Glucagon

Glucagon is a single-chain polypeptide of 29 amino acid residues and a molecular mass of 3500 Da. It is synthesized by the A-cells of the islets of Langerhans, and also by related cells found in the digestive tract. Like insulin, it is synthesized as a high molecular mass from which the mature hormone is releases by selective proteolysis.

The major biological actions of glucagon tend to oppose those of insulin, particularly with regard to regulation of metabolism. Glucagon has an overall catabolic effect, stimulating the breakdown of glycogen, lipid and protein. A prominent metabolic effect is to increase blood glucose levels (i.e. it is a hyperglycaemic hormone). Indeed, the major physiological function of glucagon is to prevent hypoglycaemia. The hormone is stored in secretory vesicles, after synthesis in the pancreatic A-cells, and released by exocytosis upon experiencing a drop in blood glucose concentration.

Glucagon initiates its metabolic (and other) effects by binding to a specific cell surface receptor, thus activating a membrane-bound adenylate kinase. This, in turn, promotes activation of a cyclic adenosine monophosphate (cAMP)-dependent protein kinase (Figure 11.6). The kinase phospho-rylates key regulatory enzymes in carbohydrate metabolism, thereby modulating their activity. Hepatic glycogen phosphorylase, for example, is activated via phosphorylation, while glycogen synthetase is inactivated, thus promoting glycogen breakdown. The rate of gluconeogenesis is also stimulated by the inactivation of pyruvate kinase and simultaneous activation of fructose 1,6-bisphosphatase.

Hypoglycaemia remains the most frequent complication of insulin administration to diabetics. It usually occurs due to (a) administration of an excessive amount of insulin; (b) administration of insulin prior to a mealtime, but with subsequent omission of the meal; or (c) due to increased physical activity. In severe cases this can lead to loss of consciousness, and even death. Although it may be treated by oral or i.v. administration of glucose, insulin-induced hypoglycaemia is sometimes treated by administration of glucagon.

Plasma membrane

Cell cytosol cAMP dependent protein kinases (less active)

Figure 11.6 Initiation of a metabolic response to the binding of glucagon to its receptor. (1) glucagon cell surface receptor; (2) G protein; (3) adenylate cyclase. (See text for further detail)

Glucagon is also used medically as a diagnostic aid during certain radiological examinations of the stomach and small and large intestine where decreased intestinal motility is advantageous (the hormone has an inhibitory effect on the motility of the smooth muscle lining the walls of the gastrointestinal tract).

Traditionally, glucagon preparations utilized therapeutically are chromatographically purified from bovine or porcine pancreatic tissue. (The structure of bovine, porcine and human glucagon is identical, thus eliminating the possibility of direct immunological complications). Such commercial preparations are generally formulated with lactose and sodium chloride and sold in freeze-dried form. Glucagon, 0.5-1.0 units (approximately 0.5-1.0 mg freeze-dried hormone), is administered to the patient by s.c. or i.m. injection.

More recently, glucagon preparations produced via recombinant means have also become available. 'GlucaGen' is the tradename given to one such product, produced by Novo Nordisk using an engineered S. cerevisiae strain. Upstream processing (aerobic batch-fed fermentation) is followed by an upward adjustment of media pH in order to dissolve precipitated product (glucagon is insoluble in aqueous-based media in the pH range 3-9.5). This facilitates subsequent removal of the yeast by centrifugation. Glucagon is then recovered and purified from the media by a series of further precipitation and high-resolution chromatographic steps. Eli Lilly also produces a recombinant glucagon product using an engineered E. coli strain.

Cell cytosol

cAMP dependent protein kinases (less active)

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Figure 11.7 Three-dimensional structure of hGH. Structural details courtesy of the Protein Data Bank, http://www.rcsb.org/pdb/
Supplements For Diabetics

Supplements For Diabetics

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