The pancreas, in addition to its digestive functions, secretes two important hormones, insulin and

glucagon, that are crucial for normal regulation of glucose, lipid, and protein metabolism. Although the pancreas secretes other hormones, such as amylin, somatostatin, and pancreatic polypeptide, their functions are not as well established.

Physiologic Anatomy of the Pancreas. The pancreas is composed of two major types of tissues: (1) the acini, which secrete digestive juices into the duodenum, and

(2) the islets of Langerhans, which secrete insulin and glucagon directly into the blood.

The human pancreas has 1 to 2 million islets of Langerhans, each only about 0.3 mm in diameter and organized around small capillaries into which its cells secrete their hormones. The islets contain three major types of cells, alpha, beta, and delta cells, which are distinguished from one another by their morphological and staining characteristics.

The beta cells, constituting about 60% of all the cells of the islets, lie mainly in the middle of each islet and secrete insulin and amylin, a hormone that is often secreted in parallel with insulin, although its function is unclear. The alpha cells, about 25% of the total, secrete glucagon. and the delta cells, about 10% of the total, secrete somatostatin. In addition, at least one other type of cell, the PP cell, is present in small numbers in the islets and secretes a hormone of uncertain function called pancreatic polypeptide.

The close interrelations among these cell types in the islets of Langerhans allow cell-to-cell communication and direct control of secretion of some of the hormones by the other hormones. For instance, insulin inhibits glucagon secretion, amylin inhibits insulin secretion, and somatostatin inhibits the secretion of both insulin and glucagon.

Insulin and Its Metabolic Effects

Insulin was first isolated from the pancreas in 1922 by Banting and Best, and almost overnight the outlook for the severely diabetic patient changed from one of rapid decline and death to that of a nearly normal person. Historically, insulin has been associated with “blood sugar,” and true enough, insulin has profound effects on carbohydrate metabolism. Yet it is abnormalities of fat metabolism, causing such conditions as acidosis and arteriosclerosis that are the usual causes of death in diabetic patients. Also, in patients with prolonged diabetes, diminished ability to synthesize proteins leads to wasting of the tissues as well as many cellular functional disorders. Therefore, it is clear that insulin affects fat and protein metabolism almost as much as it does carbohydrate metabolism.

Insulin is a Hormone Associated with Energy Abundance

Insulin plays an important role in storing the excess energy. In the case of excess carbohydrates, it causes them to be stored as glycogen mainly in the liver and muscles; the excess carbohydrates are converted, under the stimulus of insulin into fats and stored in the adipose tissue. In the case of proteins, insulin has a direct effect in promoting amino acid uptake by cells and conversion of these amino acids into protein. Also, it inhibits the breakdown of the proteins present in the cells.

 

Insulin Chemistry and Synthesis

Insulin is a small protein; human insulin has a molecular weight of 5808. It is composed of two amino acid chains connected to each other by disulfide linkages. When the two amino acid chains are split apart, the functional activity of the insulin molecule is lost. Insulin is synthesized in the beta cells by the usual cell machinery for protein synthesis beginning with translation of the insulin-RNA by ribosomes attached to the endoplasmic reticulum to form an insulin preprohormone. This initial preprohormone has a molecular weight of about11,500, but it is then cleaved in the endoplasmic reticulumto form a proinsulin with a molecular weightof about 9000; most of this is further cleaved in theGolgi apparatus to form insulin and peptide fragments before being packaged in the secretory granules. However, about one sixth of the final secreted product is still in the form of proinsulin. The proinsulin has virtually no insulin activity. When insulin is secreted into the blood, it circulates almost entirely in an unbound form; it has a plasma

half-life that averages only about 6 minutes, so that it is mainly cleared from the circulation within 10 to 15minutes. Except for that portion of the insulin that combines with receptors in the target cells, the remainder is degraded by the enzyme insulinase mainly in the liver, to a lesser extent in the kidneys and muscles, and slightly in most other tissues. This rapid removal from the plasma is important, because, at times, it is as important to turn off rapidly as to turn on the control functions of insulin.

Activation of Target Cell Receptors by Insulin and the Resulting Cellular Effects

To initiate its effects on target cells, insulin first binds with and activates a membrane receptor protein that has a molecular weight of about 300,000. It is the activated receptor, not the insulin, that causes the subsequent effects. The insulin receptor is a combination of four subunits held together by disulfide linkages: two alpha-subunits that lie entirely outside the cell membrane and two beta subunits that penetrate through the membrane, protruding into the cell cytoplasm. The insulin binds with the alpha subunits on the outside of the cell, but because of the linkages with the beta subunits, the portions of the beta subunits protruding into the cell become auto-phosphorylated. Thus, the insulin receptor is an example of an enzyme-linked receptor. Auto-phosphorylation of beta subunits of the receptor activates a local tyrosine kinase, which in turn causes phosphorylation of multiple other intracellular enzymes including a group called insulin-receptor substrates (IRS). Different types of IRS (e.g. IRS-1, IRS-2, IRS-3) are expressed in different tissues. The net effect is to activate some of these enzymes while inactivating others. In this way, insulin directs the intracellular metabolic machinery to produce the desired effects on carbohydrate, fat, and protein metabolism. The end effects of insulin stimulation are following: 1. within seconds after insulin binds with its membrane receptors, the membranes of about 80% of the body’s cells markedly increase their uptake of glucose. This is especially true of muscle cells and adipose cells but is not true of most neurons in the brain. The increased glucose transported into the cells is immediately phosphorylated and becomes a substrate for all the usual carbohydrate metabolic functions. The increased glucose transport is believed to result from translocation of multiple intracellularvesicles to the cell membranes; these vesicles carry in their own membranes multiple molecules of glucose transport proteins, which bind with the cell membrane and facilitate glucose uptake into the cells. When insulin is no longer available, these vesicles separate from the cell membrane within about 3 to 5 minutes and move back to the cell interior to be used again and again as needed.

2. The cell membrane becomes more permeable to many of the amino acids, potassium ions, and phosphate ions, causing increased transport of these substances into the cell.

3. Slower effects occur during the next 10 to 15 minutes to change the activity levels of many more intracellular metabolic enzymes. These effects result mainly from the changed states of phosphorylation of the enzymes.

4. Much slower effects continue to occur for hours and even several days. They result from changed rates of translation of messenger RNAs at the ribosomes to form new proteins and still slower effects from changed rates of transcription of DNA in the cell nucleus. In this way, insulin remolds much of the cellular enzymatic machinery to achieve its metabolic goals.

 

 

Effect of Insulin on Carbohydrate Metabolism

Immediately after a high-carbohydrate meal, the glucose that is absorbed into the blood causes rapid secretion of insulin. The insulin in turn causes rapid uptake, storage, and use of glucose by almost all tissues of the body, but especially by the muscles, adipose tissue, and liver.

Insulin Promotes Muscle Glucose Uptake and Metabolism:  Insulin can increase the rate of transport of glucose into the resting muscle cell by at least 15-fold. During much of the day, muscle tissue depends not on glucose for its energy but on fatty acids. The principal reason for this is that the normal resting muscle membrane is only slightly permeable to glucose, except when the muscle fiber is stimulated by insulin; between meals, the amount of insulin that is secreted is too small to promote significant amounts of glucose entry into the muscle cells. However, under the two conditions, the muscles do use large amounts of glucose. One of these is during moderate or heavy exercise. This usage of glucose does not require large amounts of insulin, because exercising muscle fibers become more permeable to glucose even in the absence of insulin because of the contraction process itself. The second condition for muscle usage of large amounts of glucose is during the few hours after a meal. At this time the blood glucose concentration is high and the pancreas is secreting large quantities of insulin. The extra insulin causes rapid transport of glucose into the muscle cells. This causes the muscle cell during this period to use glucose preferentially over fatty acids.

Storage of Glycogen in Muscle. If the muscles are not exercising after a meal and yet glucose is transported into the muscle cells in abundance, then most of the glucose is stored in the form of muscle glycogen instead of being used for energy, up to a limit of 2 to 3% concentration. The glycogen can later be used for energy by the muscle. It is especially useful for short periods of extreme energy use by the muscles and even to provide spurts of anaerobic energy for a few minutes at a time by glycolytic breakdown of the glycogen to lactic acid, which can occur even in the absence of oxygen.

Insulin Promotes Liver Uptake, Storage, and Use of Glucose: One of the most important of all the effects of insulin is to cause most of the glucose absorbed after a meal to be stored almost immediately in the liver in the form of glycogen. Then, between meals, when food is not available and the blood glucose concentration begins to fall, insulin secretion decreases rapidly and the liver glycogen is split back into glucose, which is released back into the blood to keep the glucose concentration from falling too low. The mechanism by which insulin causes glucose uptake and storage in the liver includes several almost simultaneous steps:

1. Insulin inactivates liver phosphorylase, the principal enzyme that causes liver glycogen to split into glucose. This prevents breakdown of the glycogen that has been stored in the liver cells.

2. Insulin causes enhanced uptake of glucose from the blood by the liver cells. It does this by increasing the activity of the enzyme glucokinase, which is one of the enzymes that causes the initial phosphorylation of glucose after it diffuses into the liver cells. Once phosphorylated, the glucose is temporarily trapped inside the liver cells because phosphorylated glucose cannot diffuse back through the cell membrane.

3. Insulin also increases the activities of the enzymes that promote glycogen synthesis, including

especially glycogen synthase, which is responsible for polymerization of the monosaccharide units to form the glycogen molecules.

The net effect of all these actions is to increase the amount of glycogen in the liver. The glycogen can increase to a total of about 5 to 6% of the liver mass, which is equivalent to almost 100 grams of stored glycogen in the whole liver.

Glucose is Released from the Liver between Meals: When the blood glucose level begins to fall to a low level between meals, several events transpire that cause the liver to release glucose back into the circulating blood:

1. The decreasing blood glucose causes the pancreas to decrease its insulin secretion.

2. The lack of insulin then reverses all the effects listed earlier for glycogen storage, essentially

stopping further synthesis of glycogen in the liver and preventing further uptake of glucose by the liver from the blood.

3. The lack of insulin (along with increase of glucagon, which is discussed later) activates the

enzyme phosphorylase, which causes the splitting of glycogen into glucose phosphate.

4. The enzyme glucose phosphatase, which had been inhibited by insulin, now becomes activated by the insulin lack and causes the phosphate radical to split away from the glucose; this allows the free glucose to diffuse back into the blood.

Thus, the liver removes glucose from the blood when it is present in excess after a meal and returns it to the blood when the blood glucose concentration falls between meals. Ordinarily, about 60% of the glucose in the meal is stored in this way in the liver and then returned later.

Insulin Promotes Conversion of Excess Glucose into Fatty Acids in the Liver. When the quantity of glucose entering the liver cells is more than can be stored as glycogen or can be used for local hepatocytes metabolism, insulin promotes the conversion of all this excess glucose into fatty acids, which  are subsequently packaged as triglycerides in very-low-density lipoproteins and transported in this form by way of the blood to the adipose tissue and deposited as fat.

Insulin also inhibits gluconeogenesis. It does this mainly by decreasing the quantities and activities of liver enzymes required for gluconeogenesis. However, part of the effect is caused by an action of insulin that decreases the release of amino acids from muscle and other extrahepatic tissues and in turn the availability of these necessary precursors required for gluconeogenesis.

Lack of Effect of Insulin on Glucose Uptake and Usage by the Brain: The brain is quite different from most other tissues of the body in that insulin has little effect on uptake or use of glucose. Instead, the brain cells are permeable to glucose and can use glucose without the intermediation of insulin. The brain cells are also quite different from most other cells of the body in that they normally use only glucose for energy and can use other energy substrates, such as fats, only with difficulty. Therefore, it is essential that the blood glucose level always be maintained above a critical level, which is one of the most important functions of the blood glucose control system. When the blood glucose falls too low, into the range of 20 to 50 mg/100 ml, symptoms of hypoglycemic shock develop, characterized by progressive nervous irritability that leads to fainting, seizures, and even coma.

Effect of Insulin on Carbohydrate Metabolism in Other Cells: Insulin increases glucose transport into and glucose usage by most other cells of the body (with the exception of the brain cells, as noted) in the same way that it affects glucose transport and usage in muscle cells. The transport of glucose into adipose cells mainly provides substrate for the glycerol portion of the fat molecule. Therefore, in this indirect way, insulin promotes deposition of fat in these cells.

Effect of Insulin on Fat Metabolism: Although not quite as visible as the acute effects of insulin on carbohydrate metabolism, insulin’s effects on fat metabolism are, in the long run, equally important. Especially dramatic is the long-term effect of insulin lack in causing extreme atherosclerosis, often leading to heart attacks, cerebral strokes, and other vascular accidents. But first, let us discuss the acute effects of insulin on fat metabolism.

Insulin Promotes Fat Synthesis and Storage: Insulin has several effects that lead to fat storage in adipose tissue. First, insulin increases the utilization of glucose by most of the body’s tissues, which automatically decreases the utilization of fat, thus functioning as a fat sparer. However, insulin also promotes fatty acid synthesis. This is especially true when more carbohydrates are ingested than can be used for immediate energy, thus providing the substrate for fat synthesis. Almost all this synthesis occurs in the liver cells, and the fatty acids are then transported from the liver by way of the blood lipoproteins to the adipose cells to be stored. The different factors that lead to increased fatty acid synthesis in the liver include the following:

1. Insulin increases the transport of glucose into the liver cells. After the liver glucogen concentration reaches 5 to 6%, this in itself inhibits further glycogen synthesis. Then all the additional glucose entering the liver cells becomes available to form fat. The glucose is first split to pyruvate in the glycolytic pathway, and the pyruvate subsequently is converted to acetyl coenzyme A (acetyl-CoA), the substrate from which fatty acids are synthesized.

2. An excess of citrate and isocitrate ions is formed by the citric acid cycle when excess amounts of glucose are being used for energy. These ions then have a direct effect in activating acetyl-CoA carboxylase, the enzyme required to carboxylate acetyl-CoA to form malonyl-CoA, the first stage of fatty acid synthesis.

3. Most of the fatty acids are then synthesized within the liver itself and used to form triglycerides, the usual form of storage fat. They are released from the liver cells to the blood in the lipoproteins. Insulin activates lipoprotein lipase in the capillary walls of the adipose tissue, which splits the triglycerides again into fatty acids, a requirement for them to be absorbed into the adipose cells, where they are again converted to triglycerides and stored.

Role of Insulin in Storage of Fat in the Adipose Cells. Insulin has two other essential effects that are required for fat storage in adipose cells:

1. Insulin inhibits the action of hormone-sensitive lipase. This is the enzyme that causes hydrolysis of the triglycerides already stored in the fat cells. Therefore, the release of fatty acids from the adipose tissue into the circulating blood is inhibited.

2. Insulin promotes glucose transport through the cell membrane into the fat cells in exactly the same ways that it promotes glucose transport into muscle cells. Some of this glucose is then used to synthesize minute amounts of fatty acids, but more important, it also forms large quantities of a-glycerol phosphate. This substance supplies the glycerol that combines with fatty acids to form

the triglycerides that are the storage form of fat in adipose cells. Therefore, when insulin is not

available, even storage of the large amounts of fatty acids transported from the liver in the lipoproteins is almost blocked.

 

Insulin Deficiency Increases Use of Fat for Energy

All aspects of fat breakdown and use for providing energy are greatly enhanced in the absence of insulin. This occurs even normally between meals when secretion of insulin is minimal, but it becomes extreme in diabetes mellitus when secretion of insulin is almost zero. The resulting effects are as follows.

Insulin Deficiency Causes Lipolysis of Storage Fat and Release of Free Fatty Acids: In the absence of insulin, all the effects of insulin noted earlier that cause storage of fat are reversed. The most important effect is that the enzyme hormone-sensitive lipase in the fat cells becomes strongly activated. This causes hydrolysis of the stored triglycerides, releasing large quantities of

fatty acids and glycerol into the circulating blood. Consequently, the plasma concentration of free fatty acids begins to rise within minutes. This free fatty acid then becomes the main energy substrate used by essentially all tissues of the body besides the brain.

 

Insulin Deficiency increases Plasma Cholesterol and Phospholipid Concentrations. The excess of fatty acids in the plasma associated with insulin deficiency also promotes liver conversion of some of the fatty acids into phospholipids and cholesterol, two of the major products of fat metabolism. These two substances, along with excess triglycerides formed at the same time in the liver, are then discharged into the blood in the lipoproteins. Occasionally the plasma lipoproteins increase as much as threefold in the absence of insulin, giving a total concentration of plasma lipids of several percent rather than the normal 0.6 %. This high lipid concentration—especially the high concentration of cholesterol—promotes the development of atherosclerosis in people with serious diabetes.

Excess Usage of Fats during Insulin Lack Causes Ketosis and Acidosis: Insulin lack also causes excessive formation of acetoacetic acid in the liver cells, due to following effect:

In the absence of insulin, but in the presence of excess fatty acids in the liver cells, the carnitine transport mechanism for transporting fatty acids into the mitochondria becomes increasingly activated. In the mitochondria, beta oxidation of the fatty acids then proceeds very rapidly, releasing extreme amounts of acetyl-CoA. A large part of this excess acetyl-CoA is then condensed to form acetoacetic acid, which in turn is released into the circulating blood. Most of this passes to the peripheral cells, where it is again converted into acetyl-CoA and used for energy in the usual manner. At the same time, absence of insulin also depresses the utilization of acetoacetic acid in the peripheral tissues. Thus, so much acetoacetic acid is released from the liver that it cannot all be metabolized by the tissues. Therefore, its concentration rises during the days after cessation of insulin secretion, sometimes reaching concentrations of 10 mEq./ L or more, which is a severe state of body fluid acidosis. Some of the acetoacetic acid is also converted into b-hydroxybutyric acid and acetone. These two substances, along with the acetoacetic acid, are called ketone bodies, and their presence in large quantities in the body fluids is called ketosis. In severe diabetes the acetoacetic acid and the b-hydroxybutyric acid can cause severe acidosis and coma, which often leads to death.

Effect of Insulin on Protein Metabolism and on Growth

Insulin Promotes Protein Synthesis and Storage: During the few hours after a meal when excess quantities of nutrients are available in the circulating blood, not only carbohydrates and fats but proteins as well are stored in the tissues; insulin is required for this to occur. The manner in which insulin causes protein storage is not as well understood as the mechanisms for both glucose and fat storage. Some of the facts are as follows;

1. Insulin stimulates transport of many of the amino acids into the cells. Among the amino acids most strongly transported are valine, leucine, isoleucine, tyrosine, and phenylalanine. Thus, insulin shares with growth hormone the capability of increasing the uptake of amino acids into cells. However, the amino acids affected are not necessarily the same ones.

2. Insulin increases the translation of messenger RNA, thus forming new proteins. In some unexplained way, insulin “turns on” the ribosomal machinery. In the absence of insulin, the ribosomes simply stop working, almost as if insulin operates an “on-off” mechanism.

3. Over a longer period of time, insulin also increases the rate of transcription of selected DNA genetic sequences in the cell nuclei, thus forming increased quantities of RNA and still more protein synthesis—especially promoting a vast array of enzymes for storage of carbohydrates, fats, and proteins.

4. Insulin inhibits the catabolism of proteins, thus decreasing the rate of amino acid release from the cells, especially from the muscle cells. Presumably this results from the ability of insulin to diminish the normal degradation of proteins by the cellular lysosomes.

5. In the liver, insulin depresses the rate of gluconeogenesis. It does this by decreasing

the activity of the enzymes that promote gluconeogenesis. Because the substrates most used for synthesis of glucose by gluconeogenesis are the plasma amino acids, this suppression of gluconeogenesis conserves the amino acids in the protein stores of the body. In summary, insulin promotes protein formation and prevents the degradation of proteins.

Insulin Lack Causes Protein Depletion and Increased Plasma Amino Acids. Virtually all protein storage comes to a halt when insulin is not available. The catabolism of proteins increases, protein synthesis stops, and large quantities of amino acids are dumped into the plasma. The plasma amino acid concentration rises considerably, and most of the excess amino acids are used either directly for energy or as substrates for gluconeogenesis. This degradation of the amino acids also leads to enhanced urea excretion in the urine. The resulting protein wasting is one of the most serious of all the effects of severe diabetes mellitus. It can lead to extreme weakness as well as many deranged functions of the organs.

Insulin and Growth Hormone Interact Synergistically to Promote Growth: Because insulin is required for the synthesis of proteins, it is as essential for growth of an animal as growth hormone. Administration of either growth hormone or insulin one at a time causes almost no growth. Yet a combination of these hormones causes dramatic growth. Thus, it appears that the two hormones function synergistically to promote growth, each performing a specific function that is separate from that of the other. Perhaps a small part of this necessity for both hormones results from the fact that each promotes cellular uptake of a different selection of amino acids, all of which are required if growth is to be achieved.

Mechanisms of Insulin Secretion

The beta cells have a large number of glucose transporters (GLUT- 2) that permit a rate of glucose influx that is proportional to the blood concentration in the physiologic range. Once inside the cells, glucose is phosphorylated to glucose-6-phosphate by glucokinase. This step appears to be the rate limiting for glucose metabolism in the beta cell and is considered the major mechanism for glucose sensing and adjustment of the amount of secreted insulin to the blood glucose levels. The glucose-6-phosphate is subsequently oxidized to form adenosine triphosphate (ATP), which inhibits the ATP-sensitive potassium channels of the cell. Closure of the potassium channels depolarizes the cell membrane, thereby opening voltage-gated calcium channels, which are sensitive to changes in membrane voltage. This produces an influx of calcium that stimulates

fusion of the docked insulin-containing vesicles with the cell membrane and secretion of insulin into the extracellular fluid by exocytosis. Other nutrients, such as certain amino acids, can also be metabolized by the beta cells to increase intracellular ATP levels and stimulate insulin secretion. Some hormones, such as glucagon and gastric inhibitory peptide, as well as acetylcholine increase intracellular calcium levels through other signaling pathways and enhance the effect of glucose, although they do not have major effects on insulin secretion in the absence of glucose. Other hormones, including somatostatin and norepinephrine (by activating a-adrenergic receptors), inhibit exocytosis of insulin. Sulfonylurea drugs stimulate insulin secretion by binding to the ATP-sensitive potassium channels and blocking their activity. This results in a depolarizing effect that triggers insulin secretion, making these drugs very useful in stimulating insulin secretion in patients with type II diabetes

Control of Insulin Secretion: Formerly, it was believed that insulin secretion was controlled almost entirely by the blood glucose concentration. However, as more has been learned about

the metabolic functions of insulin for protein and fat metabolism, it has become apparent that blood amino acids and other factors also play important roles in controlling insulin secretion.

Increased Blood Glucose Stimulates Insulin Secretion. At the normal fasting level of blood glucose of 80 to 90 mg/100 ml, the rate of insulin secretion is minimal— on the order of 25 ng/min/kg of body weight, a level that has only slight physiologic activity. If the blood glucose concentration is suddenly increased to a level two to three times normal and kept at this high level thereafter, insulin secretion increases markedly in two stages, as shown by the changes in plasma insulin concentration.

1. Plasma insulin concentration increases almost 10-fold within 3 to 5 minutes after the acute elevation of the blood glucose; this results from immediate dumping of preformed insulin from the beta cells of the islets of Langerhans. However, the initial high rate of secretion is not maintained; instead, the insulin concentration decreases about halfway back toward normal in another 5 to 10 minutes.

2. Beginning at about 15 minutes, insulin secretion rises a second time and reaches a new plateau in 2 to 3 hours, this time usually at a rate of secretion even greater than that in the initial phase. This secretion results both from additional release of preformed insulin and from activation of the enzyme system that synthesizes and releases new insulin from the cells.

Feedback Relation Between Blood Glucose Concentration and Insulin Secretion Rate: As the concentration of blood glucose rises above 100 mg/100 ml of blood, the rate of insulin secretion rises rapidly, reaching a peak some 10 to 25 times the basal level at blood glucose concentrations between 400 and 600 mg/100 ml, as shown in Figure 78–9. Thus, the increase in insulin secretion under a glucose stimulus is dramatic both in its rapidity and in the tremendous level of secretion achieved. Furthermore, the turn-off of insulin secretion is almost equally as rapid, occurring within 3 to 5 minutes after reduction in blood glucose concentration back to the fasting level. This response of insulin secretion to an elevated blood glucose concentration provides an extremely important feedback mechanism for regulating blood glucose concentration. That is, any rise in blood glucose increases insulin secretion and the insulin in turn increases transport of glucose into liver, muscle, and other cells, thereby reducing the blood glucose concentration back toward the normal value.

Other Factors that Stimulate Insulin Secretion

Amino Acids. In addition to the stimulation of insulin secretion by excess blood glucose, some of the amino acids have a similar effect.The most potent of these are arginine and lysine. This effect differs from glucose stimulation of insulin secretion in the following way: Amino acids administered in the absence of a rise in blood glucose cause only a small increase in insulin secretion. However, when administered at the same time that the blood glucose concentration is elevated, the glucose induced secretion of insulin may be as much as doubled in the presence of the excess amino acids. Thus, the amino acids strongly potentiate the glucose stimulus for insulin secretion. The stimulation of insulin secretion by amino acids is important, because the insulin in turn promotes transport of amino acids into the tissue cells as well as intracellular formation of protein. That is, insulin is important for proper utilization of excess amino acids in the same way that it is important for the utilization of carbohydrates.

Gastrointestinal Hormones. A mixture of several important gastrointestinal hormones—gastrin, secretin, cholecystokinin, and gastric inhibitory peptide (which seems to be the most potent)—causes a moderate increase in insulin secretion. These hormones are released in the gastrointestinal tract after a person eats a meal. They then cause an “anticipatory” increase in blood insulin in preparation for the glucose and amino acids to be absorbed from the meal. These gastrointestinal hormones generally act the same way as amino acids to increase the sensitivity of insulin response to increased blood glucose, almost doubling the rate of insulin secretion as the blood glucose level rises.

Glucagon and Its Functions

Glucagon, a hormone secreted by the alpha cells of the islets of Langerhans when the blood glucose concentration falls, has several functions that are diametrically opposed to those of insulin. Most important of these functions is to increase the blood glucose concentration, an effect that is exactly the opposite that of insulin.

Like insulin, glucagon is a large polypeptide. It has a molecular weight of 3485 and is composed of a chain of 29 amino acids. On injection of purified glucagon into an animal, a profound hyperglycemic effect occurs. Only 1 mg/kg of glucagon can elevate the blood glucose concentration about 20 mg/100 ml of blood (a 25 per cent increase) in about 20 minutes. For this

reason, glucagon is also called the hyperglycemic hormone.

Effects on Glucose Metabolism

The major effects of glucagon on glucose metabolism are (1) breakdown of liver glycogen (glycogenolysis) and (2) increased gluconeogenesis in the liver. Both of these effects greatly enhance the availability of glucose to the other organs of the body.

Glucagon Causes Glycogenolysis and Increased Blood Glucose Concentration. The most dramatic effect of glucagon is its ability to cause glycogenolysis in the liver, which in turn increases the blood glucose concentration within minutes. It does this by the following complex cascade of events:

1. Glucagon activates adenylyl cyclase in the hepatic cell membrane,

2. Which causes the formation of cyclic adenosine monophosphate,

3. Which activates protein kinase regulator protein,

4. Which activates protein kinase,

5. Which activates phosphorylase b kinase,

6. Which converts phosphorylase b into phosphorylase a,

7. Which promotes the degradation of glycogen into glucose-1-phosphate,

8. Which then is dephosphorylated; and the glucose is released from the liver cells.

This sequence of events is exceedingly important for several reasons. First, it is one of the most thoroughly studied of all the second messenger functions of cyclic adenosine monophosphate. Second, it demonstrates a cascade system in which each succeeding product is produced in greater quantity than the preceding product. Therefore, it represents a potent amplifying mechanism; this type of amplifying mechanism is widely used throughout the body for controlling many, if not most, cellular metabolic systems, often causing as much as a millionfold amplification in response.This explains how only a few micrograms of glucagon can cause the blood glucose level to double or increase even more within a few minutes.

Infusion of glucagon for about 4 hours can cause such intensive liver glycogenolysis that all the liver stores of glycogen become depleted.

Glucagon Increases Gluconeogenesis. Even after all the glycogen in the liver has been exhausted under the influence of glucagon, continued infusion of this hormone still causes continued hyperglycemia. This results from the effect of glucagon to increase the rate of amino acid uptake by the liver cells and then the conversion of many of the amino acids to glucose by gluconeogenesis. This is achieved by activating multiple enzymes that are required for amino acid transport and gluconeogenesis, especially activation of the enzyme system for converting pyruvate to phosphoenolpyruvate, a rate-limiting step in gluconeogenesis.

 

Other Effects of Glucagon

Most other effects of glucagon occur only when its concentration rises well above the maximum normally found in the blood. Perhaps the most important effect is that glucagon activates adipose cell lipase, making increased quantities of fatty acids available to the energy systems of the body. Glucagon also inhibits the storage of triglycerides in the liver, which prevents the liver from removing fatty acids from the blood; this also helps make additional amounts of fatty acids available for the other tissues of the body. Glucagon in very high concentrations also (1) enhances the strength of the heart; (2) increases blood flow in some tissues, especially the kidneys; (3) enhances bile secretion; and (4) inhibits gastric acid secretion. All these effects are probably of minimal importance in the normal function of the body.

Regulation of Glucagon Secretion Increased Blood Glucose Inhibits Glucagon Secretion. The blood glucose concentration is by far the most potent factor that controls glucagon secretion. Note specifically, however, that the effect of blood glucose concentration on glucagon secretion is in exactly the opposite direction from the effect of glucose on insulin secretion.

Conversely, increasing the blood glucose to hyperglycemic levels decreases plasma glucagon. Thus, in hypoglycemia, glucagon is secreted in large amounts; it then greatly increases the output of glucose from the liver and thereby serves the important function of correcting the hypoglycemia.

Increased Blood Amino Acids Stimulate Glucagon Secretion.

High concentrations of amino acids, as occur in the blood after a protein meal (especially the amino acids alanine and arginine), stimulate the secretion of glucagon.This is the same effect that amino acids have in stimulating insulin secretion. Thus, in this instance, the glucagon and insulin responses are not opposites. The importance of amino acid stimulation of glucagon secretion is that the glucagon then promotes rapid conversion of the amino acids to glucose, thus making even more glucose available to the tissues.

Exercise Stimulates Glucagon Secretion. In exhaustive exercise, the blood concentration of glucagon often increases fourfold to fivefold. What causes this is not understood, because the blood glucose concentration does not necessarily fall. A beneficial effect of the glucagon is that it prevents a decrease in blood glucose.

One of the factors that might increase glucagon secretion in exercise is increased circulating amino acids. Other factors, such as b-adrenergic stimulation of the islets of Langerhans, may also play a role.

Somatostatin Inhibits Glucagon and Insulin Secretion

The delta cells of the islets of Langerhans secrete the hormone somatostatin, a polypeptide containing only 14 amino acids that has an extremely short half-life of only 3 minutes in the circulating blood. Almost all factors related to the ingestion of food stimulate somatostatin secretion. They include (1) increased blood glucose, (2) increased amino acids, (3) increased fatty acids, and (4) increased concentrations of several of the gastrointestinal hormones released from the upper gastrointestinal tract in response to food intake.

In turn, somatostatin has multiple inhibitory effects as follows:

1. Somatostatin acts locally within the islets of Langerhans themselves to depress the secretion of

both insulin and glucagon.

2. Somatostatin decreases the motility of the stomach, duodenum, and gallbladder.

3. Somatostatin decreases both secretion and absorption in the gastrointestinal tract.

Putting all this information together, it has been suggested that the principal role of somatostatin is to extend the period of time over which the food nutrients are assimilated into the blood. At the same time, the effect of somatostatin to depress insulin and glucagon secretion decreases the utilization of the absorbed nutrients by the tissues, thus preventing rapid exhaustion of the food and therefore making it available over a longer period of time.

It should also be recalled that somatostatin is the same chemical substance as growth hormone inhibitory hormone, which is secreted in the hypothalamus and suppresses anterior pituitary gland growth hormone secretion.