Glucagon

GLUCAGON

Glucagon is a peptide hormone secreted by the α cells of the pancreatic islets of Langerhans. Glucagon, along with epinephrine, norepinephrine, cortisol, and growth hormone (the “counterregulatory” hormones), opposes many of the actions of insulin (Figure 23.10). Most importantly, glucagon acts to maintain blood glucose levels by activation of hepatic glycogenolysis and gluconeogenesis. Glucagon is composed of 29 amino acids arranged in a single polypeptide chain. [Note: Unlike insulin, the amino acid sequence of glucagon is the same in all mammalian species examined to date.] Glucagon is synthesized as a large precursor molecule (preproglucagon) that is converted to glucagon through a series of selective proteolytic cleavages, similar to those described for insulin biosynthesis (see Figure 23.3). In contrast to insulin, preproglucagon is processed to different products in different tissues, for example, GLP-1 in intestinal L cells. Like insulin, glucagon has a short half-life.

Figure 23.10 Opposing actions of insulin and glucagon plus epinephrine.

A. Stimulation of glucagon secretion

The α cell is responsive to a variety of stimuli that signal actual or potential hypoglycemia (Figure 23.11). Specifically, glucagon secretion is increased by low blood glucose, amino acids, and catecholamines.

Figure 23.11 Regulation of glucagon release from pancreatic α cells. [Note: Amino acids increase release of insulin and glucagon, whereas glucose increases release of insulin only.]

1. 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 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 produced by the adrenal medulla, norepinephrine produced by 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. Inhibition of glucagon 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 Figure 23.5). The regulation of glucagon secretion is summarized in Figure 23.11.

C. Metabolic effects of glucagon

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 breakdown 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 fatty acid synthesis through phosphorylation of ACC. The decrease in malonyl CoA production as a result of ACC inhibition removes the break on long-chain fatty acid β-oxidation. Glucagon also plays a role in lipolysis in adipose, but the major activators of hormone sensitive lipase (via phosphorylation by protein kinase A) are the catecholamines. The free fatty acids 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 of action of glucagon

Glucagon binds to high-affinity G protein–coupled receptors on the cell membrane of hepatocytes. The receptors for glucagon are distinct from those that bind insulin or epinephrine. [Note: Glucagon receptors are not found on skeletal muscle.] Glucagon binding results in activation of adenylyl cyclase in the plasma membrane (Figure 23.12;). This causes a rise in cyclic adenosine monophosphate (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. [Note: Glucagon, like insulin, affects gene transcription. For example, glucagon induces expression of phosphoenolpyruvate carboxykinase.]

Figure 23.12 Mechanism of action of glucagon. [Note: For clarity, G-protein activation of adenylyl cyclase has been omitted.] R = regulatory subunit; C = catalytic subunit; cAMP = cyclic adenosine monophosphate; ADP = adenosine diphosphate; P = phosphate.