Akt Phosphorylation in Lymphocytes Provides an Index ofin VitroInsulin-Like Growth Factor I Sensitivity Associated with Growth Hormone-Induced Growth

Abstract

Because IGF-I is the main mediator of GH action on osteogenic cells, individual differences in IGF-I sensitivity are expected to contribute to the variations of GH effects on growth. In GH-treated children, the variable responses in growth rates at a specific IGF-I target level indicate heterogeneity of responses to serum IGF-I exposures. This study tested a cell-based assay as an index of individual IGF-I sensitivity that could help dissect GH pharmacogenetics. Akt phosphorylation (P-Akt) was quantified in response to IGF-I in fresh lymphocytes from 50 short children (25 with idiopathic short stature and 25 born short for gestational age) whose growth parameters were being prospectively monitored during the first year of GH therapy (86 +/- 20 mug/kg.d). Intra-individual triplicate measurements of IGF-I-stimulated P-Akt were reasonably consistent (0.11 < or = sd; mean < or = 0.23). Among the 50 children, the distribution of P-Akt in lymphocytes stimulated by 125 ng/ml IGF-I was closely associated with the growth response to GH administration (univariate P = 0.001). Both GH dosage (P = 0.006) and the fold increase in IGF-I levels (P = 0.04) in response to GH (P = 0.04) were also correlated with the growth response. Lymphocytes are the only IGF-I target cells that can be easily studied in clinical research. IGF-I-stimulated P-Akt in these cells was found to be a predictor of GH efficacy, supporting a significant role of the first steps of IGF-I signaling in the individual variability of GH effects on growth.