Minireview: Glucagon in the pathogenesis of hypoglycemia and hyperglycemia in diabetes

Abstract

Pancreatic islet α-cell glucagon secretion is critically dependent on pancreatic islet β-cell insulin secretion. Normally, a decrease in the plasma glucose concentration causes a decrease in β-cell insulin secretion that signals an increase in α-cell glucagon secretion during hypoglycemia. In contrast, an increase in the plasma glucose concentration, among other stimuli, causes an increase in β-cell insulin secretion that signals a decrease, or at least no change, in α-cell glucagon secretion after a meal. In absolute endogenous insulin deficiency (i.e. in type 1 diabetes and in advanced type 2 diabetes), however, β-cell failure results in no decrease in β-cell insulin secretion and thus no increase in α-cell glucagon secretion during hypoglycemia and no increase in β-cell insulin secretion and thus an increase in α-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.

Fig. 1.

Physiology (in nondiabetes) and pathophysiology (in absolute endogenous insulin-deficient type 1 diabetes and advanced type 2 diabetes) of the intimate relationship between the inhibitory effect of pancreatic β-cell insulin secretion on pancreatic islet α-cell glucagon secretion in humans. Normally a decrease in plasma glucose causes a decrease in β-cell insulin secretion that signals an increase in α-cell glucagon secretion during hypoglycemia. An increase in plasma glucose, among other nutrients, causes an increase in β-cell insulin secretion that prevents an increase in α-cell glucagon secretion in response to those nutrients after a mixed meal. On the other hand, in the setting of β-cell failure in type 1 diabetes and advanced type 2 diabetes, a decrease in plasma glucose cannot cause a decrease in β-cell insulin secretion, and the absence of that signal results in no increase in pancreatic α-cell glucagon secretion during hypoglycemia. Conversely, in the setting of β-cell failure, an increase in plasma glucose, among other nutrients, cannot cause an increase in β-cell insulin secretion, and the absence of that restraining signal results in an increase in pancreatic α-cell glucagon secretion after a mixed meal.