Sheep were prepared with catheters in an artery and mesenteric, portal, and hepatic veins. Blood flows and metabolite concentration differences were measured across liver and gut. Net organ production rates were calculated for liver, portal drained viscera, and extrasplanchnic regions. Arterial glucose concentration rose for 2 h after endotoxin administration. The hyperglycemia was associated with increased hepatic glucose production. Hypoglycemia developed between 3 and 8 h when hepatic glucose production decreased closer to control values. Arterial glucagon concentrations rose to high levels during the hypoglycemic period. Neither hepatic blood flow or oxygen delivery limited glucose production; uptake of the gluconeogenic substrate lactate was reduced on some occasions. Glucose utilization was increased in shock. Portal glucose utilization accounted for 14.5% of nonhepatic glucose utilization. Increased portal glucose utilization was not related to plasma insulin concentrations or insufficient oxygen supply to the gut. Hyperglycemia drove glucose utilization. Although plasma insulin concentrations rose significantly in endotoxemia, the increase in pancreatic insulin output was much smaller and failed to attain statistical significance.