Alanine, arginine, cysteine, and proline but not glutamine are substrates for and acute mediators of the liver-alpha cell axis in female mice.

AIM: To identify the amino acids that stimulate glucagon secretion in mice and whose metabolism depends on glucagon receptor signaling. METHODS: Pancreata of female C57BL/6JRj mice were perfused with 19 individual amino acids and pyruvate (at 10 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 amino acid mixtures (in total 7 micromol/g body weight); mixture 1: alanine, arginine, cysteine, and proline; mixture 2: aspartate, 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 0.5). Plasma concentrations of total amino acids in vivo 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, cysteine, and proline but not glutamine are involved in the acute regulation of the liver-alpha cell axis in female mice as they all increased glucagon secretion and their disappearance rate was altered by GRA.