The liver is considered the main contributor of endogenous glucose production (EGP) in the postabsorptive (PA) state in mammals. However, it has been shown that the kidney, in PA and fasting states, and the intestine, in insulinopenia states, could make significant contributions to EGP. Using glucose tracer dilution combined to a vessel ligaturing approach, we studied the respective role of these organs in glucose turnover under various nutritional conditions in the rat (Rattus norvegicus). Both organs constitute key sites of glucose disposal in all situations in the non-moving rat. The kidney makes a small (12%) contribution to EGP in the PA state (9.6+/-1.3 micromol/kg min, means+/-SEM, n=5), which is dramatically increased (p<0.01) in 24 h-fasting (18.8+/-1.0 micromol/kg min) or streptozotocin diabetes (48+/-3 micromol/kg min). The small intestine contributes to EGP via two ways: a direct glucose contribution that may only take place in fasting and diabetes; an indirect contribution via the supply of alanine and lactate to liver gluconeogenesis that may account for up to 5 micromol/kg min in both PA and fasted states in the rat. These data emphasize the coordinate interactions among the three gluconeogenic organs in glucose homeostasis when nutritional conditions are changing.