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).