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http://hdl.handle.net/2445/145698
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DC Field | Value | Language |
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dc.contributor.author | Valverde, Ángela M. | - |
dc.contributor.author | Burks, Deborah J. | - |
dc.contributor.author | Fabregat, Isabel | - |
dc.contributor.author | Fisher, Tracey L. | - |
dc.contributor.author | Carretero, José | - |
dc.contributor.author | White, Morris F. | - |
dc.contributor.author | Benito, Manuel | - |
dc.date.accessioned | 2019-11-28T19:11:01Z | - |
dc.date.available | 2019-11-28T19:11:01Z | - |
dc.date.issued | 2003-09-01 | - |
dc.identifier.issn | 0012-1797 | - |
dc.identifier.uri | http://hdl.handle.net/2445/145698 | - |
dc.description.abstract | To assess the role of insulin receptor (IR) substrate (IRS)-2 in insulin action and resistance in the liver, immortalized neonatal hepatocyte cell lines have been generated from IRS-2(-/-), IRS-2(+/-), and wild-type mice. These cells maintained the expression of the differentiated liver markers albumin and carbamoyl phosphate synthetase, as well as bear a high number of IRs. The lack of IRS-2 did not result in enhanced IRS-1 tyrosine phosphorylation or IRS-1-associated phosphatidylinositol (PI) 3-kinase activity on insulin stimulation. Total insulin-induced PI 3-kinase activity was decreased by 50% in IRS-2(-/-) hepatocytes, but the translocation of PI-3,4,5-trisphosphate to the plasma membrane in these cells was almost completely abolished. Downstream PI 3-kinase, activation of Akt, glycogen synthase kinase (GSK)-3 (alpha and beta isoforms), Foxo1, and atypical protein kinase C were blunted in insulin-stimulated IRS-2(-/-) cells. Reconstitution of IRS-2(-/-) hepatocytes with adenoviral IRS-2 restored activation of these pathways, demonstrating that IRS-2 is essential for functional insulin signaling in hepatocytes. Insulin induced a marked glycogen synthase activity in wild-type and heterozygous primary hepatocytes; interestingly, this response was absent in IRS-2(-/-) cells but was rescued by infection with adenoviral IRS-2. Regarding gluconeogenesis, the induction of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase by dibutyryl cAMP and dexamethasone was observed in primary hepatocytes of all genotypes. However, insulin was not able to suppress gluconeogenic gene expression in primary hepatocytes lacking IRS-2, but when IRS-2 signaling was reconstituted, these cells recovered this response to insulin. Suppression of gluconeogenic gene expression in IRS-2-deficient primary hepatocytes was also restored by infection with dominant negative Delta 256Foxo1. | - |
dc.format.extent | 10 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | American Diabetes Association | - |
dc.relation.isformatof | Reproducció del document publicat a: https://doi.org/10.2337/diabetes.52.9.2239 | - |
dc.relation.ispartof | Diabetes, 2003, vol. 52, num. 9, p. 2239-2248 | - |
dc.relation.uri | https://doi.org/10.2337/diabetes.52.9.2239 | - |
dc.rights | cc-by-nc-nd (c) American Diabetes Association, 2003 | - |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/es | - |
dc.source | Articles publicats en revistes (Ciències Fisiològiques) | - |
dc.subject.classification | Metabolisme | - |
dc.subject.classification | Resistència a la insulina | - |
dc.subject.classification | Fisiologia | - |
dc.subject.classification | Genètica | - |
dc.subject.classification | Proteïnes quinases | - |
dc.subject.other | Metabolism | - |
dc.subject.other | Insulin resistance | - |
dc.subject.other | Physiology | - |
dc.subject.other | Genetics | - |
dc.subject.other | Protein kinases | - |
dc.title | Molecular mechanisms of insulin resistance in IRS-2-deficient hepatocytes | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/publishedVersion | - |
dc.identifier.idgrec | 579673 | - |
dc.date.updated | 2019-11-28T19:11:02Z | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
dc.identifier.pmid | 12941762 | - |
Appears in Collections: | Articles publicats en revistes (Ciències Fisiològiques) |
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579673.pdf | 458 kB | Adobe PDF | View/Open |
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