1575-P: Differential Effects of Rising Glucagon Concentrations on Hepatic Amino Acid Extraction

To understand the actions of glucagon on hepatic amino acid (AA) metabolism, we studied nondiabetic individuals on one occasion after an overnight fast. On the morning of the study, femoral artery (FA), femoral vein (FV) and hepatic vein (HV) catheters were placed under fluoroscopic guidance in the interventional radiology suite. Infusion of indocyanine green (0.25mg/min), allowed measurement of splanchnic blood flow (SBF) throughout the experiment. At the start of the experiment (0 min), somatostatin was infused (60 ng/kg/min) to block endogenous hormone secretion. Insulin was infused at 0.8 mU/Kg/min together with glucagon at 1.5 ng/kg/min. To mimic ingestion of a protein load, Clinisol (15%, 0.003ml/kg/min; 51% essential AA, 18% branched-chain AA, 9% aromatic AA; Baxter, Healthcare, Deerfield, IL) was infused. Glucose was infused to maintain peripheral arterial concentrations at 160mg/dL. At 120 min glucagon infusion was increased to 3 ng/kg/min. AAs and their metabolites were measured using derivatized standards. Samples were analyzed on a triple quadrupole mass spectrometer coupled with an Ultra Pressure Liquid Chromatography system. Distinct patterns of % hepatic AA extraction (calculated using HV-FA difference as a function of SBF) were noted. The majority of AAs’ extraction increased in response to AA and glucagon infusion (e.g. Leucine 8 ± 5 vs. 14 ± 6 %, Serine, Glycine, Tyrosine and Methionine 27 ± 5 vs. 39 ± 5 %). Notable exceptions included α-aminoadipic acid which is released by the liver in the fasting state (-9.0 ± 12%) and in response to AA and glucagon infusion (-13 ± 7%). Aspartate changed from net release (-40 ± 34%) to uptake (29 ± 14%) in response to glucagon. In other cases, hepatic extraction was unchanged (e.g. Threonine, Alanine 56 ± 10 vs. 55 ± 6%, Valine, Lysine and Cysteine). It remains to be ascertained if such patterns of hepatic extraction of AAs in response to glucagon differ in metabolic disease states thereby identifying novel therapeutic targets. Disclosure H.E. Christie: None. S. Mohan: None. A.M. Egan: None. A. Vella: Research Support; Novo Nordisk. Consultant; Hanmi Pharm. Co., Ltd., Crinetics Pharmaceuticals, Inc. Advisory Panel; Rezolute, Inc. Funding DK116723