What Is Glucagon – Definition and Function

The pancreas is a small, flat, pear shaped organ located in the abdomen. It is surrounded by the small intestine, liver and spleen. It plays an important role in digestion of food and metabolism of sugar. The part of the pancreas that is involved in sugar metabolism is made of cells called islets of Langerhans. The islets of Langerhans produce two hormones; insulin and glucagon. The beta cells of the islets of Langerhans produce insulin, while the alpha cells produce glucagon. While Insulin is involved in lowering blood sugar levels, glucagon does the opposite function of raising blood sugar levels. It is essential for insulin and glucagon to function in co-ordination with each other for normal sugar metabolism.

Structure and synthesis of glucagon

Glucagon is a 29-amino acid polypeptide (chain of amino acids) hormone, produced by the alpha cells of the islets of Langerhans. Glucagon is produced in response to protein intake, low blood glucose levels and exercise.The islets of Langerhans have a dense supply of blood vessels which help the cells to easily detect blood sugar levels. It has been reported that when the alpha cells in the islets of Langerhans detect low blood glucose concentrations, it leads to changes in the electrical activity in the cell. This causes an influx of Ca²⁺ions resulting in the secretion of glucagon from the alpha cells of the pancreas.

Function of glucagon

The function of glucagon is to increase the blood glucose levels so that the body has enough energy to function properly. Glucagon supplies glucose to the body by promoting glycogenolysis and gluconeogenesis.

Glycogenolysis: The liver stores glucose in the form of glycogen. Glycogenolysis occurs in the liver and is the process of breaking down glycogen to glucose.Liver cells also called hepatocytes possess glucagon receptors. When glucagon binds to its receptors on the hepatocytes, it initiates a chain of events in the cells which activates the enzyme protein kinase A. Protein kinase A in turn activates various intermediates, which eventually cause the breakdown of glycogen to glucose in the liver. The glucose produced is then released into the blood stream. Certain neural and hormonal signals stimulate glycogenolysis in the muscle and liver. Adrenaline, the hormone involved in the flight or fight response,also promotes glycogenolysisin the muscles.

Gluconeogenesis: This is a process whereby glucagon synthesizes glucose from amino acids and glycerol.Gluconeogenesis occurs by the activation of protein kinase A by glucagon. The liver is the major site for gluconeogenesis, although it also occurs in the kidneys during prolonged starvation. Itis an alternate method of glucose synthesis, when substrates that are carbohydrate sources are not available in the body. The body uses this process for glucose production during fasting, starvation, low intake of carbohydrates in the diet, and during excessive exercise. Glucagon has been reported to be a major contributor of glycogenolysis and gluconeogenesis in the liver during exercise.

Lipolysis: Glucagon also increases glucose levels in the blood by conserving it. It increases lipolysis of triglycerides which leads to an increase in production of fatty acids. Cells end up using these fatty acids as a fuel source instead of glucose, which is conserved in the cells. Lipases are enzymes involved in lipolysis of triglycerides. Glucagon acts on the glucagon receptors in the adipose tissue and activates protein kinase A. It, in turn,increases levels of lipases in the adipose tissue,which leads to an increase infatty acid production.

Regulation of glucagon production

Glucagon levels are increased in response to hypoglycemia or low blood sugar.
Consumption of a protein rich meal which leads to elevation of amino acid levels triggers glucagon release.Glucagon converts amino acids into glucose by gluconeogenesis.
Exercise also triggers glucagon release. It enhances the rates of glycogenolysis and gluconeogenesis to provide the body with energy during exercise.
An increase in glucagon secretion has been reported under conditions of acute stress. This occurs in response to the stimulation of adrenergic receptors in the pancreatic cells.
Glucagon secretion is increased during cold acclimatization. Glucagon is thermogenic and increases energy consumption in the body.
Glucagon secretion is also increased by cortisol (steroid hormone), acetylcholine (neurotransmitter), theophylline, infections etc.
High glucose levels, or hyperglycemia, inhibit glucagon production by the alpha cells of islets of Langerhans.
Somatostatin is also known as the growth inhibiting hormone. Apart from the hypothalamus, it is also produced by the alpha cells of the pancreas. Somatostatin produced by the alpha cells of the pancreas inhibits the production of glucagon in these cells.
Glucagon secretion is also inhibited by free fatty acids (FFA), ketones, insulin, GABA (neurotransmitter) etc.

Diabetes

Under normal conditions, when the bloods glucose levels become low, the following events occur: the beta cells of the pancreas secrete less insulin;the alpha cells of the pancreas produce glucagon which leads to an increase in blood glucose levels; glucagon also increases blood glucose levels by glycogenolysis, lipolysis etc.In the same manner, under normal conditions, when the bloods glucose levels increase, the secretion of insulin by the beta cells increases, while the secretion of glucagon by the alpha cells decreases. Insulin secreted by the beta cells in response to high blood sugar levels also has an inhibitory effect on the glucagon production by the alpha cells.

When this fine co-ordination between the insulin production by beta cells and glucagon production by alpha cells is disrupted, it leads to diabetes.In type 1 diabetes there is a destruction of beta cells in the pancreas, leading to decreased insulin production. However, the alpha cells continue to produce glucagon. This leads to an increase in blood sugar levels.In type 2 diabetes, the cells do not respond to insulin (insulin resistance)and the beta cells do not produce enough insulin. In diabetes, the inhibitory control on glucagon production exerted by insulin is lost due to low insulin levels.

Role of glucagon in diabetes

Recent studies have shown that hyperglucagonemia,the condition where glucagon is secreted in excess, precedes the decreased insulin secretion seen in the diabetic population. Experiments performed in rats show that glucotoxicity (exhaustion of beta cells due to high glucose and insulin production) first causes alpha cell dysfunction, before disrupting the beta cell function and insulin production.
There are also reports suggesting that the alpha cells produce glutamate along with glucagon. Glutamate can destroy beta cells. A protein called glial glutamate transporter 1 (GLT1) can protect beta cells.
In type 1 diabetes, patients do not secrete insulin in response to changing blood glucose levels. In some cases, type 1 diabetics also lose their ability to secrete glucagon in response to blood sugar levels, leading to severe hypoglycemia. A glucagon rescue kit, in which glucagon is administered as aninjection, is recommended for diabetics to treat severe hypoglycemia.
Glucagon-like peptide -1 (GLP-1) receptor agonists are a new line of drugs for type 2 diabetics. They mimic the action of GLP1 and increase insulin release. They reduce glucagon secretion, decrease gastric emptying, and increase satiety in diabetics.

Drugs targeting both insulin and glucagon are being recommended as a new line of treatment for diabetes.

Conclusion

The synchronized action of both insulin and glucagon helps to maintain normal blood sugar levels in the body. Disruption in the production of normal levels of insulin and glucagon can lead to diabetes.

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