Glucagon

Glucagon is a hormone produced by the pancreas in response to low blood glucose; it works to raise blood glucose levels. Its main effect is on the liver, where it promotes conversion of glycogen to glucose. It is also available as a drug that is used to treat severe low blood sugar (hypoglycemia).

Description

A pancreatic islet; the brown stain corresponds to stored glucagon and identifies the alpha cells. Source: NIH

Role of Glucagon in the Body

Glucagon is critically important in maintaining normal levels of glucose in the blood. In general, the effects of glucagon are counter to those of insulin; glucagon is sometimes referred to as a counterregulatory hormone. Whereas insulin tends to lower blood glucose levels by promoting glycogen formation in the liver, glucagon acts to promote the degradation of glycogen into individual molecules of glucose for release into the circulation.

In diabetes, glucagon levels are sometimes inappropriately elevated, suggesting that diabetes is not just a deficiency of insulin; rather, the balance between glucagon and insulin is disrupted in favor of high blood glucose levels in this condition.^[2]

How It Works

Glucagon and insulin are both released from the pancreas. Glucagon tends to raise blood glucose; insulin tends to lower it. Source:FDA

The most important immediate effect of glucagon is to increase the conversion of glycogen (a polymeric storage form of glucose) to glucose monomers. This is accomplished by a series of three enzymes known as PKA, glycogen phosphorylase kinase, and glycogen phosphorylase, the latter of which results in glucose monomers being released from the large glycogen polymer. Similar cascades of regulatory molecules and enzymes^[3] are set in motion by glucagon to

• Reduce the rate of glycogen production (glycogenesis)
• Increase the rate of glucose production from smaller precursor molecules (gluconeogenesis)
• Reduce the breakdown of glucose (glycolysis)

History

Christian de Duve was awarded the Nobel Prize in 1974 for his work on the structure of the cell, but he also provided many important advances in the biology of insulin and glucagon.^[4] Glucagon was initially purified by C. P. Kimball and John R. Murlin of the University of Rochester in 1923.^[5]

Since glucagon and insulin are stored in cells that are adjacent to one another and are both peptide hormones, many attempts to purify insulin resulted in insulin/glucagon mixtures, and for a time, glucagon was a contaminant of commercially-available insulin.

In 1998, Eli Lilly and company gained approval for glucagon as a drug in its own right; it is used to treat severe episodes of low blood sugar and is especially useful in persons who are unable to swallow sugar-containing foods or beverages.

Research

Since inappropriately high levels of glucagon contribute to high blood sugar levels in diabetes, blocking glucagon's effects may help normalize them. Several types of molecules have been investigated, including small molecules and antisense oligonucleotides.^[6] Amgen is developing a molecule (AMG477) intended to block the glucagon receptor that is currently in Phase I clinical trials.

References

1. ↑ Sutherland E. W., de Duve C. ORIGIN AND DISTRIBUTION OF THE HYPERGLYCEMIC-GLYCOGENOLYTIC FACTOR OF THE PANCREAS. J. Biol. Chem.Sep 1948; 175:663-674 PDF
2. ↑ Brown RJ, Sinaii N, Rother KI. Too much glucagon, too little insulin: time course of pancreatic islet dysfunction in new-onset type 1 diabetes. Diabetes Care. 2008 Jul;31(7):1403-4. Abstract | Full Text | PDF
3. ↑ Jiang G, Zhang BB. Glucagon and regulation of glucose metabolism. Am J Physiol Endocrinol Metab. 2003 Apr;284(4):E671-8. Abstract | Full Text | PDF
4. ↑ De Duve C. Glucagon; the hyperglycaemic glycogenolytic factor of the pancreas. Lancet. 1953 Jul 18;265(6777):99-104. Citation
5. ↑ Kimball CP, Murlin JR. Aqueous extracts of pancreas. III. Some precipitation reactions of insulin. J. Biol. Chem.. 1923 58(1):337 PDF
6. ↑ Sloop KW, Michael MD, Moyers JS. Glucagon as a target for the treatment of Type 2 diabetes. Expert Opin Ther Targets. 2005 Jun;9(3):593-600. Abstract

External Links

Daniel Drucker maintains glucagon.com as a hub for information on glucagon and related peptide hormones. Professor Drucker is an active academic scientist at the University of Toronto.