Review of Medical Physiology - William F. Ganong 2002

Endocrine System, Metabolism, and Reproduction
Endocrine Functions of the Pancreas and Regulation of Carbohydrate Metabolism
Glucagon

Chemistry

Glucagon in humans is a linear polypeptide with a Molecular Weight of 3,485, produced by the A-Cells of the pancreatic islets and the upper gastrointestinal tract. It consists of 29 amino acid residues (see Table 26-2). Glucagons of all mammals share an identical Structure. Human preproglucagon (Fig. 19-16) is a 179-amino-acid polypeptide found in A-cells, L-cells of the lower gastrointestinal tract, and the Brain. It is the product of a single mRNA transcript that undergoes differential Processing in various Tissues. In A-cells, it is initially cleaved into glucagon and major proglucagon fragment (MPGF), whereas in L-cells, it yields glicentin (a polypeptide consisting of glucagon extended by additional amino acid residues at each terminus) and glucagon-like Peptides 1 and 2 (GLP-1 and GLP-2). A certain amount of oxyntomodulin is also formed, along with glicentin-related polypeptide (GRPP) in both A- and L-cells. Glicentin retains some glucagon activity. Although GLP-1 and GLP-2 lack definitive intrinsic biological activity on their own, GLP-1 (7-36) is a potent stimulator of Insulin secretion that also enhances glucose utilization (see above). Furthermore, GLP-1 and GLP-2 are synthesized in the brain, although their Functions within the Central Nervous system remain unclear. Oxyntomodulin inhibits gastric acid secretion, yet its physiological role is unknown, and GRPP has no established physiological effects.

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Fig. 19-16. Posttranslational processing of preproglucagon in A- and L-cells; S, signal peptide; MPGF, major proglucagon fragment; Oxy, oxyntomodulin; GRPP, glicentin-related polypeptide; GLP, glucagon-like peptide (modified from Drucker DJ: Glucagon and glucagon-like peptides. Pancreas 1990;5:484).

Action

Glucagon functions as a glycogenolytic, gluconeogenic, lipolytic, and ketogenic factor. It binds to serpentine receptors with a molecular weight of approximately 190,000 and, in the Liver, acts via G_s Proteins to activate adenylate cyclase and elevate intracellular cAMP. Through protein kinase A, this cascade leads to the activation of phosphorylase, thereby promoting Glycogen breakdown and increasing plasma glucose levels. The steps involved in this classic paradigm of cAMP-mediated hormone action are discussed in Chapter 17. However, glucagon also binds to distinct receptors on the same hepatocytes to activate phospholipase C, which, via an increase in cytoplasmic Ca²⁺, additionally stimulates Glycogenolysis. Protein kinase A suppresses glucose-6-phosphate METABOLISM (Fig. 19-17) by reducing The conversion of phosphoenolpyruvate to Pyruvate and lowering the concentration of fructose-2,6-bisphosphate, which in turn prevents the conversion of fructose-6-phosphate to fructose-1,6-bisphosphate. Consequently, the accumulation of glucose-6-phosphate results in enhanced glucose release.

Fig. 19-17. Mechanisms by which glucagon increases hepatic glucose output. Solid lines indicate stimulation, and dashed lines indicate inhibition.

Glucagon does not induce glycogenolysis in Skeletal Muscle, but it enhances hepatic Gluconeogenesis from available Amino Acids and elevates the metabolic rate. It promotes ketone body formation by decreasing hepatic malonyl-CoA levels (see Chapter 17). Its lipolytic activity, which contributes to increased ketogenesis, is reviewed in Chapter 17. The calorigenic effect of glucagon itself stems not from hyperglycemia, but likely from increased hepatic AMINO ACID DEAMINATION.

Large doses of exogenous glucagon exert a positive inotropic effect on The Heart (see Chapter 29) without increasing myocardial excitability, apparently mediated by an elevation in cardiac cAMP. Although this hormone has been utilized therapeutically in cardiac conditions, there is no evidence for a Physiological Role of glucagon in the REGULATION OF CARDIAC function. Glucagon also stimulates the secretion of Growth Hormone, insulin, and pancreatic Somatostatin.

Metabolism

In the bloodstream, glucagon has a half-life of 5 to 10 minutes. It is degraded by numerous tissues, particularly the liver. Because glucagon is secreted into the portal vein and reaches the liver prior to entering the systemic Circulation, its peripheral Blood concentration is relatively low. The elevation in peripheral blood glucagon levels triggered by stimulatory signals (see below) is abnormally pronounced in patients with cirrhosis, presumably due to impaired hepatic degradation of the hormone.

Regulation of Secretion

The primary factors influencing glucagon secretion are summarized in Table 19-7. Secretion is stimulated by hypoglycemia and inhibited by rising plasma glucose levels. Notably, B-cells contain GABA; evidence also indicates that concurrently with the insulin secretion elicited by hyperglycemia, GABA is released and acts on A-cells via GABA_A receptors to suppress glucagon secretion. GABA_A receptors function as Cl^- channels, and Cl^- influx hyperpolarizes the A-cells.

Table 19-7. Factors Influencing Glucagon Secretion

Secretion is also enhanced by sympathetic nerve stimulation of the pancreas; this sympathetic effect is mediated by ß-adrenergic receptors and cAMP. A-cells appear to resemble B-cells in that stimulation of ß-adrenergic receptors increases secretion, whereas stimulation of a-adrenergic receptors inhibits it (see above). Nonetheless, the net pancreatic response to sympathetic stimulation in the absence of blocking agents is an increase in glucagon secretion. Thus, The Effect of ß-receptors predominates in glucagon-secreting cells. The stimulatory effects of various stressors and, potentially, physical exertion and infections are mediated, at least in part, by the sympathetic nervous system. Vagal nerve stimulation likewise increases glucagon secretion.

Protein-rich meals and the administration of various amino acids stimulate glucagon secretion. Gluconeogenic Amino acids are presumably particularly potent in this regard, as they are converted to glucose in the liver under The Influence of glucagon. The rise in glucagon secretion following protein ingestion is also physiologically significant: while amino acids stimulate insulin secretion, the concomitantly secreted glucagon prevents The Development of hypoglycemia, whereas insulin promotes the storage of ingested CARBOHYDRATES, fats, and Lipids. Glucagon secretion rises during fasting, reaching a peak on the third day of starvation concurrently with maximal gluconeogenesis. Thereafter, as Fatty acids and ketone bodies become the primary energy substrates, plasma glucagon levels decline.

During Physical Exercise, an increase in glucose utilization is observed (see below), which balances the enhanced hepatic glucose production driven by elevated circulating glucagon levels.

The glucagon response to oral amino acid ingestion exceeds that following intravenous administration. This suggests the existence of a glucagon-stimulating factor secreted by the intestinal epithelium. CCK and gastrin increase glucagon secretion, whereas secretin inhibits it. Because the secretion of both CCK and gastrin rises following protein consumption, either hormone may serve as a gastrointestinal mediator of the glucagon response. Inhibition by growth hormone is discussed below.

Glucagon secretion is also suppressed by FFAs and ketone bodies. However, this suppression can be overridden, as evidenced by the high plasma glucagon levels observed in diabetic ketoacidosis.

Insulin-Glucagon Molar Ratios

As noted previously, insulin exerts glycogenolytic [sic - glycogenic], antigluconeogenic, antilipolytic, and antiketogenic actions. Consequently, it promotes the storage of absorbed nutrients and acts as the hormone of energy storage. Glucagon, conversely, is a glycogenolytic, gluconeogenic, lipolytic, and ketogenic hormone; it mobilizes energy reserves and serves as the hormone of energy release. Given their opposing physiological effects, the blood levels of both Hormones must be evaluated in any given metabolic state. It is convenient to analyze their molar ratios. The insulin-glucagon molar ratio can be readily calculated for any blood sample based on hormone concentrations determined by radioimmunoassay and their respective molecular weights.

Insulin-glucagon molar ratios fluctuate markedly because the secretion of both glucagon and insulin depends on the conditions preceding any stimulus (Table 19-8). For example, the insulin-glucagon molar ratio on A balanced diet is approximately 2.3. The administration of Arginine increases the secretion of both hormones and raises the ratio to 3.0. Following a three-day fast, the ratio drops to 0.4, and administering arginine in this state further decreases it to 0.3. Conversely, this value reaches 25 in individuals receiving continuous glucose infusions, and rises as high as 170 during the combined ingestion of a protein meal and glucose. This surge is driven by a sharp increase in insulin secretion, whereas the typical glucagon response to dietary protein is blunted. Thus, when energy mobilization is required during fasting, a low insulin-glucagon molar ratio favors glycogenolysis and gluconeogenesis; conversely, when The Need for energy mobilization is low, a high ratio promotes the deposition of glycogen, protein, and fat.