title: Molecular phenotyping of multiple mouse strains under metabolic challenge uncovers a role forElovl2in glucose-induced insulin secretion.
abstract: In type 2 diabetes (T2D), pancreatic β cells become progressively dysfunctional, leading to a decline in insulin secretion over time. In this study, we aimed to identify key genes involved in pancreatic beta cell dysfunction by analyzing multiple mouse strains in parallel under metabolic stress.
  
  
  
  Male mice from six commonly used non-diabetic mouse strains were fed a high fat or regular chow diet for three months. Pancreatic islets were extracted and phenotypic measurements were recorded at 2 days, 10 days, 30 days, and 90 days to assess diabetes progression. RNA-Seq was performed on islet tissue at each time-point and integrated with the phenotypic data in a network-based analysis.
  
  
  
  A module of co-expressed genes was selected for further investigation as it showed the strongest correlation to insulin secretion and oral glucose tolerance phenotypes. One of the predicted network hub genes wasElovl2, encoding Elongase of very long chain fatty acids 2.Elovl2silencing decreased glucose-stimulated insulin secretion in mouse and human β cell lines.
  
  
  
  Our results suggest a role forElovl2in ensuring normal insulin secretory responses to glucose. Moreover, the large comprehensive dataset and integrative network-based approach provides a new resource to dissect the molecular etiology of β cell failure under metabolic stress.
authors.affiliation: Unité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Cruciani-Guglielmacci
authors.affiliation: Unité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, Paris, France.
authors.forename: Lara
authors.initials: L
authors.lastname: Bellini
authors.affiliation: Unité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, Paris, France.
authors.forename: Jessica
authors.initials: J
authors.lastname: Denom
authors.affiliation: INSERM U1016, Université Paris-Descartes, Institut Cochin, Paris, France.
authors.forename: Masaya
authors.initials: M
authors.lastname: Oshima
authors.affiliation: Unité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, Paris, France.
authors.forename: Neïké
authors.initials: N
authors.lastname: Fernandez
authors.affiliation: Unité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, Paris, France.
authors.forename: Priscilla
authors.initials: P
authors.lastname: Normandie-Levi
authors.affiliation: Centre for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Xavier P
authors.initials: XP
authors.lastname: Berney
authors.affiliation: Unité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, Paris, France.
authors.forename: Nadim
authors.initials: N
authors.lastname: Kassis
authors.affiliation: Unité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, Paris, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Rouch
authors.affiliation: Unité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Dairou
authors.affiliation: Discovery Sciences, Innovative Medicines & Early Development Biotech Unit, AstraZeneca, Cambridge Science Park, Milton Road, Cambridge CB4 0WG, UK.
authors.forename: Tracy
authors.initials: T
authors.lastname: Gorman
authors.affiliation: Discovery Sciences, Innovative Medicines & Early Development Biotech Unit, AstraZeneca, Cambridge Science Park, Milton Road, Cambridge CB4 0WG, UK.
authors.forename: David M
authors.initials: DM
authors.lastname: Smith
authors.affiliation: Discovery Sciences, Innovative Medicines & Early Development Biotech Unit, AstraZeneca, Cambridge Science Park, Milton Road, Cambridge CB4 0WG, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Marley
authors.affiliation: Vital-IT Group, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
authors.forename: Robin
authors.initials: R
authors.lastname: Liechti
authors.affiliation: Vital-IT Group, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Kuznetsov
authors.affiliation: Vital-IT Group, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
authors.forename: Leonore
authors.initials: L
authors.lastname: Wigger
authors.affiliation: Vital-IT Group, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Burdet
authors.affiliation: Recherche de Découverte, PIT Métabolisme, IdRS, 11 rue des Moulineaux, 92150 Suresnes, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Lefèvre
authors.affiliation: Recherche de Découverte, PIT Métabolisme, IdRS, 11 rue des Moulineaux, 92150 Suresnes, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Wehrle
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co, KG 88400 Biberach, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Uphues
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co, KG 88400 Biberach, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Hildebrandt
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co, KG 88400 Biberach, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Rust
authors.affiliation: Recherche de Découverte, PIT Métabolisme, IdRS, 11 rue des Moulineaux, 92150 Suresnes, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Bernard
authors.affiliation: Recherche de Découverte, PIT Métabolisme, IdRS, 11 rue des Moulineaux, 92150 Suresnes, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Ktorza
authors.affiliation: Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, London W120NN, UK.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
authors.affiliation: INSERM U1016, Université Paris-Descartes, Institut Cochin, Paris, France.
authors.forename: Raphael
authors.initials: R
authors.lastname: Scharfmann
authors.affiliation: Vital-IT Group, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Xenarios
authors.affiliation: Unité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, Paris, France; I2BC - UMR 9198 Université Paris Sud, Gif sur Yvette, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Le Stunff
authors.affiliation: Centre for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Bernard
authors.initials: B
authors.lastname: Thorens
authors.affiliation: Unité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, Paris, France. Electronic address: christophe.magnan@univ-paris-diderot.fr.
authors.forename: Christophe
authors.initials: C
authors.lastname: Magnan
authors.affiliation: Vital-IT Group, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland. Electronic address: mark.ibberson@sib.swiss.
authors.forename: Mark
authors.initials: M
authors.lastname: Ibberson
mesh_terms: D000123:Acetyltransferases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D000081031:Fatty Acid Elongases; D053263:Gene Regulatory Networks; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010641:Phenotype
chemical_list: C000630967:ELOVL2 protein, human; C000630951:ELOVL2 protein, mouse; D007328:Insulin; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases; D005947:Glucose
keywords: Beta cell dysfunction; Diabetes; Metabolic stress; Molecular phenotyping; Network analysis; Pancreas