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Mol Metab. 2019 Aug;26:30-44. doi: 10.1016/j.molmet.2019.05.011. Epub 2019 Jun 4.

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

Author information

1
Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, 81377 Munich, Germany; Graduate School of Quantitative Biosciences Munich (QBM), Gene Center, LMU Munich, 81377 Munich, Germany.
2
Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, 81377 Munich, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
3
Research Unit Analytical Pathology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
4
Chair for Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, 81377 Munich, Germany.
5
German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Chair for Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, 81377 Munich, Germany; Center for Innovative Medical Models (CiMM), LMU Munich, 85764 Oberschleißheim, Germany.
6
Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, 81377 Munich, Germany.
7
German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Chair for Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, 81377 Munich, Germany; German Mouse Clinic (GMC), Institute of Experimental Genetics, 85764 Neuherberg, Germany.
8
Research Unit of Molecular Endocrinology and Metabolism (MEM), Helmholtz Zentrum München, 85764 Neuherberg, Germany.
9
German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Hospital, Faculty of Medicine Carl Gustav Carus of TU Dresden, 01307 Dresden, Germany.
10
Lipidomix GmbH, 13125 Berlin, Germany.
11
Research Unit of Molecular Endocrinology and Metabolism (MEM), Helmholtz Zentrum München, 85764 Neuherberg, Germany; Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, 85764 Neuherberg, Germany; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
12
German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; German Mouse Clinic (GMC), Institute of Experimental Genetics, 85764 Neuherberg, Germany; Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, 85764 Neuherberg, Germany.
13
Institute of Veterinary Pathology, Center for Clinical Veterinary Medicine, LMU Munich, 80539 Munich, Germany.
14
Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, 81377 Munich, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Chair for Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, 81377 Munich, Germany; Center for Innovative Medical Models (CiMM), LMU Munich, 85764 Oberschleißheim, Germany. Electronic address: ewolf@genzentrum.lmu.de.

Abstract

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.

KEYWORDS:

Insulin deficiency; Lipidome; Liver; Metabolome; Proteome; Transcriptome

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