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1. Unseen threat: how subclinical atherosclerosis increases mortality risk in patients with type 1 diabetes

Author

Lidia Sojo-Vega, Mònica Recasens, Joan Martínez, Alexandre Aguilera, Maria Ayala, Natàlia Admetlla, Paula Pellicer, Cristina Blay, Berta Fabregat, Mariona Esteve-Serra, Lídia Riera, Rebeca Barahona, Gemma Xifra, Eduardo Esteve, Josefina Biarnés, David Pérez, Gemma Gifre, Sílvia Mauri, Elisabet Costa, Marzena Wos, Maria Buxó, and Mercè Fernández-Balsells

Subjects
Subclinical atherosclerosis, Type 1 diabetes, Cardiovascular disease mortality, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Abstract Background Cardiovascular disease (CVD), particularly ischemic heart disease, remains the leading cause of death and morbidity in patients with type 1 diabetes. Detecting subclinical atherosclerosis could enhance cardiovascular risk stratification and enable individualised therapies. The aim of this study is to investigate the prevalence and predictors of subclinical atherosclerosis in patients with type 1 diabetes without overt cardiovascular disease (CVD) and to assess its impact on patient survival over a follow-up period of at least 5 years. Methods This observational study included 507 patients treated at the Diabetes Unit of the Hospital of Girona Doctor Josep Trueta between 2015 and 2023. The inclusion criteria for patients were as follows: those aged 18 and older with diabetes for a minimum of 10 years or those aged 40 and older with a diabetes for at least 5 years. Subclinical atherosclerosis was identified via ultrasound imaging of the carotid and femoral arteries. Clinical and biochemical evaluations were also conducted. Major cardiovascular events (MACE) and deaths from other causes were monitored, and survival analysis was performed using Kaplan‒Meier methods. Results Subclinical atherosclerosis was detected in 218 patients (43%). Multivariate analysis revealed that the male sex, diabetic nephropathy, tobacco exposure, higher HbA1c levels, older age, and longer diabetes duration were significant predictors. During a mean follow-up of 70.64 ± 27.08 months, 19 patients experienced MACE, and 13 died from any cause. The probability of MACE or death was greater in patients with subclinical atherosclerosis, with a hazard ratio (HR) of 25.1 (95% CI 5.81–108, p

Published
2024
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2. Revisiting the usefulness of the short acute octreotide test to predict treatment outcomes in acromegaly

Author

Montserrat Marques-Pamies, Joan Gil, Elena Valassi, Marta Hernández, Betina Biagetti, Olga Giménez-Palop, Silvia Martínez, Cristina Carrato, Laura Pons, Rocío Villar-Taibo, Marta Araujo-Castro, Concepción Blanco, Inmaculada Simón, Andreu Simó-Servat, Gemma Xifra, Federico Vázquez, Isabel Pavón, Rogelio García-Centeno, Roxana Zavala, Felicia Alexandra Hanzu, Mireia Mora, Anna Aulinas, Nuria Vilarrasa, Soledad Librizzi, María Calatayud, Paz de Miguel, Cristina Alvarez-Escola, Antonio Picó, Miguel Sampedro, Isabel Salinas, Carmen Fajardo-Montañana, Rosa Cámara, Ignacio Bernabéu, Mireia Jordà, Susan M. Webb, Mónica Marazuela, and Manel Puig-Domingo

Subjects
acromegaly, somatostatin analogs, prediction, individualized treatment, precision medicine, acute octreotide test, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

IntroductionWe previously described that a short version of the acute octreotide test (sAOT) can predict the response to first-generation somatostatin receptor ligands (SRLs) in patients with acromegaly. We have prospectively reassessed the sAOT in patients from the ACROFAST study using current ultra-sensitive GH assays. We also studied the correlation of sAOT with tumor expression of E-cadherin and somatostatin receptor 2 (SSTR2) .MethodsA total of 47 patients treated with SRLs for 6 months were evaluated with the sAOT at diagnosis and correlated with SRLs’ response. Those patients whose IGF1 decreased to

Published
2023
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3. Molecular characterization of epithelial-mesenchymal transition and medical treatment related-genes in non-functioning pituitary neuroendocrine tumors

Author

Joan Gil, Montserrat Marques-Pamies, Elena Valassi, Guillermo Serra, Isabel Salinas, Gemma Xifra, Paula Casano-Sancho, Cristina Carrato, Betina Biagetti, Gemma Sesmilo, Jennifer Marcos-Ruiz, Helena Rodriguez-Lloveras, Anna Rueda-Pujol, Anna Aulinas, Alberto Blanco, Cristina Hostalot, Andreu Simó-Servat, Fernando Muñoz, Marta Rico, Javier Ibáñez-Domínguez, Esteban Cordero, Susan M. Webb, Mireia Jordà, and Manel Puig-Domingo

Subjects
Epithelial-mesenchymal transition, non-functioning pituitary adenomas, somatostatin receptor ligands, dopamine agonists, somatostatin analogs, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

IntroductionDifferent medical therapies have been developed for pituitary adenomas. However, Non-Functioning Pituitary Neuroendocrine Tumors (NF-PitNET) have shown little response to them. Furthermore, epithelial-mesenchymal transition (EMT) has been linked to resistance to medical treatment in a significant number of tumors, including pituitary adenomas.MethodsWe aimed to evaluate the expression of EMT-related markers in 72 NF-PitNET and 16 non-tumoral pituitaries. To further explore the potential usefulness of medical treatment for NF-PitNET we assessed the expression of somatostatin receptors and dopamine-associated genes.ResultsWe found that SNAI1, SNAI2, Vimentin, KLK10, PEBP1, Ki-67 and SSTR2 were associated with invasive NF-PitNET. Furthermore, we found that the EMT phenomenon was more common in NF-PitNET than in GH-secreting pituitary tumors. Interestingly, PEBP1 was overexpressed in recurrent NF-PitNET, and could predict growth recurrence with 100% sensitivity but only 43% specificity. In parallel with previously reported studies, SSTR3 is highly expressed in our NF-PitNET cohort. However, SSTR3 expression is highly heterogeneous among the different histological variants of NF-PitNET with very low levels in silent corticotroph adenomas.ConclusionNF-PitNET showed an enhanced EMT phenomenon. SSTR3 targeting could be a good therapeutic candidate in NF-PitNET except for silent corticotroph adenomas, which express very low levels of this receptor. In addition, PEBP1 could be an informative biomarker of tumor regrowth, useful for predictive medicine in NF-PitNET.

Published
2023
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4. Iron and obesity status-associated insulin resistance influence circulating fibroblast-growth factor-23 concentrations.

Author

José Manuel Fernández-Real, Josep Puig, Marta Serrano, Mónica Sabater, Antoni Rubió, José María Moreno-Navarrete, Marina Fontan, Roser Casamitjana, Gemma Xifra, Francisco José Ortega, Javier Salvador, Gema Frühbeck, and Wifredo Ricart

Subjects
Medicine, Science
Abstract

Fibroblast growth factor 23 (FGF-23) is known to be produced by the bone and linked to metabolic risk. We aimed to explore circulating FGF-23 in association with fatness and insulin sensitivity, atherosclerosis and bone mineral density (BMD). Circulating intact FGF-23 (iFGF-23) and C-terminal (CtFGF-23) concentrations (ELISA) were measured in 133 middle aged men from the general population in association with insulin sensitivity (Cohort 1); and in association with fat mass and bone mineral density (DEXA) and atherosclerosis (intima media thickness, IMT) in 78 subjects (52 women) with a wide range of adiposity (Cohort 2). Circulating iFGF-23 was also measured before and after weight loss. In all subjects as a whole, serum intact and C-terminal concentrations were linearly and positively associated with BMI. In cohort 1, both serum iFGF-23 and CtFGF-23 concentrations increased with insulin resistance. Serum creatinine contributed to iFGF-23 variance, while serum ferritin and insulin sensitivity (but not BMI, age or serum creatinine) contributed to 17% of CtFGF-23 variance. In cohort 2, CtFGF-23 levels were higher in women vs. men, and increased with BMI, fat mass, fasting and post-load serum glucose, insulin, HOMA-IR and PTH, being negatively associated with circulating vitamin D and ferritin levels. The associations of CtFGF-23 with bone density in the radius, lumbar spine and carotid IMT were no longer significant after controlling for BMI. Weight loss led to decreased iFGF-23 concentrations. In summary, the associations of circulating FGF-23 concentration with parameters of glucose metabolism, bone density and atherosclerosis are dependent on iron and obesity status-associated insulin resistance.

Published
2013
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5. Publisher Correction: Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women

Author

Julie Charpentier, Ottavia Porzio, Josep Puig, Matteo Serino, Iris Cardolini, Richard H. Barton, Fabienne Foufelle, Marina Cardellini, Fadila Benhamed, José Manuel Fernández-Real, Massimo Federici, Marc-Emmanuel Dumas, Mark Woodbridge, Jeremy K. Nicholson, Julien Chilloux, Antonis Myridakis, Wifredo Ricart, Vincent Blasco-Baque, Paolo Gentileschi, Christopher Tomlinson, Christophe Heymes, Francesca Davato, Elaine Holmes, José María Moreno-Navarrete, Sarah Butcher, Gemma Xifra, Jèssica Latorre Luque, Rémy Burcelin, Lesley Hoyles, Catherine Postic, Vincent Azalbert, Elodie Anthony, Laura Martinez-Gili, James Abbott, Frédéric Lopez, Imperial College London, University Hospital of Girona, University of Rome 'Tor Vergeta', Università degli Studi di Roma Tor Vergata [Roma], Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Embryology and Histopathology, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cardiff Business School, Cardiff University, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées

Subjects
0301 basic medicine, business.industry, Published Erratum, [SDV]Life Sciences [q-bio], MEDLINE, General Medicine, Bioinformatics, medicine.disease, General Biochemistry, Genetics and Molecular Biology, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Phenomics, Metagenomics, 030220 oncology & carcinogenesis, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Medicine, Steatosis, business, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), ComputingMilieux_MISCELLANEOUS, Non diabetic
Abstract

In the version of this article originally published, the received date was missing. It should have been listed as 2 January 2018. The error has been corrected in the HTML and PDF versions of this article.

Published
2018
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6. Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women

Author

Jèssica Latorre Luque, Marina Cardellini, Marc-Emmanuel Dumas, Gemma Xifra, Francesca Davato, Josep Puig, Vincent Blasco-Baque, Iris Cardolini, Elodie Anthony, José Manuel Fernández-Real, Fadila Benhamed, Laura Martinez-Gili, Massimo Federici, Rémy Burcelin, Wifredo Ricart, Lesley Hoyles, Julie Charpentier, Catherine Postic, Richard H. Barton, Frédéric Lopez, José María Moreno-Navarrete, Sarah Butcher, Antonis Myridakis, Matteo Serino, James Abbott, Fabienne Foufelle, Vincent Azalbert, Paolo Gentileschi, Christopher Tomlinson, Julien Chilloux, Christophe Heymes, Mark Woodbridge, Elaine Holmes, Ottavia Porzio, Jeremy K. Nicholson, Commission of the European Communities, Medical Research Council (MRC), Imperial College London, Instituto de Salud Carlos III [Madrid] (ISC), University of Rome 'Tor Vergeta', Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Cardiff Business School, Cardiff University, University of Rome TorVergata, Bambino Gesù Children’s Hospital [Rome, Italy], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Department of Embryology and Histopathology, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Nutrition et cerveau (U1213, U855), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Section of Diabetes, Endocrinology and Nutrition, University Hospital of Girona-Biomedical Research Institute 'Dr Josep Trueta'-CIBERobn Fisiopatología de la Obesidad y Nutrición, Department d'enginyeria quimica agraria i tecnologia agroalimentaria, Universitat de Girona (UdG), Hosp Josep Trueta, Inst Invest Biomed Girona, Dept Diabet Endocrinol & Nutr, Institut Català de la Salut (ICS), Università degli Studi di Roma Tor Vergata [Roma], Centre de Recherches en Cancérologie de Toulouse (CRCT), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Biotechnology, [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biomolecular Medicine, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Settore MED/09 - Medicina Interna, IMPACT, [SDV]Life Sciences [q-bio], Physiology, Research & Experimental Medicine, PHENOTYPE, GLUCOSE, Transcriptome, Cohort Studies, Diabetes mellitus genetics, Mice, Non-alcoholic Fatty Liver Disease, Settore MED/49 - Scienze Tecniche Dietetiche Applicate, ComputingMilieux_MISCELLANEOUS, Cells, Cultured, 11 Medical and Health Sciences, INSULIN-RESISTANCE, Settore BIO/12, Microbiota, Fatty liver, Confounding Factors, Epidemiologic, General Medicine, ASSOCIATION, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Fecal Microbiota Transplantation, 3. Good health, Medicine, Research & Experimental, CARDIOVASCULAR-DISEASE, Metabolome, Female, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, HUMAN GUT MICROBIOME, Immunology, Biology, Phenome, METABOLISM, Article, General Biochemistry, Genetics and Molecular Biology, DIET, 03 medical and health sciences, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, medicine, Diabetes Mellitus, [CHIM]Chemical Sciences, Animals, Humans, Metabolomics, Microbiome, Obesity, FATTY LIVER-DISEASE, Science & Technology, Cell Biology, medicine.disease, Confounding Factors (Epidemiology), Settore MED/18, Fatty Liver, Settore MED/18 - Chirurgia Generale, 030104 developmental biology, Metagenomics, Hepatocytes, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Steatosis
Abstract

Hepatic steatosis is a multifactorial condition that is often observed in obese patients and is a prelude to non-alcoholic fatty liver disease. Here, we combine shotgun sequencing of fecal metagenomes with molecular phenomics (hepatic transcriptome and plasma and urine metabolomes) in two well-characterized cohorts of morbidly obese women recruited to the FLORINASH study. We reveal molecular networks linking the gut microbiome and the host phenome to hepatic steatosis. Patients with steatosis have low microbial gene richness and increased genetic potential for the processing of dietary lipids and endotoxin biosynthesis (notably from Proteobacteria), hepatic inflammation and dysregulation of aromatic and branched-chain amino acid metabolism. We demonstrated that fecal microbiota transplants and chronic treatment with phenylacetic acid, a microbial product of aromatic amino acid metabolism, successfully trigger steatosis and branched-chain amino acid metabolism. Molecular phenomic signatures were predictive (area under the curve = 87%) and consistent with the gut microbiome having an effect on the steatosis phenome (>75% shared variation) and, therefore, actionable via microbiome-based therapies. Metabolic activity of specific human gut microorganisms contributes to liver steatosis in obese women.

Published
2018
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7. Brain Iron Overload, Insulin Resistance, and Cognitive Performance in Obese Subjects: A Preliminary MRI Case-Control Study

Author

Salvador Pedraza, Gerard Blasco, Xavier Molina, Josep Daunis-i-Estadella, Josep Puig, Fernando Fernández-Aranda, Gemma Xifra, Manuel Portero-Otin, José Manuel Fernández-Real, and Wifredo Ricart

Subjects
Adult, Male, medicine.medical_specialty, Iron Overload, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Iron, Population, Caudate nucleus, Insulin resistance, Cognition, Diabetes mellitus, Internal medicine, Internal Medicine, Medicine, Humans, Insulin, Obesity, Prospective Studies, education, Advanced and Specialized Nursing, Glucose tolerance test, education.field_of_study, medicine.diagnostic_test, business.industry, Lenticular nucleus, Neuropsychology, Brain, Glucose Tolerance Test, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Endocrinology, Cross-Sectional Studies, Liver, Case-Control Studies, Female, Insulin Resistance, business
Abstract

OBJECTIVE The linkage among the tissue iron stores, insulin resistance (IR), and cognition remains unclear in the obese population. We aimed to identify the factors that contribute to increased hepatic iron concentration (HIC) and brain iron overload (BIO), as evaluated by MRI, and to evaluate their impact on cognitive performance in obese and nonobese subjects. RESEARCH DESIGN AND METHODS We prospectively recruited 23 middle-aged obese subjects without diabetes (13 women; age 50.4 ± 7.7 years; BMI 43.7 ± 4.48 kg/m2) and 20 healthy nonobese volunteers (10 women; age 48.8 ± 9.5 years; BMI 24.3 ± 3.54 kg/m2) in whom iron load was assessed in white and gray matter and the liver by MRI. IR was measured from HOMA-IR and an oral glucose tolerance test. A battery of neuropsychological tests was used to evaluate the cognitive performance. Multivariate regression analysis was used to identify the independent associations of BIO and cognitive performance. RESULTS A significant increase in iron load was detected at the caudate nucleus (P < 0.001), lenticular nucleus (P = 0.004), hypothalamus (P = 0.002), hippocampus (P < 0.001), and liver (P < 0.001) in obese subjects. There was a positive correlation between HIC and BIO at caudate (r = 0.517, P < 0.001), hypothalamus (r = 0.396, P = 0.009), and hippocampus (r = 0.347, P < 0.023). The area under the curve of insulin was independently associated with BIO at the caudate (P = 0.001), hippocampus (P = 0.028), and HIC (P = 0.025). BIOs at the caudate (P = 0.028), hypothalamus (P = 0.006), and lenticular nucleus (P = 0.012) were independently associated with worse cognitive performance. CONCLUSIONS Obesity and IR may contribute to increased HIC and BIO being associated with worse cognitive performance. BIO could be a potentially useful MRI biomarker for IR and obesity-associated cognitive dysfunction.

Published
2014
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8. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug

Author

Robert Caesar, David Torrents, Marcus Ståhlman, Lisa M. Olsson, José Manuel Fernández-Real, Hao Wu, Rémy Burcelin, Wifredo Ricart, Valentina Tremaroli, Fredrik Bäckhed, Josep M. Mercader, Gemma Xifra, Rosie Perkins, Eduardo Esteve, Muhammad Tanweer Khan, Matteo Serino, Mercè Planas-Fèlix, Louise Mannerås-Holm, Inst Med, Dept Mol & Clin Med, Wallenberg Lab, University of Gothenburg (GU), Hosp Josep Trueta, Inst Invest Biomed Girona, Dept Diabet Endocrinol & Nutr, Institut Català de la Salut (ICS), Fac Med, Dept Med, Universitat de Girona (UdG), Ctr Invest Biomed Red Fisiopatol Obesidad & Nutr, Instituto de Salud Carlos III (ISC), Institut de Recherche en Santé Digestive (IRSD ), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Barcelona Supercomputing Center - Centro Nacional de Supercomputacion (BSC - CNS), Institució Catalana de Recerca i Estudis Avançats (ICREA), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Sahlgrenska University Hospital, Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), European Research Council, Consolidator grant 615362-METABASE, Instituto de Salud Carlos III [Madrid] (ISC), and Sahlgrenska University Hospital [Gothenburg]

Subjects
0301 basic medicine, Male, endocrine system diseases, microbiome, microbiote digestif, Type 2 diabetes, Pharmacology, Gut flora, Feces, Mice, Glucose tolerance test, medicine.diagnostic_test, Gastrointestinal Microbiome, digestive, oral, and skin physiology, General Medicine, Fecal Microbiota Transplantation, Middle Aged, Metformin, 3. Good health, Female, medicine.drug, DNA, Bacterial, diabète de type 2, Biology, In Vitro Techniques, Placebo, digestive system, General Biochemistry, Genetics and Molecular Biology, Bile Acids and Salts, 03 medical and health sciences, Double-Blind Method, Diabetes mellitus, medicine, Animals, Germ-Free Life, Humans, Hypoglycemic Agents, Microbiome, nutritional and metabolic diseases, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Glucose Tolerance Test, medicine.disease, biology.organism_classification, Fatty Acids, Volatile, type ii diabetes, metformine, 030104 developmental biology, Diabetes Mellitus, Type 2, Metagenomics
Abstract

Metformin is widely used in the treatment of type 2 diabetes (T2D), but its mechanism of action is poorly defined. Recent evidence implicates the gut microbiota as a site of metformin action. In a double-blind study, we randomized individuals with treatment-naive T2D to placebo or metformin for 4 months and showed that metformin had strong effects on the gut microbiome. These results were verified in a subset of the placebo group that switched to metformin 6 months after the start of the trial. Transfer of fecal samples (obtained before and 4 months after treatment) from metformin-treated donors to germ-free mice showed that glucose tolerance was improved in mice that received metformin-altered microbiota. By directly investigating metformin–microbiota interactions in a gut simulator, we showed that metformin affected pathways with common biological functions in species from two different phyla, and many of the metformin-regulated genes in these species encoded metalloproteins or metal transporters. Our findings provide support for the notion that altered gut microbiota mediates some of metformin's antidiabetic effects.

Published
2017
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9. Serum lipopolysaccharide-binding protein as a marker of atherosclerosis

Author

Josep Puig, Ester Guerra, Gemma Xifra, María Moreno, José María Moreno-Navarrete, José Manuel Fernández-Real, Marta Serrano, Wifredo Ricart, and Francisco J. Ortega

Subjects
Adult, Male, medicine.medical_specialty, Waist, Carotid Artery, Common, Population, 030204 cardiovascular system & hematology, Gastroenterology, Carotid Intima-Media Thickness, Fat mass, Body Mass Index, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Carotid Stenosis, Obesity, education, 030304 developmental biology, Aged, 0303 health sciences, education.field_of_study, High sensitivity crp, Membrane Glycoproteins, biology, Anthropometry, business.industry, Middle Aged, medicine.disease, Atherosclerosis, C-Reactive Protein, Intima-media thickness, Immunology, biology.protein, Female, Waist Circumference, Cardiology and Cardiovascular Medicine, business, Carrier Proteins, Lipopolysaccharide binding protein, Biomarkers, Acute-Phase Proteins
Abstract

Recently, serum lipopolysaccharide-binding protein (LBP) has been closely associated with coronary artery disease. Here, we aimed to investigate the possible relationship between serum LBP and markers of atherosclerosis.Serum LBP and carotid intima media thickness (C-IMT) were measured in 332 subjects (101 men and 231 women) who were recruited from an ongoing multicenter project.Serum LBP was significantly associated with obesity [BMI, fat mass and waist circumference (r 0.38, p 0.0001)], HOMA (r = 0.36, p 0.0001) and high sensitivity CRP (hsCRP) (r = 0.50, p 0.0001). Circulating LBP was also positively associated with C-IMT (r = 0.27, p 0.0001). Circulating LBP (β = 0.16; p = 0.001) contributed independently to C-IMT variance, after controlling for the effects of age, gender, BMI and hsCRP. Of note, circulating LBP was found to be increased in the population with carotid plaque (n = 50; 32.7 ± 12.5 vs 28.7 ± 10.7; p = 0.021).The consistent association between serum LBP and the carotid intima media thickness, a widely used atherosclerosis marker, reveals serum LBP as a putative factor related to atherosclerosis.

Published
2013
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11. Obesity changes the human gut mycobiome

Author

Daniel R. Perez, Joan Vendrell, Matilde R. Chacón, Wifredo Ricart, Eduardo Esteve, José Manuel Fernández Real, M. Mar Rodríguez, Gemma Xifra, Pablo Marin-Garcia, Reinald Pamplona, Manuel Portero-Otin, Felipe J. Chaves, and Mariona Jové

Subjects
medicine.medical_specialty, Adipose tissue, Physiology, Intestines -- Microbiology, Article, Palmitic acid, chemistry.chemical_compound, Weight loss, Internal medicine, Overweight persons, medicine, Internal transcribed spacer, Mucor, Multidisciplinary, biology, Mucor racemosus, Case-control study, Intestins -- Malalties, biology.organism_classification, medicine.disease, Obesity, Persones obeses, Endocrinology, Intestins -- Microbiologia, chemistry, Intestines -- Diseases, medicine.symptom
Abstract

The human intestine is home to a diverse range of bacterial and fungal species, forming an ecological community that contributes to normal physiology and disease susceptibility. Here, the fungal microbiota (mycobiome) in obese and non-obese subjects was characterized using Internal Transcribed Spacer (ITS)-based sequencing. The results demonstrate that obese patients could be discriminated by their specific fungal composition, which also distinguished metabolically “healthy” from “unhealthy” obesity. Clusters according to genus abundance co-segregated with body fatness, fasting triglycerides and HDL-cholesterol. A preliminary link to metabolites such as hexadecanedioic acid, caproic acid and N-acetyl-L-glutamic acid was also found. Mucor racemosus and M. fuscus were the species more represented in non-obese subjects compared to obese counterparts. Interestingly, the decreased relative abundance of the Mucor genus in obese subjects was reversible upon weight loss. Collectively, these findings suggest that manipulation of gut mycobiome communities might be a novel target in the treatment of obesity.

Published
2015

12. Nonalcoholic fatty liver disease and age are strong indicators for atherosclerosis in morbid obesity

Author

Rosa Ortiz, Gerard Blasco, Gemma Xifra, Massimo Federici, Josep Daunis-i-Estadella, José Manuel Fernández-Real, Josep Puig, Emili Loshuertos, Wifredo Ricart, Salvador Pedraza, Jaume Codina, and Víctor Cuba

Subjects
Adult, Male, Risk, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Biopsy, Carotid Intima-Media Thickness, Sensitivity and Specificity, Body Mass Index, Morbid obesity, Endocrinology, Non-alcoholic Fatty Liver Disease, Internal medicine, Positive predicative value, Nonalcoholic fatty liver disease, Prevalence, Medicine, Humans, Obesity, Settore MED/49 - Scienze Tecniche Dietetiche Applicate, 2. Zero hunger, medicine.diagnostic_test, Anthropometry, business.industry, Age Factors, Middle Aged, medicine.disease, Atherosclerosis, 3. Good health, Obesity, Morbid, Fatty Liver, Liver, Multivariate Analysis, Female, Steatosis, business, Body mass index
Abstract

SummaryObjective Whether nonalcoholic fatty liver disease (NAFLD) can predict atherosclerosis in obese patients remains unclear. The aim of our study was to investigate the usefulness of NAFLD and other cardiometabolic parameters in predicting subclinical atherosclerosis in obese patients. Design, Patients and Measurements We studied 314 consecutive obese subjects (223 women; mean age, 45·04 ± 9·34 years; body mass index 44·3 ± 5 kg/m2) and 47 healthy lean individuals. Hepatic steatosis and atherosclerosis [carotid intima-media thickness (cIMT) >0·8 mm and/or presence of plaques] were evaluated ultrasonographically. Liver biopsies were obtained in 51 patients. Results In obese patients, mean c-IMT was greater in those with NAFLD (P

Published
2014

13. Profiling of circulating microRNAs reveals common microRNAs linked to type 2 diabetes that change with insulin sensitization

Author

Sophie Rome, Oscar Rovira, José María Moreno-Navarrete, Eduardo Esteve, Jennifer Rieusset, Gemma Xifra, Francisco J. Ortega, José Manuel Fernández-Real, Josep M. Mercader, Ester Guerra, Wifredo Ricart, Marek Straczkowski, Monika Karczewska-Kupczewska, Cristina Martínez, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Programme Innovative Economy [UDA-POIG.01.03.01-00-128/08], European Union within the European Regional Development Fund, Spanish Ministry of Science and Innovation [FIS 2011-00214], CIBER de la Fisiopatologia de la Obesidad y la Nutricion (CIBERobn), Associacio Catalana de Diabetis, Sara Borrell fellowship, ISCIII, and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL)

Subjects
Male, endocrine system diseases, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, [SDV]Life Sciences [q-bio], administration & dosage, Pilot Projects, pharmacology"*"Insulin Resistance, Type 2 diabetes, 0302 clinical medicine, Insulin, Sensitization, 0303 health sciences, Heparin, Middle Aged, Metformin, drug therapy, medicine.anatomical_structure, genetics"*"Male"*"Metformin, Female, Type 2, medicine.drug, Adult, medicine.medical_specialty, Adolescent, 030209 endocrinology & metabolism, Adolescent"*"Adult"*"Aged"*"Biological Markers/metabolism"*"Cross-Sectional Studies"*"Diabetes Mellitus, metabolism"*"Middle Aged"*"Pilot Projects"*"Young Adult, 03 medical and health sciences, Young Adult, Insulin resistance, therapeutic use"*"MicroRNAs, Double-Blind Method, blood, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Humans, Hypoglycemic Agents, Type 2/blood/drug therapy/*genetics"*"Double-Blind Method"*"Female"*"Humans"*"Hypoglycemic Agents/administration & dosage/pharmacology"*"Insulin/administration & dosage/pharmacology"*"Insulin Resistance/*genetics"*"Male"*"Metformin/therapeutic use"*"MicroRNAs/*metabolism"*"Middle Aged"*"Pilot Projects"*"Young Adult, 030304 developmental biology, Aged, Advanced and Specialized Nursing, business.industry, pharmacology"*"Insulin, medicine.disease, Circulating MicroRNA, MicroRNAs, Endocrinology, Cross-Sectional Studies, Diabetes Mellitus, Type 2, genetics"*"Double-Blind Method"*"Female"*"Humans"*"Hypoglycemic Agents, Insulin Resistance, business, Biomarkers
Abstract

OBJECTIVE This study sought to identify the profile of circulating microRNAs (miRNAs) in type 2 diabetes (T2D) and its response to changes in insulin sensitivity. RESEARCH DESIGN AND METHODS The circulating miRNA profile was assessed in a pilot study of 12 men: 6 with normal glucose tolerance (NGT) and 6 T2D patients. The association of 10 circulating miRNAs with T2D was cross-sectionally validated in an extended sample of 45 NGT vs. 48 T2D subjects (65 nonobese and 28 obese men) and longitudinally in 35 T2D patients who were recruited in a randomized, double-blinded, and placebo-controlled 3-month trial of metformin treatment. Circulating miRNAs were also measured in seven healthy volunteers before and after a 6-h hyperinsulinemic-euglycemic clamp and insulin plus intralipid/heparin infusion. RESULTS Cross-sectional studies disclosed a marked increase of miR-140-5p, miR-142-3p, and miR-222 and decreased miR-423-5p, miR-125b, miR-192, miR-195, miR-130b, miR-532-5p, and miR-126 in T2D patients. Multiple linear regression analyses revealed that miR-140-5p and miR-423-5p contributed independently to explain 49.5% (P < 0.0001) of fasting glucose variance after controlling for confounders. A discriminant function of four miRNAs (miR-140-5p, miR-423-5p, miR-195, and miR-126) was specific for T2D with an accuracy of 89.2% (P < 0.0001). Metformin (but not placebo) led to significant changes in circulating miR-192 (49.5%; P = 0.022), miR-140-5p (−15.8%; P = 0.004), and miR-222 (−47.2%; P = 0.03), in parallel to decreased fasting glucose and HbA1c. Furthermore, while insulin infusion during clamp decreased miR-222 (−62%; P = 0.002), the intralipid/heparin mixture increased circulating miR-222 (163%; P = 0.015) and miR-140-5p (67.5%; P = 0.05). CONCLUSIONS This study depicts the close association between variations in circulating miRNAs and T2D and their potential relevance in insulin sensitivity.

Published
2014
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14. Iron and obesity status-associated insulin resistance influence circulating fibroblast-growth factor-23 concentrations

Author

Gema Frühbeck, Mònica Sabater, Javier Salvador, Gemma Xifra, Josep Puig, José Manuel Fernández-Real, Roser Casamitjana, Wifredo Ricart, Francisco Ortega, José María Moreno-Navarrete, Marta Serrano, Antoni Rubió, and Marina Fontan

Subjects
Male, Fibroblast growth factor 23, Anatomy and Physiology, Bone density, Epidemiology, medicine.medical_treatment, Blood Vessels/metabolism, lcsh:Medicine, Cardiovascular, Pathology, Blood Vessels/pathology, Insulin, lcsh:Science, Bone mineral, education.field_of_study, Glucose tolerance test, Multidisciplinary, biology, medicine.diagnostic_test, Middle Aged, Medicine, Research Article, Adult, medicine.medical_specialty, Iron, Population, Endocrine System, Insulin resistance, Diagnostic Medicine, Growth Factors, Internal medicine, Weight Loss, medicine, Humans, Obesity, education, Biology, Nutrition, Endocrine Physiology, lcsh:R, Glucose Tolerance Test, medicine.disease, Fibroblast Growth Factors, Ferritin, Fibroblast Growth Factor-23, Biomarker Epidemiology, Endocrinology, Metabolic Disorders, Ferritins, biology.protein, Blood Vessels, lcsh:Q, Insulin Resistance, Biomarkers, General Pathology
Abstract

Fibroblast growth factor 23 (FGF-23) is known to be produced by the bone and linked to metabolic risk. We aimed to explore circulating FGF-23 in association with fatness and insulin sensitivity, atherosclerosis and bone mineral density (BMD). Circulating intact FGF-23 (iFGF-23) and C-terminal (CtFGF-23) concentrations (ELISA) were measured in 133 middle aged men from the general population in association with insulin sensitivity (Cohort 1); and in association with fat mass and bone mineral density (DEXA) and atherosclerosis (intima media thickness, IMT) in 78 subjects (52 women) with a wide range of adiposity (Cohort 2). Circulating iFGF-23 was also measured before and after weight loss. In all subjects as a whole, serum intact and C-terminal concentrations were linearly and positively associated with BMI. In cohort 1, both serum iFGF-23 and CtFGF-23 concentrations increased with insulin resistance. Serum creatinine contributed to iFGF-23 variance, while serum ferritin and insulin sensitivity (but not BMI, age or serum creatinine) contributed to 17% of CtFGF-23 variance. In cohort 2, CtFGF-23 levels were higher in women vs. men, and increased with BMI, fat mass, fasting and post-load serum glucose, insulin, HOMA-IR and PTH, being negatively associated with circulating vitamin D and ferritin levels. The associations of CtFGF-23 with bone density in the radius, lumbar spine and carotid IMT were no longer significant after controlling for BMI. Weight loss led to decreased iFGF-23 concentrations. In summary, the associations of circulating FGF-23 concentration with parameters of glucose metabolism, bone density and atherosclerosis are dependent on iron and obesity status-associated insulin resistance.

Published
2013

15. Contributors

Author

Agudo, Antonio, Alarcón, Marisa, Aldasoro, Juan José, Antonopoulou, Smaragdi, Arnoni, Yardena, Arranz, Sara, Atteia, Hebatallah Husseini, Azzini, Elena, Badimon, Lina, Bastida, Sara, Beccari, Giovanni, Berry, Elliot M., Biandolino, Francesca, Bonaccio, Marialaura, Bonachela, Santiago, Bonanni, Americo, Bosco, Gerardo, Buckland, Genevieve, Calabriso, Nadia, Caliskan, Oguzhan, Carluccio, Maria Annunziata, Casas, J. Jesús, Casas, Rosa, Castro-Quezada, Itandehui, Chiva-Blanch, Gemma, Conti, Gea Oliveri, Copat, Chiara, Couture, Patrick, Covarelli, Lorenzo, De Caterina, Raffaele, De Feo, Vincenzo, de Gaetano, Giovanni, de Lorgeril, Michel, De Martino, Laura, Demetriou, Christiana A., Detopoulou, Paraskevi, Diamantopoulos, Emmanuel J., Djuric, Zora, Donati, Maria Benedetta, Doreste-Alonso, Jorge, El Rhazi, Karima, El-Swefy, Sahar Elsayed, Rodilla, Manuel Espárrago, Estruch, Ramon, Fallico, Roberto, Farajian, Paul, Fenoy, Encarnación, Fernandez, J.M., Fernandez, Maria Luz, Fernández-Real, José Manuel, Ferrante, Margherita, Fragopoulou, Elizabeth, Fuentes-Jimenez, F., Gaforio, José J., Garaulet, Marta, Garcia-Larsen, Vanessa, Gardener, Hannah, Gesteiro, Eva, Goldstein, Mark R., González, Carlos A., Gouveri, Evanthia, Granados, Sergio, Grimaldi, Keith, Hadjisavvas, Andreas, Henríquez-Sánchez, Patricia, Hernández, Joaquín, Iacoviello, Licia, Iriti, Marcello, Karageorgou, Dimitra, Kontou, Niki, Kyriacou, Kyriacos, La Torre, Giuseppe, Lairon, Denis, Lamarche, Benoît, Lee, Jaime, Loizidou, Maria A., López-Biedma, Alicia, Macpherson, Helen, Maiani, Giuseppe, Mancini, Emilia, Martin, Colin R., Martínez-González, Miguel Ángel, Mascitelli, Luca, Massaro, Marika, Medina, F. Xavier, Mendieta, Guiomar, Mesías, Marta, Micha, Renata, Moreno-Navarrete, José María, Moyano, Francisco J., Navarro, M. Pilar, Nazzaro, Filomena, Nejjari, Chakib, Nilsson, Lena Maria, Nomikos, Tzortzis, Oliviero, Francesca, Erdogan Orhan, Ilkay, Paoli, Antonio, Papandreou, Christopher, Pase, Matthew, Pellegrino, Mariangela, Pipingas, Andrew, Potenza, Concetta, Prato, Ermelinda, Preedy, Victor R., Pulido-Moran, Mario, Punzi, Leonardo, Quiles, José L., Ramírez-Tortose, M<ce:sup loc='post">a</ce:sup> del Carmen, Richard, Caroline, Rodríguez Bernal, Beatriz, Román-Viñas, Blanca, Ros, Emilio, Rosado-Alvarez, D., Ríos, José-Luis, Ruano, Cristina, Sahingoz, Semra Akar, Salen, Patricia, Sánchez Benito, José L., Soriano, Eva Sánchez, Sánchez-Muniz, Francisco J., Sánchez-Quesada, Cristina, Sánchez-Villegas, Almudena, Saulle, Rosella, Scholey, Andrew, Sciacca, Salvatore, Scoditti, Egeria, Seiquer, Isabel, Semyonov, Leda, Serra-Majem, Lluís, Sewell, Dean A., Sfriso, Paolo, Sheikh, Aziz, Skroza, Nevena, Spinella, Paolo, Tosi, Laura, Tumen, Ibrahim, Valderas-Martinez, Palmira, Varoni, Elena M., Vilahur, Gemma, Villalon, Lorena, Villarroya, Gemma Xifra, Vineis, Paolo, Warleta, Fernando, Wright, Clinton B., Zacharski, Leo R., Zampelas, Antonis, and Zuber, Sara

Published
2015
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