REVISITING GLUCAGON ACTION IN DIABETES: IS IT ALL BAD?

Abstract

Traditionally, the islet hormone glucagon has been considered as a counterbalance to insulin, preventing hypoglycemia by promoting glucose release from the liver. This model is compatible both with clinical studies demonstrating that one of the initial endocrine responses to insulin-induced hypoglycemia is a rise in glucagon and with in vitro work demonstrating that glucagon signaling activates glycogenolysis in hepatocytes. This model has been extended to implicate glucagon in diabetogenesis, positing that the increased secretion of glucagon acts as a primary driver of hyperglycemia. However, recent work suggests an alternative set of actions for glucagon, including stimulation of insulin secretion and enhancement of hepatic insulin action. These recent findings align with the results of clinical trials using novel drugs that activate the glucagon receptor as part of a multi-receptor mechanism of action. Taken together, it appears that glucagon has distinct actions in the fed and fasted states, and glucagon receptor agonism has potential as a therapeutic approach to the treatment of diabetes.