GSE122029
Transcriptome profiling of mutant INS gene-induced diabetes of youth (MIDY) and wild type pig livers.
Physiologically the liver is exposed to higher insulin concentrations than other organs. To evaluate functional consequences of insulin-deficient diabetes mellitus for the liver, we used a genetically engineered pig model of mutant INS gene induced diabetes of youth (MIDY). Liver samples of MIDY pigs and wild-type (WT) littermate controls were analyzed by RNA sequencing, label-free proteomics and targeted metabolomics/lipidomics to reveal pathways and key drivers significantly affected by chronic insulin deficiency and hyperglycemia. Gene set enrichment analysis of the ~500 transcripts that were differently abundant between MIDY and WT samples revealed pathways related to amino acid metabolism, beta-oxidation of fatty acids, gluconeogenesis and ketogenesis to be enriched in MIDY samples, whereas pathways related to extra cellular matrix and inflammation/pathogen defense response were enriched in the WT samples. Reduced insulin receptor activation and phosphorylation of protein kinase B (PKB, AKT) was associated with markedly increased levels of retinol dehydrogenase 16 (RDH16) and 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2), the apparent key drivers of stimulated gluconeogenesis and ketogenesis in MIDY pigs. Profiling of acylcarnitines provided evidence for increased activity of carnitine palmitoyltransferase 1 (CPT1) shuttling fatty acids into the mitochondrial matrix for beta-oxidation and for increased omega-oxidation. In addition, several enzymes involved in amino acid degradation and enzymes of the urea cycle were increased in abundance, consistent with an increased use of amino acids for gluconeogenesis. Transcripts and proteins related to extracellular matrix, such as collagens, and inflammatory/immune mechanisms, such as C-reactive protein, proteins involved in or regulated by Toll-like receptor signaling and components of major histocompatibility complexes, were less abundant in MIDY vs. WT liver samples. Our study provides the first multi-omics analysis of liver in a clinically relevant large animal model for insulin-deficient diabetes mellitus. Overall design: Hepatic mRNA profiles of 2-year old wild type (WT; N=5) and C94Y transgenic (MIDY; N=4) pigs.