High glucose and insulin decrease fetal lung insulin receptor mRNA and tyrosine kinase activity in vitro.

Specific insulin binding by the fetal lung insulin receptor is reduced in vitro by a combination of high glucose and insulin. Using 19-22 day fetal rat lung, we studied the effect of culture for 48 hours under conditions of low (10mM) and high (100mM) glucose with and without added insulin on insulin receptor tyrosine kinase activity, mRNA abundance, and glucose uptake. Culture in high glucose + insulin reduced tyrosine kinase activity to 77.2 +/- 5.2% of control values (p < .001); high glucose or insulin alone had no effect. Insulin-receptor mRNA abundance was reduced by high glucose + insulin to 37 +/- 6% of control values (p < .05). Again, no significant differences were seen with high glucose or insulin alone. Uptake of 3H-2-deoxy-glucose by explants cultured under high glucose + insulin conditions was also significantly reduced. These data indicate that down-regulation of fetal lung insulin receptors by high glucose + insulin occurs at the pre-translational level and that glucose transport is adversely affected under these conditions. Down-regulation of lung insulin receptors late in fetal life may limit the availability of glucose as substrate for surfactant synthesis in the perinatal period and may partially explain the increased incidence of respiratory distress syndrome in infants of poorly controlled diabetic mothers.