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Amino acids control alpha cell secretion and growth, while glucagon stimulates hepatic amino acid uptake and ureagenesis, forming the liver-alpha cell axis. Patients with nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes have increased levels of glucagon and amino acids pointing to a disrupted liver-alpha cell axis. Both glucagon agonism and antagonism are explored for diabetes and NAFLD therapy but their effects on the axis are unclear. Female C57Bl/6JRj mice were treated with a long-acting glucagon analogue (GCGA, NNC9204-0043, Novo Nordisk A/S) or PBS twice daily, or once weekly with a GCGR antibody (GCGR Ab, REGN1193, Regeneron) or control antibody (Ctl. Ab, REGN1945, Regeneron). After four weeks, total plasma amino acids were decreased by 48% in GCGA mice (P= 0.0006) and increased by 285% in GCGR Ab mice (P< 0.0001) versus week 0. At week 4, 18 of 19 amino …