Growth hormone (GH) deficiency is associated with increased sensitivity to insulin, but the molecular mechanisms involved in this association are poorly understood. In the current work, we have examined the consequences of the 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, circulating insulin concentrations are less than 4 µIU/ml, and glucose concentrations are low, concordant with a state of insulin hypersensitivity. The abundance and tyrosine phosphorylation state of the insulin receptor (IR), the IR substrate-1 (IRS-1), and Shc, the association between

IRS-1 and the p85 subunit of phosphatidylinositol (PI) 3-kinase, the IRS-1-and the phosphotyrosine-associated PI 3-kinase in liver were examined. We found that, in liver of GHR-KO mice, the lack of GHR and GH effects is associated with:(1) increased IR abundance,(2) increased insulin-stimulated IR tyrosine phosphorylation,(3) normal efficiency of IRS-1 and Shc tyrosine phosphorylation and (4) normal activation of PI 3-kinase by insulin. These alterations could represent an adaptation to the low insulin concentrations displayed by these animals, and may account for their increased insulin sensitivity.