Biological Chemistry - Berezov, T. T., Korovkin, B. F. 1998

Hormones
Pancreatic Hormones
Glucagon

Glucagon was first discovered in commercial Insulin preparations back in 1923, but it was not until 1953 that the Hungarian biochemist F. Straub obtained this hormone in a homogeneous state. Glucagon is synthesized primarily in the a-Cells of the pancreatic islets, as well as in A number of intestinal cells (see below). It is represented by a single linear polypeptide chain comprising 29 amino acid residues in the following sequence:

Class="center">H-His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-OH

The Introduction/19.html">Primary Structure of Human and Animal glucagons has proven to be identical, with the sole exception of turkey glucagon, which contains a Serine residue instead of asparagine at position 28. A distinctive structural feature of glucagon is the absence of Disulfide Bonds and Cysteine. Glucagon is produced from its precursor, proglucagon, which contains an additional octapeptide (8 residues) at the C-terminus of the polypeptide that is cleaved during postsynthetic proteolysis. Evidence indicates that proglucagon, much like proinsulin, has a precursor—preproglucagon (molecular weight 9,000)—whose structure has not yet been elucidated.

In terms of its biological action, glucagon, like epinephrine, is a hyperglycemic factor, causing an increase in Blood glucose concentration primarily through Glycogenolysis in the Liver. The target Organs for glucagon are the liver, myocardium, and adipose tissue, but not Skeletal Muscle. The Biosynthesis and secretion of glucagon are controlled mainly by glucose concentration via a feedback mechanism. Amino Acids and free Fatty acids possess this same property. Insulin and Insulin-like Growth Factors also influence glucagon secretion.

* It should be noted that in insulin-resistant patients with Diabetes Mellitus, insulin synthesis is unimpaired; however, the patients' bodies fail to respond to either endogenous or injected insulin. It turns out that some of these patients harbor a mutation in the Tyrosine kinase domain of the receptor, and although insulin binds normally to this mutant receptor, downstream signal Transduction does not occur because the tyrosine kinase is inactivated. Consequently, Treatment of patients with this form of diabetes with insulin proves ineffective.

In the MECHANISM OF ACTION of glucagon, the initial event is binding to specific Cell Membrane Receptors*; the resulting glucagon-receptor complex activates adenylate cyclase and, accordingly, The formation of cAMP. Acting as a universal effector of intracellular Enzymes, cAMP activates protein kinase, which in turn phosphorylates phosphorylase kinase and Glycogen synthase. Phosphorylation of the former enzyme promotes the formation of active Glycogen phosphorylase and, consequently, glycogenolysis with the formation of glucose-1-phosphate (see Chapter 10), whereas phosphorylation of Glycogen synthase is accompanied by its transition to an inactive form, thereby blocking Glycogenesis. The net result of glucagon action is the acceleration of glycogen breakdown and the inhibition of its synthesis in the liver, leading to an elevated blood glucose concentration.

The hyperglycemic effect of glucagon, however, is not solely due to glycogen breakdown. There is indisputable Evidence for the existence of a gluconeogenic mechanism in glucagon-induced hyperglycemia. It has been established that glucagon promotes glucose formation from intermediate products of protein and Lipid METABOLISM. Glucagon stimulates glucose production from amino acids by inducing the synthesis of gluconeogenic enzymes with the participation of cAMP, notably phosphoenolpyruvate carboxykinase, a key enzyme of this process. Unlike epinephrine, glucagon inhibits the glycolytic breakdown of glucose to lactic acid, thereby contributing to hyperglycemia. It activates tissue lipase indirectly via cAMP, exerting a potent lipolytic effect. There are also differences in physiological action: unlike epinephrine, glucagon does not elevate blood pressure or increase Heart rate. It should be noted that, alongside pancreatic glucagon, the existence of intestinal glucagon has recently been demonstrated; it is synthesized throughout the digestive tract and enters the bloodstream. The primary structure of intestinal glucagon has not yet been precisely elucidated, but its molecule has been shown to contain Amino acid sequences identical to the N-terminal and middle regions of pancreatic glucagon, alongside a distinct C-terminal Amino Acid Sequence.

Thus, the pancreatic islets, which synthesize two Hormones with opposing actions—insulin and glucagon—play a pivotal role in the molecular REGULATION OF METABOLISM.

* These are the so-called glucagon-binding Proteins, which selectively interact exclusively with glucagon.