Tuesday, August 18, 2009

Glucagons and Glucagon-Like Peptides

Glucagon is best known as a peptide hormone secreted from pancreatic islets that participates in control of glucose metabolism.

Related peptides
Glucagon is synthesized as proglucagon and proteolytically processed to yield glucagons within alpha cells of the pancreatic islets. Proglucagon is also expressed within the intestinal tract, where it is processed not into glucagon, but to a family of glucagon-like peptides. In both pancreas and gut, three types of products are generated:
* Peptides with known biological activity: glucagon and glucagon-like peptide-1 (GLP-1)
* Peptides that may have biological activity, but which are poorly characterized or active only at what are considered non-physiologic concentrations: glucagon-like peptide-2 (GLP-2) and oxyntomodulin
* Peptides without apparent biological activity: glicentin, glicentin-related pancreatic peptide, major proglucagon fragment1.

Glucagon was initially purified by C. P. Kimball and John R. Murlin of the University of Rochester in 1923. The amino acid sequence of glucagon was described in the late-1950s2.

Structural Characteristics
Glucagon is a linear peptide of 29 amino acids. Its primary sequence is almost perfectly conserved among vertebrates, and it is structurally related to the secretin family of peptide hormones1.

Mode of Action
Glucagon signals through its receptor on the cell surface. The binding of glucagon to the extracellular loops of the glucagon receptor results in conformational changes of the latter, leading to subsequent activation of the coupled G proteins. At least two classes of G proteins are known to be associated with and involved in the signal transduction of the glucagon receptor, namely Gs and Gq. The activation of Gs leads to activation of adenylate cyclase, increase in intracellular cAMP levels, and subsequent activation of protein kinase A (PKA). The activation of Gq leads to the activation of phospholipase C, production of inositol 1,4,5-triphosphate, and subsequent release of intracellular calcium3.

* Glucagon plays a key role in glucose metabolism and homeostasis. Regulates blood glucose by increasing gluconeogenesis and decreasing glycolysis. A counterregulatory hormone of insulin, raises plasma glucose levels in response to insulin-induced hypoglycemia. Plays an important role in initiating and maintaining hyperglycemic conditions in diabetes.
* GLP-1 is a potent stimulator of glucose-dependent insulin release. Play important roles on gastric motility and the suppression of plasma glucagon levels. May be involved in the suppression of satiety and stimulation of glucose disposal in peripheral tissues, independent of the actions of insulin. Have growth-promoting activities on intestinal epithelium. May also regulate the hypothalamic pituitary axis (HPA) via effects on LH, TSH, CRH, oxytocin, and vasopressin secretion. Increases islet mass through stimulation of islet neogenesis and pancreatic beta cell proliferaton. Inhibits beta cell apoptosis.
* GLP-2 stimulates intestinal growth and up-regulates villus height in the small intestine, concomitant with increased crypt cell proliferation and decreased enterocyte apoptosis. The gastrointestinal tract, from the stomach to the colon is the principal target for GLP-2 action. Plays a key role in nutrient homeostasis, enhancing nutrient assimilation through enhanced gastrointestinal function, as well as increasing nutrient disposal. Stimulates intestinal glucose transport and decreases mucosal permeability.
* Oxyntomodulin significantly reduces food intake. Inhibits gastric emptying in humans. Suppression of gastric emptying may lead to increased gastric distension, which may contribute to satiety by causing a sensation of fullness.
* Glicentin may modulate gastric acid secretion and the gastro-pyloro-duodenal activity. May play an important role in intestinal mucosal growth in the early period of life4.

1.Kieffer TJ and Habener JF (1999). The Glucagon-Like Peptides. Endocrine Reviews, 20 (6), 876-913
2.Jiang G, Zhang BB (2003). Glucagon and regulation of glucose metabolism. Am J Physiol Endocrinol Metab., 284(4), E671-8.
3.Kimball CP, Murlin JR (1923). Aqueous extracts of pancreas. III. Some precipitation reactions of insulin. J. Biol. Chem., 58(1), 337
4.Blache P, Kervran A, Bataille D (1988). Oxyntomodulin and glicentin: brain-gut peptides in the rat. Endocrinology, 123(6), 2782-7.

No comments: