Preserved inhibitory potency of GLP-1 on glucagon secretion in type 2 diabetes mellitus

Abstract

Objective: Glucagon-like peptide-1 (GLP-1) is insulinotropic, but its effect on the α-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 • kg-1 • 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 • kg-1 • 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±1083h • pmol/liter; P=NS) as compared to d 2 (1733± 193 3h • 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 • pmol/liter (d 2); P < 0.001]. Conclusions: The diabetic α-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. Copyright © 2009 by The Endocrine Society.