OBJECTIVE: Glucagon-like peptide-1 (GLP-1) is insulinotropic, but its effect on the alpha-cell is less clear. We investigated the dose-response relationship for GLP-1-induced glucagon suppression in patients with type 2 diabetes (T2DM) and healthy controls. DESIGN: Ten patients with T2DM (duration of DM, 4 +/- 1 yr; glycosylated hemoglobin, 7.1 +/- 0.3%) were studied on 2 d, with stepwise increasing GLP-1 infusions (0.25, 0.5, 1.0, and 2.0 pmol x kg(-1) x min(-1)) (d 1) or saline (d 2) with plasma glucose (PG) clamped at fasting level. On d 3, patient PG was normalized overnight using a variable insulin infusion, followed by a 3-h GLP-1 infusion as on d 1. Ten healthy subjects were examined with the same protocol on d 1 and 2. RESULTS: We observed similar dose-dependent stepwise suppression of glucagon secretion in both patients and controls. Significant suppression was observed at a GLP-1 infusion rate of 0.25 pmol x kg(-1) x min(-1) (resulting in physiological plasma concentrations) as early as time 15 min in healthy controls and time 30 min in patients (d 1 and d 3). AUC for glucagon was significantly reduced on d 1 and 3 (1096 +/- 109 and 1116 +/- 108 3h x pmol/liter; P = NS) as compared to d 2 (1733 +/- 193 3h x pmol/liter; P < 0.01) in patients with T2DM. A similar reduction in AUC for glucagon was observed in healthy controls [1122 +/- 186 (d 1) vs. 1733 +/- 312 3h x pmol/liter (d 2); P < 0.001]. CONCLUSIONS: The diabetic alpha-cell appears to be highly sensitive to the inhibitory action of GLP-1 both during high and near-normalized PG levels, but responds with a short, nevertheless significant delay.