Project Summary Glucagon and insulin are pancreatic hormones that control the glycemic response to fasting and feeding. Canonically, glucagon is secreted in the fasted state where it stimulates hepatic glycogenolysis and gluconeogenesis in order to raise glycemia. Conversely, insulin is secreted in response to elevated blood glucose to stimulate glucose uptake in peripheral tissues. These canonical, opposing effects of glucagon and insulin on the liver overlook the long understanding that amino acids in mixed nutrient feeding stimulate the islet a-cell to secrete glucagon. Moreover, our recent work has shown the importance of glucagon-stimulated insulin secretion to maintaining glucose tolerance. Therefore, the expected response to a physiologic mixed nutrient meal is the co-secretion of glucagon and insulin into portal circulation. The preliminary data presented herein support the notion that glucagon and insulin work cooperatively, not antagonistically, to control prandial glucose metabolism. We hypothesize that glucagon and insulin co-secretion controls hepatic glucose metabolism to allow glucose to reach the periphery before being stored in the liver. Successful completion of this project will alter our fundamental understanding of hepatic glucose metabolism and my provide insight for novel therapeutic targets for the treatment of metabolic disease. Importantly, completion of the proposed aims will support several new technical and conceptual developments that will provide a foundation for a career as an independent investigator.