Compensatory alterations of insulin signal transduction in liver of growthhormone receptor knockout mice

Growth hormone (GH) deficiency is associated with increased sensitivity to insulin, but the molecular mechanisms involved in this association are poor ly understood. In the current work, we have examined the consequences of th e absence of the biological effects of GH on the first steps of the insulin signaling system in vivo in liver of mice with targeted disruption of the GH receptor/GH binding protein gene (GHR-KO mice). In these animals, circul ating insulin concentrations are less than 4 mu IU/ml, and glucose concentr ations are low, concordant with a state of insulin hypersensitivity. The ab undance and tyrosine phosphorylation state of the insulin receptor (IR), th e IR substrate-1 (IRS-1), and Shc, the association between IRS-1 and the p8 5 subunit of phosphatidylinositol (PI) 3-kinase, the IRS-1- and the phospho tyrosine-associated PI 3-kinase in liver were examined. We found that. in l iver of GHR-KO mice. the lack of GHR and GH effects is associated with: (1) increased IR abundance, (2) increased insulin-stimulated IR tyrosine phosp horylation, (3) normal efficiency of IRS-1 and She tyrosine phosphorylation and (4) normal activation of PI 3-kinase by insulin. These alterations cou ld represent an adaptation to the low insulin concentrations displayed by t hese animals, and may account for their increased insulin sensitivity.