63-OR: The Physiological Effects of Extrapancreatic Glucagon in Totally Pancreatectomized Patients Evaluated Using Glucagon Receptor Antagonism

Abstract

We have recently shown a hyperglucagonemic response to meal test and oral glucose tolerance test (OGTT) in totally pancreatectomized (PX) patients. Here, we employed a glucagon receptor antagonist (GRA) to determine the physiological implications of extrapancreatic glucagon secretion in PX patients. In a double-blinded, randomized, cross-over study, 9 PX patients (age: 61.3±4.3 [mean±SEM] years; BMI: 22.6±1.6 kg/m2) and 9 matched healthy controls (age 65.9±2.9 years; BMI: 23.9±0.9 kg/m2) were examined during two 3-hour 75-OGTTs. Before the tests, subjects ingested 300 mg of the GRA, LY2409021 (Eli Lilly and Company), and placebo, respectively. Patients received their regular dose of insulin the night before each experimental day, but no insulin was given during the experiments. In the healthy controls, the GRA resulted in lower fasting levels of glucose (4.3±0.1 vs. 5.2±0.1 mmol/l, P=0.001), but higher post-OGTT plasma glucose excursions (as assessed by baseline-subtracted area under the curve (bsAUC): 926±92 vs. 467±72 mmol/l×min, P=0.002) compared to placebo. In the PX patients, the GRA and placebo resulted in similar fasting plasma glucose concentrations (11.3±0.9 vs. 12.5±0.8 mmol/l, P=0.266) and post-OGTT glucose excursions (bsAUC: 1,671±96 vs. 1,693±152 mmol/l×min, P=0.398), respectively. In the healthy controls, the GRA resulted in significantly higher fasting concentrations of glucagon (33.1±5.5 vs. 13.0±3.7 pmol/l, P=0.023), which, nevertheless, were suppressed by OGTT to similarly low levels as observed with placebo. In the PX patients, equal fasting glucagon concentrations (3.2±0.7 vs. 4.7±1.9 pmol/l, P=0.373) and similarly exaggerated plasma glucagon responses to OGTT were observed with the GRA and placebo (bsAUC: 1,636±573 vs. 1,034±542 pmol/l×min, P=0.113). In this study, antagonizing the glucagon receptor in totally pancreatectomized patients did not influence fasting or post-OGTT glucose levels. Disclosure C.T.B. Juel: None. A.B. Lund: None. J.F. Rehfeld: None. N.J. Wewer Albrechtsen: Research Support; Self; Mercodia, Novo Nordisk A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. T. Vilsbøll: None. F.K. Knop: Advisory Panel; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi. Consultant; Self; Amgen Inc., Carmot Therapeutics, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Norgine, Novo Nordisk A/S.