Data from transgenic rodent models suggest that glucagon acts as an insulin secretagogue by signalling through the Glucagon-Like Peptide-1 Receptor (GLP1R) present on β-cells. However, its net contribution to physiologic insulin secretion in humans is unknown. To address this question, we studied non-diabetic individuals in 2 separate experiments. Each subject was studied on 2 occasions in random order. In the first experiment, during a hyperglycemic clamp, glucagon was infused at 0.4ng/kg/min, increasing by 0.2ng/kg/min every hour for 5 hours. On one day exendin-9,39 (300pmol/kg/min) was infused to block GLP1R, 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 (EGP) and glucose disappearance (Rd) 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 per 5 hr, saline vs. exendin-9,39 respectively, p = 0.02). In the separate experiment, exendin-9,39 infusion, compared to saline infusion, also decreased the β-cell secretory response to a 1mg glucagon bolus. These data show that in non-diabetic humans, glucagon partially stimulates the β-cell through GLP1R.

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