36-OR: The Effect of Glucagon-Like Peptide-1 Receptor Blockade on the ß-Cell Response to Glucagon Bolus in People With and Without Type 2 Diabetes

Glucagon acts as an insulin secretagogue in part via the glucagon-like peptide-1 receptor (GLP1R) expressed on β-cells. Type 2 diabetes (DM2) is characterized by increased (and inappropriate) glucagon secretion for the prevailing hyperglycemia. Increased islet glucagon staining has also been observed in DM2. This suggests that increased glucagon signaling via GLP1R is a mechanism to maintain β-cell secretion in DM2. To ascertain if this is the case, we quantified the relative contribution of GLP1R signaling to the insulin response to glucagon in the presence and absence of DM2. We studied 12 individuals without DM2 (54 ± 2 yrs, 33 ± 1 kg/m2) and 11 with DM2 (58 ± 2 yrs, 34 ± 2 kg/m2) on 2 occasions in random order. On one occasion Exendin-9,39 (300pmol/kg/min) was infused to block GLP1R, while on the other study day saline was infused. Following an overnight fast and a 3-hour hyperglycemic clamp (~9 mmol/L), 1 mg glucagon bolus was administered intravenously with subsequent measurement of insulin, and C-peptide over 30 minutes during hyperglycemia. Exendin-9,39 infusion decreased peak and integrated insulin and C-peptide concentrations in response to the glucagon bolus in both those with and without DM2. The symmetric % change in insulin (-49 ± 8 vs -32 ± 8, DM2 vs. subjects without diabetes respectively, p = 0.2) and C-peptide (-24 ± 5 vs -15 ± 4, p = 0.18) did not differ between groups. In addition, six of the subjects without DM2 completed two additional study days (± exendin-9,39) with infusion of Intralipid® and heparin to raise free fatty acids (FFA) and cause acute insulin resistance. Acute FFA elevation also did not alter the net contribution of GLP1R stimulation to the response to glucagon in individuals without DM2 (% change insulin: -34 ± 10, p = 0.42; C-peptide: -23 ± 7, p = 0.38). These data suggest that the % contribution of glucagon to the stimulation of β-cell secretion via GLP1R does not change significantly in the presence or absence of DM2 or of FFA elevation. Disclosure A.M.Egan: None. M.Zeini: None. A.A.Welch: None. R.A.Farahani: None. M.C.Laurenti: None. C.Cobelli: None. C.Dalla man: Research Support; Sanofi-Aventis Deutschland GmbH, Becton, Dickinson and Company. A.Vella: Advisory Panel; Rezolute, Inc., Consultant; Crinetics Pharmaceuticals, Inc., Hanmi Pharm. Co., Ltd., Zealand Pharma A/S, Other Relationship; Novo Nordisk. Funding National Institutes of Health (DK126206)