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Expression data from insulin-treated human primary fibroblasts and effects of U0126 on insulin-induced gene expression

ABSTRACT: We carried out a high throughput analysis of insulin-induced kinase signaling pathways in primary fibroblasts from 35 unrelated individuals. We found that extensive individual variation exists in induction of various signaling pathways. ERK signaling displayed the greatest variation, which led to extensive variation in expression of downstream target genes. Our results suggest that phenotypic variation in kinase signaling mediates variation in downstream processes of insulin response. Future study of such phenotypic variation is important to linking genetic variants to individual susceptibility to complex diseases such as diabetes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE21891 | GEO | 2015/08/03

SECONDARY ACCESSION(S): PRJNA126905

REPOSITORIES: GEO

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Expression data from insulin-treated human primary fibroblasts and effects of U0126 on insulin-induced gene expression

Project description:We carried out a high throughput analysis of insulin-induced kinase signaling pathways in primary fibroblasts from 35 unrelated individuals. We found that extensive individual variation exists in induction of various signaling pathways. ERK signaling displayed the greatest variation, which led to extensive variation in expression of downstream target genes. Our results suggest that phenotypic variation in kinase signaling mediates variation in downstream processes of insulin response. Future study of such phenotypic variation is important to linking genetic variants to individual susceptibility to complex diseases such as diabetes. Passage-matched primary fibroblasts from 35 unrelated newborns (foreskin) were treated with 100 nM insulin. We measured gene expression levels in each of 35 individuals at baseline, and 1 hour and 6 hours after insulin treatment using expression arrays. In order to examine effects of ERK inhibition on insulin-induced gene expression, we treated fibroblasts from 4 individuals with DMSO or 10uM of U0126 for 1 hour, followed by insulin treatment for one hour and 6 hours. We then harvested cells and measured gene expression in each sample using expression arrays.

2015-08-03 | E-GEOD-21891 | biostudies-arrayexpress

NextGen Consortium: GENESiPS Study: Identifying the Gene Networks of Insulin Resistance

Project description:RNA-seq transcriptome profiling of human induced pluripotent stem cells to characterize gene expression variation across individuals and within multiple iPSC lines from the same individual The purpose of this study was to analyze the potential differential responses to HMGCR inhibition of insulin sensitive versus insulin resistant human iPSC lines.

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Kubota2012_InsulinAction_AKTpathway

Project description:This model is from the article: Temporal Coding of Insulin Action through Multiplexing of the AKT Pathway. Kubota H, Noguchi R, Toyoshima Y, Ozaki Y, Uda S, Watanabe K, Ogawa W, Kuroda S. Mol Cell. 2012 Jun 29;46(6):820-32. 22633957 , Abstract: One of the unique characteristics of cellular signaling pathways is that a common signaling pathway can selectively regulate multiple cellular functions of a hormone; however, this selective downstream control through a common signaling pathway is poorly understood. Here we show that the insulin-dependent AKT pathway uses temporal patterns multiplexing for selective regulation of downstream molecules. Pulse and sustained insulin stimulations were simultaneously encoded into transient and sustained AKT phosphorylation, respectively. The downstream molecules, including ribosomal protein S6 kinase (S6K), glucose-6-phosphatase (G6Pase), and glycogen synthase kinase-3β (GSK3β) selectively decoded transient, sustained, and both transient and sustained AKT phosphorylation, respectively. Selective downstream decoding is mediated by the molecules' network structures and kinetics. Our results demonstrate that the AKT pathway can multiplex distinct patterns of blood insulin, such as pulse-like additional and sustained-like basal secretions, and the downstream molecules selectively decode secretion patterns of insulin. Note: Created by The MathWorks, Inc. SimBiology tool, Version 3.3

2005-01-01 | MODEL1204060000 | BioModels

Phosphoproteomics reveals rewiring of the insulin signaling network and multi-nodal defects in insulin resistance

Project description:Here we employed phosphoproteomics to delineate insulin signal transduction in adipocyte cells and adipose tissue. Across a range of insults triggering insulin resistance, we observed marked rewiring of the insulin signaling network. This included both attenuated insulin-responsive phosphorylation, and the emergence of phosphorylation uniquely insulin-regulated in insulin resistance. Identifying dysregulated phosphosites common to multiple insults revealed subnetworks containing novel regulators of insulin action, such as MARK2/3, and causal drivers of insulin resistance. The presence of several GSK3 substrates among these phosphosites led us to establish a pipeline for identifying context-specific kinase substrates. This revealed widespread dysregulation of GSK3 signaling. Pharmacological inhibition of GSK3 partially reversed insulin resistance in cells and tissue explants. These data highlight that insulin resistance is multi-nodal signaling defect that includes dysregulated GSK3 activity.

2023-02-17 | PXD032913 | Pride

Active kinome in human skeletal muscle insulin resistance

Project description:Obesity-related insulin resistance (OIR) is one of the main contributors to type 2 diabetes and other metabolic diseases. Protein kinases are implicated in key signaling steps including insulin signaling and glucose metabolism. Molecular mechanisms underlying OIR involving global active kinases remain less understood. Herein, we report findings from an in vivo active kinase profiling study in skeletal muscle from lean control (Lean) and OIR human participants, which identified the 1st active kinome comprised of 54 active protein kinases in human skeletal muscle. The activities of 23 kinases were different in OIR compared to Lean muscle (11 hyper- and 12 hypo-active), while their protein abundance was the same between the two groups. The activities of multiple kinases involved in AMPK and p38 signaling were lower in OIR compared to Lean. On the contrary, multiple kinases in JNK signaling pathway exhibited higher activity in OIR vs. Lean muscle. The kinase-substrate-prediction based on experimental data further confirmed a potential down-regulation of insulin signaling (e.g., inhibited phosphorylation of insulin receptor substrate-1 and AKT1/2). These findings provide a global view of the active kinome in OIR and Lean muscle, pinpoint novel specific impairment in kinase activities in multiple signaling pathways important for skeletal muscle insulin resistance, and provide potential drug targets (i.e., abnormal active kinase) to prevent and/or reverse skeletal muscle insulin resistance in humans.

2020-01-23 | PXD011909 | Pride

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Project description:The objective of this study was to investigate the link between signaling-network activation and transcriptional regulation downstream of tumor necrosis factor (TNF), epidermal growth factor (EGF), and insulin. Microarrays were used to capture the transcriptional responses to TNF, EGF, and insulin at intermediate-to-late times after stimulation. Nine combinations of TNF, EGF, and insulin were evaluated at three time points after stimulation in biological duplicate.

2016-07-25 | E-GEOD-69639 | biostudies-arrayexpress

Transcription profiling of brown adipose tissue in a glycerol kinase (Gyk) knockout mouse model to define GyKs role in insulin resistance

Project description:Glycerol kinase (GK) is at the interface of fat and carbohydrate metabolism and has been implicated in insulin resistance and type 2 diabetes mellitus (T2DM). To define GK's role in insulin resistance, we examined gene expression in brown adipose tissue in a glycerol kinase (Gyk) knockout (KO) mouse model using microarray analysis. Global gene expression profiles of KO mice were distinct from wild type (WT) with 668 genes that were differentially expressed. These included genes involved in lipid metabolism, carbohydrate metabolism, insulin signaling, and insulin resistance. Real-Time (RT) PCR analysis confirmed the differential expression of selected genes involved in lipid and carbohydrate metabolism. PathwayAssist analysis confirmed direct and indirect connections between GK and genes in lipid metabolism, carbohydrate metabolism, insulin signaling, and insulin resistance. Network Component Analysis (NCA) showed that the transcription factors, peroxisome proliferator-activated receptor gamma (PPAR-Î³), sterol regulatory element binding factor 1 (SREBP-1), SREBP-2, signal transducer and activator of transcription 3 (STAT3), STAT5, trans-acting transcription factor 1 (SP1), CCAAT/enhancer binding protein alpha (CEBP-Î±), cAMP responsive element binding protein 1 (CREB), glucocorticoid receptor (GR), and PPAR-Î± have altered activity in the KO mice. NCA also revealed the individual contribution of these transcription factors on the expression of genes altered in the microarray data. This study elucidates the transcription network of Gyk and further confirms a role for Gyk, a simple Mendelian disorder, in insulin resistance and T2DM, a common complex genetic disorder. Experiment Overall Design: 7 samples are analyzed; 3 wildtype and 4 KO. the WT samples are used as control and KO samples are used as the experimental group.

2007-11-22 | E-GEOD-4656 | biostudies-arrayexpress

Transcription profiling of mouse Nrf2 knockout caused by ROS-mediated insulin/IGF-1 resistance

Project description:The liver is frequently challenged by surgery-induced metabolic overload, viruses, or toxins, which induce the formation of reactive oxygen species. To determine the effect of oxidative stress on liver regeneration and to identify the underlying signalling pathways, we studied liver repair in mice lacking the Nrf2 transcription factor. In these animals, expression of several cytoprotective enzymes was reduced in hepatocytes, resulting in oxidative stress. As a consequence, tissue damage was aggravated, and liver regeneration after partial hepatectomy was delayed. Using in vitro and in vivo studies we identified oxidative stress-induced insulin/insulin-like growth factor resistance as the underlying mechanism. This deficiency impaired the activation of p38 mitogen-activated kinase, Akt kinase, and downstream targets after hepatectomy, resulting in enhanced death and delayed proliferation of hepatocytes. Our results reveal novel roles of Nrf2 in the regulation of growth factor signalling and in tissue repair. In addition, they provide new insight into the mechanisms underlying oxidative stress-induced defects in liver regeneration and thus offer new avenues to improve regeneration in patients with acute or chronic liver damage. Experiment Overall Design: Livers from Nrf2 k.o. and wt mice; 3 hybridizations per genoype: RNA samples were pooled from 3 individual animals

2008-06-16 | E-GEOD-8969 | biostudies-arrayexpress

Starvation-induced changes in somatic Insulin/IGF-1R signaling drive metabolic programming across generations

Project description:Exposure to adverse nutritional and metabolic environments during critical periods of development can exert long-lasting effects on health outcomes of an individual and its descendants. Although such metabolic programming has been observed in multiple species and in response to distinct nutritional stressors, conclusive insights into signaling pathways and mechanisms responsible for initiating, mediating and manifesting changes to metabolism and behavior across generations remain scarce. By employing a multigenerational starvation paradigm in C. elegans, we show that starvation-induced changes in DAF-16/FoxO activity, the main downstream target of insulin/IGF-1 receptor signaling, are responsible for metabolic programming phenotypes. Tissue-specific depletion of DAF-16/FoxO during distinct developmental time points further demonstrates that DAF-16/FoxO acts in somatic tissues, but not directly in the germline, to both initiate and manifest metabolic programming. In conclusion, our study deciphers multifaceted and critical roles of highly conserved insulin/IGF-1 receptor signaling in determining health outcomes and behavior across generations.

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