Evidence for an intrahepatic contribution to the waning effect of glucagon on glucose production in the conscious dog.
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).
D000818:Animals; D004285:Dogs; D005260:Female; D005934:Glucagon / Q000097:blood / Q000502:physiology*; D005947:Glucose / Q000096:biosynthesis*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008099:Liver / Q000502:physiology; D008297:Male
D007328:Insulin; D005934:Glucagon; D005947:Glucose