78 Insulin, Glucagon, And Diabetes Mellitus-2

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Physiologic Anatomy of the Pancreas

The pancreas is composed of two major types of tissues, as shown in Figure 78-1: (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 digestive secretions of the pancreas

The human pancreas has 1 to 2 million islets of Langerhans, each only about 0.3 millimeter 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 percent 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 percent of the total, secrete glucagon. And the delta cells, about 10 percent 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.

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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, shown in Figure 78-2, 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.

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Insulin is synthesized in the beta cells by the usual cell machinery for protein synthesis, as explained in Chapter 3, beginning with translation of the insulin RNA by ribosomes attached to the endoplasmic reticulum to form preproinsulin. This initial preproinsulin has a molecular weight of about 11,500, but it is then cleaved in the endoplasmic reticulum to form a proinsulin with a molecular weight of about 9000 and consisting of three chains of peptides, A, B, and C. Most of the proinsulin is further cleaved in the Golgi apparatus to form insulin, composed of the A and B chain connected by disulfide linkages, and the C chain peptide, called connecting peptide (C peptide). The insulin and C peptide are packaged in the secretory granules and secreted in equimolar amounts. About 5 to 10 percent of the final secreted product is still in the form of proinsulin.

The proinsulin and C peptide have virtually no insulin activity. However, C peptide binds to a membrane structure, most likely a G protein-coupled membrane receptor, and elicits activation of at least two enzyme systems, sodium-potassium ATPase and endothelial nitric oxide synthase. Although both of these enzymes have multiple physiological functions, the importance of C peptide in regulating these enzymes is still uncertain

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Measurement of C peptide levels by radioimmunoassay can be used in insulin-treated diabetic patients to determine how much of their own natural insulin they are still producing. Patients with type 1 diabetes who are unable to produce insulin will usually have greatly decreased levels of C peptide

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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
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 autophosphorylated. Thus, the insulin receptor is an example of an enzyme-linked receptor, discussed in Chapter 74. Autophosphorylation of the 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

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The end effects of insulin stimulation are the following: 1.Within seconds after insulin binds with its membrane receptors, the membranes of about 80 percent 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 intracellular vesicles to the cell membranes; these vesicles carry 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.

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Effect of Insulin on Carbohydrate Metabolism

Insulin Promotes Muscle Glucose Uptake and Metabolism


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 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, as discussed later.

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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 percent 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.

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Insulin Promotes Liver Uptake, Storage, and Use of Glucose
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

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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.

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Insulin Promotes Conversion of Excess Glucose into Fatty Acids
When the quantity of glucose entering the liver cells is more than can be stored as glycogen or can be used for local hepatocyte metabolism, insulin promotes the conversion of all this excess glucose into fatty acids. These fatty acids 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.

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Insulin inhibits Gluconeogenesis in the Liver
Insulin also inhibits gluconeogenesis. It does this mainly by decreasing the quantities and activities of the 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. This is discussed further in relation to the effect of insulin on protein metabolism.

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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, most of 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

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Insulin Promotes Fat Synthesis
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 glycogen concentration reaches 5 to 6 percent, 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 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.

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Insulin Promotes Fat Storage
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 the same way 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 α-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.

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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. These free fatty acids then become the main energy substrate used by essentially all tissues of the body except the brain.

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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 percent. This high lipid concentration-especially the high concentration of cholesterol-promotes the development of atherosclerosis in people with serious diabetes.

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Excess Usage of Fats During Insulin Lack Causes Ketosis and Acidosis

Insulin lack also causes excessive amounts of acetoacetic acid to be formed in the liver cells due to the 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 rapidly, releasing extreme amounts of acetyl-CoA. A large part of this excess acetyl-CoA is then condensed to form acetoacetic acid, which is then 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.

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Insulin Promotes Protein Synthesis and Storage
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.

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Insulin Deficiency 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 and many deranged functions of the organs.

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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 is.
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.

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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 physiological range. Once inside the cells, glucose is phosphorylated to glucose-6-phosphate by glucokinase. This appears to be the rate limiting step 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, glucose-dependent insulinotropic peptide (gastric inhibitory peptide), and 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 α-adrenergic receptors), inhibit exocytosis of insulin.

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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 useful in stimulating insulin secretion in patients with type II diabetes, as we discuss later

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Control of 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 physiological 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
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.

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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

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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.

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Gastrointestinal Hormones


A mixture of several important gastrointestinal hormones-gastrin, secretin, cholecystokinin, and glucose-dependent insulinotrophic 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.

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Other Hormones

Other hormones that either directly increase insulin secretion or potentiate the glucose stimulus for insulin secretion include glucagon, growth hormone, cortisol, and, to a lesser extent, progesterone and estrogen. The importance of the stimulatory effects of these hormones is that prolonged secretion of any one of them in large quantities can occasionally lead to exhaustion of the beta cells of the islets of Langerhans and thereby increase the risk for developing diabetes mellitus. Indeed, diabetes often occurs in people who are maintained on high pharmacological doses of some of these hormones. Diabetes is particularly common in giants or acromegalic people with growth hormone-secreting tumors, or in people whose adrenal glands secrete excess glucocorticoids.

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the Autonomic Nervous System
Under some conditions, stimulation of the parasympathetic nerves to the pancreas can increase insulin secretion, whereas sympathetic nerve stimulation may decrease insulin secretion. However, it is doubtful that these effects play a major role in physiological regulation of insulin secretion

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Role of Insulin (and Other Hormones) in "Switching" Between Carbohydrate and Lipid Metabolism


From the preceding discussions, it should be clear that insulin promotes the utilization of carbohydrates for energy, whereas it depresses the utilization of fats. Conversely, lack of insulin causes fat utilization mainly to the exclusion of glucose utilization, except by brain tissue. Furthermore, the signal that controls this switching mechanism is principally the blood glucose concentration. When the glucose concentration is low, insulin secretion is suppressed and fat is used almost exclusively for energy everywhere except in the brain. When the glucose concentration is high, insulin secretion is stimulated and carbohydrate is used instead of fat. The excess blood glucose is stored in the form of liver glycogen, liver fat, and muscle glycogen. Therefore, one of the most important functional roles of insulin in the body is to control which of these two foods from moment to moment will be used by the cells for energy.

At least four other known hormones also play important roles in this switching mechanism: growth hormone from the anterior pituitary gland, cortisol from the adrenal cortex, epinephrine from the adrenal medulla, and glucagon from the alpha cells of the islets of Langerhans in the pancreas

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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 μg/kg of glucagon can elevate the blood glucose concentration about 20 mg/100 ml of blood (a 25 percent increase) in about 20 minutes. For this reason, glucagon is also called the hyperglycemic hormone.

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

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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

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Other Effects of Glucagon

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 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

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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.

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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.

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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 β-adrenergic stimulation of the islets of Langerhans, may also play a role

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Somatostatin Inhibits Glucagon and Insulin Secretion


The delta cells of the islets of Langerhans secrete the hormone somatostatin, a 14 amino acid polypeptide 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.

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Summary of Blood Glucose Regulation


In a normal person, the blood glucose concentration is narrowly controlled, usually between 80 and 90 mg/100 ml of blood in the fasting person each morning before breakfast

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The mechanisms for achieving this high degree of control have been presented in this chapter. Let us summarize them. 1.The liver functions as an important blood glucose buffer system. That is, when the blood glucose rises to a high concentration after a meal and the rate of insulin secretion also increases, as much as two thirds of the glucose absorbed from the gut is almost immediately stored in the liver in the form of glycogen. Then, during the succeeding hours, when both the blood glucose concentration and the rate of insulin secretion fall, the liver releases the glucose back into the blood. In this way, the liver decreases the fluctuations in blood glucose concentration to about one third of what they would otherwise be. In fact, in patients with severe liver disease, it becomes almost impossible to maintain a narrow range of blood glucose concentration.

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Importance of Blood Glucose Regulation


One might ask the question: Why is it so important to maintain a constant blood glucose concentration, particularly because most tissues can shift to utilization of fats and proteins for energy in the absence of glucose? The answer is that glucose is the only nutrient that normally can be used by the brain, retina, and germinal epithelium of the gonads in sufficient quantities to supply them optimally with their required energy. Therefore, it is important to maintain the blood glucose concentration at a sufficiently high level to provide this necessary nutrition

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It is also important that the blood glucose concentration not rise too high for four reasons: (1) Glucose can exert a large amount of osmotic pressure in the extracellular fluid, and if the glucose concentration rises to excessive values, this can cause considerable cellular dehydration. (2) An excessively high level of blood glucose concentration causes loss of glucose in the urine. (3) Loss of glucose in the urine also causes osmotic diuresis by the kidneys, which can deplete the body of its fluids and electrolytes. (4) Long-term increases in blood glucose may cause damage to many tissues, especially to blood vessels. Vascular injury associated with uncontrolled diabetes mellitus leads to increased risk for heart attack, stroke, end-stage renal disease, and blindness.

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Type I Diabetes-Deficiency of Insulin Production by Beta Cells of the Pancreas


Injury to the beta cells of the pancreas or diseases that impair insulin production can lead to type I diabetes. Viral infections or autoimmune disorders may be involved in the destruction of beta cells in many patients with type I diabetes, although heredity also plays a major role in determining the susceptibility of the beta cells to destruction by these insults. In some instances, there may be a hereditary tendency for beta cell degeneration even without viral infections or autoimmune disorders.

The usual onset of type I diabetes occurs at about 14 years of age in the United States, and for this reason it is often called juvenile diabetes mellitus. However, type I diabetes can occur at any age, including adulthood, following disorders that lead to destruction of pancreatic beta cells. Type I diabetes may develop abruptly, over a period of a few days or weeks, with three principal sequelae: (1) increased blood glucose, (2) increased utilization of fats for energy and for formation of cholesterol by the liver, and (3) depletion of the body's proteins. Approximately 5 to 10 percent of people with diabetes mellitus have the type I form of the disease.

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Increased Blood Glucose Causes Loss of Glucose in the Urine

The high blood glucose causes more glucose to filter into the renal tubules than can be reabsorbed, and the excess glucose spills into the urine. This normally occurs when the blood glucose concentration rises above 180 mg/100 ml, a level that is called the blood "threshold" for the appearance of glucose in the urine. When the blood glucose level rises to 300 to 500 mg/100 ml-common values in people with severe untreated diabetes-100 or more grams of glucose can be lost into the urine each day.

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Increased Blood Glucose Causes Dehydration


The very high levels of blood glucose (sometimes as high as 8 to 10 times normal in severe untreated diabetes) can cause severe cell dehydration throughout the body. This occurs partly because glucose does not diffuse easily through the pores of the cell membrane, and the increased osmotic pressure in the extracellular fluids causes osmotic transfer of water out of the cells.

In addition to the direct cellular dehydrating effect of excessive glucose, the loss of glucose in the urine causes osmotic diuresis. That is, the osmotic effect of glucose in the renal tubules greatly decreases tubular reabsorption of fluid. The overall effect is massive loss of fluid in the urine, causing dehydration of the extracellular fluid, which in turn causes compensatory dehydration of the intracellular fluid, for reasons discussed in Chapter 26. Thus, polyuria (excessive urine excretion), intracellular and extracellular dehydration, and increased thirst are classic symptoms of diabetes.

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Chronic High Glucose Concentration Causes Tissue Injury

When blood glucose is poorly controlled over long periods in diabetes mellitus, blood vessels in multiple tissues throughout the body begin to function abnormally and undergo structural changes that result in inadequate blood supply to the tissues. This in turn leads to increased risk for heart attack, stroke, end-stage kidney disease, retinopathy and blindness, and ischemia and gangrene of the limbs.

Chronic high glucose concentration also causes damage to many other tissues. For example, peripheral neuropathy, which is abnormal function of peripheral nerves, and autonomic nervous system dysfunction are frequent complications of chronic, uncontrolled diabetes mellitus. These abnormalities can result in impaired cardiovascular reflexes, impaired bladder control, decreased sensation in the extremities, and other symptoms of peripheral nerve damage.

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Diabetes Mellitus Causes Increased Utilization of Fats and Metabolic Acidosis

The shift from carbohydrate to fat metabolism in diabetes increases the release of keto acids, such as acetoacetic acid and β-hydroxybutyric acid, into the plasma more rapidly than they can be taken up and oxidized by the tissue cells. As a result, the patient develops severe metabolic acidosis from the excess keto acids, which, in association with dehydration due to the excessive urine formation, can cause severe acidosis. This leads rapidly to diabetic coma and death unless the condition is treated immediately with large amounts of insulin.

All the usual physiological compensations that occur in metabolic acidosis take place in diabetic acidosis. They include rapid and deep breathing, which causes increased expiration of carbon dioxide; this buffers the acidosis but also depletes extracellular fluid bicarbonate stores. The kidneys compensate by decreasing bicarbonate excretion and generating new bicarbonate that is added back to the extracellular fluid.

Although extreme acidosis occurs only in the most severe instances of uncontrolled diabetes, when the pH of the blood falls below about 7.0, acidotic coma and death can occur within hours. The overall changes in the electrolytes of the blood as a result of severe diabetic acidosis are shown in Figure 78-11.

Excess fat utilization in the liver occurring over a long time causes large amounts of cholesterol in the circulating blood and increased deposition of cholesterol in the arterial walls. This leads to severe arteriosclerosis and other vascular lesions, as discussed earlier.

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Diabetes Causes Depletion of the Body's Proteins

Failure to use glucose for energy leads to increased utilization and decreased storage of proteins and fat. Therefore, a person with severe untreated diabetes mellitus suffers rapid weight loss and asthenia (lack of energy) despite eating large amounts of food (polyphagia). Without treatment, these metabolic abnormalities can cause severe wasting of the body tissues and death within a few weeks.

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Obesity, Insulin Resistance, and "Metabolic Syndrome" Usually Precede Development of Type II Diabetes

Type II diabetes, in contrast to type I, is associated with increased plasma insulin concentration (hyperinsulinemia). This occurs as a compensatory response by the pancreatic beta cells for diminished sensitivity of target tissues to the metabolic effects of insulin, a condition referred to as insulin resistance. The decrease in insulin sensitivity impairs carbohydrate utilization and storage, raising blood glucose and stimulating a compensatory increase in insulin secretion.

Development of insulin resistance and impaired glucose metabolism is usually a gradual process, beginning with excess weight gain and obesity. The mechanisms that link obesity with insulin resistance, however, are still uncertain. Some studies suggest that there are fewer insulin receptors, especially in the skeletal muscle, liver, and adipose tissue, in obese than in lean subjects. However, most of the insulin resistance appears to be caused by abnormalities of the signaling pathways that link receptor activation with multiple cellular effects. Impaired insulin signaling appears to be closely related to toxic effects of lipid accumulation in tissues such as skeletal muscle and liver secondary to excess weight gain.

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Metabolic syndrome.

Some of the features of the metabolic syndrome include (1) obesity, especially accumulation of abdominal fat; (2) insulin resistance; (3) fasting hyperglycemia; (4) lipid abnormalities, such as increased blood triglycerides and decreased blood high-density lipoprotein-cholesterol; and (5) hypertension. All of the features of the metabolic syndrome are closely related to accumulation of excess adipose tissue in the abdominal cavity around the visceral organs.

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Other Factors That Can Cause Insulin Resistance and Type II Diabetes

Polycystic ovary syndrome (PCOS), for example, is associated with marked increases in ovarian androgen production and insulin resistance and is one of the most common endocrine disorders in women, affecting approximately 6 percent of all women during their reproductive life. Although the pathogenesis of PCOS remains uncertain, insulin resistance and hyperinsulinemia are found in approximately 80 percent of affected women. The long-term consequences include increased risk for diabetes mellitus, increased blood lipids, and cardiovascular disease.


Excess formation of glucocorticoids (Cushing's syndrome) or growth hormone (acromegaly) also decreases the sensitivity of various tissues to the metabolic effects of insulin and can lead to development of diabetes mellitus. Genetic causes of obesity and insulin resistance, if severe enough, also can lead to type II diabetes and many other features of the metabolic syndrome including cardiovascular disease.

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Physiology of Diagnosis of Diabetes Mellitus

Urinary Glucose

Simple office tests or more complicated quantitative laboratory tests may be used to determine the quantity of glucose lost in the urine. In general, a normal person loses undetectable amounts of glucose, whereas a person with diabetes loses glucose in small to large amounts, in proportion to the severity of disease and the intake of carbohydrates.

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Fasting Blood Glucose and Insulin Levels

The fasting blood glucose level in the early morning is normally 80 to 90 mg/100 ml, and 110 mg/100 ml is considered to be the upper limit of normal. A fasting blood glucose level above this value often indicates diabetes mellitus or at least marked insulin resistance.

In type I diabetes, plasma insulin levels are very low or undetectable during fasting and even after a meal. In type II diabetes, plasma insulin concentration may be severalfold higher than normal and usually increases to a greater extent after ingestion of a standard glucose load during a glucose tolerance test (see the next paragraph).

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Glucose Tolerance Test

As demonstrated by the bottom curve in Figure 78-12, called a "glucose tolerance curve," when a normal, fasting person ingests 1 gram of glucose per kilogram of body weight, the blood glucose level rises from about 90 mg/100 ml to 120 to 140 mg/100 ml and falls back to below normal in about 2 hours.
In a person with diabetes, the fasting blood glucose concentration is almost always above 110 mg/100 ml and often above 140 mg/100 ml. Also, the glucose tolerance test is almost always abnormal. On ingestion of glucose, these people exhibit a much greater than normal rise in blood glucose level, as demonstrated by the upper curve in Figure 78-12, and the glucose level falls back to the control value only after 4 to 6 hours; furthermore, it fails to fall below the control level. The slow fall of this curve and its failure to fall below the control level demonstrate that either (1) the normal increase in insulin secretion after glucose ingestion does not occur or (2) there is decreased sensitivity to insulin. A diagnosis of diabetes mellitus can usually be established on the basis of such a curve, and type I and type II diabetes can be distinguished from each other by measurements of plasma insulin, with plasma insulin being low or undetectable in type I diabetes and increased in type II diabetes.

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Acetone Breath

As pointed out in Chapter 68, small quantities of acetoacetic acid in the blood, which increase greatly in severe diabetes, are converted to acetone. This is volatile and vaporized into the expired air. Consequently, one can frequently make a diagnosis of type I diabetes mellitus simply by smelling acetone on the breath of a patient. Also, keto acids can be detected by chemical means in the urine and their quantitation aids in determining the severity of the diabetes. In the early stages of type II diabetes, however, keto acids are usually not produced in excess amounts. However, when insulin resistance becomes severe and there is greatly increased utilization of fats for energy, keto acids are then produced in persons with type II diabetes.

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Treatment of Diabetes

Effective treatment of type I diabetes mellitus requires administration of enough insulin so that the patient will have carbohydrate, fat, and protein metabolism that is as normal as possible. Insulin is available in several forms. "Regular" insulin has a duration of action that lasts from 3 to 8 hours, whereas other forms of insulin (precipitated with zinc or with various protein derivatives) are absorbed slowly from the injection site and therefore have effects that last as long as 10 to 48 hours. Ordinarily, a patient with severe type I diabetes is given a single dose of one of the longer-acting insulins each day to increase overall carbohydrate metabolism throughout the day. Then additional quantities of regular insulin are given during the day at those times when the blood glucose level tends to rise too high, such as at mealtimes. Thus, each patient is provided with an individualized pattern of treatment.

In persons with type II diabetes, dieting and exercise are usually recommended in an attempt to induce weight loss and to reverse the insulin resistance. If this fails, drugs may be administered to increase insulin sensitivity or to stimulate increased production of insulin by the pancreas. In many persons, however, exogenous insulin must be used to regulate blood glucose.

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Relation of Treatment to Arteriosclerosis

Diabetic patients, mainly because of their high levels of circulating cholesterol and other lipids, develop atherosclerosis, arteriosclerosis, severe coronary heart disease, and multiple microcirculatory lesions far more easily than do normal people. Indeed, those who have poorly controlled diabetes throughout childhood are likely to die of heart disease in early adulthood.

In the early days of treating diabetes, the tendency was to severely reduce the carbohydrates in the diet so that the insulin requirements would be minimized. This procedure kept the blood glucose from increasing too high and attenuated loss of glucose in the urine, but it did not prevent many of the abnormalities of fat metabolism. Consequently, the current tendency is to allow the patient an almost normal carbohydrate diet and to give enough insulin to metabolize the carbohydrates. This decreases the rate of fat metabolism and depresses the high level of blood cholesterol.

Because the complications of diabetes, such asatherosclerosis, increased susceptibility to infection, diabetic retinopathy, cataracts, hypertension, and chronic renal disease, are closely associated with the levels of blood lipids and blood glucose, most physicians also use lipid-lowering drugs to help prevent these disturbances

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Insulinoma-Hyperinsulinism

Although much rarer than diabetes, excessive insulin production occasionally occurs from an adenoma of an islet of Langerhans. About 10 to 15 percent of these adenomas are malignant, and occasionally metastases from the islets of Langerhans spread throughout the body, causing tremendous production of insulin by both the primary and metastatic cancers. Indeed, more than 1000 grams of glucose have had to be administered every 24 hours to prevent hypoglycemia in some of these patients.

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Insulin Shock and Hypoglycemia

in patients with insulin-secreting tumors or in patients with diabetes who administer too much insulin to themselves, the syndrome called insulin shock may occur as follows.


As the blood glucose level falls into the range of 50 to 70 mg/100 ml, the central nervous system usually becomes excitable because this degree of hypoglycemia sensitizes neuronal activity. Sometimes various forms of hallucinations result, but more often the patient simply experiences extreme nervousness, trembles all over, and breaks out in a sweat. As the blood glucose level falls to 20 to 50 mg/100 ml, clonic seizures and loss of consciousness are likely to occur. As the glucose level falls still lower, the seizures cease and only a state of coma remains. Indeed, at times it is difficult by simple clinical observation to distinguish between diabetic coma as a result of insulin-lack acidosis and coma due to hypoglycemia caused by excess insulin. The acetone breath and the rapid, deep breathing of diabetic coma are not present in hypoglycemic coma.

Proper treatment for a patient who has hypoglycemic shock or coma is immediate intravenous administration of large quantities of glucose. This usually brings the patient out of shock within a minute or more. Also, the administration of glucagon (or, less effectively, epinephrine) can cause glycogenolysis in the liver and thereby increase the blood glucose level extremely rapidly. If treatment is not administered immediately, permanent damage to the neuronal cells of the central nervous system often occurs

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