title: Cell type-specific deletion in mice reveals roles for PAS kinase in insulin and glucagon production.
abstract: Per-Arnt-Sim kinase (PASK) is a nutrient-regulated domain-containing protein kinase previously implicated in the control of insulin gene expression and glucagon secretion. Here, we explore the roles of PASK in the control of islet hormone release, by generating mice with selective deletion of the Pask gene in pancreatic beta or alpha cells.
  
  
  
  Floxed alleles of Pask were produced by homologous recombination and animals bred with mice bearing beta (Ins1 (Cre); PaskBKO) or alpha (Ppg (Cre) [also known as Gcg]; PaskAKO) cell-selective Cre recombinase alleles. Glucose homeostasis and hormone secretion in vivo and in vitro, gene expression and islet cell mass were measured using standard techniques.
  
  
  
  Ins1 (Cre)-based recombination led to efficient beta cell-targeted deletion of Pask. Beta cell mass was reduced by 36.5% (p < 0.05) compared with controls in PaskBKO mice, as well as in global Pask-null mice (38%, p < 0.05). PaskBKO mice displayed normal body weight and fasting glycaemia, but slightly impaired glucose tolerance, and beta cell proliferation, after maintenance on a high-fat diet. Whilst glucose tolerance was unaffected in PaskAKO mice, glucose infusion rates were increased, and glucagon secretion tended to be lower, during hypoglycaemic clamps. Although alpha cell mass was increased (21.9%, p < 0.05), glucagon release at low glucose was impaired (p < 0.05) in PaskAKO islets.
  
  
  
  The findings demonstrate cell-autonomous roles for PASK in the control of pancreatic endocrine hormone secretion. Differences between the glycaemic phenotype of global vs cell type-specific null mice suggest important roles for tissue interactions in the control of glycaemia by PASK.
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, Imperial Centre for Translational and Experimental Medicine, Hammersmith Hospital, du Cane Road, London, W12 0NN, UK.
authors.forename: Francesca
authors.initials: F
authors.lastname: Semplici
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, Imperial Centre for Translational and Experimental Medicine, Hammersmith Hospital, du Cane Road, London, W12 0NN, UK.
authors.forename: Angeles
authors.initials: A
authors.lastname: Mondragon
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, Imperial Centre for Translational and Experimental Medicine, Hammersmith Hospital, du Cane Road, London, W12 0NN, UK.
authors.forename: Benedict
authors.initials: B
authors.lastname: Macintyre
authors.affiliation: AstraZeneca R&D, DECS, AstraZeneca R&D, Mölndal, Sweden.|AstraZeneca R&D, HC3020, AstraZeneca R&D, Mölndal, Sweden.
authors.forename: Katja
authors.initials: K
authors.lastname: Madeyski-Bengston
authors.affiliation: AstraZeneca R&D, DECS, AstraZeneca R&D, Mölndal, Sweden.|AstraZeneca R&D, HC3020, AstraZeneca R&D, Mölndal, Sweden.
authors.forename: Anette
authors.initials: A
authors.lastname: Persson-Kry
authors.affiliation: AstraZeneca R&D, DECS, AstraZeneca R&D, Mölndal, Sweden.|AstraZeneca R&D, HC3020, AstraZeneca R&D, Mölndal, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Barr
authors.affiliation: AstraZeneca R&D, DECS, AstraZeneca R&D, Mölndal, Sweden.|AstraZeneca R&D, HC3020, AstraZeneca R&D, Mölndal, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Ramne
authors.affiliation: AstraZeneca R&D, Alderley Edge, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Marley
authors.affiliation: Photonics Group, Department of Physics, Imperial College London, London, UK.
authors.forename: James
authors.initials: J
authors.lastname: McGinty
authors.affiliation: Photonics Group, Department of Physics, Imperial College London, London, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: French
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, Imperial Centre for Translational and Experimental Medicine, Hammersmith Hospital, du Cane Road, London, W12 0NN, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Soedling
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, Imperial Centre for Translational and Experimental Medicine, Hammersmith Hospital, du Cane Road, London, W12 0NN, UK.
authors.forename: Ryohsuke
authors.initials: R
authors.lastname: Yokosuka
authors.affiliation: Université de Bordeaux, Institut de Chimie et Biologie des Membranes et des Nano-objets, CNRS UMR 5248, Pessac, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Gaitan
authors.affiliation: Université de Bordeaux, Institut de Chimie et Biologie des Membranes et des Nano-objets, CNRS UMR 5248, Pessac, France.
authors.forename: Jochen
authors.initials: J
authors.lastname: Lang
authors.affiliation: Paris Diderot University, Unit of Functional and Adaptive Biology (BFA), CNRS UMR 8251, Paris, France.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Migrenne-Li
authors.affiliation: Paris Diderot University, Unit of Functional and Adaptive Biology (BFA), CNRS UMR 8251, Paris, France.
authors.forename: Erwann
authors.initials: E
authors.lastname: Philippe
authors.affiliation: Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Herrera
authors.affiliation: Paris Diderot University, Unit of Functional and Adaptive Biology (BFA), CNRS UMR 8251, Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Magnan
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, Imperial Centre for Translational and Experimental Medicine, Hammersmith Hospital, du Cane Road, London, W12 0NN, UK. g.dasilva-xavier@imperial.ac.uk.
authors.forename: Gabriela
authors.initials: G
authors.lastname: da Silva Xavier
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, Imperial Centre for Translational and Experimental Medicine, Hammersmith Hospital, du Cane Road, London, W12 0NN, UK. g.rutter@imperial.ac.uk.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
mesh_terms: D000483:Alleles; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D050416:Glucagon-Secreting Cells / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*
chemical_list: C116037:PAS domain kinases; D017346:Protein Serine-Threonine Kinases; D005947:Glucose
keywords: Basic science; Beta cell signal transduction; Islets; Mouse; PAS kinase