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Backman, M.* ; Flenkenthaler, F.* ; Blutke, A. ; Dahlhoff, M.* ; Ländström, E.* ; Renner, S.* ; Philippou-Massier, J.* ; Krebs, S.* ; Rathkolb, B. ; Prehn, C. ; Grzybek, M. ; Coskun, Ü. ; Rothe, M.* ; Adamski, J. ; Hrabě de Angelis, M. ; Wanke, R.* ; Fröhlich, T.* ; Arnold, G.J.* ; Blum, H.* ; Wolf, E.*

Multi-omics insights into functional alterations of the liver in insulin-deficient diabetes mellitus.

Mol. Metab. 26, 30-44 (2019)
Publ. Version/Full Text Postprint DOI
Open Access Gold
Creative Commons Lizenzvertrag
Objective: The liver regulates the availability of insulin to other tissues and is the first line insulin response organ 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.Methods: 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.Results: Cross-omics analyses revealed increased activities in amino acid metabolism, oxidation of fatty acids, ketogenesis, and gluconeogenesis in the MIDY samples. In particular, the concentrations of the ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) and of retinol dehydrogenase 16 (RDH16), which catalyzes the first step in retinoic acid biogenesis, were highly increased. Accordingly, elevated levels of retinoic acid, which stimulates the expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PCK1), were measured in the MIDY samples. In contrast, pathways related to extracellular matrix and inflammation/pathogen defense response were less active than in the WT samples.Conclusions: The first multi-omics study of a clinically relevant diabetic large animal model revealed molecular signatures and key drivers of functional alterations of the liver in insulin-deficient diabetes mellitus. The multi-omics data set provides a valuable resource for comparative analyses with other experimental or clinical data sets. (C) 2019 The Authors. Published by Elsevier GmbH.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Liver ; Insulin Deficiency ; Transcriptome ; Proteome ; Metabolome ; Lipidome; Protein; Immune; Metabolism; Carnitine; Expression; Database; Pathway; Phosphorylation; Acylcarnitines; Biosynthesis
ISSN (print) / ISBN 2212-8778
e-ISSN 2212-8778
Quellenangaben Volume: 26, Issue: , Pages: 30-44 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place Amsterdam
Reviewing status Peer reviewed
Institute(s) Research Unit Analytical Pathology (AAP)
Institute of Experimental Genetics (IEG)
Molekulare Endokrinologie und Metabolismus (MEM)
Institute for Pancreatic Beta Cell Research (IPI)