Human Biochemistry, Volume 2 - Murray R. 1993

Biochemistry of Intracellular and Intercellular Communications
Pancreatic Hormones
Glucagon

Early commercially available Insulin preparations shared a common characteristic: in patients who received them, plasma glucose levels initially rose and only subsequently decreased. This fact is explained by the presence of another peptide impurity in the preparation—Glucagon, the second hormone of the pancreatic islet Cells.

Chemical Properties

Glucagon is a single-chain polypeptide (mol. wt. 3485) consisting of 29 amino acid residues (Fig. 51.18). The glucagon molecule contains no Disulfide Bonds because it lacks Cysteine residues. In certain immunological and physiological properties, glucagon is analogous to enteroglucagon, a peptide extracted from the duodenal mucosa. Furthermore, 14 of the 27 amino acid residues in glucagon are identical to those in the secretin molecule (Table 52.5).

Biosynthesis and METABOLISM

The primary site of glucagon synthesis is the A-Cells of the pancreatic islets. However, fairly large amounts of this hormone can also be produced in other Regions of the gastrointestinal tract. Glucagon is synthesized as a significantly larger precursor, proglucagon (mol. wt. approximately 9000). Although larger molecules have been detected, it remains unclear whether they are true precursors of glucagon or closely related Peptides. Only 30–40% of the immunoreactive "glucagon" in plasma accounts for pancreatic glucagon; the remainder consists of larger molecules lacking biological activity.

In plasma, glucagon exists in a free, unbound form. Because it does not bind to a carrier protein, its half-life is short (approximately 5 min). Inactivation of the hormone occurs in the Liver through the action of an enzyme that cleaves the bond between Ser-2 and Gln-3, thereby removing Two Amino Acids from the N-terminus. The liver acts as the first barrier to secreted glucagon; because it rapidly inactivates the hormone, the concentration of glucagon in the portal vein is much higher than in the peripheral Blood.

Regulation of Secretion

Glucagon secretion is suppressed by glucose—an effect that highlights the opposing metabolic roles of glucagon and insulin. Whether glucose suppresses glucagon secretion directly or whether its inhibitory effect is mediated by insulin or IGF-1 remains unclear, as both of the latter Hormones also suppress glucagon release. Numerous Other Compounds, including amino acids, Fatty acids, Ketone Bodies, Gastrointestinal Hormones, and Neurotransmitters, also influence its secretion.

Physiological Effects

The effects of glucagon are generally opposite to those of insulin. While insulin promotes energy storage by stimulating Glycogenesis, Lipogenesis, and Protein Synthesis, glucagon stimulates Glycogenolysis and lipolysis, thereby prompting the rapid mobilization of potential Energy Sources to generate glucose and fatty acids, respectively. Glucagon is the most potent stimulator of Gluconeogenesis and also exerts a ketogenic effect.

The liver is the primary target organ for glucagon. By binding to its receptors on Cell/30.html">The Plasma Membrane of hepatocytes, glucagon activates adenandlate cyclase (adenylate cyclase). The resulting cAMP, in turn, activates phosphorylase, which accelerates Glycogen breakdown, while the simultaneous inhibition of glycogen synthase halts glycogen formation (see Chapter 44). This effect exhibits both hormonal and tissue Specificity: glucagon does not affect glycogenolysis in Skeletal Muscle, whereas epinephrine is active in both muscle and liver. Elevated cAMP levels induce several gluconeogenic Enzymes, stimulating The conversion of amino acids into glucose. Among these enzymes, PEPCK plays the predominant role. Glucagon, acting via cAMP, increases the Transcription rate of the PEPCK Gene, thereby stimulating the synthesis of large quantities of PEPCK. This effect counteracts insulin, which represses PEPCK gene transcription. Further Examples are provided in Table 51.7. The net hepatic effect of glucagon is enhanced glucose production. Because the majority of this glucose leaves the liver, blood glucose concentrations rise under The Influence of glucagon.

Class="center">

Fig. 51.19. Amino Acid Sequence of Somatostatin. (Reproduced, with permission, from Karam J. H., Salber P. R., Forsham P. H. Pancreatic Hormones and Diabetes Mellitus. In: Basic and Clinical Endocrinology, 2nd ed. Greenspan F. S., Forsham P. H. (editors). Appleton and Lange. 1986.)

Table 51.7. Enzymes induced or repressed by insulin or glucagon. (Slightly modified and reproduced, with permission from Karam J. H., Sabler P. R., Forsham P. H. Pancreatic hormones and diabetes mellitus. In: Basic and Clinical Endocrinology, 2nd ed., Greenspan F. S., Forsham P. H. (eds.), Appleton a. Lange, 1986.)

Glucagon is a potent lipolytic agent. By elevating cAMP levels in adipocytes, it activates hormone-sensitive lipase. The resulting high concentrations of fatty acids can be utilized as energy sources or converted into ketone bodies (acetoacetate and ß-hydroxybutyrate). This is a critical metabolic aspect in diabetes, as glucagon levels are consistently elevated under conditions of insulin deficiency.