title: Plasma Dihydroceramides Are Diabetes Susceptibility Biomarker Candidates in Mice and Humans.
abstract: Plasma metabolite concentrations reflect the activity of tissue metabolic pathways and their quantitative determination may be informative about pathogenic conditions. We searched for plasma lipid species whose concentrations correlate with various parameters of glucose homeostasis and susceptibility to type 2 diabetes (T2D). Shotgun lipidomic analysis of the plasma of mice from different genetic backgrounds, which develop a pre-diabetic state at different rates when metabolically stressed, led to the identification of a group of sphingolipids correlated with glucose tolerance and insulin secretion. Quantitative analysis of these and closely related lipids in the plasma of individuals from two population-based prospective cohorts revealed that specific long-chain fatty-acid-containing dihydroceramides were significantly elevated in the plasma of individuals who will progress to diabetes up to 9 years before disease onset. These lipids may serve as early biomarkers of, and help identify, metabolic deregulation in the pathogenesis of T2D.
authors.affiliation: Vital-IT Group, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland; Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Leonore
authors.initials: L
authors.lastname: Wigger
authors.affiliation: Unité de Biologie Fonctionnelle et Adaptative (BFA), CNRS UMR 8251, Université Paris Diderot, Sorbonne Paris Cité, 75205 Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Cruciani-Guglielmacci
authors.affiliation: INSERM, Sorbonne Paris Cité, Centre de Recherce des Cordeliers (CRC), UMR_S 1138, 75006 Paris, France; UPMC, Sorbonne Universités, Centre de Recherce des Cordeliers (CRC), UMR_S 1138, 75006 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Centre de Recherche des Cordeliers (CRC), UMR_S 1138, 75006 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Centre de Recherches des Cordeliers (CRC), UMR_S 1138, 75006 Paris, France.
authors.forename: Anthony
authors.initials: A
authors.lastname: Nicolas
authors.affiliation: Unité de Biologie Fonctionnelle et Adaptative (BFA), CNRS UMR 8251, Université Paris Diderot, Sorbonne Paris Cité, 75205 Paris, France.
authors.forename: Jessica
authors.initials: J
authors.lastname: Denom
authors.affiliation: Unité de Biologie Fonctionnelle et Adaptative (BFA), CNRS UMR 8251, Université Paris Diderot, Sorbonne Paris Cité, 75205 Paris, France.
authors.forename: Neïké
authors.initials: N
authors.lastname: Fernandez
authors.affiliation: INSERM, Sorbonne Paris Cité, Centre de Recherce des Cordeliers (CRC), UMR_S 1138, 75006 Paris, France; UPMC, Sorbonne Universités, Centre de Recherce des Cordeliers (CRC), UMR_S 1138, 75006 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Centre de Recherche des Cordeliers (CRC), UMR_S 1138, 75006 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Centre de Recherches des Cordeliers (CRC), UMR_S 1138, 75006 Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Fumeron
authors.affiliation: Department of Medicine, Internal Medicine, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland.
authors.forename: Pedro
authors.initials: P
authors.lastname: Marques-Vidal
authors.affiliation: Recherche de Découverte, PIT Métabolisme, Institut de Recherche Servier (IdRS), 92150 Suresnes, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Ktorza
authors.affiliation: Biomedical and Scientific Consulting, 55130 Mainz, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Kramer
authors.affiliation: Diabetes Research, Islet Biology Cluster, Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, 65926 Frankfurt am Main, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Schulte
authors.affiliation: Unité de Biologie Fonctionnelle et Adaptative (BFA), CNRS UMR 8251, Université Paris Diderot, Sorbonne Paris Cité, 75205 Paris, France; Institut de biologie intégrative de la cellule (I2BC), CNRS UMR 9198, Université Paris-Sud, Université Paris-Saclay, 91190 Gif-sur-Yvette, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Le Stunff
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: Ioannis
authors.initials: I
authors.lastname: Xenarios
authors.affiliation: Department of Medicine, Internal Medicine, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Vollenweider
authors.affiliation: Department of Medicine, Internal Medicine, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland.
authors.forename: Gérard
authors.initials: G
authors.lastname: Waeber
authors.affiliation: Cardiometabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach (Riss), Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Uphues
authors.affiliation: INSERM, Sorbonne Paris Cité, Centre de Recherce des Cordeliers (CRC), UMR_S 1138, 75006 Paris, France; UPMC, Sorbonne Universités, Centre de Recherce des Cordeliers (CRC), UMR_S 1138, 75006 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Centre de Recherche des Cordeliers (CRC), UMR_S 1138, 75006 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Centre de Recherches des Cordeliers (CRC), UMR_S 1138, 75006 Paris, France.
authors.forename: Ronan
authors.initials: R
authors.lastname: Roussel
authors.affiliation: Unité de Biologie Fonctionnelle et Adaptative (BFA), CNRS UMR 8251, Université Paris Diderot, Sorbonne Paris Cité, 75205 Paris, France.
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
authors.affiliation: Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland. Electronic address: bernard.thorens@unil.ch.
authors.forename: Bernard
authors.initials: B
authors.lastname: Thorens
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000097:blood*; D001786:Blood Glucose / Q000378:metabolism; D002518:Ceramides / Q000097:blood*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000378:metabolism; D004198:Disease Susceptibility / Q000097:blood*; D005260:Female; D018149:Glucose Intolerance / Q000097:blood / Q000378:metabolism; D005951:Glucose Tolerance Test / Q000379:methods; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008875:Middle Aged; D011446:Prospective Studies; D013107:Sphingolipids / Q000097:blood
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D002518:Ceramides; D007328:Insulin; D008055:Lipids; D013107:Sphingolipids; C109343:dihydroceramide
keywords: T2D; biomarkers; ceramides; diabetes; dihydroceramides; glucose intolerance; high-fat diet; human; insulin sensitivity; lipidomics; metabolic challenge; mouse; prognostic; prospective cohort