This project continues to investigate and quantitate in dogs the role of the hepatic extraction of insulin and glucagon in regulating peripheral concentrations of these two hormones under different physiological conditions. Approximately 50 percent of the insulin presented to the liver is removed in a single transhepatic passage. Our previous studies demonstrated that administration of glucose into the duodenum markedly increased pancreatic secretion of insulin which was associated with a transient increase in hepatic extraction of insulin. Such increased hepatic clearance of insulin probably depends upon both the greater amounts of insulin reaching the liver and the increased amounts of glucose in the portal vein since a similar augmented hepatic extraction was not observed when increasing amounts of insulin were infused into the portal vein. These studies utilized anesthetized dogs with catheters in the femoral artery, portal vein, and the left common hepatic vein and electromagnetic flow probes on the portal vein and hepatic artery. When an additional catheter was placed in a mesenteric vein, significant insulin extraction in the mesenteric circulation was demonstrated. The data from these experiments permitted construction of a model for insulin metabolism in the systemic circulation as well. These studies will now be extended to measure hepatic, mesenteric and systemic extraction of glucagon during fasting and following arginine, pancreozymine and glucagon infusions. Since these materials also increase insulin secretion, their effects on insulin extraction will be monitored. Effects of various hormones on hepatic, mesenteric and systemic extraction of insulin and glucagon will be assessed. Recently it has been demonstrated that "pancreatic" glucagon increases following total pancreatectomy in dogs. This material which cross reacts with antibodies presumably specific for pancreatic glucagon is increased following arginine infusion but seems to have a molecular weight significantly greater than pancreatic glucagon. Studies would be done to further characterize this material in relationship to its biologic activity in relationship to pancreatic glucagon.