title: Aldehyde dehydrogenase activity is necessary for beta cell development and functionality in mice.
abstract: OBJECTIVE
  Pancreatic beta cells maintain glucose homeostasis and beta cell dysfunction is a major risk factor in developing diabetes. Therefore, understanding the developmental regulatory networks that define a fully functional beta cell is important for elucidating the genetic origins of the disease. Aldehyde dehydrogenase activity has been associated with stem/progenitor cells and we have previously shown that Aldh1b1 is specifically expressed in pancreas progenitor pools. Here we address the hypothesis that Aldh1b1 may regulate the timing of the appearance and eventual functionality of beta cells.
  
  
  METHODS
  We generated an Aldh1b1-knockout mouse line (Aldh1b1 (tm1lacZ)) and used this to study pancreatic development, beta cell functionality and glucose homeostasis in the absence of Aldh1b1 function.
  
  
  RESULTS
  Differentiation in the developing pancreas of Aldh1b1 (tm1lacZ) null mice was accelerated. Transcriptome analyses of newborn and adult islets showed misregulation of key beta cell transcription factors and genes crucial for beta cell function. Functional analyses showed that glucose-stimulated insulin secretion was severely compromised in islets isolated from null mice. Several key features of beta cell functionality were affected, including control of oxidative stress, glucose sensing, stimulus-coupling secretion and secretory granule biogenesis. As a result of beta cell dysfunction, homozygous mice developed glucose intolerance and age-dependent hyperglycaemia.
  
  
  CONCLUSIONS
  These findings show that Aldh1b1 influences the timing of the transition from the pancreas endocrine progenitor to the committed beta cell and demonstrate that changes in the timing of this transition lead to beta cell dysfunction and thus constitute a diabetes risk factor later in life. Gene Expression Omnibus (GEO) accession: GSE58025.
authors.affiliation: Paul Langerhans Institute Dresden of Helmholtz Center Munich at the University Clinic Carl Gustav Carus of TU Dresden, Fetscherstrasse 74, 01307, Dresden, Germany.|DZD - German Centre for Diabetes Research, Germany.
authors.forename: Vivian
authors.initials: V
authors.lastname: Anastasiou
authors.affiliation: Developmental Biology Laboratory, Biomedical Research Foundation of the Academy of Athens, Soranou Ephessiou 4, Athens, 11527, Greece.
authors.forename: Elpiniki
authors.initials: E
authors.lastname: Ninou
authors.affiliation: Deep Sequencing Group SFB655, BIOTEChnology Center (BioZ), TU Dresden, Dresden, Germany.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Alexopoulou
authors.affiliation: Paul Langerhans Institute Dresden of Helmholtz Center Munich at the University Clinic Carl Gustav Carus of TU Dresden, Fetscherstrasse 74, 01307, Dresden, Germany.|DZD - German Centre for Diabetes Research, Germany.|DFG-Center for Regenerative Therapies Dresden (CRTD), Faculty of Medicine, TU Dresden, Dresden, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Stertmann
authors.affiliation: Paul Langerhans Institute Dresden of Helmholtz Center Munich at the University Clinic Carl Gustav Carus of TU Dresden, Fetscherstrasse 74, 01307, Dresden, Germany.|DZD - German Centre for Diabetes Research, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Müller
authors.affiliation: Deep Sequencing Group SFB655, BIOTEChnology Center (BioZ), TU Dresden, Dresden, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Dahl
authors.affiliation: Paul Langerhans Institute Dresden of Helmholtz Center Munich at the University Clinic Carl Gustav Carus of TU Dresden, Fetscherstrasse 74, 01307, Dresden, Germany.|DZD - German Centre for Diabetes Research, Germany.
authors.forename: Michele
authors.initials: M
authors.lastname: Solimena
authors.affiliation: Paul Langerhans Institute Dresden of Helmholtz Center Munich at the University Clinic Carl Gustav Carus of TU Dresden, Fetscherstrasse 74, 01307, Dresden, Germany.|DZD - German Centre for Diabetes Research, Germany.|DFG-Center for Regenerative Therapies Dresden (CRTD), Faculty of Medicine, TU Dresden, Dresden, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Speier
authors.affiliation: Developmental Biology Laboratory, Biomedical Research Foundation of the Academy of Athens, Soranou Ephessiou 4, Athens, 11527, Greece. iseraf@bioacademy.gr.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Serafimidis
authors.affiliation: Paul Langerhans Institute Dresden of Helmholtz Center Munich at the University Clinic Carl Gustav Carus of TU Dresden, Fetscherstrasse 74, 01307, Dresden, Germany. anthony.gavalas@mailbox.tu-dresden.de.|DZD - German Centre for Diabetes Research, Germany, . anthony.gavalas@mailbox.tu-dresden.de.|Developmental Biology Laboratory, Biomedical Research Foundation of the Academy of Athens, Soranou Ephessiou 4, Athens, 11527, Greece. anthony.gavalas@mailbox.tu-dresden.de.|DFG-Center for Regenerative Therapies Dresden (CRTD), Faculty of Medicine, TU Dresden, Dresden, Germany. anthony.gavalas@mailbox.tu-dresden.de.
authors.forename: Anthony
authors.initials: A
authors.lastname: Gavalas
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics* / Q000502:physiology*; D000080924:Aldehyde Dehydrogenase 1 Family; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000483:Alleles; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002454:Cell Differentiation; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006003:Glycogen / Q000378:metabolism; D006706:Homeostasis; D006943:Hyperglycemia / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D060888:Real-Time Polymerase Chain Reaction; D012307:Risk Factors; D013234:Stem Cells / Q000166:cytology; D059467:Transcriptome
chemical_list: D001786:Blood Glucose; D006003:Glycogen; D000080924:Aldehyde Dehydrogenase 1 Family; C578830:ALDH1B1 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D005947:Glucose
keywords: Aldehyde dehydrogenase; Beta cell development; Beta cell dysfunction; Beta cell transcriptome; Diabetes risk factor; Hyperglycaemia; Insulin secretion