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The effect of Glucagon-Like Peptide-1 Receptor Blockade on glucagon-induced stimulation of insulin secretion

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posted on 2022-12-23, 16:27 authored by Rahele A. Farahani, Aoife M. Egan, Andrew A. Welch, Marcello C. Laurenti, Claudio Cobelli, Chiara Dalla Man, Adrian Vella

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. 

Funding

The authors acknowledge the support of the Mayo Clinic General Clinical Research Center (DK TR000135). Dr. Vella is supported by DK78646, DK116231 and DK126206. Dr. Dalla Man was supported by MIUR (Italian Minister for Education) under the initiative “Departments of Excellence” (Law 232/2016).

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