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Articles in PresS, published online ahead of print May 14, 2002
Am J Physiol Endocrinol Metab, 10.1152/ajpendo.00570.2001
Submitted on December 28, 2001
Accepted on May 4, 2002
1 Pediatrics, Indiana Universtiy, Indianapolis, IN, USA
* To whom correspondence should be addressed. E-mail: eliecht{at}iupui.edu.
The objective of the present study was to examine the mechanisms by which IGF-I and insulin regulate eIF4F formation in the ovine fetus. Amino acid and glucose concentrations were clamped to minimize the effects of alterations in circulating substrate concentrations. The results showed that insulin infusion (890 mIU/h) increased phosphorylation of eukaryotic initiation factor 4E repressor protein 1 (4EBP1) in skeletal muscle and liver. Control percentages of highly phosphorylated form 
in skeletal muscle and liver were 41% and 19% respectively. In contrast, 85% and 54% of 4EBP1 were in the form in skeletal muscle and liver after insulin infusion. IGF-I infusion (40 nmol/h) did not alter 4EBP1 phosphorylation in liver. In skeletal muscle, IGF-I increased 4EBP1 phosphorylation by 27% (p < 0.05), but the percentage of highly phosphorylated form in the IGF-I group was significantly lower than that in the insulin group. Insulin and IGF-I increased eIF4G by 9% and 21% respectively in skeletal muscle. In liver, only IGF-I increased eIF4G (200%). Both IGF-I and insulin increased eIF4E-eIF4G binding in skeletal muscle, but only insulin decreased the amount of 4EBP1 associated with eIF4E. In liver, only IGF-I increased eIF4E-eIF4G binding. The results also showed that insulin increased the phosphorylation of p70S6 kinase (p70S6K) in both skeletal muscle and liver and Protein Kinase B (PKB/Akt) in skeletal muscle, two indicative signal proteins in the phosphoinositide 3-kinase (PI 3-kinase) pathway. IGF-I increased PKB/Akt phosphorylation in skeletal muscle, but had no effect on p70S6K phosphorylation in both skeletal muscle and liver. We conclude that insulin and IGF-I modulate eIF4F formation. However, the two hormones have different regulatory mechanisms. Insulin increases phosphorylation of 4EBP1 and eIF4E-eIF4G binding in skeletal muscle, whereas IGF-I regulates eIF4F formation by increasing total eIF4G. Insulin, but not IGF-I, decreased 4EBP1 content associated with eIF4E. Insulin regulates translation initiation via the PI 3-kinase-p70S6K pathway, whereas IGF-I does so mainly via mechanisms independent of the PI 3-kinase-p70S6K pathway. Increased eIF4F complex formation will facilitate the binding of eIF4E to the mRNA and subsequently binding to ribosomes.
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