Insulin Degradation Within Fetoplacental Unit

The concentration of insulin in fetal plasma is a resultant of factors stimulating insulin secretion and/or metabolic disposition. As part of investigations of the dynamics of fetal insulin secretion, aspects of insulin disposition in placenta and fetus were studied. Inactivation of insulin could occur by cleavage of disulfide bonds with glutathione-insulin trans-hydrogenase (GIT), and/or by proteolysis with specific or non-specific peptidases. Activity of GIT is negligible in fetal liver until day 18 of gestation, when the specific activity is 21 units/mg. protein, as compared to 127 units/mg. protein at term. Activity of GIT in fetal kidney and lung, during late gestation, is comparable to adult values. Non-GIT activity was excluded by incubation with N-ethyl maleimide. Placental GIT activity was constant throughout gestation. Identification of GIT as initial step in degradation of insulin by placental homogenates, microsomes and membrane preparations was established by Sephadex chromatography following sequential incubations with 125I-insulin. Intracellular distribution of GIT differs between placenta and liver, with much less activity in placental microsomes. These studies indicate that fetal liver cannot degrade insulin until late in pregnancy. It is probable that the placenta plays a significant role in disposition of insulin and, thus, in regulation of the plasma concentration of insulin in the rat fetus.