Mattias Backman, Florian Flenkenthaler, Andreas Blutke, Maik Dahlhoff, Erik Ländström, Simone Renner, Julia Philippou-Massier, Stefan Krebs, Birgit Rathkolb, Cornelia Prehn, Michal Grzybek, Ünal Coskun, Michael Rothe, Jerzy Adamski, Martin Hrabĕ de Angelis, Rüdiger Wanke, Thomas Fröhlich, Georg J. Arnold, Helmut Blum, Eckhard Wolf
The liver is the central glucoregulatory organ and is exposed to two- to four-fold higher levels of insulin than peripheral insulin target tissues. To determine consequences of missing insulin action in the liver, Backman, Flenkenthaler, et al. used tissue from transgenic pigs expressing mutant insulin for multi-omics analyses. These revealed increased activities in amino acid metabolism, oxidation of fatty acids, ketogenesis, and gluconeogenesis. Their study provides the first multi-omics analyses of liver in insulin-deficient diabetes mellitus and identified key drivers of known functional consequences of insulin deficiency. In addition, previously unknown consequences especially for inflammatory and immune functions of the liver were revealed.
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.