Glucagon

Glucagon serves as the counter-balancing hormone to insulin, having largely the opposite effects. It is mainly expressed by pancreatic alpha-cells. Whereas insulin is secreted and active during feeding and elevated blood glucose, ensuring storage of this in liver and other tissues, glucagon ensures the release of glucose from liver when blood glucose is low during fasting and exercise. It is the balance between insulin and glucagon that ensures a tight regulation of blood glucose levels in normal subjects. The glucagon gene is expressed in many tissues and encodes several significant polypeptides including glucagon itself. In the intestine for instance the glucagon gene express GLP1 and GLP2, both very important hormones. Glucagon is a 29 amino acid protein with a very short half-life in the blood. This means that apart from the liver other tissues will experience little or no glucagon. In the liver glucagon via activation of the glucagon receptor activates glycogenolysis and gluconeogenesis producing glucose that is released to the blood stream for use in other issues.

Glucagon synthesis and degradation

Expression of the glucagon gene leads to the production of the 180 amino acid proglucagon. Alternative cleavage of this protein can result in either glucagon or various other peptide hormones such as glicentin, glicentin-related peptide, oxyntomodulin and [glucagon-like peptide 1] (DPID-5104336124) and 2 (GLP-1 and GLP-2). All these peptides have a considerable homology (i.e. they have very similar amino-acid compositions). Different tissues express different hormones or sets of hormones from the initial transcript. The 29 amino acid sequence of glucagon is the final product generated in pancreatic alpha-cells, whereas GLP-1 and GLP-2 are secreted from the intestinal L-cells.

The 29 residue glucagon peptide (figure 1) Figure 1. Amino acid sequence of glucagon.
Figure 1. Amino acid sequence of glucagon.
is thought to form an alpha-helix structure and the physico-chemical properties are rather peculiar. Synthetic or isolated glucagon is highly unstable both in vitro and in vivo, which has a negative impact on the possibilities to make it useful as therapeutic peptide. The in vivo half-life has been estimated at 5-6 min. in humans. The enzyme responsible for the initial breakdown is Dipeptidyl Peptidase IV (DPP4) which is also responsible for the fast degradation of GLP-1 and GLP-2. The short half-life in vivo ensures that glucagon released from the pancreas has little or no effect in peripheral tissues other than its major target, the liver.

Key effects of glucagon

The major effect of glucagon is to activate the glucagon receptor (GCG-R) in hepatocytes. As glucagon is released from alpha-cells when blood glucose is low, it is meant to counteract low blood glucose by increasing the release of glucose from the hepatocytes. Therefore it inhibits glycolysis and it stimulates glycogenolysis and gluconeogenesis. Upon binding to the GCG-R, glucagon activates a G-protein inside the cells. The G-protein has three subunits of which the alpha subunit is activating adenylate cyclase which in turn produces cyclic AMP (cAMP) from ATP. This second messenger in turn activates a key enzyme, the so called cAMP-dependent protein kinase or protein kinase A (PKA). PKA regulates a number of other enzymes and proteins inside the cell. Of key importance is the activation of glycogenolysis. PKA activates phosphorylase kinase, which then phosphorylates glycogen phosphorylase that becomes the active Phosphorylase A releasing glucose-1-phosphate (G-1-P) from glycogen (the carbohydrate store of the hepatocytes). Finally, G-1-P is converted to glucose-6-phosphate (G-6-P) which can be dephosphorylated to give glucose. PKA is also responsible for the inhibition of glycolysis and the stimulation of gluconeogenesis. The resulting glucose is released to the blood to elevate the blood glucose levels and provide energy to tissues in need. This is opposite to the effects of insulin, which ensure storage of energy (carbohydrates and lipids) in tissues like liver, fat and muscle. Thus, it is said that blood glucose in normal subjects is controlled by the balance between insulin and glucagon at a level close to 5 mM.

Clinical applications of glucagon

Glucagon for treatment of hypoglycaemia

A common phenomenon for diabetics is that their everyday activities and treatment regiment can lead to Hypoglycaemia. The mainstay of hypoglycaemia treatment is to eat or drink something rich in glucose or complex carbohydrates. However, in severe hypoglycaemia, when the patient has already lost consciousness, glucose is not easy to administer. For this purpose there are so called “rescue kits” available containing native human glucagon for injection. This will work only if the patient still has sufficient glycogen stores (gluconeogenesis is too slow a process) and it is recommended to alert emergency medical services when the patient does not rapidly improve following glucagon injection.

Combining insulin and glucagon in pump therapy

A potential novel application of glucagon is to use it in dual pump therapy. It is thought that combining insulin pumps with glucagon pumps in a so-called 'Artificial Pancreas' may imitate the natural counterbalancing effects of these hormones and thus result in better glucose control. In particular it is thought that the risk of hypoglycaemia can be eradicated allowing for improved use of insulin against hyperglycaemia. This should lead to much tighter blood glucose control and hopefully diminish diabetic complications long term. Unfortunately the current versions and formulations of glucagon do not allow for the full development of an Artificial Pancreas system, though the concept has been tested in small clinical trials using the available glucagon.

Glucagon receptor antagonism

Some pharma and biotech companies are currently exploring the possibility to develop ‘anti-glucagon’ or rather a GCG-R antagonist as an alternative or supplementary way to lower blood glucose. This stems from the concept that diabetics are low on insulin or insulin response and thus have relatively high glucagon. Thus, a way to counteract this imbalance is to antagonize the receptor lowering the release of glucose and aiding storage instead. It is clear from different studies that GCG-R antagonism can contribute to the control of hyperglycaemia, whether it will also contribute to more hypoglycaemia is not yet clear but certainly a possibility.

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