Plasma Dihydroceramides Are Diabetes Susceptibility Biomarker Candidates in Mice and Humans
Leonore Wigger,
Céline Cruciani-Guglielmacci,
Anthony Nicolas,
Jessica Denom,
Neïké Fernandez,
Frédéric Fumeron,
Pedro Marques-Vidal,
Alain Ktorza,
Werner Kramer,
Anke Schulte,
Hervé Le Stunff,
Robin Liechti,
Ioannis Xenarios,
Peter Vollenweider,
Gérard Waeber,
Ingo Uphues,
Ronan Roussel,
Christophe Magnan,
Mark Ibberson,
Bernard Thorens
Affiliations
Leonore Wigger
Vital-IT Group, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland; Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland
Céline Cruciani-Guglielmacci
Unité de Biologie Fonctionnelle et Adaptative (BFA), CNRS UMR 8251, Université Paris Diderot, Sorbonne Paris Cité, 75205 Paris, France
Anthony Nicolas
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
Jessica Denom
Unité de Biologie Fonctionnelle et Adaptative (BFA), CNRS UMR 8251, Université Paris Diderot, Sorbonne Paris Cité, 75205 Paris, France
Neïké Fernandez
Unité de Biologie Fonctionnelle et Adaptative (BFA), CNRS UMR 8251, Université Paris Diderot, Sorbonne Paris Cité, 75205 Paris, France
Frédéric Fumeron
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
Pedro Marques-Vidal
Department of Medicine, Internal Medicine, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland
Alain Ktorza
Recherche de Découverte, PIT Métabolisme, Institut de Recherche Servier (IdRS), 92150 Suresnes, France
Werner Kramer
Biomedical and Scientific Consulting, 55130 Mainz, Germany
Anke Schulte
Diabetes Research, Islet Biology Cluster, Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, 65926 Frankfurt am Main, Germany
Hervé Le Stunff
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
Robin Liechti
Vital-IT Group, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
Ioannis Xenarios
Vital-IT Group, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
Peter Vollenweider
Department of Medicine, Internal Medicine, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland
Gérard Waeber
Department of Medicine, Internal Medicine, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland
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
Christophe Magnan
Unité de Biologie Fonctionnelle et Adaptative (BFA), CNRS UMR 8251, Université Paris Diderot, Sorbonne Paris Cité, 75205 Paris, France
Mark Ibberson
Vital-IT Group, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland; Corresponding author
Bernard Thorens
Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland; Corresponding author
Summary: 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. : Wigger et al. find that several sphingolipids in mouse plasma correlate with glucose tolerance and insulin secretion. Quantitative analysis of these and closely related lipids in human plasma from two cohorts reveal that dihydroceramides are significantly elevated in individuals progressing to diabetes, up to 9 years before disease onset. Keywords: diabetes, T2D, ceramides, dihydroceramides, biomarkers, lipidomics, prognostic, mouse, human, high-fat diet, metabolic challenge, glucose intolerance, insulin sensitivity, prospective cohort
