Hepatic glucagon sensitivity and fasting glucose concentration in normal dogs

We assessed hepatic glucagon sensitivity in overnight-fasted, conscious dogs. Six pancreatic replacement protocols were performed in each of five animals. Somatostatin was infused to inhibit endogenous insulin and glucagon, insulin was replaced intraportally at 200 microU.min-1.kg-1, and glucagon was infused intraportally at 0, 0.6, 1, 2, 5, or 20 ng.min-1.kg-1. One intravenous glucose tolerance test was also performed in each animal for measurement of insulin sensitivity (SI). During hormone replacement at a given glucagon dose, plasma glucose differed substantially among animals (P = 0.003). Therefore the dose required for restoration of euglycemia ("glucagon requirement") varied nearly sevenfold among animals, suggesting appreciable differences in glucagon sensitivity (GS). The latter was quantitated in individual animals as the initial slope of integrated glucose output vs. glucagon concentration. GS varied from 0.22 to 3.9 mg.kg-1.pg-1.ml among various animals and was inversely and significantly related to glucagon requirement. SI varied less (approximately 4-fold) and was not associated with glucagon requirement. These observations suggested that interanimal differences in glucose during hormone replacement were the result of substantial differences in GS. In addition, we found the GS of a given animal to be highly associated (P = 0.01) with its fasting glucose level. We conclude that GS varies substantially, and as such may be an important determinant of the fasting glucose level in normal animals.