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Glucagon plays a pivotal role in hepatic amino acid metabolism; acute high-protein diet feeding and diabetic condition both induce enhanced glucagon secretion. However, it remains unknown whether these two conditions alter hepatic amino acid metabolism through the same or different pathways. In this study, streptozotocin-induced diabetic (STZ-D) and nondiabetic (ND) mice received liquid normal control (LNC) or liquid high-protein (LHP) diet. Plasma and hepatic parameters were analyzed 2 h post-feeding. LHP increased plasma essential amino acids in both groups. Hepatic amino acid accumulation in LHP-fed STZ-D mice was increased compared to that in LNC-fed STZ-D mice but not in ND mice. In addition, LHP reduced hepatic glycogen while the expression of amino acid metabolism and urea cycle genes remained unchanged both in ND and STZ-D mice. Compared with ND mice, STZ-D mice showed upregulation of genes involved in gluconeogenesis and amino acid metabolism, together with an accumulation of early glycolytic intermediates and glycogen. These findings indicate that acute high-protein intake induces non-transcriptional regulation of amino acid metabolism within 2 h. The altered hepatic amino acid profile in STZ-D mice is likely to be driven by increased hepatic amino acid uptake and accelerated gluconeogenesis.