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

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 insulindeficient diabetes mellitus. The multi-omics data set provides a valuable resource for comparative analyses with other experimental or clinical data sets.

MECHANISMS IN ENDOCRINOLOGY: Transient juvenile hypoglycemia in growth hormone receptor deficiency – mechanistic insights from Laron syndrome and tailored animal models

“…Postprandial insulin peaks promote hepatic glucose uptake and glycogen synthesis, while basal insulin inhibits gluconeogenesis and glycogenolysis through the PI3K/ AKT pathway (reviewed in 90). A multi-omics analysis of liver samples from a pig model for mutant INS geneinduced diabetes of youth (MIDY) (91) revealed increased levels of retinol dehydrogenase 16 (RDH16) and retinoic acid as mechanistic link between insulin deficiency and stimulated gluconeogenesis (92).…”