Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders

Barcelona, Spain

Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders

Barcelona, Spain
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Poveda J.,Red de Investigacion Renal REDinREN | Carrasco S.,Red de Investigacion Renal REDinREN | Cannata-Ortiz P.,IIS Inc | Sanchez-Nino M.D.,Red de Investigacion Renal REDinREN | And 10 more authors.
Journal of the American Society of Nephrology : JASN | Year: 2017

AKI is histologically characterized by necrotic cell death and inflammation. Diverse pathways of regulated necrosis have been reported to contribute to AKI, but the molecular regulators involved remain unclear. We explored the relative contributions of ferroptosis and necroptosis to folic acid (FA)-induced AKI in mice. FA-AKI in mice associates with lipid peroxidation and downregulation of glutathione metabolism proteins, features that are typical of ferroptotic cell death. We show that ferrostatin-1 (Fer-1), an inhibitor of ferroptosis, preserved renal function and decreased histologic injury, oxidative stress, and tubular cell death in this model. With respect to the immunogenicity of ferroptosis, Fer-1 prevented the upregulation of IL-33, an alarmin linked to necroptosis, and other chemokines and cytokines and prevented macrophage infiltration and Klotho downregulation. In contrast, the pancaspase inhibitor zVAD-fmk did not protect against FA-AKI. Additionally, although FA-AKI resulted in increased protein expression of the necroptosis mediators receptor-interacting protein kinase 3 (RIPK3) and mixed lineage domain-like protein (MLKL), targeting necroptosis with the RIPK1 inhibitor necrostatin-1 or genetic deficiency of RIPK3 or MLKL did not preserve renal function. Indeed, compared with wild-type mice, MLKL knockout mice displayed more severe AKI. However, RIPK3 knockout mice with AKI had less inflammation than their wild-type counterparts, and this effect associated with higher IL-10 concentration and regulatory T cell-to-leukocyte ratio in RIPK3 knockout mice. These data suggest that ferroptosis is the primary cause of FA-AKI and that immunogenicity secondary to ferroptosis may further worsen the damage, although necroptosis-related proteins may have additional roles in AKI. Copyright © 2016 by the American Society of Nephrology.

Pescador N.,Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders | Pescador N.,Institute Investigacion Sanitaria del Hospital Clinico San Carlos IdISSC | Perez-Barba M.,Institute Investigacion Sanitaria del Hospital Clinico San Carlos IdISSC | Ibarra J.M.,Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders | And 7 more authors.
PLoS ONE | Year: 2013

Background and Aim:MicroRNAs are small non-coding RNAs that play important regulatory roles in a variety of biological processes, including complex metabolic processes, such as energy and lipid metabolism, which have been studied in the context of diabetes and obesity. Some particular microRNAs have recently been demonstrated to abundantly and stably exist in serum and to be potentially disease-specific. The aim of this profiling study was to characterize the expression of miRNA in serum samples of obese, nonobese diabetic and obese diabetic individuals to determine whether miRNA expression was deregulated in these serum samples and to identify whether any observed deregulation was specific to either obesity or diabetes or obesity with diabetes.Patients and Methods:Thirteen patients with type 2 diabetes, 20 obese patients, 16 obese patients with type 2 diabetes and 20 healthy controls were selected for this study. MiRNA PCR panels were employed to screen serum levels of 739 miRNAs in pooled samples from these four groups. We compared the levels of circulating miRNAs between serum pools of each group. Individual validation of the twelve microRNAs selected as promising biomarkers was carried out using RT-qPCR.Results:Three serum microRNAs, miR-138, miR-15b and miR-376a, were found to have potential as predictive biomarkers in obesity. Use of miR-138 or miR-376a provides a powerful predictive tool for distinguishing obese patients from normal healthy controls, diabetic patients, and obese diabetic patients. In addition, the combination of miR-503 and miR-138 can distinguish diabetic from obese diabetic patients.Conclusion:This study is the first to show a panel of serum miRNAs for obesity, and compare them with miRNAs identified in serum for diabetes and obesity with diabetes. Our results support the use of some miRNAs extracted from serum samples as potential predictive tools for obesity and type 2 diabetes. © 2013 Pescador et al.

Oguiza A.,Autonomous University of Madrid | Oguiza A.,Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders | Recio C.,Autonomous University of Madrid | Recio C.,Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders | And 7 more authors.
Diabetologia | Year: 2015

Aims/hypothesis: The canonical nuclear factor-κB (NF-κB) pathway mediated by the inhibitor of NF-κB kinase (IKK) regulates the transcription of inflammatory genes involved in the pathogenesis of diabetes, from the early phase to progression and final complications. The NF-κB essential modulator binding domain (NBD) contained in IKKα/β is essential for IKK complex assembly. We therefore investigated the functional consequences of targeting the IKK-dependent NF-κB pathway in the progression of diabetes-associated nephropathy and atherosclerosis. Methods: Apolipoprotein E-deficient mice with diabetes induced by streptozotocin were treated with a cell-permeable peptide derived from the IKKα/β NBD region. Kidneys and aorta were analysed for morphology, leucocyte infiltrate, collagen, NF-κB activity and gene expression. In vitro studies were performed in renal and vascular cells. Results: NBD peptide administration did not affect the metabolic severity of diabetes but resulted in renal protection, as evidenced by dose-dependent decreases in albuminuria, renal lesions (mesangial expansion, leucocyte infiltration and fibrosis), intranuclear NF-κB activity and proinflammatory and pro-fibrotic gene expression. Furthermore, peptide treatment limited atheroma plaque formation in diabetic mice by decreasing the content of lipids, leucocytes and cytokines and increasing plaque stability markers. This nephroprotective and anti-atherosclerotic effect was accompanied by a decline in systemic T helper 1 cytokines. In vitro, NBD peptide prevented IKK assembly/activation, p65 nuclear translocation, NF-κB-regulated gene expression and cell proliferation induced by either high glucose or inflammatory stimulation. Conclusions/interpretation: Peptide-based inhibition of IKK complex formation attenuates NF-κB activation, suppresses inflammation and retards the progression of renal and vascular injury in diabetic mice, thus providing a feasible approach against diabetes inflammatory complications. © 2015, Springer-Verlag Berlin Heidelberg.

Ramirez-Dominguez M.,University of the Basque Country | Ramirez-Dominguez M.,Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders | Castano L.,University of the Basque Country | Castano L.,Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders
Cytotechnology | Year: 2015

Pancreatic islet transplantation is a promising therapy for Type I Diabetes. For many years the method used worldwide for islet purification in both rodent and human islet isolation has been Ficoll-based density gradients, such as Histopaque. However, it is difficult to purify islets in laboratories with staff limitations when large scale isolations are required. We hypothesized that filtration could be a more simple and fast alternative to obtain good quality islets. Four separate islet isolations were performed per method, comparing filtration and Histopaque purification with handpicking as the gold standard method for islet purity. Different parameters of quality were assessed: yield in number of islets per pancreas, purity by dithizone staining, viability by Fluorescein Diacetate/Propidium Iodide vital staining and in vitro functionality assessed by Glucose Stimulated Insulin Secretion. Time efficiency and cost were also analyzed. The overall quality of the islets obtained both by Histopaque and filtration was good. Filtration saved almost 90 % of the time consumed by Histopaque purification, and was also cheaper. However, one-third of the islets were lost. Since human and rodent islets share similar size but different density, filtration appears as a purification method with potential interest in translation to clinic. © 2014, Springer Science+Business Media Dordrecht.

Bernstein D.L.,University of Pennsylvania | Le Lay J.E.,University of Pennsylvania | Ruano E.G.,August Pi I Sunyer Biomedical Research Institute IDIBAPS | Ruano E.G.,Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders | Kaestner K.H.,University of Pennsylvania
Journal of Clinical Investigation | Year: 2015

Current strategies to alter disease-associated epigenetic modifications target ubiquitously expressed epigenetic regulators. This approach does not allow specific genes to be controlled in specific cell types; therefore, tools to selectively target epigenetic modifications in the desired cell type and strategies to more efficiently correct aberrant gene expression in disease are needed. Here, we have developed a method for directing DNA methylation to specific gene loci by conjugating catalytic domains of DNA methyltransferases (DNMTs) to engineered transcription activator-like effectors (TALEs). We demonstrated that these TALE-DNMTs direct DNA methylation specifically to the targeted gene locus in human cells. Further, we determined that minimizing direct nucleotide sequence repeats within the TALE moiety permits efficient lentivirus transduction, allowing easy targeting of primary cell types. Finally, we demonstrated that directed DNA methylation with a TALE-DNMT targeting the CDKN2A locus, which encodes the cyclin-dependent kinase inhibitor p16, decreased CDKN2A expression and increased replication of primary human fibroblasts, as intended. Moreover, overexpression of p16 in these cells reversed the proliferative phenotype, demonstrating the specificity of our epigenetic targeting. Together, our results demonstrate that TALE-DNMTs can selectively target specific genes and suggest that this strategy has potential application for the development of locus-specific epigenetic therapeutics. © 2015, American Society for Clinical Investigation. All rights reserved.

Ceriello A.,Hospital Clinic Of Barcelona | Ceriello A.,Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders | Novials A.,Hospital Clinic Of Barcelona | Novials A.,Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders | And 8 more authors.
Diabetes | Year: 2012

Currently there is debate on whether hypoglycemia is an independent risk factor for atherosclerosis, but little attention has been paid to the effects of recovery from hypoglycemia. In normal control individuals and in people with type 1 diabetes, recovery from a 2-h induced hypoglycemia was obtained by reaching normoglycemia or hyperglycemia for another 2 h and then maintaining normal glycemia for the following 6 h. Hyper-glycemia after hypoglycemia was also repeated with the concomitant infusion of vitamin C. Recovery with normoglycemia is accompanied by a significant improvement in endothelial dysfunction, oxidative stress, and inflammation, which are affected by hypoglycemia; however, a period of hyperglycemia after hypoglycemia worsens all of these parameters, an effect that persists even after the additional 6 h of normoglycemia. This effect is partially counterbalanced when hyperglycemia after hypoglycemia is accompanied by the simultaneous infusion of vitamin C, suggesting that when hyperglycemia follows hypogly-cemia, an ischemia-reperfusion-like effect is produced. This study shows that the way in which recovery from hypoglycemia takes place in people with type 1 diabetes could play an important role in favoring the appearance of endothelial dysfunction, oxidative stress, and inflammation, widely recognized cardiovascular risk factors. © 2012 by the American Diabetes Association.

PubMed | Rovira i Virgili University and Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders
Type: Journal Article | Journal: Analytical chemistry | Year: 2016

Studying the flow of chemical moieties through the complex set of metabolic reactions that happen in the cell is essential to understanding the alterations in homeostasis that occur in disease. Recently, LC/MS-based untargeted metabolomics and isotopically labeled metabolites have been used to facilitate the unbiased mapping of labeled moieties through metabolic pathways. However, due to the complexity of the resulting experimental data sets few computational tools are available for data analysis. Here we introduce geoRge, a novel computational approach capable of analyzing untargeted LC/MS data from stable isotope-labeling experiments. geoRge is written in the open language R and runs on the output structure of the XCMS package, which is in widespread use. As opposed to the few existing tools, which use labeled samples to track stable isotopes by iterating over all MS signals using the theoretical mass difference between the light and heavy isotopes, geoRge uses unlabeled and labeled biologically equivalent samples to compare isotopic distributions in the mass spectra. Isotopically enriched compounds change their isotopic distribution as compared to unlabeled compounds. This is directly reflected in a number of new m/z peaks and higher intensity peaks in the mass spectra of labeled samples relative to the unlabeled equivalents. The automated untargeted isotope annotation and relative quantification capabilities of geoRge are demonstrated by the analysis of LC/MS data from a human retinal pigment epithelium cell line (ARPE-19) grown on normal and high glucose concentrations mimicking diabetic retinopathy conditions in vitro. In addition, we compared the results of geoRge with the outcome of X(13)CMS, since both approaches rely entirely on XCMS parameters for feature selection, namely m/z and retention time values. To ensure data traceability and reproducibility, and enabling for comparison with other existing and future approaches, raw LC/MS files have been deposited in MetaboLights (MTBLS213) and geoRge is available as an R script at

PubMed | Rovira i Virgili University and Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders
Type: | Journal: Scientific reports | Year: 2016

Recent 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 and another with fenofibrate as an add-on to simvastatin. We further characterized the HDL surface properties using atomic force microscopy and fluorescent probes to show an abnormal lipid distribution within smaller HDL particles, a subclass particularly enriched in the DM2 patients. The reduction in the size, force cholesterol esters and triglycerides to emerge from the HDL core to the surface, making the outer surface of HDL more hydrophobic. Interestingly, pharmacological interventions had no effect on this undesired configuration, which may explain the lack of clinical benefits in DM2 subjects.

Cervantes S.,Institute dInvestigacions Biomediques August Pi i Sunyer IDIBAPS Hospital Clinic | Cervantes S.,Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders
Histology and Histopathology | Year: 2013

The gastrointestinal tract carries out essential functions for the organism, including the digestion and absorption of nutrients. The cells lining the lumen of the gut tube derive from the endoderm, one of the three germ layers formed during gastrulation. The length of the intestinal tract determines its digestive and absorptive capacity, and so the intestine expands several times the length of the whole body to ensure an adequate absorptive area to meet nutritional demands. However, the endoderm starts out as a small sheet of cells spanning less than the whole length of the head-fold embryo. In order to achieve its final shape and size, the cells in the endoderm undergo extensive growth and profound morphogenetic changes, which are governed by embryonic signaling pathways and transcription factors. This review, based on mouse development, summarizes our current knowledge of the cellular and molecular mechanisms underlying the morphogenetic changes that participate in shaping the mature intestinal tract in vertebrates.

Escudero-Lopez B.,Pablo De Olavide University | Escudero-Lopez B.,University of Parma | Calani L.,University of Parma | Fernandez-Pachon M.-S.,Pablo De Olavide University | And 5 more authors.
BioFactors | Year: 2014

Two milliliters of a fermented, pasteurized orange juice containing ~1% alcohol and 2.3 μmol of (poly)phenolic compounds was fed to rats by gavage after which plasma and urine collected over a 36 h period were analyzed by UHPLC-mass spectrometry. The main constituents in the juice were hesperetin and naringenin-O-glycosides, apigenin-6,8-C-diglucoside, and ferulic acid-4′-O-glucoside. Plasma contained seven flavanone glucuronides, with the principal metabolites, naringenin-7-O-glucuronide, naringenin-4′-O-glucuronide, and an isosakuranetin-O-glucuronide, peaking 6 h after intake at concentrations of ~10 nmol/L. Urinary excretion of four hesperetin glucuronides was equivalent to 0.28% of intake while that of the two naringenin glucuronides was 2.8% of intake. The plasma and urine data suggest that while some absorption occurred in the small intestine, the main site of uptake was the colon. Urine also contained dihydroferulic acid-4'-O-glucuronide and dihydroferulic acid-4′-O-sulfate which were excreted in quantities corresponding to 48.2% of the ingested ferulic acid-4′-glucoside. This indicates that the hydroxycinnamate is much more bioavailable than the flavanones in the rat model. Conversion of the ferulic acid glucoside to the dihydroferulic acid metabolites involves the action of colonic microbial glycosidases and reductases/hydrogenases followed by postabsorption phase II metabolism before renal excretion. © 2013 International Union of Biochemistry and Molecular Biology, Inc.

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