For optimal human body functioning, there is a need for maintenance of a near constant internal environment of cells. Conditions of osmotic pressure, temperature and blood glucose are some of the conditions that should be checked by the body’s homeostatic system. The human blood glucose level should be maintained and kept within a short range. Increased blood glucose level or unusually low blood glucose level may pose health hazards to individuals. Insulin and glucagon hormones play a significant role in regulating blood glucose level. This paper discusses the action of these hormones in regulating blood glucose level. In addition, their metabolism, secretion, pharmacodynamics and pharmacokinetics are also discussed.
The pancreas: Anatomy and Physiology
Pancreas organ remains one of the most vital organs of the human body. Without it, several metabolic reactions become impaired; carbohydrate and fat metabolism being the most affected. Pancreas is organ is located on the anterior end of the human abdomen. A normal pancreas is often approximately 15 centimeters long. It is flattened and has a bulbous head. The head of the pancreas is in most cases enclosed by the ileum while the tail-end of the pancreas is in proximity to the left kidney. In terms of location in the abdominal cavity, it can be referred to as a retroperitoneal organ. This is because it is found lies on the outside of the peritoneum, the membrane enclosing the peritoneal cavity.
Physiologically, pancreas is both an endocrine and an exocrine organ in the body. As an exocrine organ, pancreas is well known for its significant role in digestion. It produces a secretion into the alimentary canal that contains pertinent digestive enzymes such as pancreatic amylase and lipase. These contribute immensely in the breakdown of food substrates in the body. The basic nature of the pancreatic secretion is also of exceptional significance in creating favorable alkaline conditions for the action of the intestinal enzymes. The basic nature is also handy in neutralizing the acidic conditions of the food arriving from the stomach.
This paper focuses much on the endocrinal function of the pancreas. The internal pancreatic cells are aggregated into clusters of cells known as the Islets of Langherhans. These cell clusters are of four different kinds; alpha (A) cells, beta (B) cells, delta (D) cells and gamma (G) cells. All these cell types play hormone synthesizing functions with each type secreting a distinct hormone type (Walker, 341). Alpha cells secrete glucagon while beta cells secrete insulin. The delta cells and gamma cells also secrete somastotatin and pancreatic polypeptide hormone respectively. These hormones influence various aspects of metabolism, growth and development. Insulin and glucagon are particularly fundamental in regulating the amount of glucose present in the blood (Guyton, 203). They act in opposing ways to bring about a balanced blood glucose level in the body. The actions and regulation of these hormones are discussed further in the subsequent sections.
Insulin and glucagon
Insulin has an alpha chain of about 21 amino acids and a beta chain of 30 amino acids. These chains are linked by two disulphide bridges. Glucagon is also a peptide hormone composed of 29 amino acids. It is worth noting that to prevent digestion of the hormones; they are often secreted as prohormones. Other than pancreatic insulin, there has also been widespread commercial reproduction of insulin. Escherichia coli bacteria are used in commercial production of insulin. Insulin has a molecular weight of 6000g. Proinsulin is the primary material from which insulin is manufactured. Proinsulin is converted to insulin. During this process, the remaining connecting peptide, C-peptide and four primary amino acids will be removed through proteolysis.
The main organs of insulin metabolism are the liver and kidney. Insulin is released into the bloodstream. Insulin reaches the glomeruli after sometime through the renal artery. After glomerular filtration, much of the insulin is broken down in the proximal tubules. More than half of the insulin arriving at the kidney is often broken down in the liver. The insulin is often degraded proteolytically. This occurs in the lysosomes of cells in the liver and the proximal tubules. The degradation can also occur on the cell surfaces. There are degradation enzymes that help in breaking the disulfide linkages between the insulin chains. The principal degrading enzyme is the glutathione insulin transhydrogenase. One of the end products of insulin is glutathione.
Pharmacokinetics of insulin and glucagon
Insulin has a half life of approximately five minutes and undergoes degradation in the liver. Degradation and clearance of insulin also occurs in the kidney. In addition to the kidney and the liver, the plasma also forms a clearance site for glucagon. C-peptide is one of the end products of insulin metabolism in the pancreas. Both insulin and glucagon bind to protein receptors on the membranes of their target cells to bring about their intracellular effects. Like insulin, glucagon has a half life of about 5 minutes. The volume of distribution of insulin is roughly twenty percent of the body weight. Compared to insulin, glucagon has a smaller volume of distribution.
Pharmacodynamics of insulin and glucagon
Insulin acts in various ways to restore the high blood glucose levels to normality. Most often, it acts to Increase glucose uptake by cells and tissues. Insulin can decrease the blood glucose level by increasing the rate at which peripheral tissues take up glucose. It also suppresses gluconeogenesis that is production of glucose from non carbohydrate sources (Girouard, 4). It will also act against the breakdown of glycogen in the liver that would contribute to increased blood glucose level.
Insulin also increases the uptake of glucose by muscle tissues. At the muscle adipose tissues, the glucose will be rapidly oxidized to meet the high energy demand of the muscle tissues. Insulin also acts to reduce the blood glucose level by suppressing the production and secretion of enzymes that often accelerate the breakdown of glycogen into glucose in the body. Other than inhibiting the production of these enzymes, insulin also plays a key role in activating glycogen synthesizing enzymes such as glycogen synthase. As a way of reducing blood glucose level, insulin also influences lipid metabolism from glucose. Insulin stimulates the hepatocytes in the liver to take up the extra glucose that is then used to metabolize lipids and fats. During hyperglycemic conditions, the insulin will act in ways aimed at inhibiting the breakdown of tatty acids in the adipose tissues. This ensures that the main source of energy comes from oxidation of the excess glucose in the blood.
Insulin has also been observed to play a role in increasing amounts of pyruvate dehydrogenase enzyme. This is one of the active enzymes that oxidize pyruvate to fat. If not oxidized to fat, pyruvate would otherwise be oxidized to glucose and this can worsen the hyperglycemic conditions. Apart from the glucose regulating function, insulin has been found to increase the permeability of some cells to certain ions. Finally, insulin has also been noted to have hunger reducing effects in the body. It performs this action through a hypothalamic regulation.
While insulin serves to lower the blood glucose level, glucagon acts to increase the blood glucose level under hypoglycemic conditions. The secretion of insulin and glucagon is a coordinated process. During hypoglycemic conditions, glucagon is secreted which in turn inhibits insulin secretion. Glucagon acts in various ways to increase the blood glucose levels to normal (Biesalki and Grimm, 64). Most of its actions are reversed actions of insulin. Under hyperglycemic conditions, excess glucose is often converted to glycogen that is then stored in the liver. When blood glucose falls below normal levels, glucagon will stimulate the breakdown of glycogen in the liver and muscle tissues to release glucose in the body (Shimazu, 73). This process is termed glycogenolysis. Glucagon achieves glycogenolysis by stimulating the hepatocytes to activate the glycogen degrading enzymes.
To increase the blood glucose levels, glucagon also initiates hepatic glucogeneosis. This refers to the formation of glucose from non carbohydrate sources; proteins and lipids. Gluconeogenesis provides an alternative source of glucose to rectify the hypoglycemic conditions. Gluconeogenesis results from the action of the gluconeogenic enzymes present in the liver. Some studies have also linked glucagon to taste sensing. It is believed that that glucagon plays a role in how people respond to sweet tastes. The mechanism on which this is ensured remains unclear. Sweet taste is characteristic of sugar substrates. It is, therefore, deductible that it is a means increasing people’s chances of consuming sugar rich substrates. This will then contribute to increasing the blood glucose level:
Secretion of insulin as shown above is induced by increased glucose level in the blood. This occurs in a series of steps. Due to increased blood glucose level, glucose penetrates into the beta cells through the Glut2 carrier receptors. Glucokinase phosphorylates the glucose leading to synthesis of ATP. Increase in intracellular ATP initiates closing of the K+ channels that are ATP dependent while Ca2+ channels open up as a result of depolarization (Pociot, 112). C-peptide phospholipases and insulin is consequently secreted. Much as the process still remains largely unclear, it is believed that the “second messenger hypothesis” plays a key role.
The secretion of these gluco-regulatory hormones is stimulated by the blood glucose level. Hyperglycemic conditions stimulate the pancreatic cells to secrete insulin. Increased insulin in the body will inhibit the secretion of glucagon. Hypoglycemic conditions stimulate glucagon secretion. Secretion of glucagon also inhibits insulin secretion. However, some neural mechanisms also play roles in secretion and regulation of insulin. In particular, neural stimuli like sight and smell may also trigger insulin secretion. In addition, an increased level of fuel molecules such as fatty acids in the blood has also been reported to heighten insulin levels. This explains why insulin levels are notably high after meals especially meals containing a greater proportion of carbohydrates. A simple representation of insulin secretion is shown in the figure 2 below.
Glucagon is also regulated through neural mechanisms. The islet of Langherhans in the pancreas has extensively innervated. This facilitates a fast reaction to hypoglycemia which if uncontrolled can result into brain damage. The nerve endings of the sympathetic nerves in the islet of Langerhans respond to the low blood glucose conditions by releasing neurotransmitter substances. These neurotransmitters will then stimulate glucagon secretion. Parasympathetic nerves also accumulate certain neuropeptides, which can stimulate the pancreas to secrete glucagon at times of low blood sugar. Strenuous activity and physical exercises also stimulate glucagon secretion from the pancreatic cells. This is attributed to the energy demanding nature of these tasks. Glucagon secretion is stimulated to increase blood glucose that can be oxidized to provide the required energy. In addition, a hungry state in an individual will stimulate glucagon secretion.
Disorders related to Insulin and Glucagon
The role played by insulin and glucagon in regulating the blood glucose levels is indispensable. Insulin is one of the most significant hormones known with a wide range of actions in the body. As outlined by the above discussions, not only do they affect glucose metabolism but also protein and lipid metabolism. The concentrations of these hormones in the body at any given time in the body should also be regulated. Hyper-secretion or hyposecretion of either of these two hormones can result to various metabolic conditions. Some of these conditions are discussed in this section.
Diabetes mellitus is an insulin-associated condition that remains one of the greatest health concerns facing man today. Diabetes describes a metabolic condition in which an individual exhibits high blood glucose levels (Kotecki, 309). Diabetes can occur as a result of under-secretion of insulin. Sometimes, diabetes can occur as a result of the cells failing to respond to the actions of insulin (insulin resistance). Diabetes mellitus can thus be said to be of two types: type 1 diabetes and type 2 diabetes. Some of the classical symptoms associated with diabetes include frequent urination by the diabetic individuals (polyuria), and persistent feeling of thirst (polydipsia). In addition, diabetics also experience increased hunger since the body cannot store the excess glucose in the energy-saving form of glycogen. The frequent urination is as a result of the increased osmotic effects of the blood by the high blood glucose levels.
Various causes of diabetes have been identified. Most are due to inherited defects in insulin secretion and action. These defects may impair the insulin receptors making them irresponsive to insulin. Destruction of the insulin secreting beta cells can also lead to diabetes. This can be through cancer. All forms of diabetes are manageable. The diabetics can be given supplementary insulin every day to correct the hyperglycemic conditions (Caballero, 162). Various forms of insulin have been manufactured through recombinant gene technology. Diabetic persons have to adopt certain lifestyles and regulated diets to help maintain their blood glucose levels.
Increased insulin levels in the body also possess metabolic challenges to the body. Uncontrolled insulin levels in the blood can always lead to hypoglycemia. The body system will lack adequate glucose since insulin will inhibit glucagon action leading to low blood glucose levels in the body. Hypoglycemic individuals will experience increased hunger and general fatigue. This is a direct consequence of deficiency of glucose.
As mentioned above, hypoglycemia can result when there is excess insulin secretion in the body. However, under-secretion of glucagon can also result into hypoglycemic conditions. Glucagon acts towards restoring low blood glucose levels to normal levels. It acts in an antagonistic manner to insulin that reduces blood glucose concentration. When the pancreatic cells fail to secrete sufficient glucagon in the body, then the insulin effects will be dominant. This can lead to hypoglycemic conditions. Hyposecretion of glucagon can be attributed to cancer effects on the alpha cells. Glucagonoma is a cancerous condition that can lead to excessive glucagon secretion by the alpha cells.
Metabolic activities of the body require proper regulation for optimal body functioning. Concentration of the metabolites and the hormones all need to be regulated within favorable limits. The body requires various food substrates for energy production, structural development and other functions. However, of all substrates, glucose remains the most vital energy source of all. Certain body cells such as brain cells can only respire on glucose. Regulation of glucose is thus, of huge value to the body. Insulin and glucagon remain the most crucial glucose-regulating enzymes in the body. While insulin corrects hyperglycemic conditions, glucagon serves to restore hypoglycemic conditions to normal blood glucose level. These hormones are regulated by the blood glucose levels. Hyperglycemic conditions stimulate insulin secretion. Summarily, insulin inhibits gluconeogenesis, lipolysis and proteolysis. It, however, intensifies glycogen synthesis, lipid and protein metabolism. Glucagon opposes the actions of insulin during hypoglycemic conditions to restore normal blood glucose level. Insulin stands as one of the most important hormones in the human body. As mentioned beforehand, its deficiency can lead to the demanding diabetes mellitus. While various forms of diabetes are manageable, it is imperative for one to ensure positive living and diets that will ensure well maintained glucose levels.
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