The kinetics of glucagon action on the liver during insulin-induced hypoglycemia.

Glucagon's effect on hepatic glucose production is time dependent under hyperglycemic conditions, such that after an initial burst of hepatic glucose production (HGP), it slowly wanes. It is not known whether this is also the case under hypoglycemic conditions, where an increase in HGP is essential. This question was addressed using adrenalectomized dogs to avoid the confounding effects of other counterregulatory hormones. During the study, infusions of epinephrine and cortisol were given to maintain basal levels. Somatostatin and insulin (800 microU/kg/min) were infused to induce hypoglycemia. After 30 minutes, glucagon was infused at a basal rate (1 ng/kg/min, baGGN group, n=5) or a rate 8-fold basal (8 ng/kg/min, hiGGN group, n=5) for 4 hours. Glucose was infused to match the arterial glucose levels between groups. Our data showed that glucagon has a biphasic effect on the liver despite hypoglycemia. Hyperglucagonemia stimulated a rapid, transient peak in HGP (4-fold basal production) over about 60 min which was followed by a slow reduction in HGP to a rate 1.5-fold basal. During the last two hours of the experiment, elevated glucagon stimulated glucose production at a rate 5-fold greater than basal glucagon (2.5 vs. 0.5 mg/kg/min, respectively), indicating a sustained effect of the hormone. Of note, the hypoglycemia-induced rises in norepinephrine and glycerol were smaller in hiGGN compared to baGGN group despite identical hypoglycemia. This finding suggests that there is reciprocity between glucagon and the sympathetic nervous system such that when glucagon is increased the sympathetic nervous response to hypoglycemia is downregulated.