Insulin Receptor Loss Impairs Mammary Tumorigenesis in Mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE230583 | GEO | 2023/09/20
REPOSITORIES: GEO
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Project description:Purpose: The chromosomal deletion 11q affects biology and clinical outcome in CLL but del11q-deregulated genes remain incompletely characterized. Results: We have identified differential expression of the insulin receptor (INSR) in CLL, including high-level INSR expression in the majority of CLL with del11q. High INSR mRNA expression in 11q CLL (~10-fold higher mean levels than other genomic categories) was confirmed by Q-PCR in 247 CLL cases. INSR protein measurements in 257 CLL cases through FACS, compared with measurements in normal CD19+ B-cells and monocytes, confirmed that a subset of CLL aberrantly expresses high INSR levels.
2011-05-06 | GSE26526 | GEO
Project description:Purpose: The chromosomal deletion 11q affects biology and clinical outcome in CLL but del11q-deregulated genes remain incompletely characterized. Results: We have identified differential expression of the insulin receptor (INSR) in CLL, including high-level INSR expression in the majority of CLL with del11q. High INSR mRNA expression in 11q CLL (~10-fold higher mean levels than other genomic categories) was confirmed by Q-PCR in 247 CLL cases. INSR protein measurements in 257 CLL cases through FACS, compared with measurements in normal CD19+ B-cells and monocytes, confirmed that a subset of CLL aberrantly expresses high INSR levels. We have employed integrated genomic profiling approaches upon CLL cases with and without del11q to identify 11q-relevant genes. Included are 10 primary human cases with del11q and 9 cases without del11q
2011-05-05 | E-GEOD-26526 | biostudies-arrayexpress
Project description:Hyperinsulinemia is often viewed as compensatory to insulin resistance, but studies have shown that high levels of insulin may contribute to insulin resistance. The precise mechanisms by which hyperinsulinemia contributes to insulin resistance remain poorly defined. To understand direct effects of prolonged exposure to excess insulin in muscle cells, we incubated differentiated C2C12 myotubes with elevated insulin for 16 hours, followed by 6 hours serum starvation, before examining key insulin signaling nodes. Using this model, we found that prolonged high insulin treatment significantly increased the phosphorylation of insulin receptor (INSR) and AKT, but not ERK. After starvation, acute AKT and ERK signaling stimulated by 0.2 - 20 nM insulin was attenuated. INSR protein was significantly downregulated by hyperinsulinemia in a insulin-dose-dependent manner. Surface INSR was reduced proportionally to total INSR levels. Mechanistically, we found that hyperinsulinemia strongly downregulated Insr mRNA, which was correlated with increased threonine 24 phosphorylation of FOXO1. Interestingly, 6h starvation reversed the effects of high insulin on basal phosphorylation of INSR, AKT and FOXO1, and Insr transcription. Using RNAseq, bioinformatics, and follow-up RNAi studies, we identified SIN3A as a negative regulator of Insr mRNA levels and JUND, MAX and MXI as positive regulators of Irs2 mRNA. We validated our in vitro results by determining that INSR levels in mouse skeletal muscle were negatively correlated with circulating insulin in vivo. Together, our findings shed new light on the mechanisms underlying hyperinsulinemia-induced insulin resistance in muscle cells, which are likely to be relevant in the pathogenesis of type 2 diabetes.
2020-12-31 | GSE147422 | GEO
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Project description:Commonalities and dissimilarities between the IGF1R and INSR pathways Insulin and insulin-like growth factor-1 (IGF1), acting respectively via the insulin (INSR) and IGF1 (IGF1R) receptors, play key developmental and metabolic roles throughout life. In addition, both signaling pathways fulfill important roles in cancer initiation and progression. The inherent complexity of the INSR/IGF1R pathways, along with the well documented cross-talk between insulin-like ligands and receptors, translated into a disappointingly slow pace in the development of INSR/IGF1R-directed therapies in oncology. The present study was aimed at identifying mechanistic differences between INSR and IGF1R using a recently developed bioinformatics tool, the Biological Network Simulator (BioNSi). This application allows to import and merge multiple pathways and interaction information from the KEGG database into a single network representation. The BioNsi network simulation tool allowed us to exploit the availability of gene expression data derived from breast cancer cell lines with specific disruptions of the INSR or IGF1R genes in order to investigate potential differences in protein expression that might be linked to biological attributes of the specific receptor networks. Modeling-generated information was corroborated by experimental and biological assays. Our simulation analysis identified a number of commonalities and, most importantly, dissimilarities between the IGF1R and INSR pathways that were experimentally validated and that might help explain the basis for the biological differences between these networks.
2020-03-18 | GSE145787 | GEO
Project description:Insulin receptor (Insr) protein can be found at higher levels in pancreatic b-cells than in most other cell types, but the consequences of b-cell insulin resistance remain enigmatic. Ins1cre allele was used to delete Insr specifically in b-cells of both female and male mice which were compared to Ins1cre-containing littermate controls at multiple ages and on multiple diets. RNA-seq of recombined b-cells revealed significant differences in multiple pathways previously implicated in insulin secretion and cellular fate, including rewired Ras and NFkB signaling. Male, but not female, bInsrKO mice had reduced oxygen consumption rate, while action potential and calcium oscillation frequencies were increased in Insr knockout b-cells from female, but not male mice. Female bInsrKO and bInsrHET mice exhibited elevated insulin release in perifusion experiments, during hyperglycemic clamps, and following i.p. glucose challenge. Deletion of Insr did not reduce b-cell mass up to 9 months of age, nor did it impair hyperglycemia-induced proliferation. Based on our data, we adapted a mathematical model to include b-cell insulin resistance, which predicted that b-cell Insr knockout would improve glucose tolerance depending on the degree of whole-body insulin resistance. Indeed, glucose tolerance was significantly improved in female bInsrKO and bInsrHET mice when compared to controls at 9, 21 and 39 weeks. We did not observe improved glucose tolerance in adult male mice or in high fat diet-fed mice, corroborating the prediction that global insulin resistance obscures the effects of b-cell specific insulin resistance. We further validated our in vivo findings using the Ins1-CreERT transgenic line and found improved glucose tolerance 4 weeks after tamoxifen-mediated Insr deletion. Collectively, our data show that loss of b-cell Insr alone is sufficient to drive glucose-induced hyperinsulinemia, thereby improving glucose homeostasis in otherwise insulin sensitive dietary and age contexts.
2021-11-24 | GSE159527 | GEO
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Project description:Resistance to insulin and insulin-like growth factor 1 (IGF1) in pancreatic β-cells causes overt diabetes in mice; thus, therapies that sensitize β-cells to insulin may protect patients with diabetes against β-cell failure. Here we identify an inhibitor of insulin receptor (INSR) and IGF1 receptor (IGF1R) signalling in mouse β-cells, which we name the insulin inhibitory receptor (inceptor; encoded by the gene Iir). Inceptor contains an extracellular cysteine-rich domain with similarities to INSR and IGF1R4, and a mannose 6-phosphate domain that is also found in the IGF2 receptor (IGF2R)5. Knockout mice that lack inceptor (Iir-/-) exhibit signs of hyperinsulinaemia and hypoglycaemia, and die within a few hours of birth. Molecular and cellular analyses of embryonic and postnatal pancreases from Iir-/- mice showed an increase in the activation of INSR–IGF1R in Iir-/- pancreatic tissue, resulting in an increase in the proliferation and mass of β-cells. Similarly, inducible β-cell-specific Iir-/- knockout in adult mice and in ex vivo islets led to an increase in the activation of INSR–IGF1R and increased proliferation of β-cells, resulting in improved glucose tolerance in vivo. Mechanistically, inceptor interacts with INSR–IGF1R to facilitate clathrin-mediated endocytosis for receptor desensitization. Blocking this physical interaction using monoclonal antibodies against the extracellular domain of inceptor resulted in the retention of inceptor and INSR at the plasma membrane to sustain the activation of INSR–IGF1R in β-cells. Together, our findings show that inceptor shields insulinproducing β-cells from constitutive pathway activation, and identify inceptor as a potential molecular target for INSR–IGF1R sensitization and diabetes therapy.
2021-01-27 | GSE144519 | GEO