Dataset Information

Proteomic analysis of liver tissue from a pig model of mutant INS gene induced diabetes of youth (MIDY)

ABSTRACT: 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 label-free proteomics to reveal pathways and key drivers significantly affected by chronic insulin deficiency and hyperglycemia.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Sus Scrofa Domesticus (domestic Pig)

TISSUE(S): Hepatocyte, Liver

DISEASE(S): Diabetes Mellitus

SUBMITTER: Florian Flenkenthaler

LAB HEAD: Thomas Fröhlich

PROVIDER: PXD011536 | Pride | 2019-11-12

REPOSITORIES: Pride

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

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]

PMID: 31221621

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Project description: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.

Project description:Lifestyle intervention can improve insulin sensitivity in obese youth yet few studies have examined the biological mechanisms underlying improvements. Therefore, the purpose of this study was to explore biological pathways associated with intervention-induced improvements in insulin sensitivity. Fifteen (7M/8F) overweight/obese (BMI percentile=96.3M-BM-11.1) Latino adolescents (15.0M-BM-10.9 years) completed a 12-week lifestyle intervention that included weekly nutrition education and 180 minutes of moderate-vigorous exercise per week. Insulin sensitivity, estimated by an oral glucose tolerance test and the Matsuda Index, increased 29.2% post intervention (2.4M-BM-10.3 to 3.1M-BM-10.3, p=0.01). Global microarray analysis profiling from whole blood was performed to examine changes in gene expression and to explore biological pathways that were significantly changed in response to the intervention. A total of 1,459 probes corresponding to mRNA transcripts (717 up, 742 down) were differentially expressed with a fold changeM-bM-^IM-%1.2 and P<0.05. Among the genes identified were hexokinase 3 (HK3), ATPase, H+ transporting V0 subunit e2 (ATPV0E), and sterol regulatory element binding transcription factor 1 (SREBF1), and endothelial cell adhesion molecule (ESAM). There were 8 pathways identified that met the criteria for significance, including insulin signaling, type 1 diabetes, and glycerophospholipid metabolism. Participants that increased insulin sensitivity exhibited five times the number of significant genes altered compared to non-responders (1,144 vs. 230). These findings offer insight into the molecular mechanisms underlying health improvements among high-risk Latino youth. Lifestyle interventions may contribute to improved insulin sensitivity through pathways related to insulin signaling and immune response. Further, genetic factors may mediate response to lifestyle intervention. Fifteen (7M/8F) overweight/obese Latino Youth Whole blood RNA samples evaluated pre and post intervention.

			Action	DRS
	MIDY_Liver_MIDY737.raw	Raw
	MIDY_Liver_MIDY739.raw	Raw
	MIDY_Liver_MIDY740.raw	Raw
	MIDY_Liver_MIDY744.raw	Raw
	MIDY_Liver_wt736.raw	Raw