We previously showed that infusion of
glucagon at four times the basal rate into conscious dogs given
somatostatin and basal replacement amounts of
insulin caused
hyperglycemia (217 15 mg/dl) for at least 3 h and an initial increment in hepatic
glucose production of 5.5 0.8 mg/kg . min. After 3 h, however, the effect of hyperglucagonemia on
glucose production had declined by 85%. The aim of the present study was to determine the importance of
hyperglycemia in the "downregulation" of the action of
glucagon. Six overnight-fasted conscious dogs were given
somatostatin (0.8 microgram/kg . min) plus basal intraportal replacement amounts of
insulin (263 microunits/kg . min) and
glucagon (0.65 ng/kg . min).
Hyperglycemia (276 12 md/dl) was established after 2 h by the infusion of exogenous
glucose. The
glucagon infusion rate was then increased fourfold 1 h later, so that the plasma
glucagon level rose from 95 16 to 227 35 pg/ml. The
glucose concentration was maintained at a fixed value despite the increase in
glucagon by decreasing the
glucose infusion rate by an amount equal to the increase in endogenous
glucose production induced by the
hormone.
Glucose production was measured using a primed infusion of 3H-glucose. With the
insulin (11 2 microunits/ml) and
glucose levels fixed, the elevation in
glucagon caused an initial increment of 5.1 0.7 mg/kg . min in
glucose production which was followed by a fall of only 2.5 0.4 mg/kg . min (50%) over the next 3 hr. Thus, when the plasma
glucagon level is raised fourfold under conditions in which
insulin mobilization cannot occur, the effect of hyperglucagonemia on
glucose production will be partially offset by the resulting
hyperglycemia and partly inhibited by an hepatic factor(s).