Insulin and Glucagon and Diabetes Mellitus pdf - Endocrinology and Reproduction

secretion is associated with energy abundance. That is, when there is great

As we discuss insulin in the next few pages, it will become apparent that insulin

Insulin Is a Hormone Associated with Energy Abundance

cellular functional disorders. Therefore, it is clear that insulin affects fat and

of death in diabetic patients. Also, in patients with prolonged diabetes, dimin-

causing such conditions as acidosis and arteriosclerosis, that are the usual causes

effects on carbohydrate metabolism. Yet it is abnormalities of fat metabolism,

has been associated with “blood sugar,” and true enough, insulin has profound

of rapid decline and death to that of a nearly normal person. Historically, insulin

Insulin was first isolated from the pancreas in 1922 by Banting and Best, and

Insulin and Its Metabolic Effects

inhibits insulin secretion, and somatostatin inhibits the secretion of both insulin and

by the other hormones. For instance, insulin inhibits glucagon secretion, amylin

The close interrelations among these cell types in the islets of Langerhans allow

pancreatic polypeptide.

the PP cell, is present in small numbers in the islets and secretes a hormone of uncer-

In addition, at least one other type of cell,

cent of the total, secrete

And the delta cells, about 10 per

about 25 per cent of the total, secrete

secreted in parallel with insulin, although its function is unclear. The alpha cells,

, a hormone that is often

The beta cells, constituting about 60 per cent of all the cells of the islets, lie mainly

staining characteristics.

cells, which are distinguished from one another by their morphological and

, and

secrete their hormones. The islets contain three major types of cells,

The human pancreas has 1 to 2 million islets of Langerhans, each only about 0.3

directly into the blood. The digestive secretions of the pancreas are discussed in

, which secrete insulin and glucagon

duodenum, and (2) the

, which secrete digestive juices into the

tissues, as shown in Figure 78–1: (1) the

The pancreas is composed of two major types of

, caused by abnormal secretion or activity of these hormones.

insulin and glucagon and the pathophysiology of diseases, especially

tions are not as well established. The main purpose

, their func-

, and

pancreas secretes other hormones, such as

glucose, lipid, and protein metabolism. Although the

, that are crucial for normal regulation of

secretes two important hormones,

The pancreas, in addition to its digestive functions,

Insulin, Glucagon, and

961

Diabetes Mellitus

insulin and

glucagon

amylin,

somatostatin

pancreatic polypeptide

of this chapter is to discuss the physiologic roles of

diabetes

mellitus

Physiologic Anatomy of the Pancreas.

acini

islets of Langerhans

Chapter 64.

millimeter in diameter and organized around small capillaries into which its cells

alpha, beta

delta

in the middle of each islet and secrete insulin and amylin

glucagon.

somatostatin.

tain function called

cell-to-cell communication and direct control of secretion of some of the hormones

glucagon.

almost overnight the outlook for the severely diabetic patient changed from one

ished ability to synthesize proteins leads to wasting of the tissues as well as many

protein metabolism almost as much as it does carbohydrate metabolism.

cussed in Chapter 74. Autophosphorylation of the beta

, dis-

become autophosphorylated. Thus, the insulin recep-

but because of the linkages with the beta subunits, the

brane, protruding into the cell cytoplasm. The insulin

The insulin receptor is a combination of four sub-

the subsequent effects.

It is the activated receptor, not the insulin, that causes

has a molecular weight of about 300,000 (Figure 78–3).

To initiate its effects on target cells, insulin first binds

and the Resulting Cellular Effects

Activation of Target Cell Receptors by Insulin

the plasma is important, because, at times, it is as

slightly in most other tissues. This rapid removal from

liver, to a lesser extent in the kidneys and muscles, and

der is degraded by the enzyme

combines with receptors in the target cells, the remain-

minutes. Except for that portion of the insulin that

half-life that averages only about 6 minutes, so that it

almost entirely in an unbound form; it has a plasma

When insulin is secreted into the blood, it circulates

tually no insulin activity.

is still in the form of proinsulin. The proinsulin has vir-

However, about one sixth of the final secreted product

before being packaged in the secretory granules.

of about 9000; most of this is further cleaved in the

11,500, but it is then cleaved in the endoplasmic retic-

. This

RNA by ribosomes attached to the endoplasmic re-

Chapter 3, beginning with translation of the insulin

cell machinery for protein synthesis, as explained in

are split apart, the functional activity of the insulin

by disulfide linkages. When the two amino acid chains

chains, shown in Figure 78–2, connected to each other

ular weight of 5808. It is composed of two amino acid

Insulin is a small protein; human insulin has a molec-

Insulin Chemistry and Synthesis

down of the proteins that are already in the cells.

acids into protein. In addition, it inhibits the break-

teins, insulin has a direct effect in promoting amino

fats and stored in the adipose tissue. In the case of pro-

glycogen mainly in the liver and muscles. Also, all the

of excess carbohydrates, it causes them to be stored as

important role in storing the excess energy. In the case

secreted in great quantity. In turn, the insulin plays an

cially excess amounts of carbohydrates, insulin is

abundance of energy-giving foods in the diet, espe-

962

Unit XIV

Endocrinology and Reproduction

excess carbohydrates that cannot be stored as glyco-
gen are converted under the stimulus of insulin into

acid uptake by cells and conversion of these amino

molecule is lost.

Insulin is synthesized in the beta cells by the usual

ticulum to form an insulin preprohormone
initial preprohormone has a molecular weight of about

ulum to form a proinsulin with a molecular weight

Golgi apparatus to form insulin and peptide fragments

is mainly cleared from the circulation within 10 to 15

insulinase mainly in the

important to turn off rapidly as to turn on the control
functions of insulin.

with and activates a membrane receptor protein that

units held together by disulfide linkages: two alpha
subunits that lie entirely outside the cell membrane
and two beta subunits that penetrate through the mem-

binds with the alpha subunits on the outside of the cell,

portions of the beta subunits protruding into the cell

tor is an example of an enzyme-linked receptor

subunits of the receptor activates a local tyrosine

Islet of

Langerhans

Pancreatic

acini

Delta cell

Alpha cell

Beta cell

Red blood cells

Physiologic anatomy of an islet of Langerhans in the pancreas.

Figure 78–1

Lys

Tyr

Val

Tyr

Val

Tyr

Val

Gly•Ileu•

•Glu•Glu•Cy•Cy•Thr•Ser•Ileu•Cy•Ser•Leu•

•Glu•Leu•Glu•Asp•

•Cy•Asp

Phe•

•Asp•Glu•His•Leu•Cy•Gly•Ser•His•Leu•

•Glu•Ala•Leu•

•Leu•

•Cy•Gly•Glu•Arg•Gly•Phe•Phe•

•Thr•Pro•

•Thr

Figure 78–2

Human insulin molecule.

into the muscle cells in abundance, then most of the

over fatty acids, as we discuss later.

glucose into the muscle cells. This causes the muscle

insulin. The extra insulin causes rapid transport of

meal. At this time the blood glucose concentration is

The second condition for muscle usage of large

process itself.

require large amounts of insulin, because exercising

erate or heavy exercise. This usage of glucose does not

large amounts of glucose. One of these is during mod-

However, under two conditions the muscles do use

into the muscle cells.

meals, the amount of insulin that is secreted is too

when the muscle fiber is stimulated by insulin; between

brane is only slightly permeable to glucose, except

glucose for its energy but on fatty acids. The principal

During much of the day, muscle tissue depends not on

Insulin Promotes Muscle Glucose Uptake

liver.

body, but especially by the muscles, adipose tissue, and

storage, and use of glucose by almost all tissues of the

in the chapter. The insulin in turn causes rapid uptake,

secretion of insulin, which is discussed in detail later

Immediately after a high-carbohydrate meal, the

Effect of Insulin on Carbohydrate

to achieve its metabolic goals.

DNA in the cell nucleus. In this way, insulin

rates of translation of messenger RNAs at the

and even several days. They result from changed

4. Much slower effects continue to occur for hours

phosphorylation of the enzymes.

more intracellular metabolic enzymes. These

3. Slower effects occur during the next 10 to 15

phosphate ions, causing increased transport of

many of the amino acids, potassium ions, and

2. The cell membrane becomes more permeable to

the cells. When insulin is no longer available, these

of glucose transport proteins, which bind with the

vesicles to the cell membranes; these vesicles

the usual carbohydrate metabolic functions. The

. The increased glucose

their uptake of glucose. This is especially true of

80 per cent of the body’s cells markedly increase

membrane receptors, the membranes of about

1. Within seconds after insulin binds with its

protein metabolism. The end effects of insulin stimu-

produce the desired effects on carbohydrate, fat, and

of these enzymes while inactivating others. In this way,

in different tissues. The net effect is to activate some

types of IRS (e.g. IRS-1, IRS-2, IRS-3) are expressed

. Different

, which in turn causes phosphorylation of multi-

Insulin, Glucagon, and Diabetes Mellitus

Chapter 78

963

kinase
ple other intracellular enzymes including a group
called insulin-receptor substrates (IRS)

insulin directs the intracellular metabolic machinery to

lation are the following:

muscle cells and adipose cells but is not true of
most neurons in the brain
transported into the cells is immediately
phosphorylated and becomes a substrate for all

increased glucose transport is believed to result
from translocation of multiple intracellular

carry in their own membranes multiple molecules

cell membrane and facilitate glucose uptake into

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.

these substances into the cell.

minutes to change the activity levels of many

effects result mainly from the changed states of

ribosomes to form new proteins and still slower
effects from changed rates of transcription of

remolds much of the cellular enzymatic machinery

Metabolism

glucose that is absorbed into the blood causes rapid

and Metabolism

reason for this is that the normal resting muscle mem-

small to promote significant amounts of glucose entry

muscle fibers become more permeable to glucose even
in the absence of insulin because of the contraction

amounts of glucose is during the few hours after a

high and the pancreas is secreting large quantities of

cell during this period to use glucose preferentially

Storage of Glycogen in Muscle.

If the muscles are not

exercising after a meal and yet glucose is transported

glucose is stored in the form of muscle glycogen

Tyrosine

S S

Cell membrane

Glucose

Insulin

receptor

Insulin

kinase

Insulin receptor substrates (IRS)

Phosphorylation of enzymes

Glucose

transport

Fat

synthesis

Protein

synthesis

Glucose

synthesis

Growth

and gene

expression

porters are moved to the cell membrane to facilitate glucose entry

glucose, fat, and protein metabolism. For example, glucose trans-

insulin receptor substrates, that mediate the effects of glucose on

tion that increases or decreases the activity of enzymes, including

tor tyrosine kinase activity begins a cascade of cell phosphoryla-

receptor, which in turn induces tyrosine kinase activity. The recep-

its receptor, which causes autophosphorylation of the

Schematic of the insulin receptor. Insulin binds to the

Figure 78–3

a-subunit of

b-subunit

into the cell.

. These fatty

cyte metabolism,

When the quan-

and Inhibits Gluconeogenesis in the Liver.

and then returned later.

falls between meals. Ordinarily, about 60 per cent of

Thus, the liver removes glucose from the blood

split away from the glucose; this allows the free

inhibited by insulin, now becomes activated by the

, which had been

4. The enzyme

, which causes the splitting

glucagon, which is discussed later) activates the

3. The lack of insulin (along with increase of

listed earlier for glycogen storage, essentially

2. The lack of insulin then reverses all the effects

1. The decreasing blood glucose causes the pancreas

between meals, several events transpire that cause the

When the

glycogen in the whole liver.

mass, which is equivalent to almost 100 grams of stored

amount of glycogen in the liver. The glycogen can

The net effect of all these actions is to increase the

form the glycogen molecules.

, which is responsible

that promote glycogen synthesis, including

3. Insulin also increases the activities of the enzymes

through the cell membrane.

the liver cells. Once phosphorylated, the glucose is

the blood by the liver cells. It does this by

2. Insulin causes

glycogen that has been stored in the liver cells.

split into glucose. This prevents breakdown of the

, the

1. Insulin

The mechanism by which insulin causes glucose

centration from falling too low.

the liver glycogen is split back into glucose, which is

begins to fall, insulin secretion decreases rapidly and

form of glycogen. Then, between meals, when food is

Insulin Promotes Liver Uptake, Storage, and

when insulin was added. Thus, it is clear that insulin

glucose concentration rose to as high as 400 mg/100 ml

labeled “insulin” demonstrates that the intracellular

up to as high as 750 mg/100 ml. In contrast, the curve

free glucose measured inside the cell, demonstrating

curve labeled “control” shows the concentration of

experimental results shown in Figure 78–4. The lower

The quantitative

Quantitative Effect of Insulin to Facilitate Glucose Transport

absence of oxygen.

glycogen to lactic acid, which can occur even in the

used for energy by the muscle. It is especially useful

3 per cent concentration. The glycogen can later be

instead of being used for energy, up to a limit of 2 to

964

Unit XIV

Endocrinology and Reproduction

for short periods of extreme energy use by the muscles
and even to provide spurts of anaerobic energy for a
few minutes at a time by glycolytic breakdown of the

Through the Muscle Cell Membrane.

effect of insulin to facilitate glucose transport through
the muscle cell membrane is demonstrated by the

that the glucose concentration remained almost zero
despite increased extracellular glucose concentration

can increase the rate of transport of glucose into the
resting muscle cell by at least 15-fold.

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

not available and the blood glucose concentration

released back into the blood to keep the glucose con-

uptake and storage in the liver includes several almost
simultaneous steps:

inactivates liver phosphorylase

principal enzyme that causes liver glycogen to

enhanced uptake of glucose from

increasing the activity of the enzyme glucokinase,
which is one of the enzymes that causes the initial
phosphorylation of glucose after it diffuses into

temporarily trapped inside the liver cells because
phosphorylated glucose cannot diffuse back

especially glycogen synthase
for polymerization of the monosaccharide units to

increase to a total of about 5 to 6 per cent of the liver

Glucose Is Released from the Liver Between Meals.

blood glucose level begins to fall to a low level

liver to release glucose back into the circulating blood:

to decrease its insulin secretion.

stopping further synthesis of glycogen in the liver
and preventing further uptake of glucose by the
liver from the blood.

enzyme phosphorylase
of glycogen into glucose phosphate.

glucose phosphatase

insulin lack and causes the phosphate radical to

glucose to diffuse back into the blood.

when it is present in excess after a meal and returns it
to the blood when the blood glucose concentration

the glucose in the meal is stored in this way in the liver

Insulin Promotes Conversion of Excess Glucose into Fatty Acids

tity of glucose entering the liver cells is more than can
be stored as glycogen or can be used for local hepato-

insulin promotes the conversion

of all this excess glucose into fatty acids
acids are subsequently packaged as triglycerides in

900

400

Insulin

Control

300

200

100

600

300

Intracellular glucose

(mg/100 ml)

Extracellular glucose

(mg/100 ml)

Brown, 1964.)

AB: The Biochemical Aspects of Hormone Action, Boston, Little,

high extracellular glucose concentrations. (Data from Eisenstein

intracellular glucose concentration remains near zero, despite

muscle cells. Note that in the absence of insulin (control), the

Effect of insulin in enhancing the concentration of glucose inside

Figure 78–4

available, even storage of the large amounts of

in adipose cells. Therefore, when insulin is not

-glycerol phosphate. This substance supplies the

more important, it also forms large quantities of

synthesize minute amounts of fatty acids, but

muscle cells. Some of this glucose is then used to

Therefore, the release of fatty acids from the

the triglycerides already stored in the fat cells.

. This is the enzyme that causes hydrolysis of

for them to be absorbed into the adipose cells,

triglycerides again into fatty acids, a requirement

walls of the adipose tissue, which splits the

the liver cells to the blood in the lipoproteins.

usual form of storage fat. They are released from

, the

the liver itself and used to form triglycerides

Most of the fatty acids are then synthesized within

of fatty acid synthesis.

, the first stage

carboxylase,

. These ions then

by the citric acid cycle when excess amounts of

(acetyl-CoA), the substrate from which fatty acids

subsequently is converted to acetyl coenzyme A

in the glycolytic pathway, and the pyruvate

to form fat. The glucose is first split to pyruvate

further glycogen synthesis. Then all the additional

reaches 5 to 6 per cent, this in itself inhibits

. After the liver glucogen concentration

to the adipose cells to be stored. The different factors

in the liver cells, and the fatty acids are then trans-

strate for fat synthesis. Almost all this synthesis occurs

used for immediate energy, thus providing the sub-

promotes fatty acid synthesis. This is especially true

functioning as a fat sparer. However, insulin also

automatically decreases the utilization of fat, thus

of glucose by most of the body’s tissues, which

adipose tissue. First, insulin increases the utilization

Insulin Promotes Fat Synthesis and Storage

vascular accidents. But first, let us discuss the acute

leading to heart attacks, cerebral strokes, and other

in causing extreme atherosclerosis, often

insulin lack

tant. Especially dramatic is the long-term effect of

on fat metabolism are, in the long run, equally impor-

insulin on carbohydrate metabolism, insulin’s effects

Effect of Insulin on Fat Metabolism

deposition of fat in these cells.

ecule. Therefore, in this indirect way, insulin promotes

The transport of glucose into adipose cells mainly pro-

it affects glucose transport and usage in muscle cells.

tion of the brain cells, as noted) in the same way that

in Other Cells

Effect of Insulin on Carbohydrate Metabolism

nervous irritability that leads to fainting, seizures, and

develop, characterized by progressive

glycemic shock

the range of 20 to 50 mg/100 ml, symptoms of

system. When the blood glucose falls too low, into

tained above a critical level, which is one of the most

strates, such as fats, only with difficulty. Therefore, it is

The brain cells are also quite different from most

use of glucose. Instead,

The brain is quite different from most other tissues of

Lack of Effect of Insulin on Glucose Uptake

required for gluconeogenesis. This is discussed

However, part of the effect is caused by an action

the liver enzymes required for gluconeogenesis.

. It does this

Insulin, Glucagon, and Diabetes Mellitus

Chapter 78

965

very-low-density lipoproteins and transported in this
form by way of the blood to the adipose tissue and
deposited as fat.

Insulin also inhibits gluconeogenesis

mainly by decreasing the quantities and activities of

of insulin that decreases the release of amino acids
from muscle and other extrahepatic tissues and in
turn the availability of these necessary precursors

further in relation to the effect of insulin on protein
metabolism.

and Usage by the Brain

the body in that insulin has little effect on uptake or

the brain cells are permeable to

glucose and can use glucose without the intermediation
of insulin.

other cells of the body in that they normally use only
glucose for energy and can use other energy sub-

essential that the blood glucose level always be main-

important functions of the blood glucose control

hypo-

even coma.

Insulin increases glucose transport into and glucose
usage by most other cells of the body (with the excep-

vides substrate for the glycerol portion of the fat mol-

Although not quite as visible as the acute effects of

effects of insulin on fat metabolism.

Insulin has several effects that lead to fat storage in

when more carbohydrates are ingested than can be

ported from the liver by way of the blood lipoproteins

that lead to increased fatty acid synthesis in the liver
include the following:
1. Insulin increases the transport of glucose into the

liver cells

glucose entering the liver cells becomes available

are synthesized.

2. An excess of citrate and isocitrate ions is formed

glucose are being used for energy
have a direct effect in activating acetyl-CoA

the enzyme required to carboxylate

acetyl-CoA to form malonyl-CoA

Insulin activates lipoprotein lipase in the capillary

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

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

a
glycerol that combines with fatty acids to form
the triglycerides that are the storage form of fat

fatty acids transported from the liver in the
lipoproteins is almost blocked.

ones.

the uptake of amino acids into cells. However, the

. Thus, insulin shares

, and

. Among the amino acids most

and fat storage. Some of the facts follow.

the tissues; insulin is required for this to occur. The

ents are available in the circulating blood, not only car-

Effect of Insulin on Protein

, which often leads to death.

. We see later that in severe diabetes the ace-

, and their pres-

toacetic acid, are called

. These two substances, along with the ace-

As explained in Chapter 68, some of the acetoacetic

body fluid acidosis.

tions of 10 mEq/L or more, which is a severe state of

of insulin secretion, sometimes reaching concentra-

lized by the tissues. Therefore, as shown in Figure 78–5,

peripheral tissues. Thus, so much acetoacetic acid is

At the same time, the absence of insulin also

used for energy in the usual manner.

cells, where it is again converted into acetyl-CoA and

culating blood. Most of this passes to the peripheral

acetoacetic acid, which in turn is released into the cir-

releasing extreme amounts of acetyl-CoA.A large part

dation of the fatty acids then proceeds very rapidly,

increasingly activated. In the mitochondria, beta oxi-

liver cells, the carnitine transport mechanism for trans-

results from the following effect: In the absence of

to be formed in the liver cells. This

sclerosis in people with serious diabetes.

per cent rather than the normal 0.6 per cent. This high

lipoproteins. Occasionally the plasma lipoproteins

the liver, are then discharged into the blood in the

ucts of fat metabolism. These two substances, along

phospholipids and cholesterol, two of the major prod-

plasma associated with insulin deficiency also pro-

The excess of fatty acids in the

than the concentration of glucose.

tion in the plasma begins to rise, more rapidly even

removal of the pancreas, the free fatty acid concentra-

acetoacetic acid. Note that almost immediately after

plasma concentrations of free fatty acids, glucose, and

Figure 78–5 shows the effect of insulin lack on the

acids begins to rise within minutes. This free fatty acid

Consequently, the plasma concentration of free fatty

the stored triglycerides, releasing large quantities of

becomes strongly activated. This causes hydrolysis of

fat are reversed. The most important effect is that

In the absence of insulin, all the

zero. The resulting effects are as follows.

tion of insulin is minimal, but it becomes extreme in

This occurs even normally between meals when secre-

for Energy

Insulin Deficiency Increases Use of Fat

966

Unit XIV

Endocrinology and Reproduction

All aspects of fat breakdown and use for providing
energy are greatly enhanced in the absence of insulin.

diabetes mellitus when secretion of insulin is almost

Insulin Deficiency Causes Lipolysis of Storage Fat and Release
of Free Fatty Acids.

effects of insulin noted earlier that cause storage of

the enzyme hormone-sensitive lipase in the fat cells

fatty acids and glycerol into the circulating blood.

then becomes the main energy substrate used by
essentially all tissues of the body besides the brain.

Insulin Deficiency Increases Plasma Cholesterol and Phospho-
lipid Concentrations.

motes liver conversion of some of the fatty acids into

with excess triglycerides formed at the same time in

increase as much as threefold in the absence of insulin,
giving a total concentration of plasma lipids of several

lipid concentration—especially the high concentration
of cholesterol—promotes the development of athero-

Excess Usage of Fats During Insulin Lack Causes Ketosis and
Acidosis.

Insulin lack also causes excessive amounts of

acetoacetic acid

insulin but in the presence of excess fatty acids in the

porting fatty acids into the mitochondria becomes

of this excess acetyl-CoA is then condensed to form

depresses the utilization of acetoacetic acid in the

released from the liver that it cannot all be metabo-

its concentration rises during the days after cessation

acid is also converted into

b-hydroxybutyric acid and

acetone

ketone bodies

ence in large quantities in the body fluids is called
ketosis
toacetic acid and the

b-hydroxybutyric acid can cause

severe acidosis and coma

Metabolism and on Growth

Insulin Promotes Protein Synthesis and Storage.

During the

few hours after a meal when excess quantities of nutri-

bohydrates and fats but proteins as well are stored in

manner in which insulin causes protein storage is not
as well understood as the mechanisms for both glucose

1. Insulin stimulates transport of many of the amino

acids into the cells
strongly transported are valine, leucine, isoleucine,
tyrosine

phenylalanine

with growth hormone the capability of increasing

amino acids affected are not necessarily the same

Free fatty acids

Depancreatized

Control

Removal of pancreas

Acetoacetic acid

Days

Free fatty acids

Blood glucose

Depancreatized

Control

Removal of pancreas

Acetoacetic acid

Concentration

Days

tions of blood glucose, plasma free fatty acids, and acetoacetic

Effect of removing the pancreas on the approximate concentra-

Figure 78–5

acid.

blocking their activity. This results in a depolarizing

binding to the ATP-sensitive potassium channels and

tors), inhibit exocytosis of insulin.

of glucose. Other hormones, including somatostatin

enhance the effect of glucose, although they do not

peptide, as well as acetylcholine increase intracellular

hormones, such as glucagon and gastric inhibitory

lular ATP levels and stimulate insulin secretion. Some

Other nutrients, such as certain amino acids, can also

exocytosis.

voltage. This produces an influx of calcium that stimu-

, which are sensitive to changes in membrane

voltage-gated calcium chan-

brane, thereby opening

of the cell. Closure

ATP-sensitive potassium channels

form adenosine triphosphate (ATP), which inhibits the

The glucose-6-phosphate is subsequently oxidized to

secreted insulin to the blood glucose levels.

. This step

range. Once inside the cells, glucose is phosphorylated

glucose transporters (GLUT-

have a large number of

primary controller of insulin secretion. The beta cells

response to increased blood glucose concentration, the

Figure 78–7 shows the basic cellular mechanisms for

Mechanisms of Insulin Secretion

of amino acids, all of which are required if growth is

from that of the other. Perhaps a small part of this

dramatic growth. Thus, it appears that the two hor-

growth. Yet a combination of these hormones causes

Furthermore, the administration of either growth

78–6, which shows that a depancreatized, hypophysec-

growth hormone is. This is demonstrated in Figure

proteins, it is as essential for growth of an animal as

tions of the organs.

all the effects of severe diabetes mellitus. It can lead

leads to enhanced urea excretion in the urine. The

neogenesis. This degradation of the amino acids also

ably, and most of the excess amino acids are used

The plasma amino acid concentration rises consider-

proteins increases, protein synthesis stops, and large

halt when insulin is not available. The catabolism of

Virtually all protein storage comes to a

prevents the degradation of proteins.

In summary, insulin promotes protein formation and

protein stores of the body.

the plasma amino acids, this suppression of

gluconeogenesis. Because the substrates most used

. It does this by decreasing

lysosomes.

cells, especially from the muscle cells. Presumably

, thus

fats, and proteins.

array of enzymes for storage of carbohydrates,

increased quantities of RNA and still more

in the cell nuclei, thus forming

increases the rate of transcription of selected DNA

3. Over a longer period of time,

insulin operates an “on-off” mechanism.

ribosomes simply stop working, almost as if

machinery. In the absence of insulin, the

unexplained way, insulin “turns on” the ribosomal

, thus forming new proteins. In some

RNA

Insulin, Glucagon, and Diabetes Mellitus

Chapter 78

967

2. Insulin increases the translation of messenger

insulin also

genetic sequences

protein synthesis—especially promoting a vast

4. Insulin inhibits the catabolism of proteins

decreasing the rate of amino acid release from the

this results from the ability of insulin to diminish
the normal degradation of proteins by the cellular

5. In the liver, insulin depresses the rate of

gluconeogenesis
the activity of the enzymes that promote

for synthesis of glucose by gluconeogenesis are

gluconeogenesis conserves the amino acids in the

Insulin Lack Causes Protein Depletion and Increased Plasma
Amino Acids.

quantities of amino acids are dumped into the plasma.

either directly for energy or as substrates for gluco-

resulting protein wasting is one of the most serious of

to extreme weakness as well as many deranged func-

Insulin and Growth Hormone Interact Synergistically to Promote
Growth.

Because insulin is required for the synthesis of

tomized rat without therapy hardly grows at all.

hormone or insulin one at a time causes almost no

mones function synergistically to promote growth,
each performing a specific function that is separate

necessity for both hormones results from the fact that
each promotes cellular uptake of a different selection

to be achieved.

insulin secretion by the pancreatic beta cells in

2) that permit a rate of glucose influx that is propor-
tional to the blood concentration in the physiologic

to glucose-6-phosphate by glucokinase
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

of the potassium channels depolarizes the cell mem-

nels

lates fusion of the docked insulin-containing vesicles
with the cell membrane and secretion of insulin into
the extracellular fluid by

be metabolized by the beta cells to increase intracel-

calcium levels through other signaling pathways and

have major effects on insulin secretion in the absence

and norepinephrine (by activating

a-adrenergic recep-

Sulfonylurea drugs stimulate insulin secretion by

100

150

200

Depancreatized and
hypophysectomized

Growth

hormone

Insulin

Growth hormone

and insulin

250

200

150

100

250

Weight (grams)

Days

on growth in a depancreatized and hypophysectomized rat.

Effect of growth hormone, insulin, and growth hormone plus insulin

Figure 78–6

centrations between 400 and 600 mg/100 ml, as shown

of insulin secretion rises rapidly, reaching a peak some

glucose rises above 100 mg/100 ml of blood, the rate

Feedback Relation Between Blood Glucose Concentration and

releases new insulin from the cells.

phase. This secretion results both from additional

2 to 3 hours, this time usually at a rate of

2. Beginning at about 15 minutes, insulin secretion

minutes.

instead, the insulin concentration decreases about

beta cells of the islets of Langerhans. However,

elevation of the blood glucose; this results from

1. Plasma insulin concentration increases almost

centration seen in Figure 78–8.

stages, as shown by the changes in plasma insulin con-

thereafter, insulin secretion increases markedly in two

that has only slight physiologic activity. If the blood

on the order of 25 ng/min/kg of body weight, a level

90 mg/100 ml, the rate of insulin secretion is minimal—

controlling insulin secretion (see Table 78–1).

metabolism, it has become apparent that blood amino

centration. However, as more has been learned about

Formerly, it was believed that insulin secretion was

Control of Insulin Secretion

Table 78–1 summarizes some of the factors that can

patients with type II diabetes, as we will discuss later.

effect that triggers insulin secretion, making these

968

Unit XIV

Endocrinology and Reproduction

drugs very useful in stimulating insulin secretion in

increase or decrease insulin secretion.

controlled almost entirely by the blood glucose con-

the metabolic functions of insulin for protein and fat

acids and other factors also play important roles in

Increased Blood Glucose Stimulates Insulin Secretion.

the normal fasting level of blood glucose of 80 to

glucose concentration is suddenly increased to a level
two to three times normal and kept at this high level

10-fold within 3 to 5 minutes after the acute

immediate dumping of preformed insulin from the

the initial high rate of secretion is not maintained;

halfway back toward normal in another 5 to 10

rises a second time and reaches a new plateau in

secretion even greater than that in the initial

release of preformed insulin and from activation
of the enzyme system that synthesizes and

Insulin Secretion Rate.

As the concentration of blood

10 to 25 times the basal level at blood glucose con-

ATP

GLUT 2

ATP

Glucose

Glucose-6-phosphate

Depolarization

Glucokinase

Oxidation

channel

(open)

channel

(closed)

Insulin

Glucose

beta cells of the pancreas. GLUT, glucose transporter.

Basic mechanisms of glucose stimulation of insulin secretion by

Figure 78–7

Table 78–1

Factors and Conditions That Increase or Decrease

• Sulfonylurea drugs (glyburide,

• Insulin resistance; obesity

• Parasympathetic stimulation;

• Glucagon, growth hormone,

(gastrin, cholecystokinin, secretin,

• Leptin

• Gastrointestinal hormones

•

• Increased blood amino acids

• Somatostatin

• Increased blood free fatty acids

• Fasting

• Increased blood glucose

• Decreased blood glucose

Increase Insulin Secretion

Decrease Insulin Secretion

Insulin Secretion

a-Adrenergic activity

gastric inhibitory peptide)

cortisol

acetylcholine

•

b-Adrenergic stimulation

tolbutamide)

10 20 30 40 50 60 70

250

Plasma insulin (

U/ml)

Minutes

20 minutes later.

higher and continuing increase in concentration beginning 15 to

in blood glucose to two to three times the normal range. Note an

Increase in plasma insulin concentration after a sudden increase

Figure 78–8

initial rapid surge in insulin concentration and then a delayed but

in the next section of this chapter. Both growth

of Langerhans in the pancreas. Glucagon is discussed

medulla, and

growth

cells for energy.

fore, one of the most important functional roles of

of liver glycogen, liver fat, and muscle glycogen. There-

fat, and the excess blood glucose is stored in the form

When the glucose concentration is high, insulin secre-

concentration. When the glucose concentration is low,

tissue. Furthermore, the signal that controls this

to the exclusion of glucose utilization, except by brain

Conversely, lack of insulin causes fat utilization mainly

energy, whereas it depresses the utilization of fats.

From the preceding discussions, it should be clear that

Role of Insulin (and Other Hormones)

secretion. However, it is doubtful that this effect is of

Under some conditions, stimulation of the parasym-

excess glucocorticoids.

tumors, or in people whose adrenal glands secrete

hormones. Diabetes is particularly common in giants or

Indeed, diabetes often occurs in people who are main-

increase the risk for developing diabetes mellitus.

The impor-

, and, to a

growth hormone

Other Hormones and the Autonomic Nervous System.

insulin secretion as the blood glucose level rises.

increased blood glucose, almost doubling the rate of

acids to be absorbed from the meal. These gastroin-

a meal. They then cause an “anticipatory” increase in

increase in insulin secretion. These hormones are

, and

cholecystokinin

A mixture of several impor-

of carbohydrates.

intracellular formation of protein. That is, insulin is

is important, because the insulin in turn promotes

The stimulation of insulin secretion by amino acids

in the presence of the excess amino acids. Thus, the

blood glucose concentration is elevated, the glucose-

However, when administered at the same time that the

ulation of insulin secretion in the following way: Amino

This effect differs from glucose stim-

lysine.

acids have a similar effect. The most potent of these are

secretion by excess blood glucose, some of the amino

Insulin Secretion

Other Factors That Stimulate

concentration back toward the normal value.

and other cells, thereby reducing the blood glucose

turn increases transport of glucose into liver, muscle,

glucose increases insulin secretion, and the insulin in

glucose concentration. That is, any rise in blood

This response of insulin secretion to an elevated

equally as rapid, occurring within 3 to 5 minutes after

Furthermore, the turn-off of insulin secretion is almost

in Figure 78–9. Thus, the increase in insulin secretion

Insulin, Glucagon, and Diabetes Mellitus

Chapter 78

969

under a glucose stimulus is dramatic both in its rapid-
ity and in the tremendous level of secretion achieved.

reduction in blood glucose concentration back to the
fasting level.

blood glucose concentration provides an extremely
important feedback mechanism for regulating blood

Amino Acids.

In addition to the stimulation of insulin

arginine and

acids administered in the absence of a rise in blood
glucose cause only a small increase in insulin secretion.

induced secretion of insulin may be as much as doubled

amino acids strongly potentiate the glucose stimulus for
insulin secretion.

transport of amino acids into the tissue cells as well as

important for proper utilization of excess amino acids
in the same way that it is important for the utilization

Gastrointestinal Hormones.

tant gastrointestinal hormones—gastrin,

secretin,

gastric inhibitory peptide (which

seems to be the most potent)—causes a moderate

released in the gastrointestinal tract after a person eats

blood insulin in preparation for the glucose and amino

testinal hormones generally act the same way as amino
acids to increase the sensitivity of insulin response to

Other hor-

mones that either directly increase insulin secretion or
potentiate the glucose stimulus for insulin secretion
include glucagon,

, cortisol

lesser extent, progesterone and estrogen.
tance 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

tained on high pharmacological doses of some of these

acromegalic people with growth hormone-secreting

pathetic nerves to the pancreas can increase insulin

physiologic significance for regulating insulin secretion.

in “Switching” Between Carbohydrate
and Lipid Metabolism

insulin promotes the utilization of carbohydrates for

switching mechanism is principally the blood glucose

insulin secretion is suppressed and fat is used almost
exclusively for energy everywhere except in the brain.

tion is stimulated and carbohydrate is used instead of

insulin in the body is to control which of these two
foods from moment to moment will be used by the

At least four other known hormones also play

important roles in this switching mechanism:
hormone from the anterior pituitary gland, cortisol
from the adrenal cortex, epinephrine from the adrenal

glucagon from the alpha cells of the islets

hormone and cortisol are secreted in response to

100

200

300

400

500

600

Insulin secretion

(times normal)

Plasma glucose concentration

(mg/100 ml)

Approximate insulin secretion at different plasma glucose levels.

Figure 78–9

importance in the normal function of the body.

secretion. All these effects are probably of minimal

enhances bile secretion; and (4) inhibits gastric acid

flow in some tissues, especially the kidneys; (3)

enhances the strength of the heart; (2) increases blood

available for the other tissues of the body.

the liver from removing fatty acids from the blood; this

the storage of triglycerides in the liver, which prevents

energy systems of the body. Glucagon also inhibits

, making

found in the blood. Perhaps the most important effect

Other Effects of Glucagon

enolpyruvate, a rate-limiting step in gluconeogenesis.

and gluconeogenesis, especially activation of the

gluconeogenesis. This is achieved by activating multi-

hormone still causes continued hyperglycemia. This

influence of glucagon, continued infusion of this

more within a few minutes.

as much as a millionfold amplification in response. This

if not most, cellular metabolic systems, often causing

widely used throughout the body for controlling many,

mechanism; this type of amplifying mechanism is

. Therefore, it represents a potent

each succeeding product

adenosine monophosphate. Second, it demonstrates

functions of cyclic

several reasons. First, it is one of the most thoroughly

This sequence of events is exceedingly important for

is released from the liver cells.

8. Which then is dephosphorylated; and the glucose

glucose-1-phosphate,

7. Which promotes the degradation of glycogen into

6. Which converts

5. Which activates

4. Which activates

3. Which activates

2. Which causes the formation of

cell membrane,

1. Glucagon activates

minutes.

its ability to cause glycogenolysis in the liver, which in

The most dramatic effect of glucagon is

to the other organs of the body.

in the liver. Both of

The major effects of glucagon on glucose metabolism

reason, glucagon is also called the

25 per cent increase) in about 20 minutes. For this

glucose concentration about 20 mg/100 ml of blood (a

occurs. Only 1

into an animal, a profound

of 29 amino acids. On injection of purified glucagon

Like insulin, glucagon is a large polypeptide. It has

centration, an effect that is exactly the opposite that of

cally opposed to those of insulin. Most important of

tration falls, has several functions that are diametri-

Glucagon, a hormone secreted by the

and anxiety.

in such stressful states as exercise, circulatory shock,

than the enhancement of blood glucose. Therefore,

tively, the enhancement of fatty acids is far greater

blood concentration of fatty acids as well. Quantita-

hormone-sensitive lipase, thus greatly enhancing the

into the blood; (2) it also has a direct lipolytic effect

effect of causing glycogenolysis in the liver, thus

effects are as follows: (1) epinephrine has the potent

concentration at the same time. The reasons for these

However, epinephrine acts differently from the other

slowly, usually requiring many hours for maximal

glucose while promoting fat utilization. However,

hypoglycemia, and both inhibit cellular utilization of

970

Unit XIV

Endocrinology and Reproduction

the effects of both of these hormones develop

expression.

Epinephrine is especially important in increasing

plasma glucose concentration during periods of stress
when the sympathetic nervous system is excited.

hormones in that it increases the plasma fatty acid

releasing within minutes large quantities of glucose

on the adipose cells because it activates adipose tissue

epinephrine especially enhances the utilization of fat

Glucagon and Its Functions

alpha cells of the

islets of Langerhans when the blood glucose concen-

these functions is to increase the blood glucose con-

insulin.

a molecular weight of 3485 and is composed of a chain

hyperglycemic effect

mg/kg of glucagon can elevate the blood

hyperglycemic

hormone.

Effects on Glucose Metabolism

are (1) breakdown of liver glycogen (glycogenolysis)
and (2) increased gluconeogenesis
these effects greatly enhance the availability of glucose

Glucagon Causes Glycogenolysis and Increased Blood Glucose
Concentration.

turn increases the blood glucose concentration within

It does this by the following complex cascade of

events:

adenylyl cyclase in the hepatic

cyclic adenosine

monophosphate,

protein kinase regulator protein,
protein kinase,
phosphorylase b kinase,

phosphorylase b into

phosphorylase a,

studied of all the second messenger

a cascade system in which
is produced in greater quantity than the preceding
product

amplifying

explains how only a few micrograms of glucagon can
cause the blood glucose level to double or increase even

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

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

ple enzymes that are required for amino acid transport

enzyme system for converting pyruvate to phospho-

Most other effects of glucagon occur only when its
concentration rises well above the maximum normally

is that glucagon activates adipose cell lipase
increased quantities of fatty acids available to the

also helps make additional amounts of fatty acids

Glucagon in very high concentrations also (1)

control have been presented in this chapter. Let us

The mechanisms for achieving this high degree of

absorption of carbohydrates. Conversely, in starvation,

to the control level, usually within 2 hours after the last

meal, but the feedback systems for control of blood

to 140 mg/100 ml during the first hour or so after a

before breakfast. This concentration increases to 120

narrowly controlled, usually between 80 and 90 mg/

In a normal person, the blood glucose concentration is

Summary of Blood

hormone,

growth hormone inhibitory

a longer period of time.

nutrients by the tissues, thus preventing rapid exhaus-

are assimilated into the blood. At the same time, the

Putting all this information together, it has been sug-

3. Somatostatin decreases both secretion and

duodenum, and gallbladder.

2. Somatostatin decreases the motility of the stomach,

1. Somatostatin acts locally within the islets of

In turn, somatostatin has multiple inhibitory effects

tract in response to food intake.

increased amino acids, (3) increased fatty acids, and (4)

secretion. They include (1) increased blood glucose, (2)

3 minutes in the circulating blood. Almost all factors

, a polypeptide containing only 14

The

Secretion

of the islets of Langerhans, may also play a role.

acids. Other factors, such as

glucagon is that it prevents a decrease in blood glucose.

does not necessarily fall. A beneficial effect of the

understood, because the blood glucose concentration

increases fourfold to fivefold. What causes this is not

exercise, the blood concentration of glucagon often

even more glucose available to the tissues.

conversion of the amino acids to glucose, thus making

The importance of amino acid stimulation of glucagon

opposites.

glucagon. This is the same effect that amino acids have

High concentrations of amino acids, as occur in the

glucagon is secreted in large amounts; it then greatly

decreases plasma glucagon. Thus, in hypoglycemia,

concentration of glucagon severalfold. Conversely,

normal fasting level of about 90 mg/100 ml of blood

This is demonstrated in Figure 78–10, showing that

cally, however, that

factor that controls glucagon secretion. Note specifi-

The

Increased Blood Glucose Inhibits Glucagon Secretion.

Regulation of Glucagon Secretion

Insulin, Glucagon, and Diabetes Mellitus

Chapter 78

971

blood glucose concentration is by far the most potent

the effect of blood glucose concen-

tration on glucagon secretion is in exactly the opposite
direction from the effect of glucose on insulin secretion.

a decrease in the blood glucose concentration from its

down to hypoglycemic levels can increase the plasma

increasing the blood glucose to hyperglycemic levels

increases the output of glucose from the liver and
thereby serves the important function of correcting the
hypoglycemia.

Increased Blood Amino Acids Stimulate Glucagon Secretion.

blood after a protein meal (especially the amino acids
alanine and arginine), stimulate the secretion of

in stimulating insulin secretion. Thus, in this instance,
the glucagon and insulin responses are not

secretion is that the glucagon then promotes rapid

Exercise Stimulates Glucagon Secretion.

In exhaustive

One of the factors that might increase glucagon

secretion in exercise is increased circulating amino

b-adrenergic stimulation

Somatostatin Inhibits
Glucagon and Insulin

delta cells of the islets of Langerhans secrete the

hormone somatostatin
amino acids that has an extremely short half-life of only

related to the ingestion of food stimulate somatostatin

increased concentrations of several of the gastrointesti-
nal hormones released from the upper gastrointestinal

as follows:

Langerhans themselves to depress the secretion of
both insulin and glucagon.

absorption in the gastrointestinal tract.

gested that the principal role of somatostatin is to
extend the period of time over which the food nutrients

effect of somatostatin to depress insulin and glucagon
secretion decreases the utilization of the absorbed

tion of the food and therefore making it available over

It should also be recalled that somatostatin is the

same chemical substance as

which is secreted in the hypothalamus and

suppresses anterior pituitary gland growth hormone
secretion.

Glucose Regulation

100 ml of blood in the fasting person each morning

glucose return the glucose concentration rapidly back

the gluconeogenesis function of the liver provides the
glucose that is required to maintain the fasting blood
glucose level.

summarize them.

100

120

Plasma glucagon

(times normal)

Blood glucose

(mg/100 ml)

Approximate plasma glucagon concentration at different blood

Figure 78–10

glucose levels.

blood glucose, (2) increased utilization of fats for energy

or weeks, with three principal sequelae: (1) increased

may develop very abruptly, over a period of a few days

. Type I diabetes

years of age in the United States, and for this reason it

The usual onset of type I diabetes occurs at about 14

disorders.

there may be a hereditary tendency for beta cell degen-

cells to destruction by these insults. In some instances,

with type I diabetes, although heredity also plays a

autoimmune disorders

Viral infections

impair insulin production can lead to type I diabetes.

Type I Diabetes

utilization of fats and proteins increases.

utilization of glucose falls increasingly lower, and

a result, blood glucose concentration increases, cell

by most cells of the body, except those of the brain. As

the main foodstuffs is altered. The basic effect of insulin

In both types of diabetes mellitus, metabolism of all

of insulin. This reduced sensitivity to insulin is often

, is caused by decreased

, also called

Type II diabetes

, is caused by lack of

, also called

Type I diabetes

tissues to insulin. There are two general types of dia-

drate, fat, and protein metabolism caused by either lack

disease, and blindness.

increased risk for heart attack, stroke, end-stage renal

associated with uncontrolled diabetes mellitus, leads to

tissues, especially to blood vessels. Vascular injury,

the body of its fluids and electrolytes.(4) Long-term

osmotic diuresis by the kidneys, which can deplete

the urine. (3) Loss of glucose in the urine also causes

cellular dehydration.(2) An excessively high level of

rises to excessive values, this can cause considerable

extracellular fluid, and if the glucose concentration

tration not rise too high for four reasons: (1) Glucose

leaving the brain without a nutritive source.

go into the muscles and other peripheral tissues,

not secrete any insulin during this time; otherwise, the

in the brain. Indeed, it is important that the pancreas

optimally with their required energy. Therefore, it is

, and

for energy in the absence of glucose? The answer is

blood glucose concentration, particularly because

question: Why is it so important to maintain a constant

greater amounts of fat utilization. This, too, helps

most cells of the body, converting instead to

response to prolonged hypoglycemia, and they

4. And finally, over a period of hours and days, both

too, helps protect against severe hypoglycemia.

still further release of glucose from the liver. This,

the sympathetic nervous system. In turn, the

3. Also, in severe hypoglycemia, a direct effect of

valuable.

situations, the glucagon mechanism also becomes

important than the glucagon mechanism, but in

toward normal. Under most normal conditions,

glucagon secretion; the glucagon then functions in

Conversely, a decrease in blood glucose stimulates

concentration rises too high, insulin is secreted;

. When the glucose

feedback control systems for maintaining a normal

severe liver disease, it becomes almost impossible

would otherwise be. In fact, in patients with

the glucose back into the blood. In this way, the

the rate of insulin secretion fall, the liver releases

of glycogen. Then, during the succeeding hours,

rate of insulin secretion also increases, as much as

. That is, when the blood glucose

972

Unit XIV

Endocrinology and Reproduction

1. The liver functions as an important blood glucose

buffer system
rises to a high concentration after a meal and the

two thirds of the glucose absorbed from the gut is
almost immediately stored in the liver in the form

when both the blood glucose concentration and

liver decreases the fluctuations in blood glucose
concentration to about one third of what they

to maintain a narrow range of blood glucose
concentration.

2. Both insulin and glucagon function as important

blood glucose concentration

the insulin in turn causes the blood glucose
concentration to decrease toward normal.

the opposite direction to increase the glucose

the insulin feedback mechanism is much more

instances of starvation or excessive utilization of
glucose during exercise and other stressful

low blood glucose on the hypothalamus stimulates

epinephrine secreted by the adrenal glands causes

growth hormone and cortisol are secreted in

both decrease the rate of glucose utilization by

return the blood glucose concentration toward
normal.

Importance of Blood Glucose Regulation.

One might ask the

most tissues can shift to utilization of fats and proteins

that glucose is the only nutrient that normally can be
used by the brain, retina

germinal epithelium

of the gonads in sufficient quantities to supply them

important to maintain the blood glucose concentration
at a sufficiently high level to provide this necessary
nutrition.

Most of the glucose formed by gluconeogenesis

during the interdigestive period is used for metabolism

scant supplies of glucose that are available would all

It is also important that the blood glucose concen-

can exert a large amount of osmotic pressure in the

blood glucose concentration causes loss of glucose in

increases in blood glucose may cause damage to many

Diabetes Mellitus

Diabetes mellitus is a syndrome of impaired carbohy-

of insulin secretion or decreased sensitivity of the

betes mellitus:
1.

insulin-dependent

diabetes mellitus (IDDM)
insulin secretion.

non–insulin-dependent

diabetes mellitus (NIDDM)
sensitivity of target tissues to the metabolic effect

called insulin resistance.

lack or insulin resistance on glucose metabolism is to
prevent the efficient uptake and utilization of glucose

—Lack of Insulin

Production by Beta Cells
of the Pancreas

Injury to the beta cells of the pancreas or diseases that

may be

involved in the destruction of beta cells in many patients

major role in determining the susceptibility of the beta

eration even without viral infections or autoimmune

is often called juvenile diabetes mellitus

acidosis are shown in Figure 78–11.

death can occur within hours. The overall changes in the

severe instances of uncontrolled diabetes, when the pH

bicarbonate stores. The kidneys compensate by decreas-

causes increased expiration of carbon dioxide; this

, which

They include

in metabolic acidosis take place in diabetic acidosis.

This leads rapidly to

excessive urine formation, can cause severe acidosis.

acids, which, in association with dehydration due to the

oxidized by the tissue cells. As a result, the patient

-hydroxybutyric acid, into

olism in diabetes increases the release of keto acids,

The shift from carbohydrate to fat metab-

glucose.

metabolism, often develop in patients with diabetes and

, secondary to abnormal lipid

injury, and

, secondary to renal

tissues. In addition,

lial and vascular smooth muscle cells, as well as other

The precise mechanisms that cause tissue injury in

other symptoms of peripheral nerve damage.

control, decreased sensation in the extremities, and

impaired cardiovascular reflexes, impaired bladder

betes mellitus. These abnormalities can result in

frequent complications of chronic, uncontrolled dia-

nerves, and

, which is abnormal function of peripheral

damage to many other tissues. For example,

gangrene of the limbs.

disease, retinopathy and blindness, and ischemia and

increased risk for heart attack, stroke, end-stage kidney

blood supply to the tissues. This in turn leads to

diabetes mellitus, blood vessels in multiple tissues

When

Chronic High Glucose Concentration Causes Tissue Injury

classic symptoms of diabetes.

, and

Thus,

intracellular fluid, for reasons discussed in Chapter 26.

urine, causing dehydration of the extracellular fluid,

of fluid. The overall effect is massive loss of fluid in the

That is, the osmotic effect of glucose in

osmotic diuresis.

excessive glucose, the loss of glucose in the urine causes

causes osmotic transfer of water out of the cells.

through the pores of the cell membrane, and the

severe cell dehydration throughout the body. This

The very high

the urine each day.

the blood glucose level rises to 300 to 500 mg/100 ml—

old” for the appearance of glucose in the urine. When

180 mg/100 ml, a level that is called the blood “thresh-

excess glucose spills into the urine. This normally occurs

into the renal tubules than can be reabsorbed, and the

The high blood glucose causes more glucose to filter

multiple effects throughout the body.

1200 mg/100 ml. The increased plasma glucose then has

glucose production, raising plasma glucose to 300 to

The lack of insulin decreases the efficiency

Blood Glucose Concentration Rises to Very High Levels in Diabetes

depletion of the body’s proteins.

and for formation of cholesterol by the liver, and (3)

Insulin, Glucagon, and Diabetes Mellitus

Chapter 78

973

Mellitus.

of peripheral glucose utilization and augments

Increased Blood Glucose Causes Loss of Glucose in the Urine

when the blood glucose concentration rises above

common values in people with severe untreated dia-
betes—100 or more grams of glucose can be lost into

Increased Blood Glucose Causes Dehydration

levels of blood glucose (sometimes as high as 8 to 10
times normal in severe untreated diabetes) can cause

occurs partly because glucose does not diffuse easily

increased osmotic pressure in the extracellular fluids

In addition to the direct cellular dehydrating effect of

the renal tubules greatly decreases tubular reabsorption

which in turn causes compensatory dehydration of the

polyuria (excessive urine excretion), intracellular

and extracellular dehydration

increased thirst are

blood glucose is poorly controlled over long periods in

throughout the body begin to function abnormally and
undergo structural changes that result in inadequate

Chronic high glucose concentration also causes

peripheral

neuropathy

autonomic nervous system dysfunction are

diabetes are not well understood but probably involve
multiple effects of high glucose concentrations and
other metabolic abnormalities on proteins of endothe-

hypertension

atherosclerosis

amplify the tissue damage caused by the elevated

Diabetes Mellitus Causes Increased Utilization of Fats and Meta-
bolic Acidosis.

such as acetoacetic acid and

the plasma more rapidly than they can be taken up and

develops severe metabolic acidosis from the excess keto

diabetic coma and death unless the

condition is treated immediately with large amounts of
insulin.

All the usual physiologic compensations that occur

rapid and deep breathing

buffers the acidosis but also depletes extracellular fluid

ing bicarbonate excretion and generating new bicar-
bonate that is added back to the extracellular fluid.

Although extreme acidosis occurs only in the most

of the blood falls below about 7.0, acidotic coma and

electrolytes of the blood as a result of severe diabetic

Excess fat utilization in the liver occurring over a long

time causes large amounts of cholesterol in the circu-
lating blood and increased deposition of cholesterol in

Total cations

Glucose

Keto acids

Cholesterol

HCO

180 mg/dL

360 mg/dL

100 mg/dL

400

mg/dL

7.4

6.9

103 mEq

90 mEq

155 mEq

130 mEq

155 mEq

30 mEq

27 mEq

5 mEq

values (lavender bars) and diabetic coma values (red bars).

Changes in blood constituents in diabetic coma, showing normal

Figure 78–11

drates in the early stages of the disease.

maintain normal glucose regulation. As a result, mod-

With prolonged and severe insulin resistance,

Development of Type II Diabetes During Prolonged Insulin Resis-

including cardiovascular disease.

as many other features of the metabolic syndrome,

severe enough, also can lead to type II diabetes as well

litus. Genetic causes of obesity and insulin resistance, if

growth hormone

Cushing’s syn-

cardiovascular disease.

risk for diabetes mellitus, increased blood lipids, and

women. The long-term consequences include increased

remains uncertain, insulin resistance and hyperinsuline-

productive life. Although the pathogenesis of PCOS

common endocrine disorders in women, affecting ap-

, for example, is

Polycystic ovary syndrome (PCOS)

(Table 78–2).

fat, severe insulin resistance and type II diabetes can

Other Factors That Can Cause Insulin Resistance and Type II Dia-

of cardiovascular disease.

opment of type II diabetes mellitus, also a major cause

disease, and insulin resistance predisposes to the devel-

body. Several of the metabolic abnormalities associated

syndrome is cardiovascular disease, including athero-

tion. The major adverse consequence of the metabolic

unclear, although it is clear that insulin resistance is the

The role of insulin resistance in contributing to some

ceral organs.

and (5) hypertension. All of the features of the meta-

resistance; (3) fasting hyperglycemia; (4) lipid abnor-

especially accumulation of abdominal fat; (2) insulin

features of the metabolic syndrome include: (1) obesity,

.” Some of the

is often called the “

link receptor activation with multiple cellular effects.

However, most of the insulin resistance appears to be

liver, and adipose tissue, in obese than in lean subjects.

fewer insulin receptors, especially in the skeletal muscle,

are still uncertain. Some studies suggest that there are

nisms that link obesity with insulin resistance, however,

ning with excess weight gain and obesity. The mecha-

glucose metabolism is usually a gradual process, begin-

carbohydrate utilization and storage, raising blood

The decrease in insulin sensitivity impairs

resistance.

bolic effects of insulin, a condition referred to as

). This occurs as

contrast to type I, is associated with

Type II diabetes, in

Precede Development of Type II Diabetes.

Obesity, Insulin Resistance, and “Metabolic Syndrome” Usually

dren as well as in adults.

years old, with type II diabetes. This trend appears to be

in the number of younger individuals, some less than 20

recent years, however, there has been a steady increase

adult-onset diabetes.

years, and the disease develops gradually. Therefore, this

occurs after age 30, often between the ages of 50 and 60

mellitus. In most cases, the onset of type II diabetes

Type II diabetes is far more common than type I,

Metabolic Effects of Insulin

Type II Diabetes

few weeks.

treatment, these metabolic abnormalities can cause

). Without

decreased storage of proteins as well as fat. Therefore,

Failure to

Diabetes Causes Depletion of the Body’s Proteins.

and other vascular lesions, as discussed earlier.

the arterial walls. This leads to severe

974

Unit XIV

Endocrinology and Reproduction

arteriosclerosis

use glucose for energy leads to increased utilization and

a person with severe untreated diabetes mellitus suffers
rapid weight loss and asthenia (lack of energy) despite
eating large amounts of food (polyphagia

severe wasting of the body tissues and death within a

—Resistance to the

accounting for about 90 per cent of all cases of diabetes

syndrome is often referred to as

related mainly to the increasing prevalence of obesity,
the most important risk factor for type II diabetes in chil-

increased plasma

insulin concentration (hyperinsulinemia
a compensatory response by the pancreatic beta cells
for diminished sensitivity of target tissues to the meta-

insulin

glucose and stimulating a compensatory increase in
insulin secretion.

Development of insulin resistance and impaired

caused by abnormalities of the signaling pathways that

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

metabolic syndrome

malities such as increased blood triglycerides and
decreased blood high-density lipoprotein-cholesterol;

bolic syndrome are closely related to excess weight gain,
especially when it is associated with accumulation of
adipose tissue in the abdominal cavity around the vis-

of the components of the metabolic syndrome is

primary cause of increased blood glucose concentra-

sclerosis and injury to various organs throughout the

with the syndrome are risk factors for cardiovascular

betes.

Although most patients with type II diabetes are

overweight or have substantial accumulation of visceral

also occur as a result of other acquired or genetic con-
ditions that impair insulin signaling in peripheral tissues

associated with marked increases in ovarian androgen
production and insulin resistance and is one of the most

proximately 6 per cent of all women during their re-

mia are found in approximately 80 per cent of affected

Excess formation of glucocorticoids (

drome) or

(acromegaly) also decreases

the sensitivity of various tissues to the metabolic effects
of insulin and can lead to development of diabetes mel-

tance.

even the increased levels of insulin are not sufficient to

erate hyperglycemia occurs after ingestion of carbohy-

Table 78–2

• Hemochromatosis (a hereditary disease that causes tissue iron

• Mutations that cause genetic obesity (e.g., melanocortin

(PPAR

• Mutations of the peroxisome proliferators’ activator receptor

• Mutations of insulin receptor

• Autoantibodies to the insulin receptor

• Lipodystrophy (acquired or genetic; associated with lipid

• Polycystic ovary disease

• Pregnancy, gestational diabetes

• Excess growth hormone (acromegaly)

• Excess glucocorticoids (Cushing’s syndrome or steroid therapy)

• Obesity/overweight (especially excess visceral adiposity)

Some Causes of Insulin Resistance

accumulation in liver)

receptor mutations)

accumulation)

increased in type II diabetes.

measurements of plasma insulin, with plasma insulin

lished on the basis of such a curve, and type I and type

the control level. The

below

furthermore, it fails to fall

the upper curve in Figure 78–12, and the glucose level

normal rise in blood glucose level, as demonstrated by

glucose, these people exhibit a much greater than

ance test is almost always abnormal. On ingestion of

and often above 140 mg/100 ml. Also, the glucose toler-

concentration is almost always above 110 mg/100 ml

In a person with diabetes, the fasting blood glucose

about 2 hours.

140 mg/100 ml and falls back to below normal in

glucose level rises from about 90 mg/100 ml to 120 to

of glucose per kilogram of body weight, the blood

curve,” when a normal, fasting person ingests 1 gram

curve in Figure 78–12, called a “glucose tolerance

Glucose Tolerance Test.

type II diabetes, plasma insulin concentration may be

or undetectable during fasting and even after a meal. In

In type I diabetes, plasma insulin levels are very low

least marked insulin resistance.

upper limit of normal. A fasting blood glucose level

90 mg/100 ml, and 110 mg/100 ml is considered to be the

The fasting blood

and the intake of carbohydrates.

large amounts, in proportion to the severity of disease

normal person loses undetectable amounts of glucose,

the quantity of glucose lost in the urine. In general, a

Urinary Glucose.

and type II diabetes mellitus. The usual methods for

Table 78–3 compares some of clinical features of type I

Physiology of Diagnosis

glucose.

However, in the later stages of type II diabetes, insulin

, may also be used.

by the pancreas, such as

, or drugs that cause additional release of insulin

thiazolidinediones

insulin sensitivity, such as

insulin administration is required. Drugs that increase

restriction, and weight reduction, and no exogenous

treated, at least in the early stages, with exercise, caloric

In many instances, type II diabetes can be effectively

type II diabetes.

whether an individual’s pancreas can sustain the high

diabetes mellitus occurs. Some studies suggest that

from secreting large amounts of insulin, and full-blown

however, the pancreas gradually becomes exhausted

abnormalities of glucose metabolism. In others,

diabetes mellitus; apparently, the pancreas in these

glucose after a meal, never develop clinically significant

Some obese people, although having marked insulin

hyperglycemia, especially after the person ingests a

beta cells become “exhausted” and are unable to

In the later stages of type II diabetes, the pancreatic

Insulin, Glucagon, and Diabetes Mellitus

Chapter 78

975

produce enough insulin to prevent more severe

carbohydrate-rich meal.

resistance and greater than normal increases in blood

people produces enough insulin to prevent severe

genetic factors play an important role in determining

output of insulin over many years that is necessary to
avoid the severe abnormalities of glucose metabolism in

and met-

formin

sulfonylureas

administration is usually required to control plasma

of Diabetes Mellitus

diagnosing diabetes are based on various chemical tests
of the urine and the blood.

Simple office tests or more complicated

quantitative laboratory tests may be used to determine

whereas a person with diabetes loses glucose in small to

Fasting Blood Glucose and Insulin Levels.

glucose level in the early morning is normally 80 to

above this value often indicates diabetes mellitus or a

severalfold higher than normal and usually increases to
a greater extent after ingestion of a standard glucose
load during a glucose tolerance test (see the next
paragraph).

As demonstrated by the bottom

falls back to the control value only after 4 to 6 hours;

slow fall of this curve and its failure to fall below the
control level demonstrate that either (1) the normal
increase in insulin secretion after glucose ingestion does
not occur or (2) there is decreased sensitivity to insulin.
A diagnosis of diabetes mellitus can usually be estab-

II diabetes can be distinguished from each other by

being low or undetectable in type I diabetes and

Clinical Characteristics of Patients with Type I and Type II

Table 78–3

sulfonylureas,

thiazolidinediones,

Therapy

Insulin

Weight loss,

Insulin sensitivity

Normal

Reduced

Plasma glucose

Increased

suppressed

suppression

Plasma glucagon

High, can be

High, resistant to

Plasma insulin

Low or absent

Normal to high

Body mass

Low (wasted) to

Obese

20 years

Usually

Age at onset

Usually

Feature

Type I

Type II

Diabetes Mellitus

>30 years

normal

initially

metformin,

insulin

Normal

Diabetes

200

180

160

140

120

100

Blood glucose level

(mg/100 ml)

Hours

Glucose tolerance curve in a normal person and in a person with

Figure 78–12

diabetes.

Metab 285:E685, 2003.

of hepatic gluconeogenesis. Am J Physiol Endocrinol

Barthel A, Schmoll D: Novel concepts in insulin regulation

indirect? J Clin Invest 111:434, 2003.

Barrett EJ: Insulin’s effect on glucose production: direct or

nervous system often occurs.

rapidly. If treatment is not effected immediately, per-

the administration of glucagon (or, less effectively,

the patient out of shock within a minute or more. Also,

of large quantities of glucose. This usually brings

insulin. The acetone breath and the rapid, deep breath-

only a state of coma remains. Indeed, at times it is dif-

the glucose level falls still lower, the seizures cease and

seizures and loss of consciousness are likely to occur. As

blood glucose level falls to 20 to 50 mg/100 ml, clonic

trembles all over, and breaks out in a sweat. As the

the patient simply experiences extreme nervousness,

various forms of hallucinations result, but more often

hypoglycemia sensitizes neuronal activity. Sometimes

usually becomes quite excitable, because this degree of

of 50 to 70 mg/100 ml, the central nervous system

may occur as follows.

insulin shock

too much insulin to themselves, the syndrome called

depressed. Consequently, in patients with insulin-secret-

of insulin cause blood glucose to fall to low values, the

necessary for this use of glucose. However, if high levels

all its energy from glucose metabolism, and insulin is not

these patients.

the primary and the metastatic cancers. Indeed, more

body, causing tremendous production of insulin by both

adenomas are malignant, and occasionally metastases

islet of Langerhans. About 10 to 15 per cent of these

Although much rarer than diabetes, excessive insulin

prevent these disturbances.

level of blood lipids as well as the level of blood glucose,

diabetic retinopathy, cataracts, hypertension, and

erosclerosis, greatly increased susceptibility to infection,

This decreases the rate of fat metabolism and depresses

large enough insulin to metabolize the carbohydrates.

olism. Consequently, the current tendency is to allow the

high and attenuated loss of glucose in the urine, but it

that the insulin requirements would be minimized. This

In the early days of treating diabetes, the tendency

people. Indeed, those who have poorly controlled dia-

riosclerosis, severe coronary heart disease, and multiple

lesterol and other lipids, develop atherosclerosis, arte-

Diabetic patients,

Relation of Treatment to Arteriosclerosis.

ing its effectiveness.

nity and sensitization against animal insulin, thus limit-

duced by the recombinant DNA process has become

from animal pancreata. However, human insulin pro-

In the past, the insulin used for treatment was derived

insulin must be used to regulate blood glucose.

by the pancreas. In many persons, however, exogenous

fails, drugs may be administered to increase insulin sen-

weight loss and to reverse the insulin resistance. If this

In persons with type II diabetes, dieting and exercise

Thus, each patient is provided with an individualized

glucose level tends to rise too high, such as at mealtimes.

out the day. Then additional quantities of regular insulin

single dose of one of the longer-acting insulins each day

narily, a patient with severe type I diabetes is given a

fore have effects that last as long as 10 to 48 hours. Ordi-

from 3 to 8 hours, whereas other forms of insulin (pre-

“Regular” insulin has a duration of action that lasts

normal as possible. Insulin is available in several forms.

carbohydrate, fat, and protein metabolism that is as

The theory of treatment of type I diabetes mellitus is to

Treatment of Diabetes

type II diabetes.

energy, keto acids are then produced in persons with

However, when insulin resistance becomes very severe

keto acids are usually not produced in excess amounts.

betes. In the early stages of type II diabetes, however,

detected by chemical means in the urine, and their

on the breath of a patient. Also, keto acids can be

air. Consequently, one can frequently make a diagnosis

acetone. This is volatile and vaporized into the expired

increase greatly in severe diabetes, are converted to

quantities of acetoacetic acid in the blood, which

As pointed out in Chapter 68, small

976

Unit XIV

Endocrinology and Reproduction

Acetone Breath.

of type I diabetes mellitus simply by smelling acetone

quantitation aids in determining the severity of the dia-

and there is greatly increased utilization of fats for

administer enough insulin so that the patient will have

cipitated with zinc or with various protein derivatives)
are absorbed slowly from the injection site and there-

to increase overall carbohydrate metabolism through-

are given during the day at those times when the blood

pattern of treatment.

are usually recommended in an attempt to induce

sitivity or to stimulate increased production of insulin

more widely used because some patients develop immu-

mainly because of their high levels of circulating cho-

microcirculatory lesions far more easily than do normal

betes throughout childhood are likely to die of heart
disease in early adulthood.

was to severely reduce the carbohydrates in the diet so

procedure kept the blood glucose from increasing too

did not prevent many of the abnormalities of fat metab-

patient an almost normal carbohydrate diet and to give

the high level of blood cholesterol.

Because the complications of diabetes—such as ath-

chronic renal disease—are closely associated with the

most physicians also use lipid-lowering drugs to help

Insulinoma—Hyperinsulinism

production occasionally occurs from an adenoma of an

from the islets of Langerhans spread throughout the

than 1000 grams of glucose have had to be administered
every 24 hours to prevent hypoglycemia in some of

Insulin Shock and Hypoglycemia.

As already emphasized,

the central nervous system normally derives essentially

metabolism of the central nervous system becomes

ing tumors or in patients with diabetes who administer

As the blood glucose level falls into the range

ficult by simple clinical observation to distinguish
between diabetic coma as a result of insulin-lack acido-
sis and coma due to hypoglycemia caused by excess

ing of diabetic coma are not present in hypoglycemic
coma.

Proper treatment for a patient who has hypoglycemic

shock or coma is immediate intravenous administration

epinephrine) can cause glycogenolysis in the liver and
thereby increase the blood glucose level extremely

manent damage to the neuronal cells of the central

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