Metabolic Actions of Glucagon

Summary of Work Glucagon is canonically viewed as an essential counterregulatory hormone that prevents hypoglycemia by driving endogenous glucose production (EGP) in the liver. We and others have revealed additional roles for glucagon that emphasize a much more complex control of metabolism beyond hypoglycemia. For instance, glucagon is a potent insulinotropic peptide in β-cells, which we have shown to be essential for postprandial glucose control. Furthermore, hepatic glucagon receptor signaling drives an increase in insulin sensitivity, which is a paradoxical action for a counterregulatory hormone posited to limit insulin-induced hypoglycemia. However, insulin- induced hypoglycemia is only a century old phenomenon that is unlikely to have had significant evolutionary pressure. Collectively, it seems reasonable that the current dogma describing the metabolic actions of glucagon exclusively in the hypoglycemic state is limited and incomplete. To this end, we have found that enhancing endogenous glucagon secretion or providing exogenous glucagon to mice has limited efficacy at correcting insulin-induced hypoglycemia. We have also found that glucagon receptor signaling in hepatocytes can engage multiple signaling nodes. Based on these ideas, the primary hypothesis driving this work is that hepatic glucagon receptors engage div ergent signaling pathway s that differentially regulate glucose metabolism. In addition to the canonical pathways that increase EGP through G-protein signaling, glucagon can also utilize β-arrestin signaling nodes to driv e insulin sensitiv ity. We propose to test our hy pothesis by carrying out complementary physiological and pharmacological approaches in novel mouse models to resolve the role of hepatic glucagon signaling. Importantly, we also propose to perform parallel experiments in human subjects to validate the translational potential of this work. Unravelling this biology has significant implications on current and futureglucagon-based therapies for both type 1 and type 2 diabetes, obesity, and liver disease.