Glucagon, a peptide produced by the alpha cells through the proteolytic cleavage of preproglucagon, circulates freely in the body for a short period of about 6 minutes. However, the liver plays a crucial role in glucagon degradation, breaking down approximately 80% of the glucagon that enters the circulation. Since glucagon travels through the hepatic portal vein to reach the liver before entering the systemic circulation, a significant portion of the hormone never reaches the systemic circulation. The liver is the primary target organ for glucagon, although it also has some effects on adipocytes. Notably, skeletal muscle does not have glucagon receptors.

The glucagon receptor, a Gs-linked G protein-coupled receptor, enhances adenylyl cyclase activity, thereby increasing cyclic AMP (cAMP) levels. This leads to the rapid actions of glucagon through PKA signaling. Additionally, glucagon can also exert transcription effects by phosphorylating and activating transcription factors such as CREB (cAMP response element binding) protein.

The balance between insulin and glucagon in the body determines the net effect on blood glucose and metabolic pathways. A significant stimulus for glucagon secretion is a decrease in blood glucose levels. Insulin acts to inhibit glucagon secretion, so low blood glucose indirectly affects glucagon secretion by removing insulin's inhibitory effect on alpha cells.

Recent evidence suggests that low glucose levels directly stimulate alpha cells to increase glucagon secretion. Circulating catecholamines, such as epinephrine and norepinephrine, inhibit glucose-induced insulin secretion through α2-adrenergic receptors but stimulate glucagon secretion through β2-adrenergic receptors.

Another factor influencing glucagon secretion is the presence of serum amino acids (AAs). Glucagon secretion is promoted by the presence of serum AAs. Therefore, a meal containing both glucose and protein increases postprandial levels of both insulin and glucagon, providing protection against hypoglycemia. On the other hand, a carbohydrate meal stimulates only insulin secretion.

Epinephrine, the primary product of the adrenal medulla, and norepinephrine, released from postganglionic sympathetic nerve endings, are the major counterregulatory factors to insulin. Catecholamines are released in response to decreased glucose levels, stress, and exercise. Neurons in the CNS are primarily responsible for sensing decreased glucose levels and initiating an integrated response involving the counterregulatory factors glucagon and catecholamines (norepinephrine and epinephrine).
Fig. 39.11 ). Preproglucagon is proteolytically cleaved in the alpha cell in a cell-specific manner to produce the peptide glucagon. Glucagon circulates in an unbound form and has a short half-life of about 6 minutes. The predominant site of glucagon degradation is the liver, which degrades as much as 80% of circulating glucagon in one pass. Because glucagon enters the hepatic portal vein and is carried to the liver before reaching the systemic circulation, a large portion of the hormone never reaches the systemic circulation. The liver is the primary target organ of glucagon, with lesser effects on adipocytes. Skeletal muscle does not express the glucagon receptor.
The glucagon receptor is is a Gs-linked G protein– coupled receptor that increases adenylyl cyclase activity and thus cAMP levels. Glucagon exerts many rapid actions through PKA signaling. Glucagon also exerts some transcription effects through phosphorylation and activation of transcription factors such as CREB (cAMP response element binding) protein.
The insulin-glucagon ratio determines the net effect of metabolic pathways on blood glucose. A major stimulus for secretion of glucagon is a decline in blood glucose. Insulin inhibits glucagon secretion, so low blood glucose has an
CHAPTER 39 Hormonal Regulation of Energy Metabolism 709 indirect effect on glucagon secretion through removal of ˜ Cell Insulin inhibition by insulin (
Fig. 39.12 ). Some recent evidence also indicates that low glucose has a direct effect on alpha (+) cells to increase glucagon secretion.
Circulating catecholamines, which inhibit secretion of glucose insulin via α2-adrenergic receptors, stimulate secretion of glucagon via β2-adrenergic receptors (see
Fig. 39.12 (If low) Serum AAs promote secretion of glucagon. This means a glucose protein meal will increase postprandial levels of both insulin and glucagon (which protects against hypoglycemia), whereas a carbohydrate meal stimulates only insulin.
Catecholamines: Epinephrine  (–) and Norepinephrine
The other major counterregulatory factors are the catechol- amines epinephrine and norepinephrine. Epinephrine is the primary product of the adrenal medulla (see ), whereas norepinephrine is released from postganglionic sympathetic nerve endings (see ). Catecholamines are released in response to decreased glucose concentrations, various forms of stress, and exercise. Decreased glucose levels (i.e., hypoglycemia) are primarily • Fig. 39.11 Integrated regulation of blood glucose by insulin and sensed by neurons in the CNS, which initiate an integrated the counterregulatory factors glucagon and catecholamines (norepinephrine, epinephrine).