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Tyrosine kinase

Tyrosine kinase

Insulin receptor substrates (IRS) Phosphorylation of enzymes

Tyrosine kinase

Tyrosine kinase i i i i i

Insulin receptor substrates (IRS) Phosphorylation of enzymes

Glucose transport sjftt

Fat synthesis

Protein synthesis

Growth and gene expression

Glucose synthesis

Figure 78-3

Schematic of the insulin receptor. Insulin binds to the a-subunit of its receptor, which causes autophosphorylation of the b-subunit receptor, which in turn induces tyrosine kinase activity. The receptor tyrosine kinase activity begins a cascade of cell phosphorylation that increases or decreases the activity of enzymes, including insulin receptor substrates, that mediate the effects of glucose on glucose, fat, and protein metabolism. For example, glucose transporters are moved to the cell membrane to facilitate glucose entry into the cell.

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 the following: 1. Within seconds after insulin binds with its membrane receptors, the membranes of about 80 per cent 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 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, which is discussed in detail later in the chapter. 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

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 we discuss later.

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 per cent 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.

Quantitative Effect of Insulin to Facilitate Glucose Transport Through the Muscle Cell Membrane. The quantitative effect of insulin to facilitate glucose transport through the muscle cell membrane is demonstrated by the experimental results shown in Figure 78-4. The lower curve labeled "control" shows the concentration of free glucose measured inside the cell, demonstrating that the glucose concentration remained almost zero despite increased extracellular glucose concentration up to as high as 750 mg/100 ml. In contrast, the curve labeled "insulin" demonstrates that the intracellular glucose concentration rose to as high as 400 mg/100 ml when insulin was added. Thus, it is clear that insulin can increase the rate of transport of glucose into the resting muscle cell by at least 15-fold.

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 per cent 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 per cent of the glucose in the meal is stored in this way in the liver and then returned later.

0 300 600 900

Extracellular glucose (mg/100 ml)

0 300 600 900

Extracellular glucose (mg/100 ml)

Figure 78-4

Effect of insulin in enhancing the concentration of glucose inside muscle cells. Note that in the absence of insulin (control), the intracellular glucose concentration remains near zero, despite high extracellular glucose concentrations. (Data from Eisenstein AB: The Biochemical Aspects of Hormone Action, Boston, Little, Brown, 1964.)

Insulin Promotes Conversion of Excess Glucose into Fatty Acids and Inhibits Gluconeogenesis 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 hepato-cyte 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.

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.

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 hypo-glycemic 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 per cent, 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.

Figure 78-5 shows the effect of insulin lack on the plasma concentrations of free fatty acids, glucose, and acetoacetic acid. Note that almost immediately after removal of the pancreas, the free fatty acid concentration in the plasma begins to rise, more rapidly even than the concentration of glucose.

Insulin Deficiency Increases Plasma Cholesterol and Phospho-lipid 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

Figure 78-5

Effect of removing the pancreas on the approximate concentrations of blood glucose, plasma free fatty acids, and acetoacetic acid.

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 per cent rather than the normal 0.6 per cent. 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 amounts of acetoacetic acid to be formed in the liver cells. This results from 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 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, the 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, as shown in Figure 78-5, 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.

As explained in Chapter 68, some of the acetoacetic acid is also converted into b-hydroxybutyric acid and acetone. These two substances, along with the ace-toacetic acid, are called ketone bodies, and their presence in large quantities in the body fluids is called ketosis. We see later that 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 follow. 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 gluco-neogenesis. 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 is. This is demonstrated in Figure 78-6, which shows that a depancreatized, hypophysec-tomized rat without therapy hardly grows at all. Furthermore, the 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.

Growth hormone

Growth hormone

Days

Figure 78-6

Days

Figure 78-6

Effect of growth hormone, insulin, and growth hormone plus insulin on growth in a depancreatized and hypophysectomized rat.

Mechanisms of Insulin Secretion

Figure 78-7 shows the basic cellular mechanisms for insulin secretion by the pancreatic beta cells in response to increased blood glucose concentration, the primary controller 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 intracel-lular 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 t

Glucose

Glucose

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