Glucagon (0.04-0.09 mg/kg/min) was given intravenously for either 2 or 3 min to eight patients with fasting-induced
hypoglycemia. One child had hepatic
phosphorylase deficiency, two children had
glucose-6-phosphatase deficiency, two children had debrancher
enzyme (amylo-1,6-glucosidase) deficiency, and two children and one adult had decreased hepatic
fructose-1,6-diphosphatase (
FDPase) activity. Liver biopsy specimens were obtained before and immediately after the
glucagon infusion. The
glucagon caused a significant increase in the activity of
FDPase (from 50+/-10.0 to 72+/-11.7 nmol/mg
protein/min) and a significant decrease in the activities of
phosphofructokinase (PFK) (from 92+/-6.1 to 41+/-8.1 nmol/mg
protein/min) and
pyruvate kinase (PK) (from 309+/-39.4 to 165+/-23.9 nmol/mg
protein/min). The
glucagon infusion also caused a significant increase in hepatic
cyclic AMP concentrations (from 41+/-2.6 to 233+/-35.6 pmol/mg
protein). Two patients with debrancher
enzyme deficiency who had biopsy specimens taken 5 min after the
glucagon infusion had persistence of
enzyme and
cyclic AMP changes for at least 5 min. One child with
glucose-6-phosphatase deficiency was given intravenous
glucose (150 mg/kg/min) for a period of 5 min after the
glucagon infusion and biopsy. The plasma
insulin concentration increased from 8 to 152 muU/ml and
blood glucose increased from 72 to 204 mg/100 ml. A third liver biopsy specimen was obtained immediately after the
glucose infusion and showed that the
glucagon-induced effects on PFK and
FDPase were completely reversed. The
glucagon infusion caused an increase in hepatic
cyclic AMP concentration from 38 to 431 pmol/mg
protein but the
glucose infusion caused only a slight decrease in hepatic
cyclic AMP concentration (from 431 to 384 pmol/mg
protein), which did not appear to be sufficient to account for the changes in
enzyme activities. Hepatic
glucose-6-phosphatase and
fructose-1,6-diphosphate aldolase activities were not altered by either the
glucagon or the
glucose infusion in any patients.
Cyclic AMP (0.05 mmol/kg) was injected into the portal vein of adult rats and caused
enzyme changes similar to those seen with
glucagon administration in humans. Our findings suggest that rapid changes in the activities of PFK, PK, and
FDPase are important in the regulation of hepatic glycolysis and gluconeogenesis, respectively, in humans and that
cyclic AMP may mediate the
glucagon- but probably not the
glucose-
insulin-induced changes in
enzyme activities.