Ontology highlight
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.
SUBMITTER: Backman M
PROVIDER: S-EPMC6667734 | biostudies-literature | 2019 Aug
REPOSITORIES: biostudies-literature
Backman Mattias M Flenkenthaler Florian F Blutke Andreas A Dahlhoff Maik M Ländström Erik E Renner Simone S Philippou-Massier Julia J Krebs Stefan S Rathkolb Birgit B Prehn Cornelia C Grzybek Michal M Coskun Ünal Ü Rothe Michael M Adamski Jerzy J de Angelis Martin Hrabĕ MH Wanke Rüdiger R Fröhlich Thomas T Arnold Georg J GJ Blum Helmut H Wolf Eckhard E
Molecular metabolism 20190604
<h4>Objective</h4>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.<h4>Methods</h4>We analyzed liver sample ...[more]