The Effect of Glucagon-Like Peptide 1 Receptor Blockade on Glucagon-Induced Stimulation of Insulin Secretion

Abstract

Data from transgenic rodent models suggest that glucagon acts as an insulin secretagogue by signaling through the glucagon-like peptide 1 receptor (GLP-1R) present on β-cells. However, its net contribution to physiologic insulin secretion in humans is unknown. To address this question, we studied individuals without diabetes in two separate experiments. Each subject was studied on two occasions in random order. In the first experiment, during a hyperglycemic clamp, glucagon was infused at 0.4 ng/kg/min, increasing by 0.2 ng/kg/min every hour for 5 h. On one day, exendin-9,39 (300 pmol/kg/min) was infused to block GLP-1R, while on the other, saline was infused. The insulin secretion rate (ISR) was calculated by nonparametric deconvolution from plasma concentrations of C-peptide. Endogenous glucose production and glucose disappearance were measured using the tracer-dilution technique. Glucagon concentrations, by design, did not differ between study days. Integrated ISR was lower during exendin-9,39 infusion (213 ± 26 vs. 191 ± 22 nmol/5 h, saline vs. exendin-9,39, respectively; P = 0.02). In the separate experiment, exendin-9,39 infusion, compared with saline infusion, also decreased the β-cell secretory response to a 1-mg glucagon bolus. These data show that, in humans without diabetes, glucagon partially stimulates the β-cell through GLP-1R.

Figure 1

Glucose (A), glucagon (B), insulin (C), C-peptide (D), insulin secretion rate (E), and area under the curve (AUC) of insulin secretion rate (F) during saline (open circles) and exendin-9,39 infusion (solid circles) in response to a variable glucagon infusion. Values plotted are means ± SEMs.

Figure 2

Glucose infusion rate (A), specific activity (B), EGP (C), and glucose disappearance (D) during saline (open circles) and exendin-9,39 infusion (solid circles) in response to a variable glucagon infusion. Values plotted are means ± SEMs.

Figure 3

Glucose (A), insulin (B), and C-peptide (C) during saline (open circles) and exendin-9,39 infusion (solid circles) in response to a glucagon bolus. Values plotted are means ± SEMs.