Development of insulin and glucagon binding and the adenylate cyclase response in liver membranes of the prenatal, postnatal, and adult rat: Evidence of glucagon “resistance”

Although plasma glucagon levels in therat fetus are in the adult range, hepatic glycogen ispresent in far greater abundance in the fetus thanin the adult. To explain this paradox, adenylatecyclase response to glucagon was studied in partiallypurified membranes of rat livers obtained throughoutperinatal life and at 3 months of age. The adenylatecyclase response to glucagon(10⁻⁹M) was only 7%of the adult response at day 15 of fetal life and 20%on the 21st day. Not until after the 30th day postpartumdid it reach maturity. Yet, the adenylatecyclase response to stimulation by NaF was comparableto the adult response throughout fetal life. The binding of [¹²⁵I]iodoglucagon (2 × 10⁻⁹M)by these membrane preparations was only 1% of theadult level at day 15 of fetal life and increased to23% at the21st day, and, like the adenylate cyclaseresponse to glucagon, did not reach maturity until after the 30th day of postnatal life. In contrast, insulin binding on the 15th day of gestation was 11%of the adult level and on the 21st day 45%of the adult level, reaching adult levels by the 30thpostnatal day. An increase in membrane-associated particles, reflecting intramembranou protein, wasobserved during prenatal life, but the mean particlenumber per μm²reached adult levels on the 21stday of fetal life, indicating that subsequent changesin hormone binding were clearly independent ofnon-specific changes in the number of particles. The findings suggest that the fetal liver is lesssensitive to glucagon action than the adult liver, andthat thisglucagon “resistance” is mediated by areduced capacity of the hepatocyte to bind glucagonat a time when substantial binding of insulin isdemonstrable. Selective discrimination against glucagonmay be important in promoting the anabolicprocesses required for normal fetal development.