The Metabolic Clearance of Endogenous Immunoreactive Glucagon and Exogenous Glucagon in Pancreatectomized and Sham-Operated Pigs*

Abstract

Hyperglucagonemia follows feeding in the pancreatectomized pig as it does in the pancreatectomized dog and man, but the cause of the rise in glucagon concentration is unknown. We report here the metabolic clearance and t½ of exogenous porcine glucagon infused into pigs and of endogenous immunoreactive glucagon (IRG) depressed by infusion of somatostatin. Somatostatin suppressed IRG levels to 70% of basal levels in pancreatectomized (P) pigs within 20 min of commencement of infusion and to 30% thereof in shamoperated (S) pigs within 50–60 min of commencement of infusion. In the S animals there was a breakthrough rebound within 6-8 h to levels approximately 175% of basal despite continued somatostatin infusion, while in the P animals a breakthrough to levels just above basal took place at 2 h in only two of seven animals. In the remaining five animals there was no rebound phenomenon. The half-life times determined from the slopes of disappearance were 42 ± 13 min in S animals and 55 ± 10 in P animals. In contrast, when exogenous glucagon (Eli Lilly) was infused in S and P pigs to 1200–1700% of basal plasma IRG concentrations, disappearance was found to comprise a rapid and a slow component; the t½ of the first component was 2.4 min in S and 3.4 min in P animals and, of the second, was 56.6 min in S and 35.7 in P animals. Elimination constants and metabolic clearance rates were similar, but blood production rate was higher in P. Fatty infiltration of liver and kidney was invariably seen from day 4 in P animals, and associated organ dysfunction was shown by reduced sulfobromophthalein and creatinine clearance. These studies suggest that the increased IRG after feeding in P animals is caused by the increased blood production rate. Liver and kidney dysfunction in P animals does not seem to alter t½. The difference in t½ between endogenous and exogenous glucagon may be the result of secretion of a species of glucagon which differs in structure and physiological regulation from pancreatic glucagon.