Glucagon and glucose dynamics in sheep: evidence for glucagon resistance in the fetus

We compared the effects of glucagon infused at 5 and 50 ng X kg-1 X min-1 on glucose turnover (GT), production (Ra), and utilization (Rd) in the fetal (F; n = 5, gestation 129 +/- 3 days, term approximately 150 days) and nonpregnant adult (A; n = 5 and 6) sheep. Infusion of glucagon at 5 ng X kg-1 X min-1 raised fetal glucagon levels (IRG) from a basal of 168 +/- 27 to a mean sustained level of 863 +/- 160 pg/ml but had no effect on basal levels of glucose (G) of 12 +/- 3 mg/dl, insulin (IRI) of 16 +/- 3 microU/ml, GT of 21 +/- 1.3 mg/min, and Rd of 15 +/- 2 mg/min; Ra remained negligible. When fetal IRG was raised to a mean sustained level of 1,809 +/- 210 pg/ml by infusion of glucagon at 50 ng X kg-1 X min-1, G doubled to 23 +/- 1.5 mg/dl, IRI rose to 21 +/- 0.9 microU/ml, GT rose to 60 +/- 5 mg/min, Rd to 30 +/- 4.8 mg/min, and Ra to 41 +/- 6 mg/min (P less than 0.01 for each) indicating induction of F glucose production so that GT was now derived from endogenous sources. By contrast, when IRG levels were raised from 109 +/- 10 to 538 +/- 43 pg/ml by infusion of 5 ng X kg-1 X min-1 to A, basal G rose from 56 +/- 2 to 88 +/- 6 mg/dl, IRI from 24 +/- 2 to 45 +/- 6 microU/ml, GT and Ra from 93 +/- 7 to 173 +/- 17 mg/min, and Rd from 93 +/- 7 to 148 +/- 12 mg/min (P less than 0.01 for each). No further increments of these indexes occurred in A when IRG was raised to a mean sustained level of 2,275 +/- 135 pg/ml by infusion of 50 ng X kg-1 X min-1. These results indicate a relative resistance in F to the glycemic effects of glucagon, consistent with previously demonstrated decreases of hepatic glucagon receptors and glucagon-stimulated cAMP production in fetal liver.