Physiology 5th Ed.

ENDOCRINE PANCREAS

The endocrine pancreas secretes two major peptide hormones, insulin and glucagon, whose coordinated functions are to regulate glucose, fatty acid, and amino acid metabolism. The endocrine pancreas also secretes somatostatin and pancreatic polypeptide, whose functions are less well established.

The endocrine cells of the pancreas are arranged in clusters called the islets of Langerhans, which compose 1% to 2% of the pancreatic mass. There are approximately 1 million islets of Langerhans, each containing about 2500 cells. The islets of Langerhans contain four cell types, and each cell secretes a different hormone or peptide (Fig. 9-27). The β cells compose 65% of the islet and secrete insulin. The α cells compose 20% of the islet and secrete glucagon. The delta (δcells compose 10% of the islet and secrete somatostatin. The remaining cells (not shown in Fig. 9-27) secrete pancreatic polypeptide or other peptides.

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Figure 9–27 Schematic drawing showing the arrangement of cell types and the hormones they secrete in an islet of Langerhans.

The central core of the islet of Langerhans contains mostly β cells, with α cells distributed around the outer rim. The δ cells are interposed between α and β cells, and their intimate contact with the other cell types suggests a paracrine function.

There are three ways in which cells of the islets of Langerhans communicate with each other and thereby alter each other’s secretion (i.e., paracrine mechanisms). (1) Gap junctions connect α cells to each other, β cells to each other, and α cells to β cells. These gap junctions permit rapid cell-to-cell communication via either ionic current flow or transfer of molecules (up to 1000 molecular weight). (2) The islets receive about 10% of the total pancreatic blood flow. The blood supply of the endocrine pancreas is arranged so that venous blood from one cell type bathes the other cell types. Small arteries enter the core of the islet, distributing blood through a network of fenestrated capillaries and then converging into venules that carry the blood to the rim of the islet. Thus, venous blood from the β cells carries insulin to the α and δ cells. (3) The islets are innervated by adrenergic, cholinergic, and peptidergic neurons. The δ cells even have a “neuronal” appearance and send dendrite-like processes onto the β cells, suggesting intraislet neural communication.

Insulin

Insulin, which is synthesized and secreted by the β cells, boasts an impressive array of “firsts.” It was the first hormone to be isolated from animal sources in a form that could be administered therapeutically to humans; the firsthormone to have its primary and tertiary structure determined; the first hormone to have its mechanism of action elucidated; the first hormone to be measured by radioimmunoassay; the firsthormone known to be synthesized from a larger precursor (prohormone); and the first hormone to be synthesized with recombinant DNA technology.

Structure and Synthesis of Insulin

Insulin is a peptide hormone consisting of two straight chains, an A chain (21 amino acids) and a B chain (30 amino acids). Two disulfide bridges link the A chain to the B chain, and a third disulfide bridge is located within the A chain.

The synthesis of insulin is directed by a gene on chromosome 11, a member of a superfamily of genes that encode related growth factors. The mRNA directs ribosomal synthesis of preproinsulin, which contains four peptides: a signal peptide, the A and B chains of insulin, and a connecting peptide (C peptide). The signal peptide is cleaved early in the biosynthetic process (while the peptide chains are still being assembled), yielding proinsulin (Fig. 9-28). Proinsulin is then shuttled to the endoplasmic reticulum, where, with the connecting peptide still attached, disulfide bridges form to yield a “folded” form of insulin. Proinsulin is packaged in secretory granules on the Golgi apparatus. During this packaging process, proteases cleave the connecting peptide, yielding insulin.

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Figure 9–28 Structure of porcine proinsulin. The connecting peptide (C peptide) is cleaved to form insulin. (Modified from Shaw WN, Chance RR: Effect of porcine proinsulin in vitro on adipose tissue and diaphragm of the normal rat. Diabetes 17:737, 1968.)

Insulin and the cleaved connecting peptide are packaged together in secretory granules, and when the β cell is stimulated, they are released in equimolar quantities into the blood. The secretion of connecting peptide (C peptide) is the basis of a test for β-cell function in persons with type I diabetes mellitus who are receiving injections of exogenous insulin. (In these persons, serum insulin levels do not reflect endogenous secretory rates.)

Insulin is metabolized in the liver and kidney by enzymes that break disulfide bonds. The A chains and B chains are released, now inactive, and are excreted in the urine.

Regulation of Insulin Secretion

Table 9-13 summarizes the factors that influence the secretion of insulin by β cells. Of these factors, the most important is glucose. Increases in blood glucose concentration rapidly stimulate the secretion of insulin. Because of the preeminence of glucose as a stimulant, it is used to describe the mechanism of insulin secretion by the β cell, as illustrated in Figure 9-29. The circled numbers in the figure correlate with the steps described as follows:

Table 9–13 Factors Affecting Insulin Secretion

Stimulatory Factors

Inhibitory Factors

Increased glucose concentration

Increased amino acid concentration

Increased fatty acid and ketoacid concentration

Glucagon

Cortisol

Glucose-dependent insulinotropic peptide (GIP)

Potassium

Vagal stimulation; acetylcholine

Sulfonylurea drugs (e.g., tolbutamide, glyburide)

Obesity

Decreased blood glucose

Fasting

Exercise

Somatostatin

α-Adrenergic agonists

Diazoxide

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Figure 9–29 Mechanism of insulin secretion by pancreatic β cells stimulated by glucose. See the text for an explanation of the circled numbers. ATP, Adenosine triphosphate; GLUT 2, glucose transporter.

1.          Transport of glucose into the β cell. The β-cell membrane contains GLUT 2, a specific transporter for glucose that moves glucose from the blood into the cell by facilitated diffusion (Step 1).

2.          Metabolism of glucose inside the β cell. Once inside the cell, glucose is phosphorylated to glucose-6-phosphate by glucokinase (Step 2), and glucose-6-phosphate is subsequently oxidized (Step 3). ATP, one of the products of this oxidation step, appears to be the key factor that regulates insulin secretion.

3.          ATP closes ATP-sensitive K+ channels. K+ channels in the β-cell membrane are regulated (i.e., opened or closed) by changes in ATP levels. When ATP levels inside the β cell increase, the K+ channels close (Step 4), which depolarizes the β-cell membrane (Step 5). (Refer to Chapter 1 for the complete discussion of why closing the K+ channels depolarizes the cell. Briefly, when the K+ channels close, K+conductance decreases and the membrane potential moves away from the K+ equilibrium potential and is depolarized.)

4.          Depolarization opens voltage-sensitive Ca2+ channels. Ca2+ channels, also in the β-cell membrane, are regulated by changes in voltage; they are opened by depolarization and closed by hyperpolarization. The depolarization caused by ATP opens these Ca2+ channels (Step 6). Ca2+ flows into the β cell down its electrochemical gradient and the intracellular Ca2+ concentration increases (Step 7).

5.          Increased intracellular Ca2+ causes insulin secretion. Increases in intracellular Ca2+ concentration cause exocytosis of the insulin-containing secretory granules (Step 8). Insulin is secreted into pancreatic venous blood and then delivered to the systemic circulation. C peptide is secreted in equimolar amounts with insulin and is excreted unchanged in the urine. Therefore, the excretion rate of C peptide can be used to assess and monitor endogenous β-cell function.

Recall from Chapter 8 that oral glucose is a more powerful stimulant for insulin secretion than intravenous glucose. The reason for this difference is that oral glucose stimulates the secretion of glucose-dependent insulinotropic peptide (GIP), a gastrointestinal hormone that has an independent stimulatory effect on insulin secretion (adding to the direct effect of glucose on the β cells). Intravenous glucose does not cause the release of GIP and thus only acts directly.

Many of the other factors that affect insulin secretion do so by altering one or more steps in this basic mechanism. For example, the stimulatory effects of amino acids and fatty acids on insulin secretion utilize metabolic pathways parallel to those utilized by glucose. Glucagon activates a Gq protein coupled to phospholipase C, which leads to a rise in intracellular Ca2+ (i.e., IP3/Ca2+), causing exocytosis of insulin.Somatostatin inhibits the mechanism that glucagon stimulates. The sulfonylurea drugs (e.g., tolbutamide, glyburide) that are used to treat type II (non–insulin-dependent) diabetes mellitus stimulate insulin release from β cells by closing the ATP-dependent K+ channels, depolarizing the cell, and mimicking the depolarization induced by glucose.

Mechanism of Action of Insulin

The action of insulin on target cells begins when the hormone binds to its receptor in the cell membrane. The insulin receptor is a tetramer composed of two α subunits and two β subunits (Fig. 9-30). The α subunits lie in the extracellular domain, and the β subunits span the cell membrane. A disulfide bond connects the two α subunits, and each α subunit is connected to a β subunit by a disulfide bond. The β subunits have intrinsic tyrosine kinase activity.

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Figure 9–30 Structure of the insulin receptor. The two α subunits are connected by disulfide bonds; each α subunit is connected to a β subunit by a disulfide bond. The β subunits have intrinsic tyrosine kinase activity.

Insulin acts on its target cells, as described in the following steps:

1.          Insulin binds to the α subunits of the tetrameric insulin receptor, producing a conformational change in the receptor. The conformational change activates tyrosine kinase in the β subunits, which phosphorylate themselves in the presence of ATP. In other words, the β subunits autophosphorylate.

2.          Activated tyrosine kinase phosphorylates several other proteins or enzymes that are involved in the physiologic actions of insulin including protein kinases, phosphatases, phospholipases, and G proteins. Phosphorylation either activates or inhibits these proteins to produce the various metabolic actions of insulin.

3.          The insulin-receptor complex is internalized (i.e., taken in) by its target cell by endocytosis. The insulin receptor is either degraded by intracellular proteases, stored, or recycled to the cell membrane to be used again. Insulin down-regulates its own receptor by decreasing the rate of synthesis and increasing the rate of degradation of the receptor. Down-regulation of the insulin receptor is in part responsible for the decreased insulin sensitivity of target tissues in obesity and type II diabetes mellitus.

In addition to the previously described actions, insulin also binds to elements in the nucleus, the Golgi apparatus, and the endoplasmic reticulum. Thus, insulin stimulates gene transcription, similar to the actions of somatomedins, IGF-1 and IGF-2.

Actions of Insulin

Insulin is known as the hormone of “abundance” or plenty. When the availability of nutrients exceeds the demands of the body, insulin ensures that excess nutrients are stored as glycogen in the liver, as fat in adipose tissue, and as protein in muscle. These stored nutrients are then available during subsequent periods of fasting to maintain glucose delivery to the brain, muscle, and other organs. The effects of insulin on nutrient flow and the resulting changes in blood levels are summarized in Table 9-14 and shown in Figure 9-31. Insulin has the following actions on liver, muscle, and adipose tissue:

Table 9–14 Major Actions of Insulin and the Effect on Blood Levels

Action of Insulin

Effect on Blood Level

Increases glucose uptake into cells

Decreases blood [glucose]

Increases glycogen formation

 

Decreases glycogenolysis

 

Decreases gluconeogenesis

 

Increases protein synthesis (anabolic)

Decreases blood [amino acid]

Increases fat deposition

Decreases blood [fatty acid]

Decreases lipolysis

Decreases blood [ketoacid]

Increases K+ uptake into cells

Decreases blood [K+]

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Figure 9–31 Effects of insulin on nutrient flow in muscle, liver, and adipose tissue and resulting effects on blood levels of nutrients. Solid arrows indicate that the step is stimulated; dashed arrows indicate that the step is inhibited.

image Decreases blood glucose concentration. The hypoglycemic action of insulin can be described in two ways: Insulin causes a frank decrease in blood glucose concentration, and insulin limits the rise in blood glucose that occurs after ingestion of carbohydrates. The hypoglycemic action of insulin is the result of coordinated responses that simultaneously stimulate glucose oxidation and inhibit gluconeogenesis as follows: (1) Insulin increases glucose transport into target cells such as muscle and adipose by directing the insertion of glucose transporters (GLUT 4) into the cell membranes. As glucose enters the cells, the blood glucose concentration decreases. (2) Insulin promotes the formation of glycogen from glucose in the liver and in muscle and, simultaneously, inhibits glycogenolysis (glycogen breakdown). (3) Insulin inhibits gluconeogenesis (synthesis of glucose) by increasing the production of fructose 2,6-bisphosphate, which increases phosphofructokinase activity. In effect, substrates are directed away from the formation of glucose.

image Decreases blood fatty acid and ketoacid concentrations. The overall effect of insulin on fat metabolism is to inhibit the mobilization and oxidation of fatty acids and, simultaneously, to increase the storage of fatty acids. As a result, insulin decreases the circulating levels of fatty acids and ketoacids. In adipose tissue, insulin stimulates fat deposition and inhibits lipolysis. Simultaneously, insulin inhibits ketoacid (β-hydroxybutyric acid and acetoacetic acid) formation in liver because decreased fatty acid degradation means that less acetyl coenzyme A (acetyl CoA) substrate will be available for the formation of ketoacids.

image Decreases blood amino acid concentration. The overall effect of insulin on protein metabolism is anabolic. Insulin increases amino acid and protein uptake by tissues, thereby decreasing blood levels of amino acids. Insulin stimulates amino acid uptake into target cells (e.g., muscle), increases protein synthesis, and inhibits protein degradation.

image Other actions. In addition to major actions on carbohydrate, fat, and protein metabolism, insulin has several additional effects. Insulin promotes K+ uptake into cells (at the same time that it promotes glucose uptake) by increasing the activity of the Na+-K+ ATPase. This action of insulin can be viewed as “protecting” against an increase in serum K+ concentration. When K+ is ingested in the diet, insulin ensures that ingested K+ will be taken into the cells with glucose and other nutrients. Insulin also appears to have a direct effect on the hypothalamic satiety center independent of the changes it produces in blood glucose concentration.

Pathophysiology of Insulin

The major disorder involving insulin is diabetes mellitus. In one form of diabetes mellitus (type I), there is inadequate insulin secretion; in another form (type II), there is insulin-resistance of target tissues.

image Insulin-dependent diabetes mellitus, or type I diabetes mellitus, is caused by destruction of β cells, often as a result of an autoimmune process. When pancreatic β cells do not secrete adequate amounts of insulin, there are serious metabolic consequences: Carbohydrate, fat, and protein metabolism all will be disturbed.

  Type I diabetes mellitus is characterized by the following changes: increased blood glucose concentration from decreased uptake of glucose into cells, decreased glucose utilization, and increased gluconeogenesis; increased blood fatty acid and ketoacid concentration from increased lipolysis of fat, increased conversion of fatty acids to ketoacids, and decreased utilization of ketoacids by tissues; andincreased blood amino acid concentration from increased breakdown of protein to amino acids. There also is loss of lean body mass (i.e., a catabolic state) and loss of adipose tissue.

  Disturbances of fluid and electrolyte balance are present in type I diabetes mellitus. The increased levels of ketoacids cause a form of metabolic acidosis called diabetic ketoacidosis (DKA). The increased blood glucose concentration results in an increased filtered load of glucose, which exceeds the reabsorptive capacity of the proximal tubule. The nonreabsorbed glucose then acts as an osmotic solute in urine, producing an osmotic diuresis,polyuria, and thirst. The polyuria produces ECF volume contraction and hypotension. Lack of insulin also causes a shift of K+ out of cells (recall that insulin promotes K+uptake), resulting in hyperkalemia.

  Treatment of type I diabetes mellitus consists of insulin replacement therapy, which restores the ability of the body to store carbohydrates, lipids, and proteins and returns the blood values of nutrients and electrolytes to normal.

image Non–insulin-dependent diabetes mellitus, or type II diabetes mellitus, is often associated with obesity. It exhibits some, but not all, of the metabolic derangements seen in type I diabetes mellitus. Type II diabetes mellitus is caused by down-regulation of insulin receptors in target tissues and insulin resistance. Insulin is secreted normally by the β cells, but at normal concentrations, it cannot activate its receptors on muscle, liver, and adipose tissue; thus, insulin is unable to produce its usual metabolic effects. Typically, the blood glucose concentration is elevated in both fasting and postprandial (after eating) states. Treatment of type II diabetes mellitus includes caloric restriction and weight reduction; treatment with sulfonylurea drugs (e.g., tolbutamide or glyburide), which stimulate pancreatic insulin secretion; and treatment with biguanide drugs (e.g., metformin), which up-regulate insulin receptors on target tissues.

Glucagon

Glucagon is synthesized and secreted by the α cells of the islets of Langerhans. In most respects (i.e., regulation of secretion, actions, and effect on blood levels), glucagon is the “mirror image” of insulin. Thus, while insulin is the hormone of “abundance,” glucagon is the hormone of “starvation.” In contrast to insulin, which promotes storage of metabolic fuels, glucagon promotes their mobilization and utilization.

Structure and Synthesis of Glucagon

Glucagon is a single straight-chain polypeptide with 29 amino acids. It is a member of a family of peptides that includes the gastrointestinal hormones secretin and gastric inhibitory peptide (GIP). All of the peptides in the family share structural features and overlap in their physiologic actions (see Chapter 8Fig. 8-6).

As with other peptide hormones, glucagon is synthesized as preproglucagon. The signal peptide and other peptide sequences are removed to produce glucagon, which then is stored in dense granules until it is secreted by the α cells. Both glucose and insulin inhibit the synthesis of glucagon; insulin-sensitive and cAMP-sensitive elements are present on the gene for preproglucagon.

Regulation of Glucagon Secretion

The actions of glucagon are coordinated to increase and maintain the blood glucose concentration. Thus, the factors that cause stimulation of glucagon secretion are those that inform the α cells that a decrease in blood glucose has occurred (Table 9-15).

Table 9–15 Factors Affecting Glucagon Secretion

Stimulatory Factors

Inhibitory Factors

Fasting

Decreased glucose concentration

Increased amino acid concentration (especially arginine)

Cholecystokinin (CCK)

β-Adrenergic agonists

Acetylcholine

Insulin

Somatostatin

Increased fatty acid and ketoacid concentration

The major factor stimulating the secretion of glucagon is decreased blood glucose concentration. Coordinating with this stimulatory effect of low blood glucose is a separate inhibitory action of insulin. Thus, the presence of insulin reduces or modulates the effect of low blood glucose concentration to stimulate glucagon secretion. In the absence of insulin (i.e., type I diabetes mellitus), however, the glucagon response to hypoglycemia is exaggerated and may lead to severe, perpetuated hyperglycemia.

Glucagon secretion also is stimulated by the ingestion of protein, specifically by the amino acids arginine and alanine. The response of the α cells to amino acids is blunted if glucose is administered simultaneously (partially mediated by the inhibitory effect of insulin on glucagon secretion). Thus, glucose and amino acids have offsetting or opposite effects on glucagon secretion (in contrast to their effects on insulin secretion, which are complementary).

Other factors stimulating glucagon secretion are cholecystokinin (CCK), which is secreted from the gastrointestinal tract when protein or fat is ingested, and fasting and intense exercise. Some of the stimulatory effects on glucagon secretion are mediated by activation of sympathetic α-adrenergic receptors.

Actions of Glucagon

The mechanism of action of glucagon on its target cells begins with hormone binding to a cell membrane receptor, which is coupled to adenylyl cyclase via a Gs protein. The second messenger is cAMP,which activates protein kinases that phosphorylate various enzymes; the phosphorylated enzymes then mediate the physiologic actions of glucagon.

As the hormone of starvation, glucagon promotes mobilization and utilization of stored nutrients to maintain the blood glucose concentration in the fasting state. The major actions of glucagon are on the liver (in contrast to insulin, which acts on liver, adipose, and muscle tissue). The effects of glucagon on the flow of nutrients are illustrated in Figure 9-32. Glucagon has the following effects on blood levels, which are summarized in Table 9-16 and described as follows:

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Figure 9–32 Effects of glucagon on nutrient flow in liver and adipose tissue and resulting effects on blood levels of nutrients. Solid arrows indicate that the step is stimulated; dashed arrows indicate that the step is inhibited.

Table 9–16 Major Actions of Glucagon and Effect on Blood Levels

Action of Glucagon

Effect on Blood Level

Increases glycogenolysis

Increases blood [glucose]

Increases gluconeogenesis

 

Increases lipolysis

Increases blood [fatty acid]

Increases ketoacid formation

Increases blood [ketoacid]

image Increases blood glucose concentration. Glucagon increases the blood glucose concentration by the following coordinated actions: (1) Glucagon stimulates glycogenolysis and simultaneously inhibits glycogen formation from glucose, and (2) Glucagon increases gluconeogenesis by decreasing the production of fructose 2,6-bisphosphate, which decreases phosphofructokinase activity. Thus, substrate is directed toward the formation of glucose. Amino acids are utilized for gluconeogenesis, and the resulting amino groups are incorporated into urea.

image Increases blood fatty acid and ketoacid concentration. Glucagon increases lipolysis and inhibits fatty acid synthesis, which also shunts substrates toward gluconeogenesis. The ketoacids β-hydroxybutyric acid and acetoacetic acid are produced from fatty acids.

Somatostatin

Pancreatic somatostatin, a polypeptide with 14 amino acids, is secreted by the δ cells of the islets of Langerhans. (The gastrointestinal counterpart of somatostatin has 28 amino acids and shares many of the physiologic actions of the pancreatic hormone.) Secretion of somatostatin is stimulated by the ingestion of all forms of nutrients (i.e., glucose, amino acids, and fatty acids), by several gastrointestinal hormones, by glucagon, and by β-adrenergic agonists. Secretion of somatostatin is inhibited by insulin via an intraislet paracrine mechanism.

Pancreatic somatostatin inhibits secretion of insulin and glucagon via paracrine actions on the α and β cells. Thus, somatostatin is secreted by the δ cells in response to a meal, diffuses to the nearby α and β cells, and inhibits secretion of their respective hormones. Apparently, the function of somatostatin is to modulate or limit the responses of insulin and glucagon to ingestion of food.