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- Title
Molecular mechanisms of insulin resistance in IRS-2-deficient hepatocytes.
- Authors
Valverde, Angela M.; Burks, Deborah J.; Fabregat, Isabel; Fisher, Tracey L.; Carretero, José; White, Morris F.; Benito, Manuel; Carretero, José
- 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[sup -/-], IRS-2[sup +/-], 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[sup -/-] 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 (α and β isoforms), Foxo1, and atypical protein kinase C were blunted in insulin-stimulated IRS2[sup -/-] cells. Reconstitution of IRS-2[sup -/-] 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[sup -/-] 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 Δ256Foxo1.
- Subjects
INSULIN; HORMONE receptors; LIVER cells
- Publication
Diabetes, 2003, Vol 52, Issue 9, p2239
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/diabetes.52.9.2239