title: Long-Term GABA Administration Induces Alpha Cell-Mediated Beta-like Cell Neogenesis.
abstract: The recent discovery that genetically modified α cells can regenerate and convert into β-like cells in vivo holds great promise for diabetes research. However, to eventually translate these findings to human, it is crucial to discover compounds with similar activities. Herein, we report the identification of GABA as an inducer of α-to-β-like cell conversion in vivo. This conversion induces α cell replacement mechanisms through the mobilization of duct-lining precursor cells that adopt an α cell identity prior to being converted into β-like cells, solely upon sustained GABA exposure. Importantly, these neo-generated β-like cells are functional and can repeatedly reverse chemically induced diabetes in vivo. Similarly, the treatment of transplanted human islets with GABA results in a loss of α cells and a concomitant increase in β-like cell counts, suggestive of α-to-β-like cell conversion processes also in humans. This newly discovered GABA-induced α cell-mediated β-like cell neogenesis could therefore represent an unprecedented hope toward improved therapies for diabetes.
authors.affiliation: Université Côte d'Azur, Inserm, CNRS, iBV, 06108 Nice, France.
authors.forename: Nouha
authors.initials: N
authors.lastname: Ben-Othman
authors.affiliation: Université Côte d'Azur, Inserm, CNRS, iBV, 06108 Nice, France.
authors.forename: Andhira
authors.initials: A
authors.lastname: Vieira
authors.affiliation: Université Côte d'Azur, Inserm, CNRS, iBV, 06108 Nice, France.
authors.forename: Monica
authors.initials: M
authors.lastname: Courtney
authors.affiliation: Université Côte d'Azur, Inserm, CNRS, iBV, 06108 Nice, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Record
authors.affiliation: Université Côte d'Azur, Inserm, CNRS, iBV, 06108 Nice, France.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Gjernes
authors.affiliation: Université Côte d'Azur, Inserm, CNRS, iBV, 06108 Nice, France.
authors.forename: Fabio
authors.initials: F
authors.lastname: Avolio
authors.affiliation: Université Côte d'Azur, Inserm, CNRS, iBV, 06108 Nice, France.
authors.forename: Biljana
authors.initials: B
authors.lastname: Hadzic
authors.affiliation: Université Côte d'Azur, Inserm, CNRS, iBV, 06108 Nice, France.
authors.forename: Noémie
authors.initials: N
authors.lastname: Druelle
authors.affiliation: Université Côte d'Azur, Inserm, CNRS, iBV, 06108 Nice, France.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Napolitano
authors.affiliation: Université Côte d'Azur, Inserm, CNRS, iBV, 06108 Nice, France.
authors.forename: Sergi
authors.initials: S
authors.lastname: Navarro-Sanz
authors.affiliation: Université Côte d'Azur, Inserm, CNRS, iBV, 06108 Nice, France.
authors.forename: Serena
authors.initials: S
authors.lastname: Silvano
authors.affiliation: Université Côte d'Azur, Inserm, CNRS, iBV, 06108 Nice, France.
authors.forename: Keith
authors.initials: K
authors.lastname: Al-Hasani
authors.affiliation: Université Côte d'Azur, Inserm, CNRS, iBV, 06108 Nice, France.
authors.forename: Anja
authors.initials: A
authors.lastname: Pfeifer
authors.affiliation: Centre Commun de Microscopie Appliquée, Université de Nice-Sophia Antipolis, 06108 Nice, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Lacas-Gervais
authors.affiliation: Beta Cell Neogenesis, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
authors.forename: Gunter
authors.initials: G
authors.lastname: Leuckx
authors.affiliation: ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), 808 Route de Lennik, 1070 Brussels, Belgium.
authors.forename: Laura
authors.initials: L
authors.lastname: Marroquí
authors.affiliation: University Lille, Inserm, CHU Lille, U1190 Translational Research for Diabetes, European Genomic Institute for Diabetes, EGID, 59000 Lille, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Thévenet
authors.affiliation: Translational Stem Cell Biology, Danish Stem Cell Center (Danstem), University of Copenhagen, DK-2200 Copenhagen, Denmark.
authors.forename: Ole Dragsbaek
authors.initials: OD
authors.lastname: Madsen
authors.affiliation: ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), 808 Route de Lennik, 1070 Brussels, Belgium.
authors.forename: Decio Laks
authors.initials: DL
authors.lastname: Eizirik
authors.affiliation: Beta Cell Neogenesis, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
authors.forename: Harry
authors.initials: H
authors.lastname: Heimberg
authors.affiliation: University Lille, Inserm, CHU Lille, U1190 Translational Research for Diabetes, European Genomic Institute for Diabetes, EGID, 59000 Lille, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Kerr-Conte
authors.affiliation: University Lille, Inserm, CHU Lille, U1190 Translational Research for Diabetes, European Genomic Institute for Diabetes, EGID, 59000 Lille, France.
authors.forename: François
authors.initials: F
authors.lastname: Pattou
authors.affiliation: Department of Molecular Developmental Biology, Max-Planck Institute for Biophysical Chemistry, Am Fassberg, 37077 Göttingen, Germany; Department of Clinical Neurophysiology, University of Göttingen, Robert-Koch Strasse 40, 37075 Göttingen, Germany.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Mansouri
authors.affiliation: Université Côte d'Azur, Inserm, CNRS, iBV, 06108 Nice, France; Genome and Stem Cell Center, GENKOK, Erciyes University, 38039 Kayseri, Turkey. Electronic address: collombat@unice.fr.
authors.forename: Patrick
authors.initials: P
authors.lastname: Collombat
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002454:Cell Differentiation / Q000187:drug effects; D003920:Diabetes Mellitus / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D050416:Glucagon-Secreting Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology*; D007515:Islets of Langerhans / Q000166:cytology; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins; D051381:Rats; D017208:Rats, Wistar; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; D005680:gamma-Aminobutyric Acid; C498695:NEUROG3 protein, human
keywords: Arx; GABA; Pax4; diabetes; endocrine pancreas; mouse; β cell regeneration