HORMONES OF THE DIGESTIVE TRACT

The pancreas, in addition to its digestive functions, secretes two important hormones, insulin and
glucagon, that are crucial for normal regulation of glucose, lipid, and protein metabolism. Although the
pancreas secretes other hormones, such as amylin, somatostatin, and pancreatic polypeptide, their
functions are not as well established.

The pancreas is composed of two major types of tissues: (1) the acini, which secrete digestive juices into
the duodenum, and (2) the islets of Langerhans, which secrete insulin and glucagon directly into the
blood (figure 1). The human pancreas has 1 to 2 million islets of Langerhans, each only about 0.3
millimeters in diameter and organized around small capillaries into which its cells secrete their
hormones. The islets contain three major types of cells, alpha, beta, and delta cells, which are
distinguished from one another by their morphological and staining characteristics. The beta cells,
constituting about 60 per cent of all the cells of the islets, lie mainly in the middle of each islet and
secrete insulin and amylin, a hormone that is often secreted in parallel with insulin, although its function
is unclear. The alpha cells, about 25 per cent of the total, secrete glucagon. And the delta cells, about 10
per cent of the total, secrete somatostatin. In addition, at least one other type of cell, the PP cell, is
present in small numbers in the islets and secretes a hormone of uncertain function called pancreatic
polypeptide. The close interrelations among these cell types in the islets of Langerhans allow cell-to-cell
communication and direct control of secretion of some of the hormones by the other hormones. For
instance, insulin inhibits glucagon secretion, amylin inhibits insulin secretion, and somatostatin inhibits
the secretion of both insulin and glucagon.

Figure 1: Physiologic anatomy of an islet of Langerhans in the pancreas.

Insulin and Energy Abundance

Insulin secretion is associated with energy abundance. That is, when there is great abundance of
energy-giving foods in the diet, especially excess amounts of carbohydrates, insulin is secreted in great
quantity. 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. Also, all the
excess carbohydrates that cannot be stored as glycogen are converted under the stimulus of insulin into
fats and stored in the adipose tissue. In the case of proteins, insulin has a direct effect in promoting
1
amino acid uptake by cells and conversion of these amino acids into protein. In addition, it inhibits the
breakdown of the proteins that are already in the cells.

Synthesis of Insulin
Insulin is a small protein; human insulin has a molecular weight of 5808. It is composed of two amino
acid chains, shown in Figure 2, connected to each other by disulfide linkages. When the two amino acid
chains are split apart, the functional activity of the insulin molecule is lost. Insulin is synthesized in the
beta cells by the usual cell machinery for protein synthesis, beginning with translation of the insulin RNA
by ribosomes attached to the endoplasmic reticulum to form an insulin preprohormone. This initial
preprohormone has a molecular weight of about 11,500, but it is then cleaved in the endoplasmic
reticulum to form a proinsulin with a molecular weight of about 9000; most of this is further cleaved in
the Golgi apparatus to form insulin and peptide fragments before being packaged in the secretory
granules. However, about one sixth of the final secreted product is still in the form of proinsulin. The
proinsulin has virtually no insulin activity. When insulin is secreted into the blood, it circulates almost
entirely in an unbound form; it has a plasma half-life that averages only about 6 minutes, so that it is
mainly cleared from the circulation within 10 to 15 minutes. Except for that portion of the insulin that
combines with receptors in the target cells, the remainder is degraded by the enzyme insulinase mainly
in the liver, to a lesser extent in the kidneys and muscles, and slightly in most other tissues. This rapid
removal from the plasma is important, because, at times, it is as important to turn off rapidly as to turn
on the control functions of insulin.

Figure 2: Human insulin molecule

Activation of Target Cell Receptors and the Resulting Cellular Effects

To initiate its effects on target cells, insulin first binds with and activates a membrane receptor protein
that has a molecular weight of about 300,000 (Figure 3). It is the activated receptor, not the insulin that
causes the subsequent effects. The insulin receptor is a combination of four subunits held together by
disulfide linkages: two alpha subunits that lie entirely outside the cell membrane and two beta subunits
that penetrate through the membrane, protruding into the cell cytoplasm. The insulin binds with the
alpha subunits on the outside of the cell, but because of the linkages with the beta subunits, the
portions of the beta subunits protruding into the cell become autophosphorylated. Thus, the insulin
receptor is an example of an enzyme-linked receptor. Autophosphorylation of the beta subunits of the
receptor activates a local tyrosine kinase, which in turn causes phosphorylation of multiple other
intracellular enzymes including a group called insulin-receptor substrates (IRS). Different types of IRS
(e.g. IRS-1, IRS-2, IRS-3) are expressed in different tissues. The net effect is to activate some of these
enzymes while inactivating others. In this way, insulin directs the intracellular metabolic machinery to

2
produce the desired effects on carbohydrate, fat, and protein metabolism. The end effects of insulin
stimulation are the following:
1. Within seconds after insulin binds with its membrane receptors, the membranes of about 80 per cent
of the body’s cells markedly increase their uptake of glucose. This is especially true of muscle cells and
adipose cells but is not true of most neurons in the brain. The increased glucose transported into the
cells is immediately phosphorylated and becomes a substrate for all the usual carbohydrate metabolic
functions. The increased glucose transport is believed to result from translocation of multiple
intracellular vesicles to the cell membranes; these vesicles carry in their own membranes multiple
molecules of glucose transport proteins, which bind with the cell membrane and facilitate glucose
uptake into the cells. When insulin is no longer available, these vesicles separate from the cell
membrane within about 3 to 5 minutes and move back to the cell interior to be used again and again as
needed.
2. The cell membrane becomes more permeable to many of the amino acids, potassium ions, and
phosphate ions, causing increased transport of these substances into the cell.
3. Slower effects occur during the next 10 to 15 minutes to change the activity levels of many more
intracellular metabolic enzymes. These effects result mainly from the changed states of phosphorylation
of the enzymes.
4. Much slower effects continue to occur for hours and even several days. They result from changed
rates of translation of messenger RNAs at the ribosomes to form new proteins and still slower effects
from changed rates of transcription of DNA in the cell nucleus. In this way, insulin remolds much of the
cellular enzymatic machinery to achieve its metabolic goals.

Figure 3: Schematic of the insulin receptor

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Effect of Insulin on Carbohydrate Metabolism
Immediately after a high-carbohydrate meal, the glucose that is absorbed into the blood causes rapid
secretion of insulin, which 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.

Muscle Glucose Uptake and Metabolism

During much of the day, muscle tissue depends not on glucose for its energy but on fatty acids. The
principal reason for this is that the normal resting muscle membrane is only slightly permeable to
glucose, except when the muscle fiber is stimulated by insulin; between meals, the amount of insulin
that is secreted is too small to promote significant amounts of glucose entry into the muscle cells.
However, under two conditions the muscles do use large amounts of glucose. One of these is during
moderate or heavy exercise. This usage of glucose does not require large amounts of insulin, because
exercising muscle fibers become more permeable to glucose even in the absence of insulin because of
the contraction process itself. The second condition for muscle usage of large amounts of glucose is
during the few hours after a meal. At this time the blood glucose concentration is high and the pancreas
is secreting large quantities of insulin. The extra insulin causes rapid transport of glucose into the muscle
cells. This causes the muscle cell during this period to use glucose preferentially over fatty acids.
Liver Uptake, Storage, and Use of Glucose
One of the most important of all the effects of insulin is to cause most of the glucose absorbed after a
meal to be stored almost immediately in the liver in the form of glycogen. Then, between meals, when
food is not available and the blood glucose concentration begins to fall, insulin secretion decreases
rapidly and the liver glycogen is split back into glucose, which is released back into the blood to keep the
glucose concentration from falling too low. The mechanism by which insulin causes glucose uptake and
storage in the liver includes several almost simultaneous steps:
1. Insulin inactivates liver phosphorylase, the principal enzyme that causes liver glycogen to split into
glucose. This prevents breakdown of the glycogen that has been stored in the liver cells.
2. Insulin causes enhanced uptake of glucose from the blood by the liver cells. It does this by increasing
the activity of the enzyme glucokinase, which is one of the enzymes that causes the initial
phosphorylation of glucose after it diffuses into the liver cells. Once phosphorylated, the glucose is
temporarily trapped inside the liver cells because phosphorylated glucose cannot diffuse back through
the cell membrane.
3. Insulin also increases the activities of the enzymes that promote glycogen synthesis, including
especially glycogen synthase, which is responsible for polymerization of the monosaccharide units to
form the glycogen molecules.
The net effect of all these actions is to increase the amount of glycogen in the liver. The glycogen can
increase to a total of about 5 to 6 per cent of the liver mass, which is equivalent to almost 100 grams of
stored glycogen in the whole liver.

Glucose Is Released from the Liver Between Meals.

When the blood glucose level begins to fall to a low level between meals, several events transpire that
cause the liver to release glucose back into the circulating blood:
1. The decreasing blood glucose causes the pancreas to decrease its insulin secretion.
2. The lack of insulin then reverses all the effects listed earlier for glycogen storage, essentially stopping
further synthesis of glycogen in the liver and preventing further uptake of glucose by the liver from the
blood.

4
3. The lack of insulin (along with increase of glucagon, which is discussed later) activates the enzyme
phosphorylase, which causes the splitting of glycogen into glucose phosphate.
4. The enzyme glucose phosphatase, which had been inhibited by insulin, now becomes activated by the
insulin lack and causes the phosphate radical to split away from the glucose; this allows the free glucose
to diffuse back into the blood. Thus, the liver removes glucose from the blood when it is present in
excess after a meal and returns it to the blood when the blood glucose concentration falls between
meals. Ordinarily, about 60 per cent of the glucose in the meal is stored in this way in the liver and then
returned later.

Effect of Insulin on Fat Metabolism

Insulin has several effects that lead to fat storage in adipose tissue. First, insulin increases the utilization
of glucose by most of the body’s tissues, which automatically decreases the utilization of fat, thus
functioning as a fat sparer. However, insulin also promotes fatty acid synthesis. This is especially true
when more carbohydrates are ingested than can be used for immediate energy, thus providing the
substrate for fat synthesis. Almost all this synthesis occurs in the liver cells, and the fatty acids are then
transported from the liver by way of the blood lipoproteins
to the adipose cells to be stored. The different factors that lead to increased fatty acid synthesis in the
liver
include the following:
1. Insulin increases the transport of glucose into the liver cells. After the liver glucogen concentration
reaches 5 to 6 per cent, this in itself inhibits further glycogen synthesis. Then all the additional glucose
entering the liver cells becomes available to form fat. The glucose is first split to pyruvate in the
glycolytic pathway, and the pyruvate
subsequently is converted to acetyl coenzyme A (acetyl-CoA), the substrate from which fatty acids are
synthesized.
2. An excess of citrate and isocitrate ions is formed by the citric acid cycle when excess amounts of
glucose are being used for energy. These ions then have a direct effect in activating acetyl-CoA
carboxylase, the enzyme required to carboxylate acetyl-CoA to form malonyl-CoA, the first stage of fatty
acid synthesis.
3. Most of the fatty acids are then synthesized within the liver itself and used to form triglycerides, the
usual form of storage fat. They are released from the liver cells to the blood in the lipoproteins. Insulin
activates lipoprotein lipase in the capillary walls of the adipose tissue, which splits the triglycerides again
into fatty acids, a requirement for them to be absorbed into the adipose cells, where they are again
converted to triglycerides and stored.

Insulin has two other essential effects that are required for fat storage in adipose cells:
1. Insulin inhibits the action of hormone-sensitive lipase. This is the enzyme that causes hydrolysis of
the triglycerides already stored in the fat cells. Therefore, the release of fatty acids from the adipose
tissue into the circulating blood is inhibited.
2. Insulin promotes glucose transport through the cell membrane into the fat cells in exactly the same
ways that it promotes glucose transport into muscle cells. Some of this glucose is then used to
synthesize minute amounts of fatty acids, but more important, it also forms large quantities of a-
glycerol phosphate. This substance supplies the
glycerol that combines with fatty acids to form the triglycerides that are the storage form of fat in
adipose cells. Therefore, when insulin is not available, even storage of the large amounts of fatty acids
transported from the liver in the lipoproteins is almost blocked.

5
Effect of Insulin on Protein Metabolism and on Growth
During the few hours after a meal when excess quantities of nutrients are available in the circulating
blood, not only carbohydrates and fats but proteins as well are stored in the tissues; insulin is required
for this to occur. The manner in which insulin causes protein storage is not as well understood as the
mechanisms for both glucose and fat storage. Some of the facts follow.
1. Insulin stimulates transport of many of the amino acids into the cells. Among the amino acids most
strongly transported are valine, leucine, isoleucine, tyrosine, and phenylalanine. Thus, insulin shares with
growth hormone the capability of increasing the uptake of amino acids into cells. However, the amino
acids affected are not necessarily the same ones.
2. Insulin increases the translation of messenger RNA, thus forming new proteins. In some unexplained
way, insulin “turns on” the ribosomal machinery. In the absence of insulin, the ribosomes simply stop
working, almost as if insulin operates an “on-off” mechanism.
3. Over a longer period of time, insulin also increases the rate of transcription of selected DNA genetic
sequences in the cell nuclei, thus forming increased quantities of RNA and still more protein synthesis—
especially promoting a vast array of enzymes for storage of carbohydrates, fats, and proteins.
4. Insulin inhibits the catabolism of proteins, thus decreasing the rate of amino acid release from the
cells, especially from the muscle cells. Presumably this results from the ability of insulin to diminish the
normal degradation of proteins by the cellular lysosomes.
5. In the liver, insulin depresses the rate of gluconeogenesis. It does this by decreasing the activity of the
enzymes that promote gluconeogenesis. Because the substrates most used for synthesis of glucose by
gluconeogenesis are the plasma amino acids, this suppression of gluconeogenesis conserves the amino
acids in the protein stores of the body.
In summary, insulin promotes protein formation and prevents the degradation of proteins.

Mechanisms of Insulin Secretion

Glucose is the key regulator of insulin secretion by the pancreatic beta cell, although amino acids,
ketones, various nutrients, gastrointestinal peptides, and neurotransmitters also influence insulin
secretion. Glucose levels > 3.9 mmol/L (70 mg/dL) stimulate insulin synthesis, primarily by enhancing
protein translation and processing. The beta cells have a large number of glucose transporters (GLUT- 2)
that permit a rate of glucose influx that is proportional to the blood concentration in the physiologic
range (figure 4). Once inside the cells, glucose is phosphorylated to glucose-6-phosphate by glucokinase.
This step appears to be the rate limiting for glucose metabolism in the beta cell and is considered the
major mechanism for glucose sensing and adjustment of the amount of secreted insulin to the blood
glucose levels. The glucose-6-phosphate is subsequently oxidized to form adenosine triphosphate (ATP),
which inhibits the ATP-sensitive potassium channels of the cell. Closure of the potassium channels
depolarizes the cell membrane, thereby opening voltage-gated calcium channels, which are sensitive to
changes in membrane voltage. This produces an influx of calcium that stimulates fusion of the docked
insulin-containing vesicles with the cell membrane and secretion of insulin into the extracellular fluid by
exocytosis. Other nutrients, such as certain amino acids, can also be metabolized by the beta cells to
increase intracellular ATP levels and stimulate insulin secretion. Some hormones, such as glucagon and
gastric inhibitory peptide, as well as acetylcholine increase intracellular calcium levels through other
signaling pathways and enhance the effect of glucose, although they do not have major effects on
insulin secretion in the absence of glucose. Other hormones, including somatostatin and norepinephrine
(by activating a-adrenergic receptors), inhibit exocytosis of insulin. Sulfonylurea drugs stimulate insulin
secretion by binding to the ATP-sensitive potassium channels and blocking their activity. This results in a

6
depolarizing effect that triggers insulin secretion, making these drugs very useful in stimulating insulin
secretion in patients with type II diabetes.
Table 1 summarizes some of the factors that can increase or decrease insulin secretion.

Figure 4: Basic mechanisms of glucose stimulation of insulin secretion by beta cells of the pancreas.
GLUT, glucose transporter.

Table 1: Factors and Conditions That Increase or Decrease Insulin Secretion

Glucagon and Its Functions

Glucagon, a hormone secreted by the alpha cells of the islets of Langerhans when the blood glucose
concentration falls, has several functions that are diametrically opposed to those of insulin. Most
important of these functions is to increase the blood glucose concentration, an effect that is exactly the
7
opposite that of insulin. Like insulin, glucagon is a large polypeptide. It has a molecular weight of 3485
and is composed of a chain of 29 amino acids. On injection of purified glucagon into an animal, a
profound hyperglycemic effect occurs. Only 1 µg/kg of glucagon can elevate the blood glucose
concentration about 20 mg/100 ml of blood (a 25 per cent increase) in about 20 minutes. For this
reason, glucagon is also called the hyperglycemic hormone.

SIGNAL TRANSDUCTION BY GLUCAGON

The pathway for signal transduction by glucagon is one common to a number of hormones; the
glucagon receptor is coupled to adenylate cyclase and cAMP production. Glucagon, through G proteins,
activates the membrane bound adenylate cyclase, increasing the synthesis of the intracellular second
messenger 3’,5’cyclic AMP (cAMP). cAMP activates protein kinase A (cAMP-dependent protein kinase),
which changes the activity of enzymes by phosphorylating them at specific serine residues.
Phosphorylation activates some enzymes and inhibits others. The G proteins, which couple the glucagon
receptor to adenylate cyclase, are proteins in the plasma membrane that bind guanosine triphosphate
(GTP) and have dissociable subunits that interact with both the receptor and adenylate cyclase. In the
absence of glucagon, the stimulatory Gs protein complex binds guanosine diphosphate (GDP) but
cannot bind to the unoccupied receptor or adenylate cyclase. Once glucagon binds to the receptor, the
receptor also binds the Gs complex, which then releases GDP and binds GTP. The α-subunit then
dissociates from the βƳ-subunits and binds to adenylate cyclase, thereby activating it. As the GTP on the
α-subunit is hydrolyzed to GDP, the subunit dissociates and recomplexes with the β- and Ƴ-subunits.
Only continued occupancy of the glucagon receptor can keep adenylate cyclase active. Although
glucagon works by activating adenylate cyclase, a few hormones inhibit adenylate cyclase. In this case,
the inhibitory G protein complex is called a Gi complex. cAMP is very rapidly degraded to AMP by a
membrane-bound phosphodiesterase. The concentration of cAMP is thus very low in the cell so that
changes in its concentration can occur rapidly in response to changes in the rate of synthesis. The
amount of cAMP present at any time is a direct reflection of hormone binding and the activity of
adenylate cyclase. It is not affected by ATP, ADP, or AMP levels in the cell. cAMP transmits the hormone
signal to the cell by activating protein kinase A (cAMP-dependent protein kinase). As cAMP binds to the
regulatory subunits of protein kinase A, these subunits dissociate from the catalytic subunits, which are
thereby activated. Activated protein kinase A phosphorylates serine residues of key regulatory enzymes
in the pathways of carbohydrate and fat metabolism. Some enzymes are activated and others are
inhibited by this change in phosphorylation state. The message of the hormone is terminated by the
action of semispecific protein phosphatases that remove phosphate groups from the enzymes. The
activity of the protein phosphatases is also controlled through hormonal regulation. Changes in the
phosphorylation state of proteins that bind to cAMP response elements (CREs) in the promoter region
of genes contribute to the regulation of gene transcription by a number of cAMP-coupled hormones.
For instance, cAMP response element binding protein (CREB) is directly phosphorylated by protein
kinase A, a step essential for the initiation of transcription. Phosphorylation at other sites on CREB, by a
variety of kinases, also may play a role in regulating transcription. The mechanism for signal
transduction by glucagon illustrates some of the important principles of hormonal signaling
mechanisms. The first principle is that specificity of action in tissues is conferred by the receptor on a
target cell for glucagon. In general, the major actions of glucagon occur in liver, adipose tissue, and
certain cells of the kidney that contain glucagon receptors. The second principle is that signal
transduction involves amplification of the first message. Glucagon and other hormones are present in
the blood in very low concentrations. However, these minute concentrations of hormone are adequate
to initiate a cellular response because the binding of one molecule of glucagon to one receptor

8
ultimately activates many protein kinase A molecules, each of which phosphorylates hundreds of
downstream enzymes. The third principle involves integration of metabolic responses. For instance, the
glucagon-stimulated phosphorylation of enzymes simultaneously activates glycogen degradation,
inhibits glycogen synthesis, and inhibits glycolysis in the liver. The fourth principle involves
augmentation and antagonism of signals. An example of augmentation involves the actions of glucagon
and epinephrine (which is released during exercise). Although these hormones bind to different
receptors, each can increase cAMP and stimulate glycogen degradation. A fifth principle is that of rapid
signal termination. In the case of glucagon, both the termination of the Gs protein activation and the
rapid degradation of cAMP contribute to signal termination.

Effects on Glucose Metabolism

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

a. Glucagon Causes Glycogenolysis and Increased Blood Glucose Concentration

The most dramatic effect of glucagon is its ability to cause glycogenolysis in the liver, which in turn
increases the blood glucose concentration within minutes. It does this by the following complex cascade
of events:
1. Glucagon activates adenylyl cyclase in the hepatic cell membrane,
2. Which causes the formation of cyclic adenosine monophosphate,
3. Which activates protein kinase regulator protein,
4. Which activates protein kinase,
5. Which activates phosphorylase b kinase,
6. Which converts phosphorylase b into phosphorylase a,
7. Which promotes the degradation of glycogen into glucose-1-phosphate,
8. Which then is dephosphorylated; and the glucose is released from the liver cells.
This sequence of events is exceedingly important for several reasons. First, it is one of the most
thoroughly studied of all the second messenger functions of cyclic adenosine monophosphate. Second,
it demonstrates a cascade system in which each succeeding product is produced in greater quantity than
the preceding product. Therefore, it represents a potent amplifying mechanism; this type of amplifying
mechanism is widely used throughout the body for controlling many, if not most, cellular metabolic
systems, often causing as much as a millionfold amplification in response. This explains how only a few
micrograms of glucagon can cause the blood glucose level to double or increase even more within a few
minutes. Infusion of glucagon for about 4 hours can cause such intensive liver glycogenolysis that all the
liver stores of glycogen become depleted.

b. Glucagon Increases Gluconeogenesis.

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

9
c. Other Effects of Glucagon
Most other effects of glucagon occur only when its concentration rises well above the maximum
normally found in the blood. Perhaps the most important effect is that glucagon activates adipose cell
lipase, making increased quantities of fatty acids available to the energy systems of the body. Glucagon
also inhibits the storage of triglycerides in the liver, which prevents the liver from removing fatty acids
from the blood; this also helps make additional amounts of fatty acids available for the other tissues of
the body. Glucagon in very high concentrations also (1) enhances the strength of the heart; (2) increases
blood flow in some tissues, especially the kidneys; (3) enhances bile secretion; and (4) inhibits gastric
acid secretion. All these effects are probably of minimal importance in the normal function of the body.

Regulation of Glucagon Secretion

a. Increased Blood Glucose Inhibits Glucagon Secretion.
The blood glucose concentration is by far the most potent factor that controls glucagon secretion. Note
specifically, however, that the effect of blood glucose concentration on glucagon secretion is in exactly
the opposite direction from the effect of glucose on insulin secretion.
b. Increased Blood Amino Acids Stimulate Glucagon Secretion.
High concentrations of amino acids, as occur in the blood after a protein meal (especially the amino
acids alanine and arginine), stimulate the secretion of glucagon.This is the same effect that amino acids
have in stimulating insulin secretion. Thus, in this instance, the glucagon and insulin responses are not
opposites. The importance of amino acid stimulation of glucagon secretion is that the glucagon then
promotes rapid conversion of the amino acids to glucose, thus making even more glucose available to
the tissues.

Somatostatin Inhibits Glucagon and Insulin Secretion

The delta cells of the islets of Langerhans secrete the hormone somatostatin, a polypeptide containing
only 14 amino acids that has an extremely short half-life of only 3 minutes in the circulating blood.
Almost all factors related to the ingestion of food stimulate somatostatin secretion. They include (1)
increased blood glucose, (2) increased amino acids, (3) increased fatty acids, and (4) increased
concentrations of several of the gastrointestinal hormones released from the upper gastrointestinal
tract in response to food intake. In turn, somatostatin has multiple inhibitory effects as follows:
1. Somatostatin acts locally within the islets of Langerhans themselves to depress the secretion of both
insulin and glucagon.
2. Somatostatin decreases the motility of the stomach, duodenum, and gallbladder.
3. Somatostatin decreases both secretion and absorption in the gastrointestinal tract.
The principal role of somatostatin is to extend the period of time over which the food nutrients are
assimilated into the blood. At the same time, the effect of somatostatin to depress insulin and glucagon
secretion decreases the utilization of the absorbed nutrients by the tissues, thus preventing rapid
exhaustion of the food and therefore making it available over a longer period of time.

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 I diabetes, also called insulin-dependent diabetes mellitus (IDDM), is caused by lack of insulin
secretion.

10
2. Type II diabetes, also called non–insulin-dependent diabetes mellitus (NIDDM), is 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 lack or insulin resistance on glucose metabolism is to prevent the
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 I Diabetes—Lack of Insulin Production by Beta Cells of the Pancreas

Injury to the beta cells of the pancreas or diseases that impair insulin production can lead to type I
diabetes. Viral infections or autoimmune disorders may be involved in the destruction of beta cells in
many patients with type I diabetes, although heredity also plays a major role in determining the
susceptibility of the beta cells to destruction by these insults. In some instances, there may be a
hereditary tendency for beta cell degeneration even without viral infections or autoimmune disorders.
The usual onset of type I diabetes occurs at about 14 years of age in the United States, and for this
reason it is often called juvenile diabetes mellitus.Type I diabetes may develop very abruptly, over a
period of a few days or weeks, with three principal sequelae: (1) increased blood glucose, (2) increased
utilization of fats for energy and for formation of cholesterol by the liver, and (3) depletion of the body’s
proteins.

Type II Diabetes—Resistance to the Metabolic Effects of Insulin

Type II diabetes is far more common than type I, accounting for about 90 per cent of all cases of
diabetes mellitus. In most cases, the onset of type II diabetes occurs after age 30, 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 less than 20 years old, with type II diabetes. This trend appears to be related
mainly to the increasing prevalence of obesity, the most important risk factor for type II diabetes in
children as well as in adults.

Obesity, Insulin Resistance, and “Metabolic Syndrome” Usually Precede Development of Type II
Diabetes.
Type II diabetes, in contrast to type I, is associated with increased plasma insulin concentration
(hyperinsulinemia).This occurs as a compensatory response by the pancreatic beta cells for diminished
sensitivity of target tissues to the metabolic effects of insulin, a condition referred to as insulin
resistance. The decrease in insulin sensitivity impairs carbohydrate utilization and storage, raising blood
glucose and stimulating a compensatory increase in insulin secretion. Development of insulin resistance
and impaired glucose metabolism is usually a gradual process, beginning with excess weight gain and
obesity. The mechanisms that link obesity with insulin resistance, however, are still uncertain. Some
studies suggest that there are fewer insulin receptors, especially in the skeletal muscle, liver, and
adipose tissue, in obese than in lean subjects. However, most of the insulin resistance appears to be
caused by abnormalities of the signaling pathways that link receptor activation with multiple cellular
effects. Impaired insulin signaling appears to be closely related to toxic effects of lipid accumulation in
tissues such as skeletal muscle and liver secondary to excess weight gain. 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

11
decreased blood high-density lipoprotein-cholesterol; and (5) hypertension. All of the features of the
metabolic syndrome are closely related to excess weight gain, especially when it is associated with
accumulation of adipose tissue in the abdominal cavity around the visceral organs. The 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 are risk factors for cardiovascular disease, and insulin resistance predisposes to the
development of type II diabetes mellitus, also a major cause of cardiovascular disease.

Somatostatin
Preprosomatostatin, a 116–amino acid peptide, is encoded on the long arm of chromosome 3.
Somatostatin (SS-14), a cyclic peptide with a molecular weight of 1,600, is produced from the 14 amino
acids at the C-terminus of this precursor molecule. SS-14 was first isolated from the hypothalamus and
named for its ability to inhibit the release of growth hormone (GH, somatotropin) from the anterior
pituitary. It also inhibits the release of insulin. In addition to the hypothalamus, somatostatin is also
secreted from the D cells (δ cells) of the pancreatic islets, many areas of the central nervous system
outside of the hypothalamus, and in gastric and duodenal mucosal cells. SS-14 predominates in the
central nervous system (CNS) and is the sole form secreted by the δ cells of the pancreas. In the gut,
however, prosomatostatin (SS-28), which has 14 additional amino acids extending from the C-terminal
portion of the precursor, makes up 70 to 75% of the immunoreactivity (the amount of hormone that
reacts with antibodies to SS-14). The prohormone SS-28 is 7 to 10 times more potent in inhibiting the
release of GH and insulin than is SS-14.

SECRETION OF SOMATOSTATIN
The secretagogues for somatostatin are similar to those that cause secretion of insulin. The metabolites
that increase somatostatin release include glucose, arginine, and leucine. The hormones that stimulate
somatostatin secretion include glucagon, vasoactive intestinal polypeptide (VIP), and cholecystokinin
(CCK). Insulin, however, does not directly influence somatostatin secretion.

PHYSIOLOGIC EFFECTS OF SOMATOSTATIN

Five somatostatin receptors have been identified and characterized, all of which are members of the G
protein–coupled receptor superfamily. Four of the five receptors do not distinguish between SS-14 and
SS-28. Somatostatin binds to its plasma membrane receptors on target cells. These “activated”
receptors interact with inhibitory G proteins of adenylate cyclase. As a result, the production of cAMP is
inhibited, and protein kinase A is not activated. This inhibitory effect suppresses secretion of GH and
thyroid-stimulating hormone (TSH) from the anterior pituitary gland as well as the secretion of insulin
and glucagon from the pancreatic islets. If one were to summarize the action of somatostatin in one
phrase, it would be “somatostatin inhibits the secretion of many other hormones.” As such, it acts to
regulate the effects of those other hormones. In addition to these effects on hormones that regulate
fuel metabolism, somatostatin also reduces nutrient absorption from the gut by prolonging gastric
emptying time (through a decrease in the secretion of gastrin, which reduces gastric acid secretion), by
diminishing pancreatic exocrine secretions (i.e., digestive enzymes, bicarbonate, and water), and by
decreasing visceral blood flow. Thus, somatostatin exerts a broad, albeit indirect, influence on nutrient
absorption and, therefore, the utilization of fuels. Somatostatin and its synthetic analogs are used
clinically to treat a variety of secretory neoplasms such as GH-secreting tumors of the pituitary. Such
tumors can cause gigantism if growth hormone is secreted in excess before the closure of the growth

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centers of the ends of long bones or acromegaly if excess growth hormone is chronically secreted after
the closure of these centers.

Hormones of the gut Gastrointestinal-Derived Hormones Affecting Fuel Metabolism

Of the over two dozen hormones that have been identified in the various parts of the gastrointestinal
system, most of them are peptides, many of them are also found in other tissues, especially the brain,
many act in a paracrine manner as well as being carried in the blood as true hormones. In addition to
insulin and the counterregulatory hormones discussed, a variety of peptides synthesized in the
endocrine cells of the pancreatic islets, or the cells of the enteric nervous system, or the endocrine cells
of the stomach, small bowel and large bowel, as well as certain cells of the central and peripheral
nervous system, influence fuel metabolism directly. Some of these peptides and their tissue of origin,
their actions on fuel metabolism, and the factors that stimulate (or suppress) their secretion are listed in
Table 2. In addition to these peptides, others such as gastrin, motilin, pancreatic polypeptide (PP),
peptide YY (PYY), and secretin may also influence fuel metabolism but by indirect effects on the
synthesis or secretion of insulin or the counterregulatory hormones (Table 3). For example, gastrin
induces gastric acid secretion, which ultimately affects nutrient absorption and metabolism. Motilin,
secreted by enteroendocrine M cells of the proximal small bowel, stimulates gastric and pancreatic
enzyme secretion, which, in turn, influences nutrient digestion. Pancreatic polypeptide (PP) from the
pancreatic islets reduces gastric emptying and slows upper intestinal motility. Peptide YY (PYY) from the
alpha cells in the mature pancreatic islets inhibits gastric acid secretion. Finally, secretin, produced by
the enteroendocrine S cells in the proximal small bowel, regulates pancreatic enzyme secretion and
inhibits gastrin release and gastric acid secretion. Although not directly influencing fuel metabolism,
these “gut” hormones have a significant impact on how ingested nutrients are digested and prepared
for absorption. If digestion or absorption of fuels is altered through a disturbance in the delicate
interplay of all of the peptides, fuel metabolism will be altered as well.

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Table 2: Gastrointestinal-Derived Hormones Directly Affecting Fuel Metabolism

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Table 3: Gastrointestinal-Derived Hormones Indirectly Affecting Fuel Metabolism

Gastrin
Gastrin is itself a hormone secreted by gastrin cells, also called G cells. These cells are located in the
pyloric glands in the distal end of the stomach. Gastrin is a large polypeptide secreted in two forms: a
large form called G-34, which contains 34 amino acids, and a smaller form, G-17, which contains 17
amino acids. Although both of these are important, the smaller is more abundant. When meats or other
protein-containing foods reach the antral end of the stomach, some of the proteins from these foods
have a special stimulatory effect on the gastrin cells in the pyloric glands to cause release of gastrin into
the digestive juices of the stomach. The vigorous mixing of the gastric juices transports the gastrin
rapidly to the enterochromaffin-like cells (ECL cells) in the body of the stomach, causing release of
histamine directly into the deep oxyntic glands. The histamine then acts quickly to stimulate gastric
hydrochloric acid secretion. The ECL cells lie in the deep recesses of the oxyntic glands and therefore
release histamine in direct contact with the parietal cells of the glands. The rate of formation and
secretion of hydrochloric acid by the parietal cells is directly related to the amount of histamine
secreted by the ECL cells. In turn, the ECL cells can be stimulated to secrete histamine in several
different ways: (1) Probably the most potent mechanism for stimulating histamine secretion is by the
hormonal substance gastrin, which is formed almost entirely in the antral portion of the stomach
mucosa in response to proteins in the foods being digested. (2) In addition, the ECL cells can be
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stimulated by (a) acetylcholine released from stomach vagal nerve endings and (b) probably also by
hormonal substances secreted by the enteric nervous system of the stomach wall.

Phases of Gastric Secretion

Gastric secretion is said to occur in three “phases” (as shown in 6): a cephalic phase, a gastric phase, and
an intestinal phase.
Cephalic Phase. The cephalic phase of gastric secretion occurs even before food enters the stomach,
especially while it is being eaten. It results from the sight, smell, thought, or taste of food, and the
greater the appetite, the more intense is the stimulation. Neurogenic signals that cause the cephalic
phase of gastric secretion originate in the cerebral cortex and in the appetite centers
of the amygdala and hypothalamus. They are transmitted through the dorsal motor nuclei of the vagi
and thence through the vagus nerves to the stomach. This phase of secretion normally accounts for
about 20 per cent of the gastric secretion associated with eating a meal.
Gastric Phase. Once food enters the stomach, it excites (1) long vagovagal reflexes from the stomach to
the brain and back to the stomach, (2) local enteric reflexes, and (3) the gastrin mechanism, all of which
in turn cause secretion of gastric juice during several hours while food remains in the stomach. The
gastric phase of secretion accounts for about 70 per cent of the total gastric secretion associated with
eating a meal and therefore accounts for most of the total daily gastric secretion of about 1500
milliliters.
Intestinal Phase. The presence of food in the upper portion of the small intestine, particularly in the
duodenum, will continue to cause stomach secretion of small amounts of gastric juice, probably partly
because of small amounts of gastrin released by the duodenal mucosa.

Figure 6: Phases of gastric secretion and their regulation

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