Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/145698
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dc.contributor.authorValverde, Ángela M.-
dc.contributor.authorBurks, Deborah J.-
dc.contributor.authorFabregat, Isabel-
dc.contributor.authorFisher, Tracey L.-
dc.contributor.authorCarretero, José-
dc.contributor.authorWhite, Morris F.-
dc.contributor.authorBenito, Manuel-
dc.date.accessioned2019-11-28T19:11:01Z-
dc.date.available2019-11-28T19:11:01Z-
dc.date.issued2003-09-01-
dc.identifier.issn0012-1797-
dc.identifier.urihttp://hdl.handle.net/2445/145698-
dc.description.abstractTo 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.extent10 p.-
dc.format.mimetypeapplication/pdf-
dc.language.isoeng-
dc.publisherAmerican Diabetes Association-
dc.relation.isformatofReproducció del document publicat a: https://doi.org/10.2337/diabetes.52.9.2239-
dc.relation.ispartofDiabetes, 2003, vol. 52, num. 9, p. 2239-2248-
dc.relation.urihttps://doi.org/10.2337/diabetes.52.9.2239-
dc.rightscc-by-nc-nd (c) American Diabetes Association, 2003-
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/es-
dc.subject.classificationMetabolisme-
dc.subject.classificationResistència a la insulina-
dc.subject.classificationFisiologia-
dc.subject.classificationGenètica-
dc.subject.classificationProteïnes quinases-
dc.subject.otherMetabolism-
dc.subject.otherInsulin resistance-
dc.subject.otherPhysiology-
dc.subject.otherGenetics-
dc.subject.otherProtein kinases-
dc.titleMolecular mechanisms of insulin resistance in IRS-2-deficient hepatocytes-
dc.typeinfo:eu-repo/semantics/article-
dc.typeinfo:eu-repo/semantics/publishedVersion-
dc.identifier.idgrec579673-
dc.date.updated2019-11-28T19:11:02Z-
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess-
Appears in Collections:Articles publicats en revistes (Ciències Fisiològiques)

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