The pancreatic hormone glucagon contributes to diabetic hyperglycemia and glucagon receptor antagonists lower blood glucose in patients with type 2 diabetes. A liver-alpha cell axis has recently been identified which when disrupted leads to hypersecretion of glucagon and may contribute to the development of diabetes. Here, we investigated the hepatic effects of glucagon receptor signaling in rodents and hypothesized that intact glucagon receptor signaling is necessary for amino acid metabolism via non-transcriptional changes leading to increased ureagenesis. Female C57BL/6JRj mice (n=64) were given a glucagon receptor antagonist (GRA) or vehicle orally three hours prior to an intraperitoneal injection with amino acids (Vamin, 3.6 µmol/g body weight), glucagon (200 ng/g body weight), or both, and blood samples were obtained at 0, 4, 12, and 20 minutes after injection. GRA treated animals had a significant decrease in plasma urea (8.6±0.3 vs. 11.1±0.4 mmol/L, p<0.0001) and blood glucose (8.1±0.2 vs. 9.0±0.2, p<0.001 mmol/L) and a concomitant increase in plasma amino acids (3.5±0.1 vs. 2.7±0.1 mmol/L, p<0.0001) and glucagon (32.5±3.5 vs. 12.5±1.7 pmol/L, p<0.0001). In addition, amino acid-stimulated ureagenesis, reflected by increased plasma urea, was inhibited in GRA treated mice compared to controls (incremental area under the curve: 27.6±3.3 vs. 41.2±5.3 min × mmol/L, p<0.05). Production of urea in perfused rat livers (n=6) increased rapidly upon administration of amino acids (1 mM) compared to baseline (683±254 vs. 518±198 pmol/min/100 g body weight, p<0.05) and was further increased in response to amino acids + glucagon (10 nM) stimulation (846±229 vs. 518±198 pmol/min/100 g body weight, p<0.001). Glucagon therefore acutely regulates hepatic amino acid metabolism through increased ureagenesis via non-transcriptional mechanism(s), and disruption of this, due to e.g., nonalcoholic liver disease, may therefore contribute to the diabetogenic effect of hyperglucagonemia.


M. Winther-Soerensen: None. K.D. Galsgaard: None. R.E. Kuhre: None. J. Pedersen: None. N.J. Wewer Albrechtsen: Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Other Relationship; Self; Mercodia, Alpco. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics.

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