PT - JOURNAL ARTICLE AU - Katrine D. Galsgaard AU - Sara Lind Jepsen AU - Sasha A.S. Kjeldsen AU - Berit Svendsen AU - Jens Pedersen AU - Nicolai J. Wewer Albrechtsen AU - Jens J. Holst TI - Alanine, arginine, and proline but not glutamine are the feed-back regulators in the liver-alpha cell axis in mice AID - 10.1101/792119 DP - 2019 Jan 01 TA - bioRxiv PG - 792119 4099 - http://biorxiv.org/content/early/2019/10/04/792119.short 4100 - http://biorxiv.org/content/early/2019/10/04/792119.full AB - Aim To identify the amino acids that stimulate glucagon secretion in mice and whether the metabolism of these relies on glucagon receptor signaling.Methods Pancreata of female C57BL/6JRj mice were perfused with 19 individual amino acids (1 mM) and secretion of glucagon was assessed using a specific glucagon radioimmunoassay. Separately, a glucagon receptor antagonist (GRA; 25-2648, 100 mg/kg) or vehicle was administered to female C57BL/6JRj mice three hours prior to an intraperitoneal injection of four different isomolar (in total 7 µmol/g body weight) amino acid mixtures; mixture 1: alanine, arginine, cysteine, and proline; mixture 2: asparatate, glutamate, histidine, and lysine; mixture 3: citrulline, methionine, serine, and threonine; and mixture 4: glutamine, leucine, isoleucine, and valine. Blood glucose, plasma glucagon, amino acid, and insulin concentrations were measured using well characterized methodologies.Results Alanine (P=0.03), arginine (P<0.001), and proline (P=0.03) but not glutamine (P=0.2) stimulated glucagon secretion from the perfused mouse pancreas. Cysteine had the numerically largest effect on glucagon secretion but did not reach statistical significance (P=0.08). However, when the four isomolar amino acid mixtures were administered there were no significant difference (P>0.5) in plasma concentrations of glucagon across mixture 1-4. Plasma concentrations of total amino acids were higher after administration of GRA when mixture 1 (P=0.004) or mixture 3 (P=0.04) were injected.Conclusion Our data suggest that alanine, arginine, and proline but not glutamine are involved in the liver-alpha cell axis in mice as they all increased glucagon secretion and their disappearance rate was altered by GRA.