Low blood glucose: A decrease in plasma glucose concentration is the primary stimulus for glucagon release. During an overnight or prolonged fast, elevated glucagon levels prevent hypoglycemia (see Section IV below for a discussion of hypoglycemia).
2.
Amino acids: Amino acids (for example, arginine) derived from a meal containing protein stimulate the release of glucagon. The glucagon effectively prevents the hypoglycemia that would otherwise occur as a result of the increased insulin secretion that also occurs after a protein meal.
3.
Catecholamines: Elevated levels of circulating epinephrine (from the adrenal medulla), norepinephrine (from sympathetic innervation of the pancreas), or both stimulate the release of glucagon. Thus, during periods of physiologic stress, the elevated catecholamine levels can override the effect on the α cell of circulating substrates. In these situations, regardless of the concentration of blood glucose, glucagon levels are elevated in anticipation of increased glucose use. In contrast, insulin levels are depressed.
B. Decreased secretion
Glucagon secretion is significantly decreased by elevated blood glucose and by insulin. Both substances are increased following ingestion of glucose or a carbohydrate-rich meal (see Fig. 23.5). The regulation of glucagon secretion is summarized in Figure 23.11.
C. Metabolic effects
Glucagon is a catabolic hormone that promotes the maintenance of blood glucose levels. Its primary target is the liver.
1.
Effects on carbohydrate metabolism: The IV administration of glucagon leads to an immediate rise in blood glucose. This results from an increase in the degradation of liver glycogen and an increase in hepatic gluconeogenesis.
2.
Effects on lipid metabolism: The primary effect of glucagon on lipid metabolism is inhibition of FA synthesis through phosphorylation and subsequent inactivation of ACC by adenosine monophosphate (AMP)– activated protein kinase (see p. 184). The resulting decrease in malonyl CoA production removes the inhibition on long-chain FA β-oxidation (see p. 191). Glucagon also plays a role in lipolysis in adipocytes, but the major activators of hormone-sensitive lipase (via phosphorylation by protein kinase A) are the catecholamines. The free FA released are taken up by liver and oxidized to acetyl CoA, which is used in ketone body synthesis.
3.
Effects on protein metabolism: Glucagon increases uptake by the liver of amino acids supplied by muscle, resulting in increased availability of carbon skeletons for gluconeogenesis. As a consequence, plasma levels of amino acids are decreased.
D. Mechanism
Glucagon binds to high-affinity G protein–coupled receptors (GPCR) on the cell membrane of hepatocytes. The GPCR for glucagon is distinct from the GPCR that bind epinephrine. [Note: Glucagon receptors are not found on skeletal muscle.] Glucagon binding results in activation of adenylyl cyclase in the plasma membrane (Fig. 23.12; also see p. 94). This causes a rise in cyclic AMP (cAMP), which, in turn, activates cAMP-dependent protein kinase A and increases the phosphorylation of specific enzymes or other proteins. This cascade of increasing enzymic activities results in the phosphorylation-mediated activation or inhibition of key regulatory enzymes involved in carbohydrate and lipid metabolism. An example of such a cascade in glycogen degradation is shown in Figure 11.9 on p. 131. [Note: Glucagon, like insulin, affects gene transcription. For example, glucagon induces expression of phosphoenolpyruvate carboxykinase (see p. 122).]