Akt phosphorylation in lymphocytes provides an index of in vitro insulin-like growth factor I sensitivity associated with growth hormone-induced growth.
BACKGROUND
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.


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


METHODS
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).


RESULTS
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.


CONCLUSIONS
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.
Lotton
Chantal
C
Department of Pediatric Endocrinology, Saint Vincent de Paul Hospital, Paris V University, 75014 Paris, France.
Rodrigue
Danielle
D
Elie
Caroline
C
Rothenbühler
Anya
A
Lahlou
Najiba
N
Le Stunff
Catherine
C
Bougnères
Pierre
P
D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D006128:Growth / Q000187:drug effects*; D019382:Human Growth Hormone / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D051057:Proto-Oncogene Proteins c-akt