dc.contributor |
Universitat de Barcelona |
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 |
2019-11-28T19:11:01Z |
dc.date |
2019-11-28T19:11:01Z |
dc.date |
2003-09-01 |
dc.date |
2019-11-28T19:11:02Z |
dc.identifier.citation |
0012-1797 |
dc.identifier.citation |
579673 |
dc.identifier.uri |
http://hdl.handle.net/2445/145698 |
dc.format |
10 p. |
dc.format |
application/pdf |
dc.language.iso |
eng |
dc.publisher |
American Diabetes Association |
dc.relation |
Reproducció del document publicat a: https://doi.org/10.2337/diabetes.52.9.2239 |
dc.relation |
Diabetes, 2003, vol. 52, num. 9, p. 2239-2248 |
dc.relation |
https://doi.org/10.2337/diabetes.52.9.2239 |
dc.rights |
cc-by-nc-nd (c) American Diabetes Association, 2003 |
dc.rights |
info:eu-repo/semantics/openAccess |
dc.rights |
http://creativecommons.org/licenses/by-nc-nd/3.0/es |
dc.subject |
Metabolisme |
dc.subject |
Resistència a la insulina |
dc.subject |
Fisiologia |
dc.subject |
Genètica |
dc.subject |
Proteïnes quinases |
dc.subject |
Metabolism |
dc.subject |
Insulin resistance |
dc.subject |
Physiology |
dc.subject |
Genetics |
dc.subject |
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.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. |