay (ELISA). The adhesion of platelet-leukocyte aggregates to tumor necrosis factor-α (TNFα)-stimulated arterial endothelium was investigated using the dynamic model of the parallel-plate flow chamber. PH patients presented greater percentage of Mon 3 monocytes, Th2 and Th17 lymphocytes, activated platelets, and leukocytes than controls. The higher percentages of circulating platelet-neutrophil, monocyte and lymphocyte aggregates in patients caused increased platelet-leukocyte adhesion to dysfunctional arterial endothelium. Circulating CXCL8, CCL2, CX₃CL1, and IL-6 levels positively correlated with key lipid features of PH, whereas negative correlations were found for IL-4 and IL-10. We provide the first evidence that increased platelet and leukocyte activation leads to elevated platelet-leukocyte aggregates in PH and augmented arterial leukocyte adhesiveness, a key event in atherogenesis. Accordingly, modulation of immune system behavior might be a powerful target in the control of further cardiovascular disease in PH.
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http://dx.doi.org/10.3390/jcm8010018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352074PMC
December 2018

Functional role of endothelial CXCL16/CXCR6-platelet-leucocyte axis in angiotensin II-associated metabolic disorders.

Cardiovasc Res 2018 11;114(13):1764-1775

Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain.

Aims: Angiotensin-II (Ang-II) is the main effector peptide of the renin-angiotensin system (RAS) and promotes leucocyte adhesion to the stimulated endothelium. Because RAS activation and Ang-II signalling are implicated in metabolic syndrome (MS) and abdominal aortic aneurysm (AAA), we investigated the effect of Ang-II on CXCL16 arterial expression, the underlying mechanisms, and the functional role of the CXCL16/CXCR6 axis in these cardiometabolic disorders.

Methods And Results: Results from in vitro chamber assays revealed that CXCL16 neutralization significantly inhibited mononuclear leucocyte adhesion to arterial but not to venous endothelial cells. Flow cytometry and immunofluorescence studies confirmed that Ang-II induced enhanced endothelial CXCL16 expression, which was dependent on Nox5 up-regulation and subsequent RhoA/p38-MAPK/NFκB activation. Flow cytometry analysis further showed that MS patients had higher levels of platelet activation and a higher percentage of circulating CXCR6-expressing platelets, CXCR6-expressing-platelet-bound neutrophils, monocytes, and CD8+ lymphocytes than age-matched controls, leading to enhanced CXCR6/CXCL16-dependent adhesion to the dysfunctional (Ang-II- and TNFα-stimulated) arterial endothelium. Ang-II-challenged apolipoprotein E-deficient (apoE-/-) mice had a higher incidence of AAA, macrophage, CD3+, and CXCR6+ cell infiltration and neovascularization than unchallenged animals, which was accompanied by greater CCL2, CXCL16, and VEGF mRNA expression within the lesion together with elevated levels of circulating soluble CXCL16. Significant reductions in these parameters were found in animals co-treated with the AT1 receptor antagonist losartan or in apoE-/- mice lacking functional CXCR6 receptor (CXCR6GFP/GFP).

Conclusion: CXCR6 expression on platelet-bound monocytes and CD8+ lymphocytes may constitute a new membrane-associated biomarker for adverse cardiovascular events. Moreover, pharmacological modulation of this axis may positively affect cardiovascular outcome in metabolic disorders linked to Ang-II.
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http://dx.doi.org/10.1093/cvr/cvy135DOI Listing
November 2018

Upregulation of angiostatic chemokines IP-10/CXCL10 and I-TAC/CXCL11 in human obesity and their implication for adipose tissue angiogenesis.

Int J Obes (Lond) 2018 08 24;42(8):1406-1417. Epub 2018 May 24.

Institute of Health Research-INCLIVA, Valencia, Spain.

Background/aims: Impaired angiogenesis is linked to adipose tissue (AT) dysfunction, inflammation, and insulin resistance in human obesity. Chemokine (C-X-C motif) receptor. (CXCR3) ligands are important regulators of angiogenesis in different disease contexts such as cancer; however, their role in human morbid obesity is unknown. We investigated the role of the CXCR3 axis in AT angiogenesis in morbidly obese patients.

Subjects/methods: The study group comprised 50 morbidly obese patients (mean age 44 ± 1 years, body mass index 44 ± 1 kg/m) who had undergone laparoscopic Roux-Y-gastric bypass surgery, and 25 age-matched non-obese control subjects. We measured the circulating levels of the CXCR3 ligands monokine induced by interferon-γ (MIG/CXCL9), interferon-γ inducible protein 10 (IP-10/CXCL10), and interferon-γ-inducible T-cell alpha chemoattractant (I-TAC/CXCL11) in all studied subjects. Additionally, the expression of CXCR3 ligands was analyzed in paired biopsies of subcutaneous and visceral AT obtained during the laparoscopic procedure in morbidly obese patients. Additionally, we explored the functional role of CXCR3 ligands on angiogenesis in AT from morbidly obese patients using an ex vivo assay.

Results: Plasma levels of CXCL10 and CXCL11 were significantly higher in morbidly obese patients than in controls (p < 0.01). In ex vivo assays, angiogenic growth was markedly lower in visceral AT than in subcutaneous AT (p < 0.05), which was related to significant tissue upregulation of CXCL10, CXCL11 and CXCR3 (p < 0.05). CXCL10 or CXCL11 inhibited AT angiogenesis (p < 0.05), and blockade of CXCR3 function significantly increased capillary sprouting in visceral fat deposits (p < 0.05). Western blot analysis showed that the p38 mitogen-activated protein kinase signaling pathway was implicated in the angiostatic effects of CXCR3 in AT.

Conclusions: CXCL10 and CXCL11 may play. deleterious role in obesity as potential inhibitors of AT angiogenesis. Accordingly, pharmacological blockade of CXCR3 could represent. therapy to prevent AT dysfunction in obesity.
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http://dx.doi.org/10.1038/s41366-018-0102-5DOI Listing
August 2018

Autosomal Recessive Hypercholesterolemia: Long-Term Cardiovascular Outcomes.

J Am Coll Cardiol 2018 01;71(3):279-288

Center for Outcomes Research and Clinical Epidemiology, Coreresearch, Inc., Pescara, Italy.

Background: Autosomal recessive hypercholesterolemia (ARH) is a rare lipid disorder characterized by premature atherosclerotic cardiovascular disease (ASCVD). There are sparse data for clinical management and cardiovascular outcomes in ARH.

Objectives: Evaluation of changes in lipid management, achievement of low-density lipoprotein cholesterol (LDL-C) goals and cardiovascular outcomes in ARH.

Methods: Published ARH cases were identified by electronic search. All corresponding authors and physicians known to treat these patients were asked to provide follow-up information, using a standardized protocol.

Results: We collected data for 52 patients (28 females, 24 males; 31.1 ± 17.1 years of age; baseline LDL-C: 571.9 ± 171.7 mg/dl). During a mean follow-up of 14.1 ± 7.3 years, there was a significant increase in the use of high-intensity statin and ezetimibe in combination with lipoprotein apheresis; in 6 patients, lomitapide was also added. Mean LDL-C achieved at nadir was 164.0 ± 85.1 mg/dl (-69.6% from baseline), with a better response in patients taking lomitapide (-88.3%). Overall, 23.1% of ARH patients reached LDL-C of <100 mg/dl. During follow-up, 26.9% of patients had incident ASCVD, and 11.5% had a new diagnosis of aortic valve stenosis (absolute risk per year of 1.9% and 0.8%, respectively). No incident stroke was observed. Age (≥30 years) and the presence of coronary artery disease at diagnosis were the major predictors of incident ASCVD.

Conclusions: Despite intensive treatment, LDL-C in ARH patients remains far from targets, and this translates into a poor long-term cardiovascular prognosis. Our data highlight the importance of an early diagnosis and treatment and confirm the fact that an effective treatment protocol for ARH is still lacking.
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http://dx.doi.org/10.1016/j.jacc.2017.11.028DOI Listing
January 2018

Autosomal recessive hypercholesterolemia in Spain.

Atherosclerosis 2018 02 6;269:1-5. Epub 2017 Dec 6.

Unidad de Medicina Vascular y Metabolica, Unidad de Investigación en Lipidos y Arterioesclerosis, Hospital Universitario "Sant Joan", Universitat Rovira i Virgili, IISPV, CIBERDEM, Reus, Madrid, Spain.

Background And Aims: Autosomal recessive hypercholesterolemia (ARH) is a very rare disease, caused by mutations in LDL protein receptor adaptor 1 (LDLRAP1). It is characterized by high levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of premature cardiovascular disease. We aimed to characterize ARH in Spain.

Methods: Data were collected from the Dyslipidemia Registry of the Spanish Atherosclerosis Society. A literature search was performed up to June 2017, and all diagnostic genetic studies for familial hypercholesterolemia of Spain were reviewed.

Results: Seven patients with ARH were identified, 6 true homozygous and one compound heterozygous with a novel mutation: c.[863C>T];p.[Ser288Leu]. High genetic heterogeneity was found in this cohort. True homozygous subjects for LDLRAP1 have more severe phenotypes than the compound heterozygous patient, but similar to patients with homozygous familial hypercholesterolemia (HoFH). Cardiovascular disease was present in 14% of the ARH patients. LDL-C under treatment was above 185 mg/dl and the response to PCSK9 inhibitors was heterogeneous. Finally, the estimated prevalence in Spain is very low, with just 1 case per 6.5 million people.

Conclusions: ARH is a very rare disease in Spain, showing high genetic heterogeneity, similarly high LDL-C concentrations, but lower incidence of ASCVD than HoFH.
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http://dx.doi.org/10.1016/j.atherosclerosis.2017.12.006DOI Listing
February 2018

Altered Semmes-Weinstein monofilament test results are associated with oxidative stress markers in type 2 diabetic subjects.

J Transl Med 2017 09 6;15(1):187. Epub 2017 Sep 6.

Service of Endocrinology and Nutrition, Hospital Clínico Universitario de Valencia, Avda Blasco Ibañez, 17, 46010, Valencia, Spain.

Background: Different lines of evidence suggest that oxidative stress (OS) is implicated in the pathogenesis of diabetic neuropathy. The Semmes-Weinstein monofilament (SWM) test is an efficient tool for evaluating diabetic polyneuropathy and diabetic foot. In this study, we analyzed the association between OS markers and altered SWM test results in type 2 diabetes (T2DM) patients.

Methods: Seventy T2DM patients were studied and 34 showed altered SWM results. The clinical and biochemical parameters were determined using standardized methods. Levels of oxidized glutathione (GSSG) and malondialdehyde (MDA) were measured in circulating mononuclear cells using high-performance liquid chromatography.

Results: We found that T2DM patients with altered SWM test results had significantly higher GSSG (3.53 ± 0.31 vs. 3.31 ± 0.35 mmol/ml, p < 0.05) and MDA (1.88 ± 0.16 vs. 1.75 ± 0.19 nmol/ml, p < 0.01) values compared to diabetic patients with normal SWM test outcomes. Moreover, altered SWM test results were independently related to age, glycosylated hemoglobin, and GSSG levels, but there was no association between OS markers and altered neuropathy sensitivity score (NSS) values.

Conclusions: Alteration of the glutathione system and MDA values in T2DM patients are associated with loss of proprioceptive (pressure) sensitivity, but not with symptomatic polyneuropathy (as evaluated by NSS). This finding may be important for understanding how OS affects distal symmetric polyneuropathy in diabetic patients.
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http://dx.doi.org/10.1186/s12967-017-1291-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5586059PMC
September 2017

PAI-1 levels are related to insulin resistance and carotid atherosclerosis in subjects with familial combined hyperlipidemia.

J Investig Med 2018 01 19;66(1):17-21. Epub 2017 Aug 19.

Service of Endocrinology and Nutrition, University Clinical Hospital of Valencia, INCLIVA, Valencia, Spain.

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 (IMT) was measured by the same investigator by standardized protocol. No differences in age, body mass index (BMI) or waist circumference were observed between the two groups. HOMA and PAI-1 values were higher in the FCH group, reaching statistical significance in those subjects with insulin resistance. In addition, PAI-1 values correlated significantly with metabolic syndrome components and carotid IMT. It is known that the elevated cardiovascular risk that characterizes FCH is frequently associated with insulin resistance. We have detected that two known proinflammatory and proatherothrombotic factors (MPO and PAI-1) are significantly elevated in FCH subjects with insulin resistance. These results could partly explain the high cardiovascular risk present in FCH subjects.
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http://dx.doi.org/10.1136/jim-2017-000468DOI Listing
January 2018

The GLP-1 analogue lixisenatide decreases atherosclerosis in insulin-resistant mice by modulating macrophage phenotype.

Diabetologia 2017 09 12;60(9):1801-1812. Epub 2017 Jun 12.

Institute of Health Research-INCLIVA, Avda Menéndez Pelayo 4, 46010, Valencia, Spain.

Aims/hypothesis: Recent clinical studies indicate that glucagon-like peptide-1 (GLP-1) analogues prevent acute cardiovascular events in type 2 diabetes mellitus but their mechanisms remain unknown. In the present study, the impact of GLP-1 analogues and their potential underlying molecular mechanisms in insulin resistance and atherosclerosis are investigated.

Methods: Atherosclerosis development was evaluated in Apoe Irs2 mice, a mouse model of insulin resistance, the metabolic syndrome and atherosclerosis, treated with the GLP-1 analogues lixisenatide or liraglutide. In addition, studies in Apoe Irs2 mice and mouse-derived macrophages treated with lixisenatide were performed to investigate the potential inflammatory intracellular pathways.

Results: Treatment of Apoe Irs2 mice with either lixisenatide or liraglutide improved glucose metabolism and blood pressure but this was independent of body weight loss. Both drugs significantly decreased atheroma plaque size. Compared with vehicle-treated control mice, lixisenatide treatment generated more stable atheromas, with fewer inflammatory infiltrates, reduced necrotic cores and thicker fibrous caps. Lixisenatide-treated mice also displayed diminished IL-6 levels, proinflammatory Ly6C monocytes and activated T cells. In vitro analysis showed that, in macrophages from Apoe Irs2 mice, lixisenatide reduced the secretion of the proinflammatory cytokine IL-6 accompanied by enhanced activation of signal transducer and activator of transcription (STAT) 3, which is a determinant for M2 macrophage differentiation. STAT1 activation, which is essential for M1 phenotype, was also diminished. Furthermore, atheromas from lixisenatide-treated mice showed higher arginase I content and decreased expression of inducible nitric oxide synthase, indicating the prevalence of the M2 phenotype within plaques.

Conclusions/interpretation: Lixisenatide decreases atheroma plaque size and instability in Apoe Irs2 mice by reprogramming macrophages towards an M2 phenotype, which leads to reduced inflammation. This study identifies a critical role for this drug in macrophage polarisation inside plaques and provides experimental evidence supporting a novel mechanism of action for GLP-1 analogues in the reduction of cardiovascular risk associated with insulin resistance.
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http://dx.doi.org/10.1007/s00125-017-4330-3DOI Listing
September 2017

Neuropeptide FF increases M2 activation and self-renewal of adipose tissue macrophages.

J Clin Invest 2017 Jun 5;127(7):2842-2854. Epub 2017 Jun 5.

Institute of Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany.

The quantity and activation state of adipose tissue macrophages (ATMs) impact the development of obesity-induced metabolic diseases. Appetite-controlling hormones play key roles in obesity; however, our understanding of their effects on ATMs is limited. Here, we have shown that human and mouse ATMs express NPFFR2, a receptor for the appetite-reducing neuropeptide FF (NPFF), and that NPFFR2 expression is upregulated by IL-4, an M2-polarizing cytokine. Plasma levels of NPFF decreased in obese patients and high-fat diet-fed mice and increased following caloric restriction. NPFF promoted M2 activation and increased the proliferation of murine and human ATMs. Both M2 activation and increased ATM proliferation were abolished in NPFFR2-deficient ATMs. Mechanistically, the effects of NPFF involved the suppression of E3 ubiquitin ligase RNF128 expression, resulting in enhanced stability of phosphorylated STAT6 and increased transcription of the M2 macrophage-associated genes IL-4 receptor α (Il4ra), arginase 1 (Arg1), IL-10 (Il10), and alkylglycerol monooxygenase (Agmo). NPFF induced ATM proliferation concomitantly with the increase in N-Myc downstream-regulated gene 2 (Ndrg2) expression and suppressed the transcription of Ifi200 cell-cycle inhibitor family members and MAF bZIP transcription factor B (Mafb), a negative regulator of macrophage proliferation. NPFF thus plays an important role in supporting healthy adipose tissue via the maintenance of metabolically beneficial ATMs.
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http://dx.doi.org/10.1172/JCI90152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490745PMC
June 2017

Homozygous Familial Hypercholesterolemia in Spain: Prevalence and Phenotype-Genotype Relationship.

Circ Cardiovasc Genet 2016 Dec 26;9(6):504-510. Epub 2016 Oct 26.

Background: Homozygous familial hypercholesterolemia (HoFH) is a rare disease characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) and extremely high risk of premature atherosclerotic cardiovascular disease. HoFH is caused by mutations in several genes, including LDL receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), and LDL protein receptor adaptor 1 (LDLRAP1). No epidemiological studies have assessed HoFH prevalence or the clinical and molecular characteristics of this condition. Here, we aimed to characterize HoFH in Spain.

Methods And Results: Data were collected from the Spanish Dyslipidemia Registry of the Spanish Atherosclerosis Society and from all molecular diagnoses performed for familial hypercholesterolemia in Spain between 1996 and 2015 (n=16 751). Clinical data included baseline lipid levels and atherosclerotic cardiovascular disease events. A total of 97 subjects were identified as having HoFH-of whom, 47 were true homozygous (1 for APOB, 5 for LDLRAP1, and 41 for LDLR), 45 compound heterozygous for LDLR, 3 double heterozygous for LDLR and PSCK9, and 2 double heterozygous for LDLR and APOB. No PSCK9 homozygous cases were identified. Two variants in LDLR were identified in 4.8% of the molecular studies. Over 50% of patients did not meet the classical HoFH diagnosis criteria. The estimated HoFH prevalence was 1:450 000. Compared with compound heterozygous cases, true homozygous cases showed more aggressive phenotypes with higher LDL-C and more atherosclerotic cardiovascular disease events.

Conclusions: HoFH frequency in Spain was higher than expected. Clinical criteria would underestimate the actual prevalence of individuals with genetic HoFH, highlighting the importance of genetic analysis to improve familial hypercholesterolemia diagnosis accuracy.
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http://dx.doi.org/10.1161/CIRCGENETICS.116.001545DOI Listing
December 2016

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

PLoS One 2016 18;11(8):e0161400. Epub 2016 Aug 18.

Service of Endocrinology and Nutrition, Hospital Clínico Universitario Valencia, Valencia, Spain.

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 both groups, insulin, HOMA, oxidized/reduced glutathione ratio, and malondialdehyde significantly decreased in the postprandial state after the OFLT. All these parameters were significantly higher in the abdominal obesity group at baseline and during all the postprandial points, but the reduction from the baseline levels was significantly higher in the abdominal obesity group.

Conclusion: Unsaturated fat improves insulin resistance and oxidative stress status. It is possible that a consumption of unsaturated fat could be beneficial even in subjects with abdominal obesity in postprandial state.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0161400PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4990252PMC
July 2017

[Plasma homocysteine, Lp(a), and oxidative stress markers in peripheral macroangiopathy in patients with type 2 diabetes mellitus].

Clin Investig Arterioscler 2016 Jul-Aug;28(4):188-94. Epub 2016 Jun 25.

Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valencia, Valencia, España; CIBER de Diabetes y Enfermedades Metabólicas asociadas (CIBERDEM), Barcelona, España; Departamento de Medicina, Universidad de Valencia e INCLIVA, Valencia, España. Electronic address:

Aim: To study new risk factors for peripheral macroangiopathy (PM) in patients with diabetes, as oxidative stress (OS) and its interaction with classical risk factors: age, Lp(a), plasma homocysteine values and HbA1c.

Subjects And Methods: We studied 204 type2 diabetic (T2DM) patients, consecutive selected form a reference hospital and a secondary hospital form our Community (2009-2010). Design was a case (ABI<0.89) control (ABI0.9-1.2) study. PM was defined using ankle brachial index (ABI). Thirty nine T2DM subjects presented ABI>1.2 and were excluded. Clinical and biological parameters were determined using standard methods.

Results: Comparing clinical and biological parameters obtained in both studied groups (T2DM+ABI<0.9 vs T2DM+ABI0.9-1.2), we found statistical significant differences in age, evolution time of diabetes, Lp(a) and plasma homocysteine values. No differences were found in OS parameters: reduced glutathione, oxidized glutathione and maloldialdehide between studied groups. Plasma homocysteine values were an independent risk factor for the presence of PM and were related to evolution time of diabetes and reduced glutathione.

Conclusions: We have confirmed that Lp(a) and independently plasma homocysteine values were related to PM in T2DM subjects. No association with PM and OS markers (GSH, GSSG and MDA) were found in T2DM with more than 10years of evolution time of their disease and high prevalence of chronic complications.
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http://dx.doi.org/10.1016/j.arteri.2016.05.007DOI Listing
May 2017
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