Hormonal regulation of glucogen metabolism in human fetal liver. I. Normal development and effects of dibutyryl cyclic AMP, glucagon, and insulin in liver explants

Glycogen accumulates in human fetal liver beginning at the 8th wk of gestation. A parallel increase in total glycogen synthase activity is found, although the I form activity remains low and constant throughout the first two thirds of gestation. Total phosphorylase activity increases slightly during this period, with the proportion in the active form amounting to about one half of the total throughout. After an initial rapid decline, the glycogen concentration in explants of human fetal liver remained constant for 20 to 40 hr at about 20% of the in vivo level. Incubation with glucagon, cyclic AMP (adenosine 3',5' monophosphate) or its dibutyryl derivative markedly reduced tissue glycogen concentrations while insulin brought about a small increase. The effect of maximal doses of dibutyryl cyclic AMP and glucagon were the same, and the combination of agents produced no further effect. The response to dibutyryl cyclic AMP was apparent by 1 hr and maximal by 3 to 6 hr, whereas the response to insulin required about 6 hr to be detected, and it continued for at least 18 hr. Insulin antagonized the glycogenolytic effect of low doses of glucagon or theophylline but was without significant effect in the presence of high glucagon concentrations. Glucagon stimulated cyclic AMP output from explants, and this effect was further augmented by theophylline. Insulin had no consistent effect on cyclic AMP output in either the presence or the absence of glucagon or theophylline. Incubation with dibutyryl cyclic AMP resulted in a decrease of glycogen synthase I form activity, while insulin tended to increase this enzyme activity. In neither circumstance was the proportion of active phosphorylase altered. These results suggest that the regulation of glycogen levels in human fetal liver by cyclic AMP, glucagon, and insulin may entail alterations in the activity of glycogen synthase activity without necessitating alterations in phosphorylase activity. Cyclic AMP or glucagon was capable of depleting tissue glycogen stores in tissue from fetuses of 6 weeks' gestation. Insulin increased tissue glycogen concentrations in tissue from fetuses of 7 or more wk. (Journal received: 27 Jan. 1977)