This paper provides molecular evidence for a liver glyconeogenic pathway, i.e. a concomitant activation of hepatic gluconeogenesis and glycogenesis, which could participate in the mechanisms which cope with amino acid excess in high protein (HP) fed rats. This evidence is based on the concomitant up-regulation of phosphoenolpyruvate carboxykinase (PEPCK) gene expression, down-regulation of glucose 6-phosphatase catalytic subunit (G6PC1) gene expression, an absence of glucose release from isolated hepatocytes and restored hepatic glycogen stores in the fed state in HP fed rats. These effects are mainly due to the ability of high physiological concentrations of portal blood amino acids to counteract glucagon-induced liver G6PC1 but not PEPCK gene expression. These results agree with the idea that the metabolic pathway involved in glycogen synthesis is dependant upon the pattern of nutrient availability. This non-oxidative glyconeogenic disposal pathway of gluconeogenic substrates copes with amino excess and participates in adjusting both amino acid and glucose homeostasis. In addition, the pattern of PEPCK and G6PC1 gene expression provides evidence that neither the kidney nor the small intestine participated in gluconeogenic glucose production under our experimental conditions. Moreover, the main G6Pase isoform expressed in the small intestine is the ubiquitous isoform of G6Pase (G6PC3) rather than the G6PC1 isoform expressed in gluconeogenic organs.