Minireview: Glucagon in the Pathogenesis of Hypoglycemia and Hyperglycemia in Diabetes

Pancreatic islet alpha-cell glucagon secretion is critically dependent on pancreatic islet beta-cell insulin secretion. Normally, a decrease in the plasma glucose concentration causes a decrease in beta-cell insulin secretion that signals an increase in alpha-cell glucagon secretion during hypoglycemia. In contrast, an increase in the plasma glucose concentration, among other stimuli, causes an increase in beta-cell insulin secretion that signals a decrease, or at least no change, in alpha-cell glucagon secretion after a meal. In absolute endogenous insulin deficiency (i.e. in type 1 diabetes and in advanced type 2 diabetes), however, beta-cell failure results in no decrease in beta-cell insulin secretion and thus no increase in alpha-cell glucagon secretion during hypoglycemia and no increase in beta-cell insulin secretion and thus an increase in alpha-cell glucagon secretion after a meal. In type 1 diabetes and advanced type 2 diabetes, the absence of an increment in glucagon secretion, in the setting of an absent decrement in insulin secretion and an attenuated increment in sympathoadrenal activity, in response to falling plasma glucose concentrations plays a key role in the pathogenesis of iatrogenic hypoglycemia. In addition, there is increasing evidence that, in the aggregate, suggests that relative hyperglucagonemia, in the setting of deficient insulin secretion, plays a role in the pathogenesis of hyperglycemia in diabetes. If so, abnormal glucagon secretion is involved in the pathogenesis of both hypoglycemia and hyperglycemia in diabetes. (Endocrinology 153: 1039-1048, 2012)