To evaluate the responsiveness of the liver to various levels of plasma glucagon, we infused glucagon into normal humans at sequentially increasing or decreasing dose levels. In the first series of experiments, glucagon was initially infused at 6 ng⁄kg-min for 150 min and was then reduced to 3 ng⁄kg-min for an additional 150 min. In a second series of studies, the order of the infusions was reversed (3 ng⁄kg-min, followed by 6 ng⁄kg-min). When the 6 ng⁄kg-min infusion was given as the initial dose, plasma glucagon rose 5-fold (to 600–700 pg) and glucose production increased 2-fold, returning to baseline by 75 min. When the glucagon infusion was reduced to 3 ng⁄kgmin, plasma glucagon fell to 300–400 pg⁄ml and glucose production fell 35% below basal, returning to basal rates by 45 min.Discontinuation of the glucagon infusion resulted in a second transient decline in glucose production to 30% below basal despite normal basal plasma glucagon (120 pg⁄ml). Plasma insulin remained at basal levels at each decrease in glucagon dose. When the lower glucagon dose (3 ng⁄kg-min) wasgiven as the intial infusion and plasma glucagon rose (rather than fell) to 300–350 pg⁄ml, glucose production rose (rather than fell) to values 50% above basal.

To ensure that altered portal insulin did not account for these results, somatostatin and replacement doses of insulin were given and the rate of glucagon infusion was varied. As in the case of the studies without somatostatin, a plasma glucagon level of 300–400 pg⁄ml was associated with a decline in glucose production when preceded by a level of 600 pg⁄ml but was associated with a rise in glucose production when preceded by basal plasma glucagon levels (100 pg⁄ml).

We conclude that absolute hyperglucagonemia (300–400 pg⁄ ml) is associated with a transient rise in glucose production if plasma glucagon has been acutely raised but is associated with a transient fall in glucose production if the plasma glucagon concentration has been acutely lowered. These findings cannot be ascribed to altered levels of plasma insulin. The liver is thus responsive to changes in rather than absolute concentrations of plasma glucagon but adapts to the new glucagon level, returning to basal rates of glucose production within 30–60 min.