358-OR: 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 signalling through the Glucagon-Like Peptide-1 Receptor (GLP1R) present on β-cells. This occurs at high concentrations as are present within the islet. However, its net contribution to physiologic insulin secretion is unknown. To address this question, we studied 12 non-diabetic, weight-stable individuals (26±1 years,25±1 kg/m2) on 2 occasions. During a hyperglycemic clamp (∼8.9mmol/l) where glucose was labeled with [3-3H] glucose, glucagon was infused at 0.4ng/kg/min, for 1 hour, increasing by 0.2ng/kg/min every hour for a total of 5 hours. Subjects were studied on two occasions in random order. On one occasion Exendin-9,39 (300pmol/kg/min) was infused to block the GLP1R, while on the control day 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 rose from baseline (6.6±2.1 vs. 5.4±1.5 pmol/l, saline vs. exendin-9,39 respectively, p=0.22) to values that, by design, did not differ between study days (17.8±1.8 vs. 17.1±1.1 pmol/l, p>0.1) . This was accompanied by a rise in C-peptide from fasting concentrations. Integrated C-peptide concentrations were slightly, but significantly, decreased during exendin-9,39 infusion (721±65 vs. 648±55 nmol per 5hr, p=0.02) . In addition, integrated insulin secretion rate was lower during exendin-9,39 infusion (213±26 vs. 191±22 nmol per 5 hr, saline vs. exendin-9,39 respectively, p = 0.03) . Both EGP and Rd did not differ significantly on either experimental day. These data show that in non-diabetic humans, during hyperglycemia as seen in the postprandial period, glucagon partially stimulates the β-cell through GLP1R. It remains to be ascertained if this also applies to individuals with type 2 diabetes. Disclosure R.A. Farahani: None. A.A. Welch: None. M.C. Laurenti: None. C. Cobelli: None. C. Dalla Man: Research Support; Becton, Dickinson and Company, Sanofi-Aventis Deutschland GmbH. A. Vella: Advisory Panel; Crinetics Pharmaceuticals, Inc., Rezolute, Inc., vTv Therapeutics, Zealand Pharma A/S. Other Relationship; Novo Nordisk. Funding National Institutes of Health (DK126206)