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Multi-Omics Insights into Functional Alterations of the Liver in Insulin-Deficient Diabetes Mellitus

49 Pages Posted: 26 Feb 2019 Sneak Peek Status: Review Complete

See all articles by Mattias Backman

Mattias Backman

Ludwig Maximilian University of Munich - Laboratory for Functional Genome Analysis (LAFUGA)

Florian Flenkenthaler

Ludwig Maximilian University of Munich - Laboratory for Functional Genome Analysis (LAFUGA)

Andreas Blutke

Helmholtz Zentrum München - Research Unit Analytical Pathology

Maik Dahlhoff

Ludwig Maximilian University of Munich - Chair for Molecular Animal Breeding and Biotechnology

Erik Ländström

Ludwig Maximilian University of Munich - Laboratory for Functional Genome Analysis (LAFUGA)

Simone Renner

Ludwig Maximilian University of Munich - Chair for Molecular Animal Breeding and Biotechnology

Julia Philippou-Massier

Ludwig Maximilian University of Munich - Laboratory for Functional Genome Analysis (LAFUGA)

Stefan Krebs

Ludwig Maximilian University of Munich - Laboratory for Functional Genome Analysis (LAFUGA)

Birgit Rathkolb

Ludwig Maximilian University of Munich - Chair for Molecular Animal Breeding and Biotechnology

Cornelia Prehn

Independent

Michal Grzybek

German Center for Diabetes Research (DZD)

Ünal Coskun

German Center for Diabetes Research (DZD)

Jerzy Adamski

Technische Universität München (TUM) - Chair of Experimental Genetics

Martin Hrabĕ de Angelis

German Center for Diabetes Research (DZD)

Rüdiger Wanke

Ludwig Maximilian University of Munich - Institute of Veterinary Pathology

Thomas Fröhlich

Ludwig Maximilian University of Munich - Laboratory for Functional Genome Analysis (LAFUGA)

Georg J. Arnold

Ludwig Maximilian University of Munich - Laboratory for Functional Genome Analysis (LAFUGA)

Helmut Blum

Ludwig Maximilian University of Munich

Eckhard Wolf

Ludwig Maximilian University of Munich - Laboratory for Functional Genome Analysis (LAFUGA)

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Abstract

The liver regulates the availability of insulin to other tissues and is the first line insulin response organ being physiologically exposed to higher insulin concentrations than the periphery. Basal insulin during fasting inhibits hepatic gluconeogenesis and glycogenolysis, whereas postprandial insulin peaks stimulate glycogen synthesis. The molecular consequences of chronic insulin deficiency for the liver have not been studied systematically. We analyzed liver samples of a genetically diabetic pig model (MIDY) and of wild-type (WT) littermate controls by RNA sequencing, proteomics and targeted metabolomics/lipidomics. Cross-omics analyses revealed increased activity in gluconeogenesis, ketogenesis, amino acid metabolism and oxidation of fatty acids in the MIDY samples, whereas pathways related to extracellular matrix and inflammation/pathogen defense response were less active than in the WT samples. Our study identified key drivers of these alterations, such as RDH16 and HMGCS2 for stimulated gluconeogenesis and ketogenesis, in a clinically relevant large animal model for insulin-deficient diabetes mellitus.

Keywords: liver, insulin deficiency, transcriptome, proteome, Metabolome, lipidome, gluconeogenesis, ketogenesis, immune functions

Suggested Citation

Backman, Mattias and Flenkenthaler, Florian and Blutke, Andreas and Dahlhoff, Maik and Ländström, Erik and Renner, Simone and Philippou-Massier, Julia and Krebs, Stefan and Rathkolb, Birgit and Prehn, Cornelia and Grzybek, Michal and Coskun, Ünal and Adamski, Jerzy and Angelis, Martin Hrabĕ de and Wanke, Rüdiger and Fröhlich, Thomas and Arnold, Georg J. and Blum, Helmut and Wolf, Eckhard, Multi-Omics Insights into Functional Alterations of the Liver in Insulin-Deficient Diabetes Mellitus (December 30, 2018). Available at SSRN: https://ssrn.com/abstract=3307901 or http://dx.doi.org/10.2139/ssrn.3307901
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Mattias Backman (Contact Author)

Ludwig Maximilian University of Munich - Laboratory for Functional Genome Analysis (LAFUGA)

Geschwister-Scholl-Platz 1
Munich, Bavaria 80539
Germany

Florian Flenkenthaler

Ludwig Maximilian University of Munich - Laboratory for Functional Genome Analysis (LAFUGA)

Geschwister-Scholl-Platz 1
Munich, Bavaria 80539
Germany

Andreas Blutke

Helmholtz Zentrum München - Research Unit Analytical Pathology

Ingolstaedter Landstraße 1
Neuherberg, Bavaria D-85764
Germany

Maik Dahlhoff

Ludwig Maximilian University of Munich - Chair for Molecular Animal Breeding and Biotechnology

Geschwister-Scholl-Platz 1
Munich, Bavaria 80539
Germany

Erik Ländström

Ludwig Maximilian University of Munich - Laboratory for Functional Genome Analysis (LAFUGA)

Geschwister-Scholl-Platz 1
Munich, Bavaria 80539
Germany

Simone Renner

Ludwig Maximilian University of Munich - Chair for Molecular Animal Breeding and Biotechnology

Geschwister-Scholl-Platz 1
Munich, Bavaria 80539
Germany

Julia Philippou-Massier

Ludwig Maximilian University of Munich - Laboratory for Functional Genome Analysis (LAFUGA)

Geschwister-Scholl-Platz 1
Munich, Bavaria 80539
Germany

Stefan Krebs

Ludwig Maximilian University of Munich - Laboratory for Functional Genome Analysis (LAFUGA)

Geschwister-Scholl-Platz 1
Munich, Bavaria 80539
Germany

Birgit Rathkolb

Ludwig Maximilian University of Munich - Chair for Molecular Animal Breeding and Biotechnology

Geschwister-Scholl-Platz 1
Munich, Bavaria 80539
Germany

Cornelia Prehn

Independent

No Address Available

Michal Grzybek

German Center for Diabetes Research (DZD)

85764 Neuherberg
Germany

Ünal Coskun

German Center for Diabetes Research (DZD)

85764 Neuherberg
Germany

Jerzy Adamski

Technische Universität München (TUM) - Chair of Experimental Genetics

Arcisstrasse 21
Munich, 80333
Germany

Martin Hrabĕ de Angelis

German Center for Diabetes Research (DZD)

85764 Neuherberg
Germany

Rüdiger Wanke

Ludwig Maximilian University of Munich - Institute of Veterinary Pathology

Geschwister-Scholl-Platz 1
Munich, Bavaria 80539
Germany

Thomas Fröhlich

Ludwig Maximilian University of Munich - Laboratory for Functional Genome Analysis (LAFUGA)

Geschwister-Scholl-Platz 1
Munich, Bavaria 80539
Germany

Georg J. Arnold

Ludwig Maximilian University of Munich - Laboratory for Functional Genome Analysis (LAFUGA)

Geschwister-Scholl-Platz 1
Munich, Bavaria 80539
Germany

Helmut Blum

Ludwig Maximilian University of Munich ( email )

Geschwister-Scholl-Platz 1
Munich, Bavaria 80539
Germany

Eckhard Wolf

Ludwig Maximilian University of Munich - Laboratory for Functional Genome Analysis (LAFUGA) ( email )

Geschwister-Scholl-Platz 1
Munich, Bavaria 80539
Germany

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