8 results on '"Amrit Singh-Estivalet"'
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2. Glucocorticoids Inhibit Basal and Hormone-Induced Serotonin Synthesis in Pancreatic Beta Cells.
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Moina Hasni Ebou, Amrit Singh-Estivalet, Jean-Marie Launay, Jacques Callebert, François Tronche, Pascal Ferré, Jean-François Gautier, Ghislaine Guillemain, Bernadette Bréant, Bertrand Blondeau, and Jean-Pierre Riveline
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Medicine ,Science - Abstract
Diabetes is a major complication of chronic Glucocorticoids (GCs) treatment. GCs induce insulin resistance and also inhibit insulin secretion from pancreatic beta cells. Yet, a full understanding of this negative regulation remains to be deciphered. In the present study, we investigated whether GCs could inhibit serotonin synthesis in beta cell since this neurotransmitter has been shown to be involved in the regulation of insulin secretion. To this aim, serotonin synthesis was evaluated in vitro after treatment with GCs of either islets from CD1 mice or MIN6 cells, a beta-cell line. We also explored the effect of GCs on the stimulation of serotonin synthesis by several hormones such as prolactin and GLP 1. We finally studied this regulation in islet in two in vivo models: mice treated with GCs and with liraglutide, a GLP1 analog, and mice deleted for the glucocorticoid receptor in the pancreas. We showed in isolated islets and MIN6 cells that GCs decreased expression and activity of the two key enzymes of serotonin synthesis, Tryptophan Hydroxylase 1 (Tph1) and 2 (Tph2), leading to reduced serotonin contents. GCs also blocked the induction of serotonin synthesis by prolactin or by a previously unknown serotonin activator, the GLP-1 analog exendin-4. In vivo, activation of the Glucagon-like-Peptide-1 receptor with liraglutide during 4 weeks increased islet serotonin contents and GCs treatment prevented this increase. Finally, islets from mice deleted for the GR in the pancreas displayed an increased expression of Tph1 and Tph2 and a strong increased serotonin content per islet. In conclusion, our results demonstrate an original inhibition of serotonin synthesis by GCs, both in basal condition and after stimulation by prolactin or activators of the GLP-1 receptor. This regulation may contribute to the deleterious effects of GCs on beta cells.
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- 2016
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3. Novel transgenic mice for inducible gene overexpression in pancreatic cells define glucocorticoid receptor-mediated regulations of beta cells.
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Bertrand Blondeau, Iman Sahly, Emmanuelle Massouridès, Amrit Singh-Estivalet, Bérengère Valtat, Delphine Dorchene, Frédéric Jaisser, Bernadette Bréant, and Francois Tronche
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Medicine ,Science - Abstract
Conditional gene deletion in specific cell populations has helped the understanding of pancreas development. Using this approach, we have shown that deleting the glucocorticoid receptor (GR) gene in pancreatic precursor cells leads to a doubled beta-cell mass. Here, we provide genetic tools that permit a temporally and spatially controlled expression of target genes in pancreatic cells using the Tetracycline inducible system. To efficiently target the Tetracycline transactivator (tTA) in specific cell populations, we generated Bacterial Artificial Chromosomes (BAC) transgenic mice expressing the improved Tetracycline transactivator (itTA) either in pancreatic progenitor cells expressing the transcription factor Pdx1 (BAC-Pdx1-itTA), or in beta cells expressing the insulin1 gene (BAC-Ins1-itTA). In the two transgenic models, itTA-mediated activation of reporter genes was efficient and subject to regulation by Doxycycline (Dox). The analysis of a tetracycline-regulated LacZ reporter gene shows that in BAC-Pdx1-itTA mice, itTA is expressed from embryonic (E) day 11.5 in all pancreatic precursor cells. In the adult pancreas, itTA is active in mature beta, delta cells and in few acinar cells. In BAC-Ins1-itTA mice tTA is active from E13.5 and is restricted to beta cells in fetal and adult pancreas. In both lines, tTA activity was suppressed by Dox treatment and re-induced after Dox removal. Using these transgenic lines, we overexpressed the GR in selective pancreatic cell populations and found that overexpression in precursor cells altered adult beta-cell fraction but not glucose tolerance. In contrast, GR overexpression in mature beta cells did not alter beta-cell fraction but impaired glucose tolerance with insufficient insulin secretion. In conclusion, these new itTA mouse models will allow fine-tuning of gene expression to investigate gene function in pancreatic biology and help us understand how glucocorticoid signaling affects on the long-term distinct aspects of beta-cell biology.
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- 2012
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4. Ultrarare heterozygous pathogenic variants of genes causing dominant forms of early-onset deafness underlie severe presbycusis
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Christian Renard, Christine Petit, Yosra Bouyacoub, Sedigheh Delmaghani, Magali Niasme-Grare, Nicolas Michalski, Hung Thai-Van, Olivier Deguine, Anne Aubois, Arnaud Deveze, Jean-Pierre Lavieille, Valérie Franco-Vidal, Anne-Laure Roudevitch-Pujol, Amrit Singh-Estivalet, Arnaud Coez, Vincent Michel, Christophe Vincent, Hugues Aschard, Claire Thibult-Apt, Amel Bahloul, Sophie Boucher, E. Ionescu, Bernard Fraysse, Fabienne Wong Jun Tai, Fabrice Giraudet, Vincent Darrouzet, Typhaine Dupont, Nicolas Wolff, Didier Bouccara, Lionel Collet, Crystel Bonnet, Gaelle M. Lefèvre, Jean-Louis Kemeny, Andrea Lelli, Eric Bizaguet, Paul Avan, Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), ED 515 - Complexité du vivant, Sorbonne Université (SU), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Université d'Angers (UA), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Récepteurs Canaux - Channel Receptors, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Toulouse [Toulouse], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Hôpital Edouard Herriot [CHU - HCL], Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, Université Clermont Auvergne (UCA), Hôpital Nord [CHU - APHM], Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), Hôpital Roger Salengro [Lille], Laboratoire d’Audiologie Renard, Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Laboratoire de correction auditive Eric Bizaguet, CEA- Saclay (CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), This work was supported by a grant from Fondation pour l’Audition (to C.P.), LabEx Lifesenses Grant ANR-10-LABX-65, and Light4deaf Grant ANR-15-RHUS-0001., We thank the patients for participating in this study and Céline Trébeau for technical assistance. S.B. received funding from the University of Angers (Medical School), the University Hospital of Angers, and the Collège Français d’oto-rhino-laryngologistes., ANR-10-LABX-0065,LIFESENSES,DES SENS POUR TOUTE LA VIE(2010), ANR-15-RHUS-0001,LIGHT4DEAF,ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER(2015), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Collège de France - Chaire Génétique et physiologie cellulaire, Bonnet, Crystel, DES SENS POUR TOUTE LA VIE - - LIFESENSES2010 - ANR-10-LABX-0065 - LABX - VALID, and ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER - - LIGHT4DEAF2015 - ANR-15-RHUS-0001 - RHUS - VALID
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0301 basic medicine ,Presbycusis ,[SDV.GEN] Life Sciences [q-bio]/Genetics ,Deafness ,Cohort Studies ,Mice ,0302 clinical medicine ,MESH: Presbycusis ,MESH: Animals ,Age of Onset ,MESH: Cohort Studies ,Genes, Dominant ,Early onset ,MESH: Heterozygote ,Genetics ,Multidisciplinary ,monogenic disorder ,Age Factors ,Biological Sciences ,Phenotype ,MESH: Case-Control Studies ,Mitochondria ,3. Good health ,age-related hearing loss ,symbols ,MESH: Membrane Proteins ,medicine.symptom ,Heterozygote ,MESH: Mutation ,Hearing loss ,MESH: Mitochondria ,MESH: Age of Onset ,MESH: Deafness ,Biology ,03 medical and health sciences ,symbols.namesake ,MESH: Whole Exome Sequencing ,Exome Sequencing ,medicine ,Animals ,Humans ,Allele frequency ,Gene ,ultrarare variants ,MESH: Mice ,MESH: Age Factors ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,MESH: Humans ,Membrane Proteins ,Tmc1 ,medicine.disease ,Comorbidity ,MicroRNAs ,030104 developmental biology ,Case-Control Studies ,Mutation ,Mendelian inheritance ,MESH: Genes, Dominant ,presbycusis ,MESH: MicroRNAs ,030217 neurology & neurosurgery - Abstract
International audience; Presbycusis, or age-related hearing loss (ARHL), is a major public health issue. About half the phenotypic variance has been attributed to genetic factors. Here, we assessed the contribution to presbycusis of ultrarare pathogenic variants, considered indicative of Mendelian forms. We focused on severe presbycusis without environmental or comorbidity risk factors and studied multiplex family age-related hearing loss (mARHL) and simplex/sporadic age-related hearing loss (sARHL) cases and controls with normal hearing by whole-exome sequencing. Ultrarare variants (allele frequency [AF] < 0.0001) of 35 genes responsible for autosomal dominant early-onset forms of deafness, predicted to be pathogenic, were detected in 25.7% of mARHL and 22.7% of sARHL cases vs. 7.5% of controls ( P = 0.001); half were previously unknown (AF < 0.000002). MYO6 , MYO7A , PTPRQ , and TECTA variants were present in 8.9% of ARHL cases but less than 1% of controls. Evidence for a causal role of variants in presbycusis was provided by pathogenicity prediction programs, documented haploinsufficiency, three-dimensional structure/function analyses, cell biology experiments, and reported early effects. We also established Tmc1 N321I/+ mice, carrying the TMC1 :p.(Asn327Ile) variant detected in an mARHL case, as a mouse model for a monogenic form of presbycusis. Deafness gene variants can thus result in a continuum of auditory phenotypes. Our findings demonstrate that the genetics of presbycusis is shaped by not only well-studied polygenic risk factors of small effect size revealed by common variants but also, ultrarare variants likely resulting in monogenic forms, thereby paving the way for treatment with emerging inner ear gene therapy.
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- 2020
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5. An innovative strategy for the molecular diagnosis of Usher syndrome identifies causal biallelic mutations in 93% of European patients
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Christine Petit, Eberhart Zrenner, Shzeena Dad, Martina Jarc-Vidmar, Maria Antonia Claveria, Alberto Auricchio, Ana Fakin, Marko Hawlina, Gaelle M. Lefèvre, Susanne Kohl, Anne Kurtenbach, Aziz El-Amraoui, Loreto Martorell Sampol, Jesus Rodriguez Jorge, Ditta Zobor, Saddek Mohand-Said, Crystel Bonnet, Ieva Sliesoraityte, Charles Marcaillou, Francesco Testa, Saba Battelino, Jaume Mora, Mélanie Letexier, José-Alain Sahel, Francesca Simonelli, Lisbeth Birk Møller, Sandra Chantot-Bastaraud, Jean-Pierre Hardelin, Isabelle Audo, Zied Riahi, Andrej Zupan, Luce Smagghe, Amrit Singh-Estivalet, Damjan Glavač, Souad Gherbi, Sandro Banfi, Sandrine Marlin, Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), IntegraGen SA, Génétique et Physiologie de l'Audition, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), University of Tuebingen, Centre de référence des Surdités Génétiques [CHU Necker, Paris], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Naples Federico II = Università degli studi di Napoli Federico II, Telethon Institute of Genetics and Medicine = Istituto Telethon di Genetica e Medicina (TIGEM), Seconda Università degli Studi di Napoli = Second University of Naples, University Medical Centre Ljubljana [Ljubljana, Slovenia] (UMCL), University of Ljubljana, Hospital Sant Joan de Déu [Barcelona], Kennedy Center, Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), This work was supported by the European Union Seventh Framework Programme under the grant agreement HEALTH-F2-2010-242013 (TREATRUSH), ANR-15-RHUS-001 (LIGHT4DEAF), LHW-Stiftung, Fondation Raymonde & Guy Strittmatter, FAUN Stiftung, Conny Maeva Charitable Foundation, Fondation Orange, Fondation BNP Paribas, LABEX Lifesenses [ANR-10-LABX-65], 'the Foundation Fighting Blindness Paris Center Grant', and the Slovenian research agency (ARRS P3-0333)., We are grateful to the patients and their families for their participation in the study. DNA samples included in this study originated from the NeuroSensCol** DNA bank, part of the BioCollections network for research in neuroscience (PI: JA Sahel, co-PI: I Audo, in partnership with the CHNO des Quinze-Vingts, Inserm and the CNRS), and the Tuebingen RetDis biobank (PI: B Wissinger, co-PI S Kohl)., ANR-15-RHUS-0001,LIGHT4DEAF,ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER(2015), ANR-10-LABX-0065,LIFESENSES,DES SENS POUR TOUTE LA VIE(2010), European Project: 242013,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,TREATRUSH(2010), Bonnet, Crystel, ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER - - LIGHT4DEAF2015 - ANR-15-RHUS-0001 - RHUS - VALID, DES SENS POUR TOUTE LA VIE - - LIFESENSES2010 - ANR-10-LABX-0065 - LABX - VALID, Fighting blindness of Usher syndrome: diagnosis, pathogenesis and retinal treatment (TreatRetUsher) - TREATRUSH - - EC:FP7:HEALTH2010-02-01 - 2014-01-31 - 242013 - VALID, Riahi, Zied, Chantot Bastaraud, Sandra, Smagghe, Luce, Letexier, Mélanie, Marcaillou, Charle, Lefèvre, Gaëlle M, Hardelin, Jean Pierre, El Amraoui, Aziz, Singh Estivalet, Amrit, Mohand Saïd, Saddek, Kohl, Susanne, Kurtenbach, Anne, Sliesoraityte, Ieva, Zobor, Ditta, Gherbi, Souad, Testa, Francesco, Simonelli, Francesca, Banfi, Sandro, Fakin, Ana, Glavač, Damjan, Jarc Vidmar, Martina, Zupan, Andrej, Battelino, Saba, Martorell Sampol, Loreto, Claveria, Maria Antonia, Catala Mora, Jaume, Dad, Shzeena, Møller, Lisbeth B, Rodriguez Jorge, Jesu, Hawlina, Marko, Auricchio, Alberto, Sahel, José Alain, Marlin, Sandrine, Zrenner, Eberhart, Audo, Isabelle, Petit, Christine, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de référence des Surdités Génétiques, University of Naples Federico II, Seconda Università degli studi di Napoli, and Chaire Génétique et physiologie cellulaire
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0301 basic medicine ,MESH: Extracellular Matrix Proteins ,MESH: Sequence Analysis, DNA ,Usher syndrome ,[SDV]Life Sciences [q-bio] ,Bioinformatics ,0302 clinical medicine ,Exome ,Exome sequencing ,Genetics (clinical) ,Genetics ,Comparative Genomic Hybridization ,Extracellular Matrix Proteins ,MESH: Exome ,medicine.diagnostic_test ,MESH: Genetic Testing ,3. Good health ,Europe ,[SDV] Life Sciences [q-bio] ,Medical genetics ,MESH: Genes, Modifier ,Usher Syndromes ,medicine.medical_specialty ,MESH: Mutation ,Genetic counseling ,Biology ,Sensitivity and Specificity ,Article ,03 medical and health sciences ,Molecular genetics ,medicine ,otorhinolaryngologic diseases ,Humans ,Genetic Testing ,MESH: Usher Syndromes ,Alleles ,Genetic testing ,Genes, Modifier ,MESH: Humans ,Genetic heterogeneity ,MESH: Alleles ,Sequence Analysis, DNA ,medicine.disease ,MESH: Sensitivity and Specificity ,MESH: Comparative Genomic Hybridization ,030104 developmental biology ,Mutation ,030221 ophthalmology & optometry ,MESH: Europe - Abstract
International audience; Usher syndrome (USH), the most prevalent cause of hereditary deafness-blindness, is an autosomal recessive and genetically heterogeneous disorder. Three clinical subtypes (USH1-3) are distinguishable based on the severity of the sensorineural hearing impairment, the presence or absence of vestibular dysfunction, and the age of onset of the retinitis pigmentosa. A total of 10 causal genes, 6 for USH1, 3 for USH2, and 1 for USH3, and an USH2 modifier gene, have been identified. A robust molecular diagnosis is required not only to improve genetic counseling, but also to advance gene therapy in USH patients. Here, we present an improved diagnostic strategy that is both cost- and time-effective. It relies on the sequential use of three different techniques to analyze selected genomic regions: targeted exome sequencing, comparative genome hybridization, and quantitative exon amplification. We screened a large cohort of 427 patients (139 USH1, 282 USH2, and six of undefined clinical subtype) from various European medical centers for mutations in all USH genes and the modifier gene. We identified a total of 421 different sequence variants predicted to be pathogenic, about half of which had not been previously reported. Remarkably, we detected large genomic rearrangements, most of which were novel and unique, in 9% of the patients. Thus, our strategy led to the identification of biallelic and monoallelic mutations in 92.7% and 5.8% of the USH patients, respectively. With an overall 98.5% mutation characterization rate, the diagnosis efficiency was substantially improved compared with previously reported methods.
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- 2016
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6. Glucocorticoids Inhibit Basal and Hormone-Induced Serotonin Synthesis in Pancreatic Beta Cells
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Jean-Marie Launay, Moina Hasni Ebou, Ghislaine Guillemain, B. Blondeau, Pascal Ferré, Bernadette Breant, Jean-Pierre Riveline, François Tronche, Jacques Callebert, Jean-François Gautier, Amrit Singh-Estivalet, Centre de Recherche des Cordeliers ( CRC ), 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 ), Service de Biochimie et de Biologie Moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Physiopathologie des Maladies du Système Nerveux Central, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Lariboisière, Université Paris Diderot - Paris 7 ( UPD7 ), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris Diderot - Paris 7 (UPD7), HAL UPMC, Gestionnaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE)
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0301 basic medicine ,Physiology ,Peptide Hormones ,lcsh:Medicine ,Gene Expression ,Tryptophan Hydroxylase ,Biochemistry ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Glucocorticoid receptor ,Endocrinology ,Aromatic Amino Acids ,Glucagon-Like Peptide 1 ,Insulin-Secreting Cells ,Insulin Secretion ,Medicine and Health Sciences ,Amino Acids ,Neurotransmitter ,lcsh:Science ,Multidisciplinary ,TPH1 ,geography.geographical_feature_category ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,TPH2 ,Organic Compounds ,Monosaccharides ,Tryptophan ,Neurochemistry ,Neurotransmitters ,Islet ,3. Good health ,Chemistry ,Physical Sciences ,Beta cell ,Anatomy ,hormones, hormone substitutes, and hormone antagonists ,Research Article ,medicine.medical_specialty ,Biogenic Amines ,Serotonin ,endocrine system ,Carbohydrates ,030209 endocrinology & metabolism ,Endocrine System ,Biology ,Cell Line ,03 medical and health sciences ,Exocrine Glands ,Extraction techniques ,Internal medicine ,[ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology ,medicine ,Genetics ,Animals ,Glucocorticoids ,Pancreas ,geography ,Endocrine Physiology ,Venoms ,lcsh:R ,Organic Chemistry ,Chemical Compounds ,Correction ,Biology and Life Sciences ,Proteins ,Tryptophan hydroxylase ,Hormones ,RNA extraction ,Prolactin ,Research and analysis methods ,030104 developmental biology ,Glucose ,chemistry ,Exenatide ,lcsh:Q ,Peptides ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,Neuroscience - Abstract
International audience; Diabetes is a major complication of chronic Glucocorticoids (GCs) treatment. GCs induce insulin resistance and also inhibit insulin secretion from pancreatic beta cells. Yet, a full understanding of this negative regulation remains to be deciphered. In the present study, we investigated whether GCs could inhibit serotonin synthesis in beta cell since this neurotransmitter has been shown to be involved in the regulation of insulin secretion. To this aim, serotonin synthesis was evaluated in vitro after treatment with GCs of either islets from CD1 mice or MIN6 cells, a beta-cell line. We also explored the effect of GCs on the stimulation of serotonin synthesis by several hormones such as prolactin and GLP 1. We finally studied this regulation in islet in two in vivo models: mice treated with GCs and with liraglutide, a GLP1 analog, and mice deleted for the glucocorticoid receptor in the pancreas. We showed in isolated islets and MIN6 cells that GCs decreased expression and activity of the two key enzymes of serotonin synthesis, Tryptophan Hydroxylase 1 (Tph1) and 2 (Tph2), leading to reduced serotonin contents. GCs also blocked the induction of serotonin synthesis by prolactin or by a previously unknown serotonin activator, the GLP-1 analog exendin-4. In vivo, activation of the Glucagon-like-Peptide-1 receptor with liraglutide during 4 weeks increased islet serotonin contents and GCs treatment prevented this increase. Finally, islets from mice deleted for the GR in the pancreas displayed an increased expression of Tph1 and Tph2 and a strong increased serotonin content per islet. In conclusion, our results demonstrate an original inhibition of serotonin synthesis by GCs, both in basal condition and after stimulation by prolactin or activators of the GLP-1 receptor. This regulation may contribute to the deleterious effects of GCs on beta cells.
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- 2016
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7. Fetal PGC-1 alpha Overexpression Programs Adult Pancreatic beta-Cell Dysfunction
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Jean-Pierre Riveline, Pascal Ferré, Ping Zhang, Bérengère Valtat, Nicolas Venteclef, Jean-François Gautier, B. Blondeau, Mathieu Armanet, A. Besseiche, Bernadette Breant, Amrit Singh-Estivalet, Daniel P. Kelly, François Tronche, Expression des Gènes et comportement adaptatifs = Molecular Genetics, Neurophysiology and Behavior (NPS-15), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ministere de l'Enseignement Superieur et de la Recherche, Fondation pour la Recherche Medicale, INSERM, CNRS, European Union [FP5 Nutrix QLK1-CT-2000-00083, FP6 Earnest Food-CT-2005-007036], Agence Nationale de la Recherche [A05245DS], Societe Francophone du Diabete, Institut Benjamin Delessert, Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)
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Blood Glucose ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Cell ,030209 endocrinology & metabolism ,Biology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,Insulin-Secreting Cells ,Internal medicine ,Internal Medicine ,medicine ,Animals ,Insulin ,RNA, Messenger ,Receptor ,Psychological repression ,Transcription factor ,Cells, Cultured ,Original Research ,030304 developmental biology ,Homeodomain Proteins ,Regulation of gene expression ,0303 health sciences ,Fetus ,16. Peace & justice ,Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ,Glucose ,medicine.anatomical_structure ,Endocrinology ,Gene Expression Regulation ,Islet Studies ,Trans-Activators ,PDX1 ,Female ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Food Deprivation ,Transcription Factors - Abstract
International audience; Adult beta-cell dysfunction, a hallmark of type 2 diabetes, can be programmed by adverse fetal environment. We have shown that fetal glucocorticoids (GCs) participate in this programming through inhibition of beta-cell development. Here we have investigated the molecular mechanisms underlying this regulation. We showed that GCs stimulate the expression of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha), a coregulator of the GCs receptor (GR), and that the overexpression of PGC-1 alpha represses genes important for beta-cell development and function. More precisely, PGC-1 alpha inhibited the expression of the key beta-cell transcription factor pancreatic duodenal homeobox 1 (Pdx1). This repression required the GR and was mediated through binding of a GR/PGC-1 alpha complex to the Pdx1 promoter. To explore PGC-1 alpha function, we generated mice with inducible beta-cell PGC-1 alpha overexpression. Mice overexpressing PGC-1 alpha exhibited at adult age impaired glucose tolerance associated with reduced insulin secretion, decreased beta-cell mass, and beta-cell hypotrophy. Interestingly, PGC-1 alpha expression in fetal life only was sufficient to impair adult beta-cell function whereas beta-cell PGC-1 alpha overexpression from adult age had no consequence on beta-cell function. Altogether, our results demonstrate that the GR and PGC-1 alpha participate in the fetal programming of adult beta-cell function through inhibition of Pdx1 expression. Diabetes 62:1206-1216, 2013
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- 2013
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8. 081 Régulation de la masse et de la fonction des cellules beta par les glucocorticoïdes : implication de la sérotonine
- Author
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Bernadette Breant, A. Bailly, Bérengère Valtat, J. Callebert, Mathieu Armanet, B. Blondeau, Jean-Pierre Riveline, Emmanuelle Massouridès, J.F. Gautier, Arndt Benecke, Amrit Singh-Estivalet, and François Tronche
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Endocrinology ,Endocrinology, Diabetes and Metabolism ,Internal Medicine ,General Medicine - Abstract
Introduction Notre objectif est de comprendre les mecanismes qui regulent le developpement et la fonction des cellules β pour apprehender les places respectives des anomalies de masse et de fonction β dans l’etiologie du diabete de type 2. Nos travaux precedents ont montre que les glucocorticoides (GC) inhibent le developpement des cellules β et que l’invalidation conditionnelle chez la souris du recepteur des GC (GR) dans les precurseurs pancreatiques (souris GR-Prec) aboutissait a un doublement de masse β. Le but de cette etude etait de comprendre les mecanismes impliques dans l’accroissement de cellules β. Materiels et methodes Nous avons etudie chez les souris GR-Prec et temoins adultes la tolerance au glucose sous regime normal ou hyperlipidique, mesure la masse et la proliferation des cellules beta et defini le transcriptome des ilots par micropuces a ARN. Resultats Les souris GR-Prec presentent une augmentation de la masse beta associee paradoxalement a une intolerance au glucose due a une alteration de l’insulinosecretion sous regime normal ou hyperlipidique. L’analyse du transcriptome des ilots de souris GR-Prec a identifie les genes Tph1 et 2 (Tryptophane hydroxylase), enzyme de synthese de serotonine, neurotransmetteur recemment implique dans la regulation de masse et fonction beta. Chez les souris GR-Prec, l’augmentation de Tph1 et 2 entraine une augmentation du contenu en serotonine dans les ilots. L’absence de signalisation GC stimule donc le systeme serotonine des cellules beta. A l’inverse, l’activation de la voie des GC dans des cellules beta in vitro diminue l’expression des genes Tph1 et Tph2 et la synthese de serotonine et contre-regule la stimulation de serotonine induite par la prolactine et l’exendine-4. Conclusion Les GC sont des puissants inhibiteurs de la synthese de serotonine dans les cellules beta, suggerant que la serotonine est un intermediaire des effets des GC sur la masse et fonction beta.
- Published
- 2012
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- View/download PDF
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