The newly discovered intestinal hormone, glucagon-like peptide-1 (GLP-1) (proglucagon 78-107amide), stimulates insulin secretion and inhibits glucagon secretion in man and may therefore be anticipated to influence hepatic glucose production. To study this, we infused synthetic GLP-1 sequentially at rates of 25 and 75 pmol · kg⁻¹ · h⁻¹ into eight healthy volunteers after an overnight fast and measured plasma concentrations of glucose, insulin, and glucagon and glucose turnover by a technique involving infusion of 3-³H-glucose. Plasma levels of GLP-1 increased by 21.3 ± 3.1 and 75.4 ± 3.2 pmol/L during the infusion, changes that were within physiologic limits. In a control experiment only saline was infused. During GLP-1 infusion, plasma glucose level decreased significantly (from 5.3 ± 0.1 to 4.7 ± 0.1 and 4.3 ± 0.1 pmol/L at the end of the two infusion periods). Despite this, plasma insulin level increased significantly (from 20.5 ± 2.9 to a peak value of 33.5 ± 5.2 pmol/L during the second period), and plasma glucagon level decreased (from 9.3 ± 1.7 to 7.1 ± 1.0 pmol/L). Glucose rate of appearance (R_a) decreased significantly to 75% ± 6% of the preinfusion values during GLP-1 infusion. Glucose disappearance rate (R_d) did not change significantly, but glucose clearance increased significantly compared with saline. All parameters of glucose turnover remained constant during saline infusion. We conclude that GLP-1 may potently control hepatic glucose production and glucose clearance through its effects on the pancreatic glucoregulatory hormones. The effect of GLP-1 on glucose production is consistent with its proposed use in the treatment of type II diabetes.