The effect of tolbutamide and hepatic extraction of insulin and glucagon and hepatic glucose output in anesthetized dogs.

The effects of tolbutamide and insulin infusion on hepatic extraction of insulin and glucagon and on hepatic glucose output were compared in anesthetized dogs. The basal hepatic extraction of insulin was not significantly different in the two experiments (62 +/- 7% vs. 49 +/- 8%). The fraction of insulin extracted by the liver was not changed by either tolbutamide or insulin administration. In contrast, hepatic extraction of glucagon significantly increased from a basal value of 12 +/- 8% to 41 +/- 12% 30 min after tolbutamide, coincident with hypoglycemia and increased secretion of glucagon. The percent hepatic extraction of glucagon did not change during insulin infusion despite similar hypoglycemia and an even greater increase in the amount of glucagon reaching the liver. Tolbutamide and insulin produced a transient fall in hepatic glucose output which was associated with a significant increase in the insulin to glucagon molar ratio of the portal vein. Despite the persistence of hypoglycemia, hepatic glucose production returned to control values, and the portal venous insulin to glucagon molar ratio returned toward normal. Thus, the initial hypoglycemia after tolbutamide and insulin treatment reflects decreased hepatic glucose production, while the later effects represent increased peripheral glucose utilization. Hepatic glucose output correlated better with the portal venous insulin to glucagon molar ratio than the ratio of the hormones removed by the liver. These findings indicate that insulin and glucagon extraction by the liver are quite different and are independently regulated. Tolbutamide directly increases the fraction of glucagon removed by the liver. Because of changes in hepatic extraction after tolbutamide, increased pancreatic secretion of glucagon might not be reflected in its peripheral concentration.