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1 Pediatrics/Neonatology, University of Colorado Health Sciences Center, Denver, CO, USA
2 Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
* To whom correspondence should be addressed. E-mail: marianne.anderson{at}uchsc.edu.
To test the effects of acute fetal hyperinsulinemia on the pattern and time course of insulin signaling in ovine fetal skeletal muscle, we measured selected signal transduction proteins in the mitogenic, protein synthetic, and metabolic pathways in the skeletal muscle of normally growing fetal sheep in utero. In experiment #1, 4-hour hyperinsulinemic-euglycemic clamps were conducted in anesthetized twin fetuses to produce selective fetal hyperinsulinemia-euglycemia in one twin and euinsulinemia-euglycemia in the other. Serial skeletal muscle biopsies were taken from each fetus during the clamp and assayed by Western blot for selected insulin signal transduction proteins. Tyrosine phosphorylation of the insulin receptor, insulin receptor substrate-1, and the p85 subunit of PI3-kinase doubled at 30 minutes and gradually returned to control values by 240 minutes. Phosphorylation of ERK1,2 was increased 5-fold through 120 minutes of insulin infusion and decreased to control concentration by 240 minutes. Akt phosphorylation doubled at 30 minutes and remained elevated throughout the study. Phosphorylation of p70 S6K increased 4-fold at 30, 60 and 120 minutes. In the second experiment, a separate group of non-anesthetized singleton fetuses was clamped to intermediate and high hyperinsulinemic-euglycemic conditions for 1 hour. GLUT4 increased 4-fold in the plasma membrane at 1 hour and hindlimb glucose uptake increased significantly at the higher insulin concentration. These data demonstrate that an acute increase in fetal plasma insulin concentration stimulates a unique pattern of insulin signal transduction proteins in intact skeletal muscle, thereby increasing pathways for mRNA translation, glucose transport, and cell growth.
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