# Metabolomics/Hormones/Glucagon

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Glucagon is a peptide hormone that works in conjunction with insulin to maintain a stable blood glucose level. In situations of high blood glucose, or hyperglycemia, insulin takes over, stimulating the storage of excess blood glucose in the form of glycogen for later use. However, when blood glucose levels fall, it is the duty of glucagon to stimulate gluconeogenesis and glycogen breakdown, whereby replenishing glucose levels in the blood, and inhibit glycolysis. In doing so, glucagon plays a key role in regulating blood glucose levels, providing the fuel necessary for our cells to function even when our bodies are experiencing a low sugar or starved state.

# Discovery

Physiologists C.P. Kimball and John Murlin from the University of Rochester in Rochester, NY, published a paper in 1923 discussing their attempts to find an inexpensive method of concentrating insulin for medicinal use as well as begin experimenting on methods to isolate the pure substance. The paper explains their efforts to test a variety of inorganic and organic materials on rabbits and test pancreatic synthesis by measuring blood sugar. First observed in December 1922, addition of acetone would throw down an unknown substance that had a distinctly hyperglycemic effect. Purifying this substance and injecting it into a depancreatized dog raised its blood sugar, and the duo named the material glucagon (Kimball, 1923).

# Physiology
## Purpose

The objective of glucagon is to increase the amount of glucose in the blood for use by cells of the body. When there is a lack of glucose in the blood, the islets of langerhans on the pancreas are stimulated to create and release glucagon into the bloodstream. Once glucagon has been released, it travels through the bloodstream until it reaches the liver where it binds to specific glucagon binding sites. Although the liver is the main target of glucagon, receptors for this hormone have also been found in the kidney, intestinal smooth muscle, brain and adipose tissue as well as on insulin producing beta cells where it acts as a feedback mechanism to stimulate the creation of insulin. Because its effects on the liver are extremely important and well understood, however, this will be our main focus. Once bound, the glucagon activates adenylyl cyclase which is the first step in a cascade reaction which ultimately lowers the levels of fructose 2,6-bisphosphate. Fructose 2,6-bisphosphate is an important regulatory molecule in glycolysis/gluconeogenesis. At high levels, this molecule stimulates glycolysis by allosterically binding to phosphofructokinase-1, which increases its ability to function and so stimulates glycolysis. In this case, by lowering the concentration of fructose 2,6-bisphosphate the opposite occurs. Glycolysis is disengaged and gluconeogenesis is stimulated to help restore glucose levels in the body.
Another very important function of glucagon is its stimulation of glycogen breakdown. Activation of glycogen breakdown hinges on the same cascade reaction described in the previous paragraph. When glucagon binds to receptors in the liver it activates the adenylyl cyclase which increases cyclic AMP. The end result is an activation of glycogen phosphorylase which begins the glycogen breakdown process leading to increased blood sugar levels.

## Function

Glucagon is an important regulatory hormone and is integral to our ability to properly regulate the amount of glucose in our bodies. Composed of 29 amino acids, the endocrine producing cells known as the Islets of Langerhans on the pancreas are responsible for the synthesis and excretion of this hormone. The specialized cells that produce this molecule are known as alpha cells but several others, including beta cells which produce glucagon's sister hormone insulin, are also located here.

## Regulation

Although we know of several molecules other than glucose that are important in the regulation of glucagon, many of the exact mechanisms by which this is done are still not fully understood. For example, presence of the hormone insulin down regulates the production of glucagon by alpha cells but details of this process are still being worked out by researchers. Other molecules known to regulate glucagon include somatostatin and GLP-1. Because understanding such processes have the potential to further enhance our ability to treat metabolic diseases such as diabetes, much current research is being put towards understanding these mechanisms.
There are two conditions that are known to trigger glucagon secretion. The first is elevated blood levels of amino acids. Persistat after a protein-rich meal, glucagon is utilized to convert the excess amino acids to glucose by gluconeogenesis. Worth noting is that this is one of the rare situations where both insulin and glucagon are active, as high levels of amino acids in the blood stream triggers its release as well. The second condition of significant glucagon increase is during exercise, although at the time of the latest update(2002), it was unknown whether exercise was a stimulus or if the increased synthesis was due to the induced depletion of glucose.
Postabsorptive plasma glucose concentration has been discovered to be physiologically maintained within the range of 70 mg/dl [3.9 mmol/l] to 110 mg/dl [6.1 mmol/l] in humans. This is accomplished via increased glucose levels from glucagon and decreased glucose levels from insulin. However, there has not yet been any convincing evidence of the involvement of glucagon in postabsorptive plasma glucose concentration maintenance.
Combined deficiency of insulin and glucagon results in an initial drop in plasma glucose levels, but is followed by an increase in plasma glucose levels. This indicates that there is support of postabsorptive plasma glucose concentrations from glucagon, when in concert with insulin. Changes in plasma glucose concentrations also result from changes in glucose production but not from glucose utilization. Furthermore, during insulin and partial glucagon deficiency, and the exclusive partial deficiency glucagon, the rate of glucose appearance increases to a point greater than the rate of glucose disappearance. This rate increase seems to be even larger than during insulin and glucagon deficiency, as well as when glucagon is made exclusively deficient. Both scenarios result in much higher plasma glucose concentrations.
Increases in plasma glucose levels are ultimately followed by plateaus. These plateaus occur within a postabsorptive physiological range, and after octreotide-induced suppression of insulin and glucagon secretion. It has been determined that hormones and additional factors are involved in postabsorptive glucose level maintenance, after short periods of time. However, chronic insulin and glucagon deficiencies still remain victims of diabetes. Therefore, insulin has been proven to contribute to the maintenance of postabsorptive plasma glucose concentrations, while high levels of glucagon are not required to onset diabetes.
These findings do not distinguish the individual roles of insulin and of glucagon. However, chronic insulin and glucagon deficiencies have been proven to cause hyperglycemia and, therefore, strongly suggest that insulin is the predominant factor of postabsorptive glucose levels.
Link to article:
http://diabetes.diabetesjournals.org/cgi/content/full/56/10/2442#SEC3

## Pathology

While there are many Americans affected by an inbalance of insulin (diabetes types I and II ), there are only very specific and very uncommon situations in which glucagon has been shown to cause disease in humans.

### Excessive glucagon secretion

Diseases associated with excessively high or low secretion of glucagon are bad. Cancers of alpha cells (glucagonomas) are one situation known to cause excessive glucagon secretion. These tumors typically lead to a wasting syndrome and, interestingly, rash and other skin lesions.

### Hyperglycemia

Hyperglycemia occurs when blood glucose levels are too high, usually over 11 mmol/L, and occurs most often an hour or so after a large meal, especially one heavily laced with sugars. Hyperglycaemia occurs when there is too little insulin in the blood, or in the rare situation of an overabundance of glucagon. Thanks to fairly dependable regulation of glucagon, our body typically prevents an overabundance of glucagon when it senses high blood glucose levels.

# Resources

1. glucagon.com
This website can be located at: http://www.glucagon.com/index.html
This webpage was a very useful and informative description of not only the hormone glucagon but of all relating molecules, pathways, regulators, and diseases associated with the molecule. It contains effective descriptions of all information known about glucagon and related molecules up to this point in time. Because this topic has so much research dedicated to it, the site also provides useful links to primary articles most of which demonstrate the most recent discoveries linked to glucagon and related pathways.
Proglucagon - Precursor of glucagon which is also secreted by alpha cells of the islets of Langerhans.
Prohormone - A molecule produced as a precursor to the actual hormone.
Hyperplasia - The overproduction of cells within an organ or tissue.
Exocytotic - The process by which a cell excretes vesicles containing the desired molecule or protein.
Polymorphism - Multiple alleles of a gene within a population.
The information found on this website is extremely relevant to topics learned in class. It fully explains factors involved in the regulation of blood glucose levels which we studied in detail in chapter 15 this quarter. It goes beyond just the functions of insulin and glucagon, however, and describes other mechanisms and molecules which are or are thought to be involved in this important metabolic process.
2. Relationship of Glucagon Suppression by Insulin and Somatostatin to the Ambient Glucose Concentration
This journal can be found in full text for free at: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=423975&blobtype=pdf
The main point of this article was to determine the amount of glucagon suppression exhibited by the molecules insulin and somatostatin. Although both are known to regulate this hormone, the exact effects they have on glucagon regulation are not yet confirmed.
Hyperglucagonemia - Abnormally high levels of glucagon in the blood.
Phloridzin - A dihydrochalcone occurring in many parts of the apple tree which is used experimentally to produce glycosuria in animals.
Glycosuria - An abnormal condition of osmotic diuresis due to excretion of glucose by the kidneys.
Diuresis - The increased production of urine by the kidney.
Normoglycemic - The presence of normal concentrations of glucose in the blood.
This is an important and relevant article because it delves further into the mechanisms used by the body to keep levels of glucagon regulated. This study is also important to further understand how to control diabetes and other abnormalities in this metabolic pathway.
3. Aquaeous Extracts of Pancreas
This journal can be found in full text for free at: http://www.jbc.org/cgi/reprint/58/1/337
As mentioned above in the Discovery section, this paper was the first to identify and name the compound glucagon, making it very relevant to this article, as well as our text. At the time of publication, 1923, the researchers were looking to synthesize insulin for medical purposes, by adding various compounds to the pancreas. The subjects involved were rabbits and dogs, and the paper hints at the difficulty of science publication during the era. Because the paper uses terminology from almost a century ago and the paper's main focus was on insulin, not glucagon, it seems only right to include only the terms that would appear relevant to this wikibook entry.
glucagon - a substance that exhibits a highly hyperglycemic effect. When given to a depancreatized dog by subcutaneous injection, blood sugar was reported to rise significantly in 3 hours.
4. Colorado State Hypertexts of Biomedical Sciences
This website can be found at: http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/pancreas/glucagon.html
In an effort similar to this wikibook, Colorado State University created an online textbook pertaining to the Endocrine Pancreas in 2000. Focusing on the page that deals with glucagon, this article lists many new definitions that pertain to biochemistry and enhance the reading. If the images were available, the source offers several simple but effective images and diagrams that show the pathway and function of not only glucagon but insulin as well. Information from this source is used in several locations within the 'Physiology' section of this article.
Secretin - a hormone that is structurally similar to glucagon, secretin is released in response to acid in the small intestine and stimulates the pancreas and bile ducts to release a flood of bicarbonate base, which neutralizes the acid.
Enteroglucagon - the precursor of glucagon, the proglucagon gene, can also expressed in the terminal small intestine and large intestine, where it is cleaved into a number of peptides other than glucagon. Also known as enteroglucagon or glucagon-like peptides, this alternative pathway for processing of proglucagon occurs in gut endocrinocytes called L cells.
Hypoglycemia - in Greek the term literally means "under-sweet blood", hypoglycemia is the term for lower than normal blood glucose levels. Treatment is typically oral or inject glucose.
Hyperglycemia -"over sweetened blood", the polar opposite of hypoglycemia, this is the term for higher than normal blood glucose levels, and is typically treated with additional insulin. And as mentioned in the wikibook entry, this is the more likely scenario to be created by an irregular level of glucagon, that is, too much in the blood.
Somatostatin - Metabolomics/Hormones/Somatostatin is another hormone discussed in this Wikibook, but does play some role with glucagon, in which somatostatin is known to inhibit glucagon when it prevents all pancreatic hormones from being distributed in an effort to regulate the endocrine system,
Glucagonoma - Cancer of α-cells of the pancreas, which has been known to cause excessive glucagon secretion.