Context: Since IGF-1 is the main mediator of GH action on osteogenic cells, individual differences in IGF-1 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-1 target level indicates heterogeneity of responses to serum IGF-1 exposures.

Objectives: This study tested a cell-based assay as an index of individual IGF-1 sensitivity that could help dissect GH pharmacogenetics.

Design: Akt phosphorylation (P-Akt) was quantified in response to IGF-1 in fresh lymphocytes from 50 short children (25 with « idiopathic short stature » ISS, 25 born « short for gestational age » SGA)whose growth parameters were being prospectively monitored during the 1st year of GH therapy (86 ± 20µg/k.d.).

Results: Intra-individual triplicate measurements of IGF-1 stimulated of P-Akt were reasonably consistent (0.11 SD/mean 0.23). Among the 50 children, the distribution of Akt phosphorylation in lymphocytes stimulated by 125 ng/ml IGF-1 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-1 levels (P = 0.04) in response to GH (P = 0.04) were also correlated with the growth response.

Conclusion: Lymphocytes are the only IGF-1 target cells that can be easily studied in clinical research. IGF-1 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-1 signaling in the individual variability of GH effects on growth.