Week 3 Readings PDF - Endocrinology & Reproduction

CHAPTER 79 The pancreas, in addition to its digestive functions, secretes two major 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. The main purpose of this chapter is to discuss the physiological roles of insulin and glucagon and the pathophysiology of diseases, especially diabetes mellitus, caused by abnormal secretion or activity of these hormones. associated with “blood sugar,” and true enough, insulin has profound eﬀects on carbohydrate metabolism. However, abnormalities of fat metabolism that cause conditions such as acidosis and arteriosclerosis are also important causes of morbidity and death in patients with diabetes mellitus. Patients with prolonged, untreated diabetes have diminished ability to synthesize proteins which leads to wasting of the tissues and many cellular functional disorders. Therefore, it is clear that insulin aﬀects fat and protein metabolism almost as much as it aﬀects carbohydrate metabolism. Physiological Anatomy of the Pancreas The pancreas is composed of two major types of tissues, as shown in Figure 79-1: (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 are discussed in Chapter 65. The human pancreas has 1 to 2 million islets of Langerhans. Each islet is only about 0.3 millimeter in diameter and is organized around small capillaries, into which its cells secrete their hormones. The islets contain three major types of cells— alpha, beta, and delta cells—that 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 not well understood. 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 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 example, 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 rescued patients with severe cases of diabetes mellitus from a rapid decline in health and early death. Historically, insulin has been INSULIN IS A HORMONE ASSOCIATED WITH ENERGY ABUNDANCE As we discuss insulin in the next few pages, it will become apparent that insulin secretion is associated with energy abundance. That is, when a person’s diet includes a great abundance of foods that provide energy, especially excess amounts of carbohydrates, insulin secretion increases. In turn, the 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. Furthermore, all the excess carbohydrates that cannot be stored as glycogen are converted under the stimulus of insulin into fats and stored in adipose tissue. In the case of proteins, insulin has a direct eﬀect Islet of Langerhans Pancreatic acini Delta cell Alpha cell Red blood cells Beta cell Figure 79-1. Physiological anatomy of an islet of Langerhans in the pancreas. 973 UNIT XIV Insulin, Glucagon, and Diabetes Mellitus UNIT XIV Endocrinology and Reproduction Proinsulin C chain –COOH 21 Cleavage 1 –NH2 1 30 Cleavage A chain B chain Secretory granule C peptide Insulin Figure 79-2. A schematic of the human proinsulin molecule, which is cleaved in the Golgi apparatus of the pancreatic beta cells to form connecting peptide (C peptide), and insulin, which is composed of the A and B chains connected by disulfide bonds. The C peptide and insulin are packaged in granules and secreted in equimolar amounts, along with a small amount of proinsulin. in promoting amino acid uptake by cells and conversion of these amino acids into protein. In addition, it inhibits breakdown of proteins that are already in the cells.␣ INSULIN CHEMISTRY AND SYNTHESIS Human insulin, which has a molecular weight of 5808, is composed of two amino acid chains, shown in Figure 79-2, that are connected to each other by disulfide linkages. When the two amino acid chains are split apart, insulin’s functional activity is lost. Insulin is synthesized in 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, which is composed of the A and B chains connected by disulfide linkages, and the C chain peptide, called connecting 974 peptide (C peptide). The insulin and C peptide are packaged in secretory granules and secreted in equimolar amounts. About 5% to 10% 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 adenosine triphosphatase 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. C peptide levels can be measured by radioimmunoassay 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 also have greatly decreased levels of C peptide. When insulin is secreted into the blood, it circulates almost entirely in an unbound form. Because it has a plasma half-life that averages only about 6 minutes, it is mainly cleared from the circulation within 10 to 15 minutes. Except for the portion of the insulin that combines with receptors in the target cells, the insulin 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 rapidly turn oﬀ the control functions of insulin as it is to turn them on.␣ ACTIVATION OF TARGET CELL RECEPTORS BY INSULIN AND THE RESULTING CELLULAR EFFECTS To initiate its eﬀects on target cells, insulin must first bind with and activate a membrane receptor protein that has a molecular weight of about 300,000 (Figure 79-3). 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. Insulin binds with the alpha subunits on the outside of the cell, but because of the linkages with the beta subunits, 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 75. 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, and 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 Chapter 79 Insulin, Glucagon, and Diabetes Mellitus Insulin Insulin receptor α S S S S S S Glucose β β Cell membrane Tyrosine kinase Tyrosine kinase Insulin receptor substrates (IRS) Phosphorylation of enzymes Fat synthesis Glucose transport Protein synthesis Growth and gene expression Glycogen synthesis Figure 79-3. A schematic of the insulin receptor. Insulin binds to the α subunit of its receptor, which causes autophosphorylation of the β-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 on glucose, fat, and protein metabolism. For example, glucose transporters are moved to the cell membrane to assist glucose entry into the cell. eﬀects on carbohydrate, fat, and protein metabolism. The following are the main end eﬀects of insulin stimulation: 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 action is especially true of muscle cells and adipose cells, but it 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 EFFECT OF INSULIN ON CARBOHYDRATE METABOLISM Immediately after a high-carbohydrate meal is consumed, 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 but on fatty acids for its energy. The principal reason for this dependence on fatty acids 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 muscle contraction increases translocation of glucose transporter 4 (GLUT 4) from intracellular storage depots to the cell membrane, which, in turn, facilitates diﬀusion of glucose into the cell. The second condition for usage of large amounts of glucose by muscles 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, which causes the muscle cell to use glucose preferentially over fatty acids during this period, as will be discussed later. Storage of Glycogen in Muscle. If the muscles are not exercised after a meal and yet glucose is transported into the muscle cells in abundance, instead of being used for energy, most of the glucose is stored in the form of muscle glycogen, up to a limit of 2% to 3% concentration. The glycogen can be used by the muscle later for energy. Glycogen is especially useful for short periods of extreme energy usage by the muscles and even to provide spurts of anaerobic energy for a few minutes at a time via glycolytic 975 UNIT XIV α mainly from the changed states of phosphorylation of the enzymes. 4. Much slower eﬀects continue to occur for hours and even several days. These 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 some of its metabolic eﬀects.␣ Intracellular glucose (mg/100 ml) UNIT XIV Endocrinology and Reproduction 400 Insulin 300 200 100 Control 0 0 300 600 Extracellular glucose (mg/100 ml) 900 Figure 79-4. The 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.) 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 79-4. 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 eﬀects of insulin is to cause most of the glucose absorbed after a meal to be rapidly stored 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 inactivation prevents breakdown of the glycogen that has been stored in liver cells. 2. Insulin enhances uptake of glucose from the blood by the liver cells by increasing the activity of the 976 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 increases the activities of enzymes that promote glycogen synthesis, including especially glycogen synthase. This is responsible for polymerization of the monosaccharide units to form 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 entire 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 increased 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 lack of insulin and causes the phosphate radical to split away from the glucose, allowing 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 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 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, which are transported in the blood to adipose tissue, and deposited as fat. Insulin also inhibits gluconeogenesis 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 release of amino acids from muscle and other extrahepatic tissues Chapter 79 Insulin, Glucagon, and Diabetes Mellitus 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 level 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 most 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, the eﬀects of insulin on fat metabolism are, in the long run, equally important. Especially dramatic is the long-term eﬀect of insulin deficiency in causing extreme atherosclerosis, often leading to heart attacks, cerebral strokes, and other vascular accidents. First, however, 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 glucose utilization by most of the body’s tissues, which automatically decreases fat utilization, thus functioning as a fat sparer. However, insulin also promotes fatty acid synthesis, especially 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 following factors lead to increased fatty acid synthesis in the liver: 1. Insulin increases glucose transport into the liver cells. After the liver glycogen concentration reaches 5% to 6%, further glycogen synthesis is inhibited. All the additional glucose entering the liver cells then 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 used for energy. These ions then have a direct eﬀect to activate 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 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. Lipase is the enzyme that causes hydrolysis of triglycerides already stored in fat cells. Therefore, release of fatty acids from adipose tissue into the circulating blood is inhibited. 2. Insulin promotes glucose transport through cell membranes into 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 triglycerides, 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 lipoproteins is almost blocked.␣ Insulin Deficiency Increases Use of Fat for Energy All aspects of fat breakdown and its use for providing energy are greatly enhanced in the absence of insulin. This enhancement occurs even normally between meals when secretion of insulin is minimal, but it becomes extreme in persons with diabetes mellitus when secretion of insulin is almost zero. 977 UNIT XIV and in turn the availability of these necessary precursors required for gluconeogenesis. This phenomenon is discussed further in relation to the eﬀect of insulin on protein metabolism.␣ UNIT XIV Endocrinology and Reproduction Control Depancreatized Concentration Removal of pancreas Blood glucose Free fatty acids Acetoacetic acid 0 1 2 Days 3 4 Figure 79-5. The effect of removing the pancreas on the approximate concentrations of blood glucose, plasma free fatty acids, and acetoacetic acid. 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 activation causes hydrolysis of stored triglycerides, releasing large quantities of fatty acids and glycerol into the circulating blood. Consequently, 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. Figure 79-5 shows the eﬀect of a lack of insulin 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 Phospholipid Concentrations. The excess of fatty ac- ids 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 development of atherosclerosis in people with severe diabetes.␣ Excess Usage of Fats During Insulin Deficiency Causes Ketosis and Acidosis. Insulin deficiency also causes exces- sive amounts of acetoacetic acid to be formed in liver cells. In the absence of insulin but in the presence of excess fatty acids 978 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 acetoacetic acid 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 utilization of acetoacetic acid in peripheral tissues. Thus, so much acetoacetic acid is released from the liver that it cannot all be metabolized by the tissues. As shown in Figure 79-5, the concentration of acetoacetic acid 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 69, some of the acetoacetic acid is also converted into β-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. We will see later that in severe diabetes, the acetoacetic acid and the β-hydroxybutyric acid can cause severe acidosis and coma, which may lead to death.␣ EFFECT OF INSULIN ON PROTEIN METABOLISM AND GROWTH Insulin Promotes Protein Synthesis and Storage Proteins, carbohydrates, and fats are stored in the tissues during the few hours after a meal when excess quantities of nutrients are available in the circulating blood; insulin is required for this storage to occur. The manner in which insulin causes protein storage is not as well understood as the mechanisms for both glucose and fat storage. Here are some of the facts: 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 uptake of amino acids into cells. However, the amino acids aﬀected are not necessarily the same ones. 2. Insulin increases translation of messenger RNA, thus forming new proteins. Insulin “turns on” the ribosomal machinery and, in the absence of insulin, the ribosomes stop working, almost as if insulin operates by an “on-oﬀ ” mechanism. 3. Over a longer period, 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. Chapter 79 Insulin, Glucagon, and Diabetes Mellitus Growth hormone and insulin 200 Glucose Depancreatized and hypophysectomized 150 Growth hormone 100 Insulin GLUT 2 Insulin UNIT XIV Weight (grams) 250 Glucose Glucokinase 50 Glucose-6-phosphate 0 0 50 100 150 Days 200 Oxidation 250 Figure 79-6. The effect of growth hormone, insulin, and growth hormone plus insulin on growth in a depancreatized and hypophysectomized rat. 4. Insulin inhibits catabolism of proteins, thus decreasing the rate of amino acid release from the cells, especially from muscle cells. Presumably this results from the ability of insulin to diminish the normal degradation of proteins by cellular lysosomes. 5. In the liver, insulin depresses the rate of gluconeogenesis by decreasing activity of the enzymes that promote gluconeogenesis. Because the substrates used most for synthesis of glucose by gluconeogenesis are plasma amino acids, this suppression of gluconeogenesis conserves amino acids in the protein stores of the body. In summary, insulin promotes formation of protein and prevents degradation of proteins.␣ Insulin Deficiency Causes Protein Depletion and Increased Plasma Amino Acids Virtually all protein storage comes to a halt when insulin is not available. Catabolism of proteins increases, protein synthesis stops, and large quantities of amino acids are dumped into the plasma. Amino acid concentration in the plasma rises considerably, and most of the excess amino acids are used either directly for energy or as substrates for gluconeogenesis. This degradation of 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.␣ Insulin and Growth Hormone Interact Synergistically to Promote Growth Because insulin is required for synthesis of proteins, it is as essential as growth hormone for the growth of an animal. As demonstrated in Figure 79-6, a depancreatized, hypophysectomized rat without replacement therapy hardly grows at all. Furthermore, administration of either growth hormone or insulin one at a time causes almost no growth. However, a combination of these hormones causes dramatic growth. Thus, it appears that ATP Ca2+ K+ Depolarization ATP + K+ channel (closed) Ca2+ channel (open) Figure 79-7. The basic mechanisms of glucose stimulation of insulin secretion by beta cells of the pancreas. GLUT, Glucose transporter. the two hormones function synergistically to promote growth, with each performing a specific function separate from that of the other. Perhaps a small part of the necessity for both hormones results from the fact that each hormone promotes cellular uptake of a diﬀerent selection of amino acids, all of which are required for growth.␣ MECHANISMS OF INSULIN SECRETION Figure 79-7 shows the basic cellular mechanisms for insulin secretion by the pancreatic beta cells in response to increased blood glucose concentration, which is the primary controller of insulin secretion. The beta cells have a large number of glucose transporters 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 phosphorylation 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 eﬀect 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. 979 TABLE 79-1 Factors and Conditions That Increase or Decrease Insulin Secretion Increase Insulin Secretion Decrease Insulin Secretion Increased blood glucose Increased blood free fatty acids Increased blood amino acids Gastrointestinal hormones (gastrin, cholecystokinin, secretin, glucose-dependent insulinotropic peptide, glucagon-like peptide-1) Glucagon, growth hormone, cortisol Parasympathetic stimulation; acetylcholine β-Adrenergic stimulation Insulin resistance; obesity Sulfonylurea drugs (glyburide, tolbutamide) Decreased blood glucose Fasting Somatostatin α-Adrenergic activity Leptin 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, glucagon-like peptide-1 (GLP1), 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. Sulfonylurea drugs stimulate insulin secretion by binding to the ATP-sensitive potassium channels and blocking their activity. This mechanism results in a depolarizing eﬀect that triggers insulin secretion, making these drugs useful in stimulating insulin secretion in patients with type 2 diabetes, as we will discuss later. Table 79-1 summarizes some of the factors that can increase or decrease secretion of insulin.␣ CONTROL OF INSULIN SECRETION At one time it was believed that insulin secretion was controlled almost entirely by the concentration of glucose in the blood. 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 (see Table 79-1). 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 980 Plasma insulin (!U/ml) UNIT XIV Endocrinology and Reproduction 250 80 60 40 20 0 −10 0 10 20 30 40 50 60 70 80 Minutes Figure 79-8. An increase in plasma insulin concentration after a sudden increase in blood glucose to two to three times the normal range. Note an initial rapid surge in insulin concentration and then a delayed but higher and continuing increase in concentration beginning 15 to 20 minutes later. times normal and is kept at this high level thereafter, insulin secretion increases markedly in two stages, as shown by the changes in plasma insulin concentration in Figure 79-8. 1. The concentration of insulin in plasma increases almost 10-fold within 3 to 5 minutes after acute elevation of the blood glucose. This increase 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 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 the Insulin Secretion Rate. As blood glu- cose concentration rises above 100 mg/100 ml of blood, secretion of insulin 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 79-9. Thus, the increase in insulin secretion during a glucose stimulus is dramatic both in its rapidity and in the high level of secretion that is achieved. Furthermore, the turnoﬀ of insulin secretion is almost equally as rapid, occurring within 3 to 5 minutes after a 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 the rate of transport of glucose into liver, muscle, and other cells, thereby reducing blood glucose concentration back toward the normal value.␣ Chapter 79 Insulin, Glucagon, and Diabetes Mellitus 15 10 5 X 0 0 100 200 300 400 500 Plasma glucose concentration (mg/100 ml) 600 Figure 79-9. Approximate insulin secretion at different plasma glucose levels. Other Factors That Stimulate Insulin Secretion Amino Acids. Some of the amino acids have an eﬀect similar to excess blood glucose in stimulating insulin secretion. The most potent of these amino acids 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, 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 the 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 utilization of carbohydrates.␣ Gastrointestinal Hormones. A mixture of several important gastrointestinal hormones—gastrin, secretin, cholecystokinin, glucagonlike peptide–1 (GLP-1), and glucose-dependent insulinotropic peptide (GIP)—can cause moderate increases in insulin secretion. Two of these hormones, GLP-1 and GIP, appear to be the most potent and are often called incretins because they enhance the rate of insulin release from the pancreatic beta cells in response to an increase in plasma glucose. They also inhibit glucagon secretion from the alpha cells of the islets of Langerhans. 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. As discussed later in the chapter, several drugs have been developed to mimic or enhance the actions of incretins for treatment of diabetes mellitus.␣ Other Hormones and the Autonomic Nervous System. 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 development of diabetes mellitus. Indeed, diabetes often occurs in people who receive high pharmacological maintenance doses of some of these hormones. Diabetes is particularly common in giants or in acromegalic people who have tumors that secrete growth hormone, as well as in people whose adrenal glands secrete excess glucocorticoids. The pancreas islets are richly innervated with sympathetic and parasympathetic nerves. Stimulation of the parasympathetic nerves to the pancreas can increase insulin secretion during hyperglycemic conditions, whereas sympathetic nerve stimulation may increase glucagon secretion and decrease insulin secretion during hypoglycemia. Glucose concentrations are believed to be detected by specialized neurons of the hypothalamus and brain stem, as well as by glucose-sensing cells in peripheral locations such as the liver.␣ THE ROLE OF INSULIN (AND OTHER HORMONES) IN “SWITCHING” BETWEEN CARBOHYDRATE AND LIPID METABOLISM From the preceding discussions, it should be clear that insulin promotes utilization of carbohydrates for energy and depresses 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 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 will be used by the cells for energy from moment to moment. 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. Glucagon is discussed in the next section of this chapter. Both growth hormone and cortisol are secreted in response to hypoglycemia, and both inhibit cellular utilization of glucose while promoting fat utilization. However, the eﬀects of both of these hormones develop slowly, usually requiring many hours for maximal expression. Epinephrine is especially important in increasing plasma glucose concentration during periods of stress when the sympathetic nervous system is excited. However, epinephrine acts diﬀerently from the other hormones in that it increases plasma fatty acid concentration at the same time. The reasons for these eﬀects are as 981 UNIT XIV Insulin secretion (!"normal) 20 UNIT XIV Endocrinology and Reproduction follows: (1) epinephrine has the potent eﬀect of causing glycogenolysis in the liver, thus releasing large quantities of glucose into the blood within minutes, and (2) it also has a direct lipolytic eﬀect on the adipose cells because it activates adipose tissue hormone-sensitive lipase, thus greatly enhancing blood concentration of fatty acids as well. Quantitatively, the enhancement of fatty acids is far greater than the enhancement of blood glucose. Therefore, epinephrine especially increases utilization of fat in such stressful states as exercise, circulatory shock, and anxiety.␣ GLUCAGON AND ITS FUNCTIONS Glucagon, a hormone secreted by the alpha cells of the islets of Langerhans when blood glucose concentration falls, has several functions that are diametrically opposed to those of insulin. The most important of these functions is to increase the blood glucose concentration, an eﬀect that is opposite to 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. Upon injection of purified glucagon into an animal, a profound hyperglycemic eﬀect occurs. Only 1 µg/kg of glucagon can elevate the blood glucose concentration approximately 20 mg/100 ml of blood (a 25% increase) in about 20 minutes. For this reason, glucagon is also called the hyperglycemic hormone. 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 (cAMP). 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 mechanism 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 hyperglycemia 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 eﬀect 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.␣ EFFECTS ON GLUCOSE METABOLISM Other Effects of Glucagon 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. 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 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. These eﬀects of glucagon are probably of much less importance in the normal function of the body compared with its eﬀects on glucose.␣ 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 performs this function through 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. 982 REGULATION OF GLUCAGON SECRETION Increased Blood Glucose Inhibits Glucagon Secretion. 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. This is demonstrated in Figure 79-10, which shows that a decrease in the blood glucose concentration from Chapter 79 Insulin, Glucagon, and Diabetes Mellitus 3 2 1 0 60 80 100 Blood glucose (mg/100 ml) 120 Figure 79-10. The approximate plasma glucagon concentration at different blood glucose levels. its normal fasting level of about 90 mg/100 ml of blood down to hypoglycemic levels can increase the plasma concentration of glucagon severalfold. Conversely, increasing blood glucose to hyperglycemic levels decreases plasma glucagon concentration. 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 Secretion of Glucagon. High concentrations of amino acids, such as those that occur in the blood after a meal containing protein (especially the amino acids alanine and arginine), stimulate 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 Secretion of Glucagon. During exhaustive exercise, blood glucagon concentration often increases fourfold to fivefold. The cause of this increase is not well 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 during exercise is increased circulating amino acids. Other factors, such as β-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 14–amino acid polypeptide that has an extremely short half-life of only 3 minutes in the circulating blood. Almost all factors related to ingestion of food stimulate somatostatin secretion. These factors 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 secretion of both insulin and glucagon. 2. Somatostatin decreases motility of the stomach, duodenum, and gallbladder. 3. Somatostatin decreases both secretion and absorption in the gastrointestinal tract. In putting all this information together, it has been suggested that the principal role of somatostatin is to extend the period over which the food nutrients are assimilated into the blood. At the same time, the eﬀect of somatostatin in depressing insulin and glucagon secretion decreases utilization of the absorbed nutrients by the tissues, thus preventing rapid exhaustion of the food and therefore making it available over a longer period. Somatostatin is also the same chemical substance as growth hormone inhibitory hormone, which is secreted in the hypothalamus and suppresses secretion of growth hormone by the anterior pituitary gland.␣ SUMMARY OF BLOOD GLUCOSE REGULATION The blood glucose concentration is narrowly controlled normally, usually between 80 and 90 mg/100 ml of blood in the fasting person each morning before breakfast. This concentration increases to 120 to 140 mg/100 ml during the first hour or so after a meal, but the feedback systems for controlling blood glucose rapidly return glucose concentration back to the control level, usually within 2 hours after the last absorption of carbohydrates. Conversely, in a state of starvation, the gluconeogenesis function of the liver provides the glucose required to maintain the fasting blood glucose level. The mechanisms for achieving this high degree of control have been presented in this chapter and may be summarized as follows: 1. The liver functions as an important blood glucose buﬀer system. That is, when blood glucose rises to a high concentration after a meal and insulin secretion also increases, as much as two-thirds of the glucose absorbed from the gut is rapidly stored as glycogen in the liver. Then, during the succeeding hours, when blood glucose concentration and insulin secretion fall, the liver releases the glucose back into the blood. In this way, the liver decreases fluctuations in blood glucose concentration to about one-third of what they would be otherwise. In fact, in patients with severe liver disease, it becomes almost impossible to maintain a narrow range of blood glucose concentration. 2. Both insulin and glucagon function as important feedback control systems for maintaining a normal blood glucose concentration. When the glucose concentration rises too high, increased insulin secretion causes blood glucose concentration to decrease 983 UNIT XIV Plasma glucagon (!"normal) 4 UNIT XIV Endocrinology and Reproduction toward normal. Conversely, a decrease in blood glucose stimulates glucagon secretion; the glucagon then functions in the opposite direction to increase glucose toward normal. Under most normal conditions, the insulin feedback mechanism is more important than the glucagon mechanism, but in instances of starvation or excessive utilization of glucose during exercise and other stressful situations, the glucagon mechanism also becomes valuable. 3. In severe hypoglycemia, a direct eﬀect of low blood glucose on the hypothalamus also stimulates the sympathetic nervous system. The epinephrine secreted by the adrenal glands further increases release of glucose from the liver, which also helps protect against severe hypoglycemia. 4. Finally, over a period of hours and days, both growth hormone and cortisol are secreted in response to prolonged hypoglycemia. They both decrease the rate of glucose utilization by most cells of the body, converting instead to greater fat utilization. This process, too, helps return blood glucose concentration toward normal. Importance of Blood Glucose Regulation. One might ask, “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 blood glucose concentration at a level suﬃcient to provide this necessary nutrition. Most of the glucose formed by gluconeogenesis during the interdigestive period is used for metabolism in the brain. Indeed, it is important that the pancreas not secrete insulin during this time; otherwise, the scant supplies of glucose that are available would all go into the muscles and other peripheral tissues, leaving the brain without a nutritive source. It is also important that blood glucose concentration not rise too high for several reasons: 1. Glucose can exert a large amount of osmotic pressure in the extracellular fluid, and a rise in glucose concentration to excessive values 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.␣ 984 Diabetes Mellitus Diabetes mellitus is a syndrome of impaired carbohydrate, fat, and protein metabolism caused by either lack of insulin secretion or decreased sensitivity of the tissues to insulin. There are two general types of diabetes mellitus: 1. Type 1 diabetes, also called insulin-dependent diabetes mellitus, is caused by lack of insulin secretion. 2. Type 2 diabetes, also called non–insulin-dependent diabetes mellitus, is initially caused by decreased sensitivity of target tissues to the metabolic eﬀect of insulin. This reduced sensitivity to insulin is often called insulin resistance. In both types of diabetes mellitus, metabolism of all the main foodstuﬀs is altered. The basic eﬀect of insulin deficiency or insulin resistance on glucose metabolism is to prevent eﬃcient uptake and utilization of glucose by most cells of the body, except those of the brain. As a result, blood glucose concentration increases, cell utilization of glucose falls increasingly lower, and utilization of fats and proteins increases. Type 1 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 1 diabetes. Viral infections or autoimmune disorders may be involved in the destruction of beta cells in many patients with type 1 diabetes, although heredity also plays a major role in determining the susceptibility of the beta cells to destruction by these insults. In some cases, persons may have a hereditary tendency for beta cell degeneration even without viral infections or autoimmune disorders. The usual onset of type 1 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 1 diabetes can occur at any age, including adulthood, following disorders that lead to the destruction of pancreatic beta cells. Type 1 diabetes may develop abruptly, over a period of a few days or weeks, with three principal sequelae: (1) increased blood glucose levels, (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% of people with diabetes mellitus have the type 1 form of the disease. Blood Glucose Concentration Rises to High Levels in Diabetes Mellitus. Lack of insulin decreases the eﬃciency of peripheral glucose utilization and augments glucose production, raising plasma glucose to 300 to 1200 mg/100 ml. The increased plasma glucose then has multiple adverse effects throughout the body.␣ Increased Blood Glucose Causes Loss of Glucose in the Urine. High levels of blood glucose cause more glucose to filter into the renal tubules than can be reabsorbed, and the excess glucose spills into the urine as explained in Chapter 28. This spillage normally occurs when the blood glucose concentration rises above about 200 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.␣ Chapter 79 Insulin, Glucagon, and Diabetes Mellitus 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 situation 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. The precise mechanisms that cause tissue injury in diabetes are not well understood but probably involve multiple eﬀects of high glucose concentrations and other metabolic abnormalities on proteins of endothelial and vascular smooth muscle cells, as well as other tissues. In addition, hypertension, secondary to renal injury, and atherosclerosis, secondary to abnormal lipid metabolism, often develop in patients with diabetes and amplify the tissue damage caused by elevated glucose levels.␣ 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, metabolic acidosis develops from the excess keto acids, which, in association with dehydration, can cause severe acidosis. This scenario leads rapidly to diabetic coma and death unless the patient is treated immediately with large amounts of insulin. All the usual physiological compensations that occur in metabolic acidosis take place in diabetic acidosis, as discussed in Chapter 31. They include rapid and deep breathing, which causes increased expiration of carbon dioxide; this mechanism 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. Glucose Keto acids Total cations HCO3– Cl– pH Cholesterol 100 mg/dl 400+ mg/dl 1 mEq UNIT XIV Increased Blood Glucose Causes Dehydration. Extremely 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 dehydration 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, 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. Thus, polyuria (excessive urine excretion), intracellular and extracellular dehydration, and increased thirst are classic symptoms of diabetes.␣ 30 mEq 155 mEq 130 mEq 27 mEq 5 mEq 103 mEq 90 mEq 7.4 6.9 180 mg/dl 360 mg/dl Figure 79-11. Changes in blood constituents in diabetic coma, showing normal values (blue bars) and diabetic coma values (red bars). Although extreme acidosis occurs only in the most severe cases 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 blood electrolytes as a result of severe diabetic acidosis are shown in Figure 79-11. Excess fat utilization in the liver over a long time causes large amounts of cholesterol in the circulating blood and increased deposition of cholesterol in the arterial walls. This situation leads to severe arteriosclerosis and other vascular lesions, as discussed earlier.␣ 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 experiences 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.␣ Treatment of Type 1 Diabetes. Eﬀective treatment of type 1 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 1 diabetes is given a single dose of one of the longer-acting insulins each day to increase overall carbohydrate metabolism throughout the day. Additional quantities of regular insulin are then given during the day at the 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 the past, the insulin used for treatment was derived from animal pancreata. However, human insulin produced 985 UNIT XIV Endocrinology and Reproduction by the recombinant DNA process has become more widely used because immunity and sensitization against animal insulin develops in some patients, thus limiting its eﬀectiveness.␣ Type 2 Diabetes—Resistance to the Metabolic Effects of Insulin Type 2 diabetes is far more common than type 1 diabetes, accounting for about 90% to 95% of all cases of diabetes mellitus. In most cases, the onset of type 2 diabetes occurs after age 30 years, often between the ages of 50 and 60 years, and the disease develops gradually. Therefore, this syndrome is often referred to as adult-onset diabetes. In recent years, however, there has been a steady increase in the number of younger individuals, some younger than 20 years old, with type 2 diabetes. This trend appears to be related mainly to the increasing prevalence of obesity, the most important risk factor for type 2 diabetes in children and adults. Obesity, Insulin Resistance, and “Metabolic Syndrome” Usually Precede Development of Type 2 Diabetes. Type 2 diabetes, in contrast to type 1 diabetes, is associated with increased plasma insulin concentration. The hyperinsulinemia occurs as a compensatory response by the pancreatic beta cells for insulin resistance, a diminished sensitivity of target tissues to the metabolic eﬀects of insulin. The decrease in insulin sensitivity impairs carbohydrate utilization and storage, raising blood glucose and stimulating a compensatory increase in insulin secretion. The development of insulin resistance and impaired glucose metabolism is usually a gradual process, beginning with excess weight gain and obesity. Some studies suggest that obese subjects have fewer insulin receptors, especially in the skeletal muscle, liver, and adipose tissue, than do 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 may be closely related to toxic effects of lipid accumulation in tissues such as skeletal muscle and liver as a result of excess weight gain. Insulin resistance is part of a cascade of disorders that is often called the “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 highdensity 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. The role of insulin resistance in contributing to some of the components of the metabolic syndrome is uncertain, although it is clear that insulin resistance is the primary cause of increased blood glucose concentration. A major adverse consequence of the metabolic syndrome is cardiovascular disease, including atherosclerosis and injury to various organs throughout the body. Several of the metabolic abnormalities associated with the syndrome increase the risk for cardiovascular disease, and insulin resistance predisposes to the development of type 2 diabetes mellitus, which is also a major cause of cardiovascular disease.␣ 986 TABLE 79-2 Some Causes of Insulin Resistance therapy) accumulation in liver) receptor γ (PPARγ) receptor mutations) iron accumulation) Other Factors That Can Cause Insulin Resistance and Type 2 Diabetes. Although most patients with type 2 dia- betes are overweight or have substantial accumulation of visceral fat, severe insulin resistance and type 2 diabetes can also occur as a result of other acquired or genetic conditions that impair insulin signaling in peripheral tissues (Table 79-2). Polycystic ovary syndrome (PCOS), for example, is associated with marked increases in ovarian androgen production and insulin resistance. PCOS is one of the most common endocrine disorders in women, aﬀecting approximately 6% of all women during their reproductive life. Although the pathogenesis of PCOS remains uncertain, insulin resistance and hyperinsulinemia are found in approximately 80% 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 excess formation of 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 2 diabetes and many other features of the metabolic syndrome, including cardiovascular disease.␣ Development of Type 2 Diabetes During Prolonged Insulin Resistance. With prolonged and severe insulin resist- ance, even the increased levels of insulin are not suﬃcient to maintain normal glucose regulation. As a result, moderate hyperglycemia occurs after ingestion of carbohydrates in the early stages of the disease. In the later stages of type 2 diabetes, the pancreatic beta cells become “exhausted” or damaged and are unable to produce enough insulin to prevent more severe hyperglycemia, especially after the person ingests a carbohydraterich meal. Clinically significant diabetes mellitus may not develop in some obese people, even though they have marked insulin resistance and greater than normal increases in blood glucose after a meal; apparently, the pancreas in these people produces enough insulin to prevent severe abnormalities of glucose metabolism. In other obese people, however, the pancreas gradually becomes exhausted from secreting Chapter 79 Insulin, Glucagon, and Diabetes Mellitus Treatment of Type 2 Diabetes by Lifestyle Modifications, Increasing Insulin Sensitivity, and Enhancing Insulin Secretion. In many cases, type 2 diabetes can be eﬀectively treated, at least in the early stages, with lifestyle modifications aimed at increasing physical activity, caloric restriction, and weight reduction, and no exogenous administration of insulin is required. Drugs that increase insulin sensitivity, such as thiazolidinediones, drugs that suppress liver glucose production, such as metformin, or drugs that cause additional release of insulin by the pancreas, such as sulfonylureas, may also be used. However, in the later stages of type 2 diabetes, insulin administration is usually required to control plasma glucose levels. Incretin drugs that mimic the actions of the GLP-1 have been developed for treatment of type 2 diabetes. These drugs enhance insulin secretion and are intended to be used in conjunction with other antidiabetic drugs. Another therapeutic approach is to inhibit the enzyme dipeptidyl peptidase 4 (DPP-4), which inactivates GLP-1 and GIP. By blocking the actions of DPP-4, the incretin eﬀects of GLP-1 and GIP can be prolonged, leading to increased insulin secretion and improved control of blood glucose levels.␣ Treatment of Type 2 Diabetes by Inhibition of SodiumGlucose Transporter 2 (SGLT2). As discussed in Chapter 28, approximately 90% of the glucose filtered by renal glomerular capillaries is reabsorbed from the proximal tubules by the sodium glucose co-transporter 2 (SGLT2). Several medications, called gliflozins, have been developed to treat type 2 diabetes by inhibiting SGLT2. These SGLT2 inhibitors greatly reduce renal glucose reabsorption, causing large amounts of glucose to be excreted in the urine and reducing the blood glucose concentration. SGLT2 inhibitors are often used in combination with other drugs that enhance insulin sensitivity or stimulate insulin secretion and have been shown in clinical trials to provide significant protection against cardiovascular and kidney disease in patients with diabetes. In addition to increasing glucose excretion, SGLT2 inhibitors also cause marked diuresis due to the osmotic effect of the glucose remaining in the renal tubules. The diuresis can be beneficial for causing small reductions in blood pressure in patients with type 2 diabetes who often suﬀer from hypertension, but may also increase the risk for dehydration and hypotension in patients who are already taking other diuretics and antihypertensive mediations.␣ Treatment of Type 2 Diabetes With Surgery. In many people who suﬀer from severe obesity and type 2 diabetes, treatment regimens focused on diet, exercise, and pharmacotherapy do not produce adequate reductions in adiposity and blood glucose. In these cases, various bariatric surgery procedures can be used to reduce fat mass and achieve improved control of blood glucose. The two most widely used procedures, gastric bypass surgery and vertical sleeve gastrectomy (discussed in Chapter 72), are often called “meta- TABLE 79-3 Clinical Characteristics of Patients With Feature Type 1 Type 2 Age at onset Usually 30 yr Body mass Low (wasted) to normal Visceral obesity Plasma insulin Low or absent Normal to high initially suppressed suppression UNIT XIV large amounts of insulin or damaged by factors associated with lipid accumulation in the pancreas, and full-blown diabetes mellitus occurs. Some studies suggest that genetic factors play an important role in determining whether an individual’s pancreas can sustain the high output of insulin over many years that is necessary to avoid the severe abnormalities of glucose metabolism in type 2 diabetes.␣ Plasma glucagon Plasma glucose Increased Increased Insulin sensitivity Normal Reduced Therapy Insulin Weight loss, bariatric surgery, thiazolidinediones, metformin, sulfonylureas, SGLT2 inhibitors, insulin SGLT2, Sodium glucose co-transporter 2. bolic surgery” because many patients who undergo these operations experience complete remission of diabetes and no longer require antidiabetic drugs. Improvements of blood glucose, lipids and blood pressure often occur within a few days or weeks after surgery, suggesting that the mechanisms for these cardiovascular and metabolic benefits may extend beyond weight loss and reductions in adiposity. However, the physiological factors that contribute to the favorable metabolic eﬀects of these surgical procedures are still unclear.␣ Physiology of Diagnosis of Diabetes Mellitus Table 79-3 compares some of the clinical features of type 1 and type 2 diabetes mellitus. The usual methods for diagnosing diabetes are based on various chemical tests of the urine and the blood. Urinary Glucose. Simple oﬃce tests or more complicated quantitative laboratory tests may be used to determine the quantity of glucose excreted in the urine. In general, a nondiabetic person excretes undetectable amounts of glucose, whereas a person with diabetes loses glucose in small to large amounts, in proportion to the severity of the disease and the intake of carbohydrates.␣ Fasting Blood Glucose and Insulin Concentrations. Fasting blood glucose concentration in the early morning is normally 80 to 90 mg/100 ml, and 115 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 and prediabetes. In persons with type 1 diabetes, plasma insulin levels are very low or undetectable during fasting and even after a meal. In persons with type 2 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 section).␣ Glycated Hemoglobin. When blood glucose levels are elevated for prolonged periods of time, glucose attaches to 987 UNIT XIV Endocrinology and Reproduction Blood glucose level (mg/100 ml) 200 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 2 diabetes.␣ Diabetes 180 160 140 120 Relation of Treatment to Arteriosclerosis and Chronic Kidney Disease. Mainly because of the hypertension and Normal 100 80 0 1 2 3 Hours 4 5 Figure 79-12. Glucose tolerance curve in a normal person and in a person with diabetes. hemoglobin in red blood cells to form glycated hemoglobin, often called hemoglobin A1c (HbA1c). The longer hyperglycemia occurs, the more glucose binds to hemoglobin and once hemoglobin is glycated, it remains that way for the life of the cell. Therefore, buildup of HbA1c in a red blood cell reflects the average glucose concentration to which the cell has been exposed during its life-cycle. Because the average lifespan of red blood cells is about 120 days and individual cells have varying lifespans, the HbA1c test is used mainly to assess average blood glucose concentrations for the previous three months and can provide a diagnostic test for diabetes mellitus or an assessment test of glycemic control in people with diabetes.␣ Glucose Tolerance Test. As demonstrated by the bottom curve in Figure 79-12, 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 115 mg/100 ml and often is above 140 mg/100 ml. In addition, results of the glucose tolerance test are almost always abnormal. After ingestion of glucose, these people exhibit a much greater than normal rise in blood glucose level, as demonstrated by the upper curve in Figure 79-12, 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) the person has decreased sensitivity to insulin. A diagnosis of diabetes mellitus can usually be established on the basis of such a curve, and type 1 and type 2 diabetes can be distinguished from each other by measurements of plasma insulin, with plasma insulin being low or undetectable in type 1 diabetes and increased in type 2 diabetes.␣ Acetone Breath. As pointed out in Chapter 69, small quantities of acetoacetic acid in the blood, which increase greatly in severe diabetes, are converted to acetone. Acetone is volatile and is vaporized into the expired air. Consequently, one can frequently make a diagnosis of type 1 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 2 988 high levels of circulating cholesterol and other lipids in diabetic patients, atherosclerosis, arteriosclerosis, severe coronary heart disease, chronic kidney disease, and multiple microcirculatory lesions develop far more easily than in nondiabetic people. Indeed, persons who have poorly controlled diabetes throughout childhood are likely to die of heart disease in early adulthood. In the early days of diabetes treatment, the tendency was to severely reduce carbohydrates in the diet to minimize insulin requirements. This approach kept the blood glucose from reaching too high a level and attenuated the loss of glucose in the urine, but it did not prevent many of the abnormalities of fat metabolism. Consequently, the current tendency is to permit the patient to consume an almost normal carbohydrate diet while administering enough insulin to metabolize the carbohydrates. This approach decreases the rate of fat metabolism and depresses the high level of cholesterol in the blood. Because complications of diabetes such as atherosclerosis, increased susceptibility to infection, diabetic retinopathy, cataracts, hypertension, and chronic renal disease are closely associated with the levels of lipids and glucose in the blood, most physicians also prescribe lipid-lowering drugs to help prevent these disturbances.␣ Insulinoma—Hyperinsulinism Although excessive insulin production occurs much more rarely than does diabetes, it occasionally can be a consequence of an adenoma of an islet of Langerhans. About 10% to 15% 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, some of these patients have required more than 1000 grams of glucose every 24 hours to prevent hypoglycemia. Insulin Shock and Hypoglycemia. As already emphasized, the central nervous system normally derives essentially all its energy from glucose metabolism, and insulin is not necessary for this use of glucose. However, if high levels of insulin cause blood glucose to fall to low levels, the metabolism of the central nervous system becomes depressed. Consequently, 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 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 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, when using simple clinical observation, it is sometimes diﬃcult to distinguish Chapter 79 Insulin, Glucagon, and Diabetes Mellitus Bibliography Alicic RZ, Neumiller JJ, Johnson EJ, et al: Sodium-glucose cotransporter 2 inhibition and diabetic kidney disease. Diabetes 68:248, 2019. Andersen A, Lund A, Knop FK, Vilsbøll T: Glucagon-like peptide 1 in health and disease. Nat Rev Endocrinol 14:390, 2018. Bentsen MA, Mirzadeh Z, Schwartz MW: Revisiting how the brain senses glucose -and why. Cell Metab 29:11, 2018. Capozzi ME, DiMarchi RD, Tschöp MH, et al: Targeting the incretin/glucagon system with triagonists to treat diabetes. Endocr Rev 39:719, 2018. Clemmensen C, Finan B, Müller TD, et al: Emerging hormonal-based combination pharmacotherapies for the treatment of metabolic diseases. Nat Rev Endocrinol 15:90, 2019. DiMeglio LA, Evans-Molina C, Oram RA: Type 1 diabetes. Lancet 391:2449, 2018. Gancheva S, Jelenik T, Álvarez-Hernández E, Roden M: Interorgan metabolic crosstalk in human insulin resistance. Physiol Rev 98:1371, 2018. Haeusler RA, McGraw TE, Accili D: Biochemical and cellular properties of insulin receptor signalling. Nat Rev Mol Cell Biol 19:31, 2018. Kahn CR, Wang G, Lee KY: Altered adipose tissue and adipocyte function in the pathogenesis of metabolic syndrome. J Clin Invest 129:3990, 2019. Klip A, McGraw TE, James DE: Thirty sweet years of GLUT4. J Biol Chem 294:11369, 2019. Lee YS, Wollam J, Olefsky JM: An integrated view of immunometabolism. Cell 172(1-2):22, 2018. Mann JP, Savage DB: What lipodystrophies teach us about the metabolic syndrome. J Clin Invest 130:4009, 2019. Müller TD, Finan B, Clemmensen C, et al: The new biology and pharmacology of glucagon. Physiol Rev 97:721, 2017. Oram RA, Sims EK, Evans-Molina C: Beta cells in type 1 diabetes: mass and function; sleeping or dead? Diabetologia 62:567, 2019. Pareek M, Schauer PR, Kaplan LM, et al: Metabolic surgery: weight loss, diabetes, and beyond. J Am Coll Cardiol 71:670, 2018. Petersen MC, Shulman GI: Mechanisms of insulin action and insulin resistance. Physiol Rev 98:2133, 2018. Rorsman P, Ashcroft FM: Pancreatic β-cell electrical activity and insulin secretion: of mice and men. Physiol Rev 98:117, 2018. Ruegsegger GN, Creo AL, Cortes TM, Dasari S, Nair KS: Altered mitochondrial function in insulin-deficient and insulin-resistant states. J Clin Invest 128:3671, 2018. Taylor R, Al-Mrabeh A, Sattar N: Understanding the mechanisms of reversal of type 2 diabetes. Lancet Diabetes Endocrinol 7:726, 2019. Viner R, White B, Christie D: Type 2 diabetes in adolescents: a severe phenotype posing major clinical challenges and public health burden. Lancet 389:2252, 2017. Wright EM, Loo DD, Hirayama BA: Biology of human sodium glucose transporters. Physiol Rev 91:733, 2011. Yang Q, Vijayakumar A, Kahn BB: Metabolites as regulators of insulin sensitivity and metabolism. Nat Rev Mol Cell Biol 19:654, 2018. 989 UNIT XIV between diabetic coma as a result of acidosis caused by a lack of insulin and coma due to hypoglycemia caused by excess insulin. The acetone breath and the rapid, deep breathing of persons in a diabetic coma are not present in persons in a hypoglycemic coma. Proper treatment for a patient who has hypoglycemic shock or coma is immediate intravenous administration of large quantities of glucose. This treatment usually brings the patient out of shock within a minute or more. Also, 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. CHAPTER 80 The physiology of calcium and phosphate metabolism, formation of bone and teeth, and regulation of vitamin D, parathyroid hormone (PTH), and calcitonin are all closely intertwined. The extracellular calcium ion concentration, for example, is determined by the interplay of calcium absorption from the intestine, renal excretion of calcium, and bone uptake and release of calcium, each of which is regulated by the hormones just noted. Because phosphate homeostasis and calcium homeostasis are closely associated, they are discussed together in this chapter. OVERVIEW OF CALCIUM AND PHOSPHATE REGULATION IN EXTRACELLULAR FLUID AND PLASMA Extracellular fluid calcium concentration is normally regulated precisely; it seldom rises or falls more than a few percent from the normal value of about 9.4 mg/dl, which is equivalent to 2.4 millimoles of calcium per liter. This precise control is essential because calcium plays a key role in many physiological processes, including contraction of skeletal, cardiac, and smooth muscles, blood clotting, and transmission of nerve impulses, to name just a few. Excitable cells such as neurons are sensitive to changes in calcium ion concentrations, and increases above normal (hypercalcemia) cause progressive depression of the nervous system; conversely, decreases in calcium concentration (hypocalcemia) cause the nervous system to become more excited. An important feature of extracellular calcium regulation is that only about 0.1% of the total body calcium is in the extracellular fluid, about 1% is in the cells and its organelles, and the rest is stored in bones. Therefore, the bones can serve as large reservoirs, storing excess calcium and releasing calcium when extracellular fluid concentration decreases. Approximately 85% of the body's phosphate is stored in bones, 14% to 15% is in the cells, and less than 1% is in the extracellular fluid. Although extracellular fluid phosphate concentration is not nearly as well regulated as calcium concentration, phosphate serves several important functions and is controlled by many of the same factors that regulate calcium. CALCIUM IN THE PLASMA AND INTERSTITIAL FLUID Calcium in the plasma is present in three forms, as shown in Figure 80-1: (1) About 41% (1 mmol/L) of the calcium is combined with plasma proteins and in this form is nondiﬀusible through the capillary membrane; (2) about 9% of the calcium (0.2 mmol/L) is diﬀusible through the capillary membrane but is combined with anionic substances of the plasma and interstitial fluids (e.g., citrate and phosphate) in such a manner that it is not ionized; and (3) the remaining 50% of the calcium in plasma is diﬀusible through the capillary membrane and ionized. Thus, the plasma and interstitial fluids have a normal calcium ion concentration of about 1.2 mmol/L (or 2.4 mEq/L, because it is a divalent ion), a level only onehalf the total plasma calcium concentration. This ionic calcium is the form that is important for most functions of calcium in the body, including the eﬀect of calcium on the heart, the nervous system, and bone formation.␣ INORGANIC PHOSPHATE IN THE EXTRACELLULAR FLUIDS Inorganic phosphate in the plasma is mainly in two forms, HPO4= and H2PO4−. The concentration of HPO4= is about Calcium complexed to anions 9% (0.2 mmol/L) Ionized calcium 50% (1.2 mmol/L) Protein-bound calcium 41% (1.0 mmol/L) Figure 80-1. Distribution of ionized calcium (Ca2+), diffusible but un-ionized calcium complexed to anions, and nondiffusible proteinbound calcium in blood plasma. 991 UNIT XIV Parathyroid Hormone, Calcitonin, Calcium and Phosphate Metabolism, Vitamin D, Bone, and Teeth UNIT XIV Endocrinology and Reproduction 1.05 mmol/L, and the concentration of H2PO4− is about 0.26 mmol/L. When the total quantity of phosphate in the extracellular fluid rises, so does the quantity of each of these two types of phosphate ions. Furthermore, when the pH of the extracellular fluid becomes more acidic, there is a relative increase in H2PO4− and a decrease in HPO4=, whereas the opposite occurs when the extracellular fluid becomes alkaline. These relations were presented in the discussion of acid-base balance in Chapter 31. Because it is diﬃcult to determine chemically the exact quantities of HPO4= and H2PO4− in the blood, ordinarily the total quantity of phosphate is expressed in terms of milligrams of phosphorus per deciliter (100 milliliters) of blood. The average total quantity of inorganic phosphorus represented by both phosphate ions is about 4 mg/dl, varying between normal limits of 3 to 4 mg/dl in adults and 4 to 5 mg/dl in children.␣ NONBONE PHYSIOLOGICAL EFFECTS OF ALTERED CALCIUM AND PHOSPHATE CONCENTRATIONS IN THE BODY FLUIDS Changing the level of phosphate in the extracellular fluid from far below normal to two to three times normal does not cause major immediate eﬀects on the body. In contrast, even slight increases or decreases of calcium ion in the extracellular fluid can cause extreme immediate physiological eﬀects. In addition, chronic hypocalcemia or hypophosphatemia greatly decreases bone mineralization, as is explained later in the chapter. Hypocalcemia Causes Nervous System Excitement and Tetany. When the extracellular fluid concentration of calcium ions falls below normal, the nervous system becomes progressively more excitable because of increased neuronal membrane permeability to sodium ions, allowing easy initiation of action potentials. At plasma calcium ion concentrations about 50% below normal, the peripheral nerve fibers become so excitable that they begin to discharge spontaneously, initiating trains of nerve impulses that pass to the peripheral skeletal muscles to elicit tetanic muscle contraction. Consequently, hypocalcemia causes tetany. It also occasionally causes seizures because of its action of increasing excitability in the brain. Figure 80-2 shows tetany in the hand, which usually occurs before tetany develops in most other parts of the body. This is called carpopedal spasm. Tetany ordinarily occurs when the blood concentration of calcium falls from its normal level of 9.4 mg/dl to about 6 mg/dl, which is only 35% below the normal calcium concentration, and it is usually lethal at about 4 mg/dl. In laboratory animals, extreme hypocalcemia can cause other eﬀects that are seldom evident in patients, such as marked dilation of the heart, changes in cellular enzyme activities, increased membrane permeability in some cells (in addition to nerve cells), and impaired blood clotting.␣ 992 Figure 80-2. Hypocalcemic tetany in the hand, called carpopedal spasm. Hypercalcemia Depresses Nervous System and Muscle Activity. When calcium concentration in the body fluids rises above normal, the nervous system becomes depressed and reflex activities of the central nervous system are sluggish. Also, increased calcium ion concentration decreases the QT interval of the heart and causes lack of appetite and constipation, probably because of depressed contractility of the muscle walls of the gastrointestinal tract. These depressive eﬀects begin to appear when the blood level of calcium rises above about 12 mg/dl, and they can become marked as the calcium level rises above 15 mg/dl. When the calcium concentration rises above about 17 mg/dl in the blood, calcium phosphate crystals are likely to precipitate throughout the body; this condition is discussed later in connection with parathyroid poisoning.␣ ABSORPTION AND EXCRETION OF CALCIUM AND PHOSPHATE Intestinal Absorption and Fecal Excretion of Calcium and Phosphate. The usual rates of intake are approxi- mately 1000 mg/day each for calcium and phosphorus, about the amounts in 1 liter of milk. Normally, divalent cations such as calcium ions are poorly absorbed from the intestines. However, as discussed later, vitamin D promotes calcium absorption by the intestines, and about 35% (350 mg/day) of the ingested calcium is usually absorbed; the remaining calcium in the intestine is excreted in the feces. An additional 250 mg/day of calcium enters the intestines via secreted gastrointestinal juices and sloughed mucosal cells. Thus, about 90% (900 mg/day) of the daily intake of calcium is excreted in the feces (Figure 80-3). Intestinal absorption of phosphate occurs easily. Except for the portion of phosphate that is excreted in the feces in combination with nonabsorbed calcium, almost all the dietary phosphate is absorbed into the blood from the gut and later excreted in the urine.␣ Chapter 80 Parathyroid Hormone, Calcitonin, Calcium and Phosphate Metabolism, Vitamin D, Bone, and Teeth Calcium intake (1000 mg/day) Cells (13,000 mg) Bone (1,000,000 mg) Cartilage Secretion (250 mg/day) Feces (900 mg/day) Extracellular fluid (1300 mg) Filtration (9980 mg/day) Urine (100 mg/day) Deposition (500 mg/day) Cortical (compact) bone Epiphyseal line Resorption (500 mg/day) Reabsorption (9880 mg/day) Trabecular (spongy) bone Red marrow Kidneys Figure 80-3. Overview of calcium exchange between different tissue compartments in a person ingesting 1000 mg of calcium per day. Note that most of the ingested calcium is normally eliminated in the feces, although the kidneys have the capacity to excrete large amounts by reducing tubular reabsorption of calcium. Renal Excretion of Calcium and Phosphate. Approxi- mately 10% (100 mg/day) of the ingested calcium is excreted in the urine. About 41% of the plasma calcium is bound to plasma proteins and is therefore not filtered by the glomerular capillaries. The remainder is combined with anions such as phosphate (9%) or ionized (50%) and filtered through the glomeruli into the renal tubules. Normally, the renal tubules reabsorb 99% of the filtered calcium, and about 100 mg/day are excreted in the urine (see Chapter 30 for further discussion of renal calcium excretion). Approximately 90% of the calcium in the glomerular filtrate is reabsorbed in the proximal tubules, loops of Henle, and early distal tubules. In the late distal tubules and early collecting ducts, reabsorption of the remaining 10% is more variable, depending on the calcium ion concentration in the blood. When calcium concentration is low, this reabsorption is great, and almost no calcium is lost in the urine. Conversely, even a minute increase in blood calcium ion concentration above normal increases calcium excretion markedly. We shall see later in this chapter that the most important factor controlling this reabsorption of calcium in the distal portions of the nephron, and therefore controlling the rate of calcium excretion, is PTH. Renal phosphate excretion is controlled by an overflow mechanism, as explained in Chapter 30. That is, when phosphate concentration in the plasma is below the critical value of about 1 mmol/L, all the phosphate in the glomerular filtrate is reabsorbed and no phosphate is lost in the urine. Above this critical concentration, however, the rate of phosphate loss is directly proportional to the additional increase. Thus, the kidneys regulate the phosphate concentration in the extracellular fluid by altering the rate of phosphate excretion in accordance with the plasma phosphate concentration and the rate of phosphate filtration by the kidneys. Medullary cavity Trabeculae Yellow marrow Figure 80-4. Cortical (compact) and trabecular (spongy) bone. However, as discussed later in this chapter, PTH can greatly increase phosphate excretion by the kidneys, thereby playing an important role in the control of plasma phosphate and calcium concentrations.␣ BONE AND ITS RELATIONSHIP TO EXTRACELLULAR CALCIUM AND PHOSPHATE There are two general type of bony tissue—cortical (compact) and trabecular (spongy) bone (Figure 80-4). Cortical bone forms the hard outer (cortex) layer, is much denser than trabecular bone, and accounts for about 80% of the total

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