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 decreas...