title: Rfx6 maintains the functional identity of adult pancreatic β cells.
abstract: Increasing evidence suggests that loss of β cell characteristics may cause insulin secretory deficiency in diabetes, but the underlying mechanisms remain unclear. Here, we show that Rfx6, whose mutation leads to neonatal diabetes in humans, is essential to maintain key features of functionally mature β cells in mice. Rfx6 loss in adult β cells leads to glucose intolerance, impaired β cell glucose sensing, and defective insulin secretion. This is associated with reduced expression of core components of the insulin secretion pathway, including glucokinase, the Abcc8/SUR1 subunit of KATP channels and voltage-gated Ca(2+) channels, which are direct targets of Rfx6. Moreover, Rfx6 contributes to the silencing of the vast majority of "disallowed" genes, a group usually specifically repressed in adult β cells, and thus to the maintenance of β cell maturity. These findings raise the possibility that changes in Rfx6 expression or activity may contribute to β cell failure in humans.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale U964, Centre National de Recherche Scientifique UMR7104, Université de Strasbourg, Illkirch 67404, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Piccand
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale U964, Centre National de Recherche Scientifique UMR7104, Université de Strasbourg, Illkirch 67404, France.
authors.forename: Perrine
authors.initials: P
authors.lastname: Strasser
authors.affiliation: Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, Hammersmith Hospital, du Cane Road, London W12 0NN, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Hodson
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale U964, Centre National de Recherche Scientifique UMR7104, Université de Strasbourg, Illkirch 67404, France.
authors.forename: Aline
authors.initials: A
authors.lastname: Meunier
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale U964, Centre National de Recherche Scientifique UMR7104, Université de Strasbourg, Illkirch 67404, France.
authors.forename: Tao
authors.initials: T
authors.lastname: Ye
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale U964, Centre National de Recherche Scientifique UMR7104, Université de Strasbourg, Illkirch 67404, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Keime
authors.affiliation: Institut Clinique de la Souris-ICS-MCI, PHENOMIN, Illkirch 67404, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Birling
authors.affiliation: Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, Hammersmith Hospital, du Cane Road, London W12 0NN, UK.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale U964, Centre National de Recherche Scientifique UMR7104, Université de Strasbourg, Illkirch 67404, France. Electronic address: gradwohl@igbmc.fr.
authors.forename: Gérard
authors.initials: G
authors.lastname: Gradwohl
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005089:Exocytosis; D020868:Gene Silencing; D005941:Glucokinase / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D018149:Glucose Intolerance / Q000235:genetics*; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D000071701:Regulatory Factor X Transcription Factors; D064233:Sulfonylurea Receptors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C577508:Abcc8 protein, mouse; D015220:Calcium Channels; D004268:DNA-Binding Proteins; D007328:Insulin; D000071701:Regulatory Factor X Transcription Factors; C547963:Rfx6 protein, mouse; D064233:Sulfonylurea Receptors; D014157:Transcription Factors; D005941:Glucokinase; D005947:Glucose