Insulin plays a central role in metabolic control after a mixed meal. In the absence of adequate meal insulin release, abnormal circulating concentrations of most meal-derived metabolic substrates can be expected. To quantify these abnormalities in depth, responses of six pancreatectomized dogs on long-term intravenous insulin replacement were compared to those of five normal control dogs. Blood samples were drawn hourly for 24 h via a chronic indwelling catheter, and all animals ate a single mixed meal. To establish whether there were route-related differences, insulin was delivered into either the portal or the peripheral circulation of the diabetic animals at constant rates. These insulin infusion rates resulted in premeal fasting normoglycemia and in normal levels of insulin, glucagon, lactate, pyruvate, 3-hydroxybutyrate, nonesterified fatty acids, and 9 of 13 amino acids. In the absence of enhanced meal insulin infusion, the subsequent responses of glucose, lactate, pyruvate, alanine, and 10 of 13 other blood amino acids were exaggerated in terms of both amplitude and duration. Only minor or transient differences were attributable to the routes of insulin infusion. Remarkably, in spite of these abnormal postmeal responses, basal insulin alone (with constant circulating levels) succeeded in restoring all metabolite and hormonal levels during the postabsorptive period 16-23 h after the meal. Thus, with intravenous insulin infusions, the requirements for fasting metabolic normalization may be considered independently of those for metabolic control following caloric intake. It remains to be shown how prolonged deprivation of the postprandial insulin supplement results in metabolic decompensation under these conditions.