Both glutamine and glucose are highly utilized by the small intestine in various animal species. They are, however, very partially oxidized, the major known fate of glucose being lactate and alanine, and that of glutamine being citrulline or proline. At variance with the current view that only the liver and kidney are gluconeogenic organs, because both are the only tissues to express the glucose-6 phosphatase gene, this gene is also expressed in the small intestine in rats and humans, and is strongly induced in insulinopenic states, such as fasting and diabetes. Under the latter conditions, the small intestine contributes 20-25% of whole-body endogenous glucose production. The main small intestine gluconeogenic substrate is glutamine and, to a lesser extent, glycerol. Accounting for these fluxes, the phosphoenolpyruvate carboxykinase gene is strongly induced in insulinopenia and, although up to now it had been considered absent from this tissue, the glycerokinase gene is expressed in the small intestine. The production of glucose by the small intestine may be acutely blunted upon insulin infusion. These new data also emphasize the central role of alanine aminotransferase in the coupling of glutamine and glucose metabolisms in the small intestine.