The present study examines the question of whether lowering the basal plasma glucagon concentration alters the response of the liver to an intravenous glucose load under conditions where insulin is present at near-basal concentrations. Acute hyperglycaemia of 220–240 mg/dl was induced by peripheral venous glucose infusion in two groups of normal men who had undergone hepatic vein catheterization. Somatostatin (0.9 mg/h) was infused in both groups together with an infusion of insulin (0.15 mU/kg/min) to maintain arterial insulin levels at 7–12 μU/ml. Glucagon (1.5 ng/kg/min) was infused in one group resulting in a rise in plasma glucagon levels from 148±37 to 228±25 pg/ml, thus mimicking basal portal glucagon concentrations, whereas in the second group glucagon was not replaced, resulting in a fall in circulating glucagon levels from 132±21 to 74±15 pg/ml. In the glucagon-deprived group, net splanchnic glucose production (NSGP) fell from 143±31 to −72.5±39 mg/ min (p<0.01), indicating that net splanchnic glucose uptake had occurred. By contrast, NSGP did not change significantly (137±20 vs 151±60 mg/min) in the group in which both insulin and glucagon were replaced during hyperglycaemia. These data thus suggest that during hyperglycaemia, when the insulin concentration is fixed at basal levels, glucagon may play an important role in determining whether or not the liver diminishes its output of glucose and stores glucose in response to a glucose load.