Glucagon-like peptide-1 (GLP-1) is an intestinal insulinotropic hormone that augments insulin secretion in response to meals and lowers blood glucose levels in both type 1 and type 2 diabetic subjects. It has been proposed that a substantial component of the glucose-lowering effects of GLP-1 occurs via insulin-independent mechanisms. However, the interpretations of the studies have been controversial. This study was conducted to examine whether glucagon-like peptide (GLP-1) has an insulin-like effect during euglycemia. Nine young lean men (age, 25 +/- 1.4 yr; body mass index, 24.0 +/- 0.7 kg/m2) volunteered to participate in two euglycemic clamp studies (n = 18 clamps) for 120 min. The initial clamp was performed with a primed continuous infusion of GLP-1 at a final rate of 1.5 pmol/kg.min from 0-60 min. At 60 min, the GLP-1 infusion was terminated, and euglycemia was maintained from 60-120 min. After the GLP-1 study, each individual's plasma insulin level was measured. A second study was performed that was identical to the first, with the infusion of regular insulin in place of GLP-1. Insulin infusion rates were designed in each individual to simulate plasma insulin levels produced during the GLP-1 infusion. The rate of disappearance of glucose was calculated for each subject. Basal plasma insulin levels were similar between studies and averaged 49 +/- 5 pmol/L. Basal GLP-1 levels were also similar (6.0 +/- 1.0 pmol/L). In response to the GLP-1 infusion, although basal plasma glucose levels were clamped, significant increases in insulin occurred in all subjects (P < 0.001). With the nearly identical plasma insulin levels during the two studies (30-60 min levels: GLP-1 study, 151 +/- 48; insulin study, 146 +/- 31 pmol/L), the rate of disappearance of glucose progressively increased in response to both GLP-1 and insulin infusions, but was not significantly different between the studies. The design of the study necessitated conducting the GLP-1 study first, which may have been accompanied by a greater stress than the second study. We, therefore, measured cortisol levels. Basal cortisol (and ACTH) levels were not different. However, cortisol levels significantly increased during the GLP-1 infusions, and this was preceded by an increase in ACTH levels. Somatostatin levels were not different either basally or during the clamps. We conclude that in the euglycemic state, an acute infusion of GLP-1 does not have insulin-like effects in lean nondiabetic men. Intravenous administration of GLP-1 activates hypothalamic neuroendocrine neurons.