Epinephrine (0.1 micrograms.kg-1.min-1) was infused with or without somatostatin (0.1 microgram.kg-1.min-1) in six depancreatized dogs, studied under normo- and hypoinsulinemia to determine whether the participation of glucagon in epinephrine-induced hepatic glucose overproduction is governed by the degree of metabolic control. When normoglycemia was achieved by basal intraportal insulin replacement, insulin levels remained constant during the epinephrine infusion, and there was a twofold increase in extrapancreatic immunoreactive glucagon (eIRG) and glucose production (Ra). Although eIRG increments were prevented by somatostatin, the increase in Ra was undiminished, indicating that epinephrine can act independently of glucagon as in normal animals. During subbasal intraportal insulin infusion in the depancreatized dogs, insulin levels remained 35% lower than with basal replacement, and the animals were hyperglycemic. Epinephrine induced a similar twofold increase in eIRG as during normoglycemia, and again this rise was prevented by somatostatin. There was a significantly greater, threefold increase in Ra with epinephrine when the animals were hyperglycemic. This exaggerated response to epinephrine was not seen during eIRG suppression by somatostatin, suggesting that glucagon participated in the epinephrine-induced hepatic glucose overproduction when the depancreatized dogs were in poor metabolic control, as seen previously in alloxan-diabetic dogs. However, in the depancreatized, unlike in the alloxan-diabetic dogs, epinephrine-induced glucagon release was small. Thus, hypoinsulinemia appears to sensitize the liver to eIRG during epinephrine infusion. The fact that epinephrine induces hyperglycemia both in physiology and diabetes could indicate an important role in enhancing glucose transport in insulin-insensitive tissues.