Two specific enzymes, glucokinase (GK) and glucose-6 phosphatase (Glc6Pase) enable the liver to play a crucial role in glucose homeostasis. The activity of Glc6Pase, which enables the liver to produce glucose, is increased during short-term fasting, in agreement with the enhancement of liver gluconeogenesis. During long-term fasting, Glc6Pase activity is increased in the kidney, which contributes significantly to the glucose supply at that time. On the other hand, GK activity, which allows the liver to utilize glucose, is decreased during fasting. In the fed state, the mechanisms of short-term regulation of the activity of both enzymes takes place during the postprandial period. Liver GlcPase activity is inhibited after refeeding in rats. The inhibition mechanism could involve intracellular metabolites of glutamine and glutamic acid, such as alpha-ketoglutarate, and/or of triglycerides, such as unsaturated fatty acids and acyl-CoA esters. Liver GK activity is activated during the postprandial period. The activation mechanism involves a regulatory protein and the intrahepatic metabolites of fructose, ie fructose-1 phosphate and fructose-6 phosphate.