In order to separate direct effects of epinephrine on fuel metabolism from those mediated by glucagon, epinephrine (0.1 microng/kg-min) was infused for 120 min in 18- and 65-h fasted, nonanesthetized baboons with and without a concomitant somatostatin infusion. At both stages of fasting, epinephrine stimulated glucagon, secretion, and this was blocked by somatostatin. At 18 h, with epinephrine alone, glucose rose early and remained elevated throughout the infusion. In the glycogen-depleted 65-h fasted animals, there was attenuation of the early glucose rise, with glucose reaching a maximum level at 100-120 min. With somatostatin blockade of glucagon release in the 18-h fasted animals, a pattern of attenuated early glucose rise similar to that of the 65-h fasted animals occurred. Somatostatin also inhibited this early glycogenolytic response when the epinephrine dose was increased fivefold. The behavior of FFA, glycerol, and beta-hydroxybutyrate was unchanged by the addition of somatostatin to epinephrine at either stage of fasting. Thus, glucagon mediates the early glycogenolytic response to epinephrine, but not the delayed hyperglycemia and probably not the lipolysis.