MEDICAL PHYSIOLOGY RHOADES TANNER - PART 9 pps

TSH Regulates Thyroid Hormone Synthesis and Secretion When the concentrations of free T4 and T3 fall in theblood, the anterior pituitary gland is stimulated to secrete thyroid-stimulatin

cells, which face the lumen, are covered with microvilli.Pseudopods formed from the apical membrane extend intothe lumen The lateral membranes of the follicular cells areconnected by tight junctions, which provide a seal for thecontents of the lumen The basal membranes of the follicu-lar cells are close to the rich capillary network that pene-trates the stroma between the follicles.

The lumen of the follicle contains a thick, gel-like

sub-stance called colloid (see Fig 33.1) The colloid is a tion composed primarily of thyroglobulin, a large protein

solu-that is a storage form of the thyroid hormones The highviscosity of the colloid is due to the high concentration (10

to 25%) of thyroglobulin

The thyroid follicle produces and secretes two thyroid

hormones, thyroxine (T4) and triiodothyronine (T3).

Their molecular structures are shown in Figure 33.2 roxine and triiodothyronine are iodinated derivatives ofthe amino acid tyrosine They are formed by the coupling

Thy-of the phenyl rings Thy-of two iodinated tyrosine molecules in

an ether linkage The resulting structure is called an

iodothyronine The mechanism of this process is

dis-cussed in detail later

Thyroxine contains four iodine atoms on the 3, 5, 3⬘,and 5⬘ positions of the thyronine ring structure, whereastriiodothyronine has only three iodine atoms, at ring posi-tions 3, 5, and 3⬘ (see Fig 33.2) Consequently, thyroxine

is usually abbreviated as T4and triiodothyronine as T3 cause T4and T3contain the element iodine, their synthesis

Be-by the thyroid follicle depends on an adequate supply ofiodine in the diet

Parafollicular Cells Are the Sites of Calcitonin Synthesis

In addition to the epithelial cells that secrete T4and T3, thewall of the thyroid follicle contains small numbers of

parafollicular cells (see Fig 33.1) The parafollicular cell is

usually embedded in the wall of the follicle, inside the basallamina surrounding the follicle However, its plasma mem-brane does not form part of the wall of the lumen Parafol-licular cells produce and secrete the hormone calcitonin.Calcitonin and its effects on calcium metabolism are dis-cussed in Chapter 36

SYNTHESIS, SECRETION, AND METABOLISM

OF THE THYROID HORMONES

T4and T3are not directly synthesized by the thyroid cle in their final form Instead, they are formed by thechemical modification of tyrosine residues in the peptidestructure of thyroglobulin as it is secreted by the follicularcells into the lumen of the follicle Therefore, the T4and T3formed by this chemical modification are actually part ofthe amino acid sequence of thyroglobulin

folli-The high concentration of thyroglobulin in the colloidprovides a large reservoir of stored thyroid hormones forlater processing and secretion by the follicle The synthesis

of T4and T3is completed when thyroglobulin is retrievedthrough pinocytosis of the colloid by the follicular cells.Thyroglobulin is then hydrolyzed by lysosomal enzymes

carry out their physiological functions The thyroid

hor-mones exert their regulatory functions by influencing gene

expression, affecting the developmental program and the

amount of cellular constituents needed for the normal rate

of metabolism

FUNCTIONAL ANATOMY OF THE

THYROID GLAND

The human thyroid gland consists of two lobes attached to

either side of the trachea by connective tissue The two

lobes are connected by a band of thyroid tissue or isthmus,

which lies just below the cricoid cartilage A normal

thy-roid gland in a healthy adult weighs about 20 g

Each lobe of the thyroid receives its arterial blood

sup-ply from a superior and an inferior thyroid artery, which

arise from the external carotid and subclavian artery,

re-spectively Blood leaves the lobes of the thyroid by a series

of thyroid veins that drain into the external jugular and

in-nominate veins This circulation provides a rich blood

sup-ply to the thyroid gland, giving it a higher rate of blood

flow per gram than even that of the kidneys

The thyroid gland receives adrenergic innervation from

the cervical ganglia and cholinergic innervation from the

vagus nerves This innervation regulates vasomotor

func-tion to increase the delivery of TSH, iodide, and metabolic

substrates to the thyroid gland The adrenergic system can

also affect thyroid function by direct effects on the cells

Thyroxine and Triiodothyronine Are Synthesized

and Secreted by the Thyroid Follicle

The lobes of the thyroid gland consist of aggregates of

many spherical follicles, lined by a single layer of epithelial

cells (Fig 33.1) The apical membranes of the follicular

Colloid

Follicular cell

Capillary

Parafollicular cell

A cross-sectional view through a portion of the human thyroid gland

FIGURE 33.1

to its constituent amino acids, releasing T4and T3

mole-cules from their peptide linkage T4 and T3are then

se-creted into the blood

Follicular Cells Synthesize

Iodinated Thyroglobulin

The steps involved in the synthesis of iodinated

thyroglob-ulin are shown in Figure 33.3 This process involves the

synthesis of a thyroglobulin precursor, the uptake of

io-dide, and the formation of iodothyronine residues

Synthesis and Secretion of the Thyroglobulin Precursor.

The synthesis of the protein precursor for thyroglobulin is

the first step in the formation of T4and T3 This substance

is a 660-kDa glycoprotein composed of two similar

330-kDa subunits held together by disulfide bridges The

sub-units are synthesized by ribosomes on the rough ER and

then undergo dimerization and glycosylation in the

smooth ER The completed glycoprotein is packaged into

vesicles by the Golgi apparatus These vesicles migrate to

the apical membrane of the follicular cell and fuse with it

The thyroglobulin precursor protein is then extruded onto

the apical surface of the cell, where iodination takes place

Iodide Uptake. The iodide used for iodination of the

thy-roglobulin precursor protein comes from the blood

perfus-ing the thyroid gland The basal plasma membranes of

fol-licular cells, which are near the capillaries that supply the

follicle, contain iodide transporters These transporters

move iodide across the basal membrane and into the

cy-tosol of the follicular cell The iodide transporter is an

ac-tive transport mechanism that requires ATP, is saturable,

and can also transport certain other anions, such as

bro-mide, thiocyanate, and perchlorate It enables the follicular

cell to concentrate iodide many times over the

concentra-tion of iodide present in the blood; therefore, follicularcells are efficient extractors of the small amount of iodidecirculating in the blood Once inside follicular cells, the io-dide ions diffuse rapidly to the apical membrane, wherethey are used for iodination of the thyroglobulin precursor.Formation of the Iodothyronine Residues. The next step

in the formation of thyroglobulin is the addition of one ortwo iodine atoms to certain tyrosine residues in the precur-sor protein The precursor of thyroglobulin contains 134tyrosine residues, but only a small fraction of these becomeiodinated A typical thyroglobulin molecule contains only

20 to 30 atoms of iodine

The iodination of thyroglobulin is catalyzed by the

en-zyme thyroid peroxidase, which is bound to the apical

membranes of follicular cells Thyroid peroxidase binds

an iodide ion and a tyrosine residue in the thyroglobulinprecursor, bringing them in close proximity The enzymeoxidizes the iodide ion and the tyrosine residue to short-lived free radicals, using hydrogen peroxide that has beengenerated within the mitochondria of follicular cells Thefree radicals then undergo addition The product formed

is a monoiodotyrosine (MIT) residue, which remains in

peptide linkage in the thyroglobulin structure A secondiodine atom may be added to a MIT residue by this same

enzymatic process, forming a diiodotyrosine (DIT)

residue (see Fig 33.3)

Iodinated tyrosine residues that are close together in

the thyroglobulin precursor molecule undergo a coupling

reaction, which forms the iodothyronine structure

Thy-roid peroxidase, the same enzyme that initially oxidizesiodine, is believed to catalyze the coupling reactionthrough the oxidation of neighboring iodinated tyrosineresidues to short-lived free radicals These free radicalsundergo addition, as shown in Figure 33.4 The addition

reaction produces an iodothyronine residue and a

dehy-droalanine residue, both of which remain in peptide

link-age in the thyroglobulin structure For example, when twoneighboring DIT residues couple by this mechanism, T4isformed (see Fig 33.4) After being iodinated, the thy-roglobulin molecule is stored as part of the colloid in thelumen of the follicle

Only about 20 to 25% of the DIT and MIT residues inthe thyroglobulin molecule become coupled to formiodothyronines For example, a typical thyroglobulin mol-ecule contains five to six uncoupled residues of DIT andtwo to three residues of T4 However, T3is formed in onlyabout one of three thyroglobulin molecules As a result, thethyroid secretes substantially more T4than T3

Thyroid Hormones Are Formed From the Hydrolysis of Thyroglobulin

When the thyroid gland is stimulated to secrete thyroidhormones, vigorous pinocytosis occurs at the apical mem-branes of follicular cells Pseudopods from the apical mem-brane reach into the lumen of the follicle, engulfing bits of

the colloid (see Fig 33.3) Endocytotic vesicles or colloid

droplets formed by this pinocytotic activity migrate

to-ward the basal region of the follicular cell Lysosomes,which are mainly located in the basal region of resting fol-

hor-FIGURE 33.2

licular cells, migrate toward the apical region of the

stimu-lated cells The lysosomes fuse with the colloid droplets

and hydrolyze the thyroglobulin to its constituent amino

acids As a result, T4and T3and the other iodinated amino

acids are released into the cytosol

Secretion of Free T 4 and T 3 T4and T3formed from the

hydrolysis of thyroglobulin are released from the follicular

cell and enter the nearby capillary circulation, however, the

mechanism of transport of T4 and T3 across the basal

plasma membrane has not been defined The DIT and MIT

generated by the hydrolysis of thyroglobulin are

deiodi-nated in the follicular cell The released iodide is then

re-utilized by the follicular cell for the iodination of

thy-roglobulin (see Fig 33.3)

Binding of T4and T3to Plasma Proteins. Most of the T4

and T3 molecules that enter the bloodstream become

bound to plasma proteins About 70% of the T4and 80% of

the T3 are noncovalently bound to thyroxine-binding

globulin (TBG), a 54-kDa glycoprotein that is synthesized

and secreted by the liver Each molecule of TBG has a

sin-gle binding site for a thyroid hormone molecule The

re-maining T4and T3in the blood are bound to transthyretin

or to albumin Less than 1% of the T4and T3in blood is in

the free form, and it is in equilibrium with the large

protein-bound fraction It is this small amount of free thyroid

hor-mone that interacts with target cells

The protein-bound form of T4 and T3 represents a

large reservoir of preformed hormone that can replenish

the small amount of circulating free hormone as it is

cleared from the blood This reservoir provides the bodywith a buffer against drastic changes in circulating thyroidhormone levels as a result of sudden changes in the rate of

T4and T3secretion The protein-bound T4and T3cules are also protected from metabolic inactivation andexcretion in the urine As a result of these factors, the thy-roid hormones have long half-lives in the bloodstream.The half-life of T4 is about 7 days; the half-life of T3isabout 1 day

mole-Thyroid Hormones Are Metabolized by Peripheral Tissues

Thyroid hormones are both activated and inactivated bydeiodination reactions in the peripheral tissues The en-zymes that catalyze the various deiodination reactions areregulated, resulting in different thyroid hormone concen-trations in various tissues in different physiological andpathophysiological conditions

Conversion of T4to T3. As noted earlier, T4is the major cretory product of the thyroid gland and is the predominantthyroid hormone in the blood However, about 40% of the

se-T4secreted by the thyroid gland is converted to T3by matic removal of the iodine atom at position 5⬘ of the thyro-nine ring structure (Fig 33.5) This reaction is catalyzed by a

enzy-5 ⬘-deiodinase (type 1) located in the liver, kidneys, and

thy-roid gland The T3formed by this deiodination and that creted by the thyroid react with thyroid hormone receptors

se-in target cells; therefore, T3is the physiologically active form

of the thyroid hormones A second 5⬘-deiodinase (type 2) is

Blood

Iodide transporter

Tight junction

I-ER Golgi

Thyroglobulin (Tg) precursor

Deiodination

DIT MIT

Pseudopod

Endosomes Micropinocytosis

Macropinocytosis

MIT DIT

Iodination and coupling

present in skeletal muscle, the CNS, the pituitary gland, and

the placenta Type 2 deiodinase is believed to function

pri-marily to maintain intracellular T3in target tissues, but it may

also contribute to the generation of circulating T3 All of the

deiodinases contain selenocysteine in the active center This

rare amino acid has properties that make it ideal to catalyze

deiodination reactions

Deiodinations That Inactivate T 4 and T 3 Whereas the

5⬘-deiodination of T4to produce T3can be viewed as a

metabolic activation process, both T4and T3undergo

en-zymatic deiodinations, particularly in the liver and kidneys,

which inactivate them For example, about 40% of the T4

secreted by the human thyroid gland is deiodinated at the

5 position on the thyronine ring structure by a

5-deiodi-nase This produces reverse T3(see Fig 33.5) Since reverse

T3has little or no thyroid hormone activity, this

deiodina-tion reacdeiodina-tion is a major pathway for the metabolic

inactiva-tion or disposal of T4 Triiodothyronine and reverse T3also

undergo deiodination to yield 3,3⬘-diiodothyronine This

inactivate metabolite may be further deiodinated before

be-ing excreted

Regulation of 5 ⬘-Deiodination. The 5⬘-deiodination tion is a regulated process influenced by certain physiolog-ical and pathological factors The result is a change in therelative amounts of T3and reverse T3produced from T4.For example, a human fetus produces less T3from T4than

reac-a child or reac-adult becreac-ause the 5⬘-deiodination reaction is lessactive in the fetus Also, 5⬘-deiodination is inhibited duringfasting, particularly in response to carbohydrate restriction,but it can be restored to normal when the individual is fedagain Trauma, as well as most acute and chronic illnesses,also suppresses the 5⬘-deiodination reaction Under all ofthese circumstances, the amount of T3produced from T4isreduced and its blood concentration falls However, theamount of reverse T3rises in the circulation, mainly be-cause its conversion to 3,3⬘-diiodothyronine by 5⬘-deiodi-nation is reduced A rise in reverse T3in the blood may sig-nal that the 5⬘-deiodination reaction is suppressed.Note that during fasting or in the disease states mentionedabove, the secretion of T4is usually not increased, despite thedecrease of T3in the circulation This response indicates that,under these circumstances, a T3decrease in the blood doesnot stimulate the hypothalamic-pituitary-thyroid axis

Minor Degradative Pathways. T4and, to a lesser extent,

T3 are also metabolized by conjugation with glucuronicacid in the liver The conjugated hormones are secretedinto the bile and eliminated in the feces Many tissues alsometabolize thyroid hormones by modifying the three-car-bon side chain of the iodothyronine structure These mod-ifications include decarboxylation and deamination Thederivatives formed from T4, such as tetraiodoacetic acid

(tetrac), may also undergo deiodinations before being

ex-creted (see Fig 33.5)

TSH Regulates Thyroid Hormone Synthesis and Secretion

When the concentrations of free T4 and T3 fall in theblood, the anterior pituitary gland is stimulated to secrete

thyroid-stimulating hormone (TSH), raising the

concen-tration of TSH in the blood This action results in increasedinteractions between TSH and its receptors on thyroid fol-licular cells

TSH Receptors and Second Messengers. The receptor forTSH is a transmembrane glycoprotein thought to be located

on the basal plasma membrane of the follicular cell These ceptors are coupled by Gsproteins, mainly to the adenylyl cy-clase-cAMP-protein kinase A pathway, however, there is alsoevidence for effects via phospholipase C (PLC), inositoltrisphosphate, and diacylglycerol (see Chapter 1) The phys-iological importance of TSH-stimulated phospholipid me-tabolism in human follicular cells is unclear, since very highconcentrations of TSH are needed to activate PLC

re-TSH and Thyroid Hormone Formation and Secretion.TSH stimulates most of the processes involved in thyroidhormone synthesis and secretion by follicular cells Therise in cAMP produced by TSH is believed to cause many

of these effects TSH stimulates the uptake of iodide by licular cells, usually after a short interval during which io-

2 DIT free radicals

Radical addition

Quinoid intermediate O

O

CO NH

NH CO

CO CH

CH2

CH

CH2

NH CO

Thyroxine residue

+

Theoretical model for the coupling reaction between two diiodotyrosine (DIT) residues

in iodinated thyroglobulin This model is based on free radical

formation catalyzed by thyroid peroxidase (Adapted from

Tau-rog AM Hormone synthesis: Thyroid iodine metabolism In:

Braverman LE, Utiger RD, eds Werner & Ingbar’s The Thyroid: A

Fundamental and Clinical Text 8th Ed Philadelphia: Lippincott

Williams & Wilkins, 2000;61–85.)

FIGURE 33.4

dide transport is actually depressed TSH also stimulates

the iodination of tyrosine residues in the thyroglobulin

pre-cursor and the coupling of iodinated tyrosines to form

iodothyronines Moreover, it stimulates the pinocytosis of

colloid by the apical membranes, resulting in a great

in-crease in endocytosis of thyroglobulin and its hydrolysis

The overall result of these effects of TSH is an increased

re-lease of T4and T3into the blood In addition to its effects

on thyroid hormone synthesis and secretion, TSH rapidly

increases energy metabolism in the thyroid follicular cell

TSH and Thyroid Size. Over the long term, TSH

pro-motes protein synthesis in thyroid follicular cells,

main-taining their size and structural integrity Evidence of this

trophic effect of TSH is seen in a hypophysectomized

pa-tient, whose thyroid gland atrophies, largely as a result of a

reduction in the height of follicular cells However, the

chronic exposure of an individual to excessive amounts of

TSH causes the thyroid gland to increase in size This

en-largement is due to an increase in follicular cell height and

number Such an enlarged thyroid gland is called a goiter.

These trophic and proliferative effects of TSH on the

thy-roid are primarily mediated by cAMP

Dietary Iodide Is Essential for the

Synthesis of Thyroid Hormones

Because iodine atoms are constituent parts of the T4and T3

molecules, a continual supply of iodide is required for the

synthesis of these hormones If an individual’s diet is

se-verely deficient in iodide, as in some parts of the world, T4and T3synthesis is limited by the amount of iodide avail-able to the thyroid gland As a result, the concentrations of

T4and T3in the blood fall, causing a chronic stimulation ofTSH secretion, which, in turn, produces a goiter Enlarge-ment of the thyroid gland increases its capacity to accumu-late iodide from the blood and to synthesize T4and T3.However, the degree to which the enlarged gland can pro-duce thyroid hormones to compensate for their deficiency

in the blood depends on the severity of the deficiency of dide in the diet To prevent iodide deficiency and the con-sequent goiter formation in the human population, iodide

io-is added to the table salt (iodized salt) sold in most oped countries

devel-THE MECHANISM OF THYROID HORMONE ACTION

Most cells of the body are targets for the action of thyroidhormones The sensitivity or responsiveness of a particularcell to thyroid hormones correlates to some degree withthe number of receptors for these hormones The cells ofthe CNS appear to be an exception As is discussed later,the thyroid hormones play an important role in CNS de-velopment during fetal and neonatal life, and developingnerve cells in the brain are important targets for thyroidhormones In the adult, however, brain cells show little re-sponsiveness to the metabolic regulatory action of thyroidhormones, although they have numerous receptors forthese hormones The reason for this discrepancy is unclear

matically deiodinated at the 5 position to form the inactive

metabolite, reverse T3 T3 and reverse T3 undergo additional

ex-creted A small amount of T4 is also decarboxylated and nated to form the metabolite, tetraiodoacetic acid (tetrac) Tetrac may then be deiodinated before being excreted.

deami-Thyroid hormone receptors (TR) are located in the

nu-clei of target cells bound to thyroid hormone response

el-ements (TRE) in the DNA TRs are protein molecules of

about 50 kDa that are structurally similar to the nuclear

ceptors for steroid hormones and vitamin D Thyroid

re-ceptors bound to the TRE in the absence of T3generally act

to repress gene expression

The free forms of T3and T4are taken up by target cells

from the blood through a carrier-mediated process that

re-quires ATP Once inside the cell, T4is deiodinated to T3,

which enters the nucleus of the cell and binds to its

recep-tor in the chromatin The TR with bound T3forms a

com-plex with other nuclear receptors (called a heterodimer) or

with another TR (homodimer) to activate transcription

Other transcription factors may also complex with the TR

heterodimer or homodimer As a result, the production of

mRNA for certain proteins is either increased or decreased,

changing the cell’s capacity to make these proteins

(Fig 33.6) T3can influence differentiation by regulating

the kinds of proteins produced by its target cells and can

in-fluence growth and metabolism by changing the amounts

of structural and enzymatic proteins present in the cells

The mechanisms by which T3alters gene expression

con-tinue to be investigated

The gene expression response to T3is slow to appear

When T3is given to an animal or human, several hours

elapse before its physiological effects can be detected This

delayed action undoubtedly reflects the time required for

changes in gene expression and consequent changes in the

synthesis of key proteins to occur When T4is

adminis-tered, its course of action is usually slower than that of T3

because of the additional time required for the body to

convert T4to T3

Thyroid hormones also have effects on cells that occur

much faster and do not appear to be mediated by nuclear

TR receptors, including effects on signal transduction ways that alter cellular respiration, cell morphology, vascu-lar tone, and ion homeostasis The physiological relevance

path-of these effects is currently being investigated

ROLE OF THE THYROID HORMONES

IN DEVELOPMENT, GROWTH, AND METABOLISM

Thyroid hormones play a critical role in the development

of the central nervous system (CNS) They are also tial for normal body growth during childhood, and in basalenergy metabolism

essen-Thyroid Hormones Are Essential for Development of the Central Nervous System

The human brain undergoes its most active phase of growthduring the last 6 months of fetal life and the first 6 months

of postnatal life During the second trimester of pregnancy,the multiplication of neuroblasts in the fetal brain reaches apeak and then declines As pregnancy progresses and therate of neuroblast division drops, neuroblasts differentiateinto neurons and begin the process of synapse formationthat extends into postnatal life

Thyroid hormones first appear in the fetal blood duringthe second trimester of pregnancy, and levels continue torise during the remaining months of fetal life Thyroid hor-mone receptors increase about 10-fold in the fetal brain atabout the time the concentrations of T4and T3begin to rise

in the blood These events are critical for normal brain velopment because thyroid hormones are essential for tim-ing the decline in nerve cell division and the initiation ofdifferentiation and maturation of these cells

de-If thyroid hormones are deficient during these prenataland postnatal periods of differentiation and maturation ofthe brain, mental retardation occurs The cause is thought

to be inadequate development of the neuronal circuitry ofthe CNS Thyroid hormone therapy must be given to athyroid hormone-deficient child during the first fewmonths of postnatal life to prevent mental retardation.Starting thyroid hormone therapy after behavioral deficitshave occurred cannot reverse the mental retardation (i.e.,thyroid hormone must be present when differentiation nor-mally occurs) Thyroid hormone deficiency during infancycauses both mental retardation and growth impairment, asdiscussed below Fortunately, this occurs rarely today be-cause thyroid hormone deficiency is usually detected innewborn infants and hormone therapy is given at theproper time

The exact mechanism by which thyroid hormones ence differentiation of the CNS is unknown Animal stud-ies have demonstrated that thyroid hormones inhibit nervecell replication in the brain and stimulate the growth ofnerve cell bodies, the branching of dendrites, and the rate

influ-of myelinization influ-of axons These effects influ-of thyroid mones are presumably due to their ability to regulate theexpression of genes involved in nerve cell replication anddifferentiation However, the details, particularly in the hu-man, are unclear

T3RXR

DNA

The activation of transcription by thyroid hormone.T4 is taken up by the cell and deiod- inated to T3, which then binds to the thyroid hormone receptor

(TR) The activated TR heterodimerizes with a second

transcrip-tion factor, 9-cis retinoic acid receptor (RXR), and binds to the

thyroid hormone response element (TRE) The binding of

TR/RXR to the TRE displaces repressors of transcription and

re-cruits additional coactivators The final result is the activation of

RNA polymerase II and the transcription of the target gene.

FIGURE 33.6

Thyroid Hormones Are Essential for

Normal Body Growth

The thyroid hormones are important factors regulating the

growth of the entire body For example, an individual who

is deficient in thyroid hormones, who does not receive

thy-roid hormone therapy during childhood, will not grow to a

normal adult height

Thyroid Hormones and the Gene for GH. A major way

thyroid hormones promote normal body growth is by

stimulating the expression of the gene for growth

hor-mone (GH) in the somatotrophs of the anterior pituitary

gland In a thyroid hormone-deficient individual, GH

synthesis by the somatotrophs is greatly reduced and

con-sequently GH secretion is impaired; therefore, a thyroid

hormone-deficient individual will also be GH-deficient If

this condition occurs in a child, it will cause growth

retar-dation, largely a result of the lack of the

growth-promot-ing action of GH (see Chapter 32)

Other Effects of Thyroid Hormones on Growth. The

thyroid hormones have additional effects on growth In

tis-sues such as skeletal muscle, the heart, and the liver, thyroid

hormones have direct effects on the synthesis of a variety

of structural and enzymatic proteins For example, they

stimulate the synthesis of structural proteins of

mitochon-dria, as well as the formation of many enzymes involved in

intermediary metabolism and oxidative phosphorylation

Thyroid hormones also promote the calcification and,

hence, the closure, of the cartilaginous growth plates of the

bones of the skeleton This action limits further linear body

growth How the thyroid hormones promote calcification

of the growth plates of bones is not understood

Thyroid Hormones Regulate the Basal

Energy Economy of the Body

When the body is at rest, about half of the ATP produced

by its cells is used to drive energy-requiring membrane

transport processes The remainder is used in involuntary

muscular activity, such as respiratory movements,

peri-stalsis, contraction of the heart, and in many metabolic

reactions requiring ATP, such as protein synthesis The

energy required to do this work is eventually released as

body heat

Basal Oxygen Consumption and Body Heat Production.

The major site of ATP production is the mitochondria,

where the oxidative phosphorylation of ADP to ATP takes

place The rate of oxidative phosphorylation depends on

the supply of ADP for electron transport The ADP supply

is, in turn, a function of the amount of ATP used to do work

For example, when more work is done per unit time, more

ATP is used and more ADP is generated, increasing the rate

of oxidative phosphorylation The rate at which oxidative

phosphorylation occurs is reflected in the amount of oxygen

consumed by the body because oxygen is the final electron

acceptor at the end of the electron transport chain

Activities that occur when the body is not at rest, such

as voluntary movements, use additional ATP for the work

involved; the amounts of oxygen consumed and body heatproduced depend on total body activity

Thermogenic Action of the Thyroid Hormones. Thyroidhormones regulate the basal rate at which oxidative phos-phorylation takes place in cells As a result, they set thebasal rate of body heat production and of oxygen con-

sumed by the body This is called the thermogenic action

of thyroid hormones

Thyroid hormone levels in the blood must be withinnormal limits for basal metabolism to proceed at the rateneeded for a balanced energy economy of the body For ex-ample, if thyroid hormones are present in excess, oxidativephosphorylation is accelerated, and body heat productionand oxygen consumption are abnormally high The con-verse occurs when the blood concentrations of T4and T3are lower than normal The fact that thyroid hormones af-fect the amount of oxygen consumed by the body has beenused clinically to assess the status of thyroid function Oxy-gen consumption is measured under resting conditions andcompared with the rate expected of a similar individualwith normal thyroid function This measurement is the

basal metabolic rate (BMR) test.

Tissues Affected by the Thermogenic Action of Thyroid Hormones. Not all tissues are sensitive to the thermo-genic action of thyroid hormones Tissues and organs thatgive this response include skeletal muscle, the heart, theliver, and the kidneys These are also tissues in which thy-roid hormone receptors are abundant The adult brain,skin, lymphoid organs, and gonads show little thermogenicresponse to thyroid hormones With the exception of theadult brain, these tissues contain few thyroid hormone re-ceptors, which may explain their poor response

Molecular and Cellular Mechanisms. The genic action of the thyroid hormones is poorly under-stood at the molecular level The thermogenic effecttakes many hours to appear after the administration ofthyroid hormones to a human or animal, probably be-cause of the time required for changes in the expression

thermo-of genes involved T3is known to stimulate the synthesis

of cytochromes, cytochrome oxidase, and Na⫹/K⫹Pase in certain cells This action suggests that T3 mayregulate the number of respiratory units in these cells, af-fecting their capacity to carry out oxidative phosphory-lation A greater rate of oxidative phosphorylation wouldresult in greater heat production

-AT-Thyroid hormone also stimulates the synthesis of

uncou-pling protein-1 (UCP-1) in brown adipose tissue ATP is

synthesized by ATP synthase in the mitochondria when tons flow down their electrochemical gradient UCP-1 acts

pro-as a channel in the mitochondrial membrane to dissipate theion gradient without making ATP As the protons move

down their electrochemical gradient uncoupled from ATP

syn-thesis, energy is released as heat Adult humans have littlebrown adipose tissue, so it is not likely that UCP-1 makes asignificant contribution to nutrient oxidation or body heatproduction However, several uncoupling proteins (UCP-2and UCP-3) have recently been discovered in many tissues,and their expression is regulated by thyroid hormones

These novel uncoupling proteins may be involved in the

thermogenic action of thyroid hormones

Thyroid Hormones Stimulate Intermediary

Metabolism

In addition to their ability to regulate the rate of basal

en-ergy metabolism, thyroid hormones influence the rate at

which most of the pathways of intermediary metabolism

operate in their target cells When thyroid hormones are

deficient, pathways of carbohydrate, lipid, and protein

me-tabolism are slowed, and their responsiveness to other

reg-ulatory factors, such as other hormones, is decreased

How-ever, these same metabolic pathways run at an abnormally

high rate when thyroid hormones are present in excess

Thyroid hormones, therefore, can be viewed as amplifiers

of cellular metabolic activity The amplifying effect of

thy-roid hormones on intermediary metabolism is mediated

through the activation of genes encoding enzymes

in-volved in these metabolic pathways

Thyroid Hormones Regulate Their Own Secretion

An important action of the thyroid hormones is the ability

to regulate their own secretion As discussed in Chapter 32,

T3exerts an inhibitory effect on TSH secretion by

rotrophs in the anterior pituitary gland by decreasing

thy-rotroph sensitivity to thyrotropin-releasing hormone

(TRH) Consequently, when the circulating concentration

of free thyroid hormones is high, thyrotrophs are relatively

insensitive to TRH, and the rate of TSH secretion

de-creases The resulting fall of TSH levels in the blood

re-duces the rate of thyroid hormone release from the

follicu-lar cells in the thyroid When the free thyroid hormone

level falls in the blood, however, the negative-feedback

ef-fect of T3on thyrotrophs is reduced, and the rate of TSH

secretion increases The rise in TSH in the blood stimulates

the thyroid gland to secrete thyroid hormones at a greater

rate This action of T3on thyrotrophs is thought to be due

to changes in gene expression in these cells

The physiological actions of the thyroid hormones

de-scribed above are summarized in Table 33.1

THYROID HORMONE DEFICIENCY AND

EXCESS IN ADULTS

A deficiency or an excess of thyroid hormones produces

characteristic changes in the body These changes result

from dysregulation of nervous system function and altered

metabolism

Thyroid Hormone Deficiency Causes Nervous

and Metabolic Disorders

Thyroid hormone deficiency in humans has a variety of

causes For example, iodide deficiency may result in a

re-duction in thyroid hormone prore-duction Autoimmune

dis-eases, such as Hashimoto’s disease, impair thyroid

hor-mone synthesis (see Clinical Focus Box 33.1) Other causes

of thyroid hormone deficiency include heritable diseasesthat affect certain steps in the biosynthesis of thyroid hor-mones and hypothalamic or pituitary diseases that interferewith TRH or TSH secretion Obviously, radioiodine abla-tion or surgical removal of the thyroid gland also causes

thyroid hormone deficiency Hypothyroidism is the

dis-ease state that results from thyroid hormone deficiency.Thyroid hormone deficiency impairs the functioning

of most tissues in the body As described earlier, a ciency of thyroid hormones at birth that is not treatedduring the first few months of postnatal life causes irre-versible mental retardation Thyroid hormone deficiencylater in life also influences the function of the nervous sys-tem For example, all cognitive functions, includingspeech and memory, are slowed and body movementsmay be clumsy These changes can usually be reversedwith thyroid hormone therapy

defi-Metabolism is also reduced in thyroid cient individuals Basal metabolic rate is reduced, resulting

hormone-defi-in impaired body heat production Vasoconstriction occurs

in the skin as a compensatory mechanism to conserve bodyheat Heart rate and cardiac output are reduced Food in-take is reduced, and the synthetic and degradativeprocesses of intermediary metabolism are slowed In severehypothyroidism, a substance consisting of hyaluronic acidand chondroitin sulfate complexed with protein is de-posited in the extracellular spaces of the skin, causing wa-ter to accumulate osmotically This effect gives a puffy ap-

pearance to the face, hands, and feet called myxedema All

of the above disorders can be normalized with thyroid mone therapy

hor-An Excess of Thyroid Hormone Produces Nervous and Other Disorders

The most common cause of excessive thyroid hormone

production in humans is Graves’ disease, an autoimmune

TABLE 33.1 The Physiological Actions of

Thyroid Hormones

Development of CNS Inhibit nerve cell replication

Stimulate growth of nerve cell bodies Stimulate branching of dendrites Stimulate rate of axon myelinization Body growth Stimulate expression of gene for

GH in somatotrophs Stimulate synthesis of many structural and enzymatic proteins Promote calcification of growth plates of bones

Basal energy economy of Regulate basal rates of oxidative the body phosphorylation, body heat

production, and oxygen consumption (thermogenic effect) Intermediary metabolism Stimulate synthetic and degradative

pathways of carbohydrate, lipid, and protein metabolism Thyroid-stimulating Inhibit TSH secretion by decreasing hormone (TSH) secretion sensitivity of thyrotrophs to

thyrotropin-releasing hormone (TRH)

disorder caused by antibodies directed against the TSH

re-ceptor in the plasma membranes of thyroid follicular cells

These antibodies bind to the TSH receptor, resulting in an

increase in the activity of adenylyl cyclase The consequent

rise in cAMP in follicular cells produces effects similar to

those caused by the action of TSH The thyroid gland

en-larges to form a diffuse toxic goiter, which synthesizes and

secretes thyroid hormones at an accelerated rate, causing

thyroid hormones to be chronically elevated in the blood

Feedback inhibition of thyroid hormone production by the

thyroid hormones is also lost

Less common conditions that cause chronic elevations

in circulating thyroid hormones include adenomas of the

thyroid gland that secrete thyroid hormones and excessive

TSH secretion caused by malfunctions of the

hypothala-mic-pituitary-thyroid axis The disease state that develops

in response to excessive thyroid hormone secretion, called

hyperthyroidism or thyrotoxicosis, is characterized by

many changes in the functioning of the body that are theopposite of those caused by thyroid hormone deficiency.Hyperthyroid individuals are nervous and emotionallyirritable, with a compulsion to be constantly movingaround However, they also experience physical weaknessand fatigue Basal metabolic rate is increased and, as a re-sult, body heat production is increased Vasodilation inthe skin and sweating occur as compensatory mechanisms

to dissipate excessive body heat Heart rate and cardiacoutput are increased Energy metabolism increases, asdoes appetite However, despite the increase in food in-take, a net degradation of protein and lipid stores occurs,resulting in weight loss All of these changes can be re-versed by reducing the rate of thyroid hormone secretionwith drugs or by removal of the thyroid gland by radioac-tive ablation or surgery

C L I N I C A L F O C U S B O X 3 3 1

Autoimmune Thyroid Disease—Postpartum Thyroiditis

Certain diseases affecting the function of the thyroid gland

occur when an individual’s immune system fails to

recog-nize particular thyroid proteins as “self” and reacts to the

proteins as if they were foreign This usually triggers both

humoral and cellular immune responses As a result,

anti-bodies to these proteins are generated, which then alter

thyroid function Two common autoimmune diseases with

opposite effects on thyroid function are Hashimoto’s

dis-ease and Graves’ disdis-ease In Hashimoto’s disdis-ease, the

thy-roid gland is infiltrated by lymphocytes, and elevated

lev-els of antibodies against several components of thyroid

tissue (e.g., antithyroid peroxidase and antithyroglobulin

antibodies) are found in the serum The thyroid gland is

de-stroyed, resulting in hypothyroidism In Graves’ disease,

stimulatory antibodies to the TSH receptor activate thyroid

hormone synthesis, resulting in hyperthyroidism (see text

for details).

A third, fairly common autoimmune disease is

postpar-tum thyroiditis, which usually occurs within 3 to 12 months

after delivery The disease is characterized by a transient

thyrotoxicosis (hyperthyroidism) often followed by a

pe-riod of hypothyroidism lasting several months Many

pa-tients eventually return to the euthyroid state Often only

the hypothyroid phase of the disease may be observed,

oc-curring in more than 30% of women with antibodies to roid peroxidase detectable preconception The disease is also observed in patients known to have Graves’ disease The postpartum occurrence of the disorder is likely due to increased immune system function following the suppres- sion of its activity during pregnancy.

thy-It has been estimated that 5 to 10% of women develop postpartum thyroiditis Of these women, about 50% have transient thyrotoxicosis alone, 25% have transient hy- pothyroidism alone, and the remaining 25% have both phases of the disease The prevalence of the disease has prompted a clinical recommendation suggesting that thy- roid function (serum T 4 , T 3 , and TSH levels) be surveyed postpartum at 2, 4, 6, and 12 months in all women with thy- roid peroxidase antibodies or symptoms suggestive of thy- roid dysfunction Patients who have experienced one episode of postpartum thyroiditis should also be consid- ered at risk for recurrence after pregnancy.

Treatment for thyrotoxicosis commonly involves hibiting thyroid hormone synthesis and secretion Thion- amides are a class of drugs that inhibit the oxidation and organic binding of thyroid iodide to reduce thyroid hor- mone production Some drugs in this class also inhibit the conversion of T 4 to T 3 in the peripheral tissues Thyroid hormone replacement is required to treat hypothyroidism.

in-DIRECTIONS: Each of the numbered

items or incomplete statements in this

section is followed by answers or by

completions of the statement Select the

ONE lettered answer or completion that is

the BEST in each case.

1 The effects of TSH on thyroid

follicular cells include

(A) Stimulation of endocytosis of thyroglobulin stored in the colloid (B) Release of a large pool of T4 and T3 stored in secretory vesicles in the cell

(C) Stimulation of the uptake of iodide from the thyroglobulin stored in the colloid

(D) Increase in perfusion by the blood

(E) Stimulation of the binding of T4 and T3 to thyroxine-binding globulin (F) Increased cAMP hydrolysis

2 A child is born with a rare disorder in which the thyroid gland does not respond to TSH What would be the predicted effects on mental ability, body growth rate, and thyroid gland size when the child reaches 6 years of age?

R E V I E W Q U E S T I O N S

(continued)

(A) Mental ability would be impaired,

body growth rate would be slowed,

and thyroid gland size would be larger

than normal

(B) Mental ability would be unaffected,

body growth rate would be slowed,

and thyroid gland size would be

smaller than normal

(C) Mental ability would be impaired,

body growth rate would be slowed,

and thyroid gland size would be

smaller than normal

(D) Mental ability would be

unaffected, body growth rate would be

unaffected, and thyroid gland size

would be smaller than normal

(E) Mental ability would be impaired,

body growth rate would be slowed,

and thyroid gland size would be

normal

(F) Mental ability would be unaffected,

body growth rate would be unaffected,

and thyroid gland size would be

unaffected

3 If the 6-year-old child described in the

previous question is now treated with

thyroid hormones, how would mental

ability, body growth rate, and thyroid

gland size be affected?

(A) Mental ability would remain

impaired, body growth rate would be

improved, and thyroid gland size

would be smaller than normal

(B) Mental ability would be improved,

body growth rate would be improved,

and thyroid gland size would be

normal

(C) Mental ability would remain

impaired, body growth rate would be

improved, and thyroid gland size

would be normal

(D) Mental ability would remain

impaired, body growth rate would be

improved, and thyroid gland size

would be larger than normal

(E) Mental ability would be improved,

body growth rate would remain

slowed, and thyroid gland size would

be normal

(F) Mental ability would be improved,

body growth rate would remain

slowed, and thyroid gland size would

larger than normal

4 Uncoupling proteins

(A) Utilize the proton gradient across

the mitochondrial membrane to

facilitate ATP synthesis

(B) Are decreased by thyroid hormones (C) Dissipate the proton gradient across the mitochondrial membrane to generate heat

(D) Are present exclusively in brown fat (E) Uncouple fatty acid oxidation from glucose oxidation in mitochondria (F) Are essential for maintaining body temperature in mammals

5 Triiodothyronine (T3) (A) Is produced in greater amounts by the thyroid gland than T4

(B) Is bound by the thyroid receptor present in the cytosol of target cells (C) Is formed from T4 through the action of a 5-deiodinase

(D) Has a half-life of a few minutes in the bloodstream

(E) Is released from thyroglobulin through the action of thyroid peroxidase

(F) Can be produced by the deiodination of T4 in pituitary thyrotrophs

6 A 40-year-old man complains of chronic fatigue, aching muscles, and occasional numbness in his fingers.

Physical examination reveals a modest weight gain but no goiter is detected.

Laboratory findings include TSH ⬎ 10

␮U/L (normal range, 0.5 to 5 ␮U/L);

free T4, low to low-normal These findings are most consistent with a diagnosis of

(A) Hypothyroidism secondary to a hypothalamic-pituitary defect (B) Hyperthyroidism secondary to a hypothalamic-pituitary defect (C) Hyperthyroidism as a result of iodine excess

(D) Hypothyroidism as a result of autoimmune thyroid disease (E) Hypothyroidism as a result of iodine deficiency

(F) Hyperthyroidism as a result of autoimmune thyroid disease

7 The reaction catalyzed by thyroid peroxidase

(A) Produces hydrogen peroxide as an end-product

(B) Couples two iodotyrosine residues

to form an iodothyronine residue (C) Occurs on the basal membrane of the follicular cell

(D) Catalyzes the release of thyroid hormones into the circulation (E) Couples MIT and DIT to thyroglobulin

(F) Couples dehydroalanine with a thyroxine residue

8 A 25-year-old woman complains of weight loss, heat intolerance, excessive sweating, and weakness TSH and thyroid hormones are elevated, goiter

is present, but no antithyroid antibodies are detected Which of the following diagnoses is consistent with these symptoms?

(A) Graves’ disease (B) Resistance to thyroid hormone action

(C) Plummer’s disease (thyroid gland adenoma)

(D) A 5 ⬘-deiodinase deficiency (E) Acute Hashimoto’s disease (F) TSH-secreting pituitary tumor

S U G G E S T E D R E A D I N G

Apriletti JW, Ribeiro RC, Wagner RL, et

al Molecular and structural biology of thyroid hormone receptors Clin Exp Pharmacol Physiol Suppl

1998;25:S2–S11.

Braverman LE, Utiger RD Werner and Ingbar’s The Thyroid: A Fundamental and Clinical Text 8th Ed

Philadelphia: Lippincott Williams & Wilkins, 2000.

Goglia F, Moreno M, Lanni A Action of thyroid hormones at the cellular level: The mitochondrial target FEBS Lett 1999;452:115–120.

Larsen PR, Davies TF, Hay ID The roid gland In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR, eds: Williams Textbook of Endocrinology 9th Ed Philadelphia: WB Saunders, 1998.

thy-Meier CA Thyroid hormone and ment: Brain and peripheral tissue In: Hauser P, Rovet J, eds Thyroid Dis- eases of Infancy and Childhood Wash- ington, DC: American Psychiatric Press, 1999.

develop-Motomura K, Brent GA Mechanisms of thyroid hormone action Endocrinol Metab Clin North Am 1998;27:1–23 Munoz A, Bernal J Biological activities of thyroid hormone receptors Eur J En- docrinol 1997;137:433–445.

Reitman ML, He Y, Gong D-W Thyroid hormone and other regulators of un- coupling proteins Int J Obes Relat Metab Disord 1999;23(Suppl 6):S56–S59.

The Adrenal Gland

Robert V Considine, Ph.D.

34

C H A P T E R

34

To remain alive, the organs and tissues of the human

body must have a finely regulated extracellular

envi-ronment This environment must contain the correct

con-centrations of ions to maintain body fluid volume and to

enable excitable cells to function The extracellular

envi-ronment must also have an adequate supply of metabolic

substrates for cells to generate ATP Salts, water, and other

organic substances are continually lost from the body as a

result of perspiration, respiration, and excretion Metabolic

substrates are constantly used by cells Under normal

con-ditions, these critical constituents of the body’s

extracellu-lar environment are replenished by the intake of food andliquids However, a person can survive for weeks on littleelse but water because the body has a remarkable capacityfor adjusting the functions of its organs and tissues to pre-serve body fluid volume and composition

The adrenal glands play a key role in making these justments This is readily apparent from the fact that anadrenalectomized animal, unlike its normal counterpart,cannot survive prolonged fasting Its blood glucose supplydiminishes, ATP generation by the cells becomes inade-quate to support life, and the animal eventually dies Even

ad-■FUNCTIONAL ANATOMY OF THE ADRENAL GLAND

■HORMONES OF THE ADRENAL CORTEX

■PRODUCTS OF THE ADRENAL MEDULLA

C H A P T E R O U T L I N E

1 The adrenal gland is comprised of an outer cortex

sur-rounding an inner medulla The cortex contains three

his-tologically distinct zones (from outside to inside): the zona

glomerulosa, zona fasciculata, and zona reticularis.

2 Hormones secreted by the adrenal cortex include

glucocor-ticoids, aldosterone, and adrenal androgens.

3 The glucocorticoids cortisol and corticosterone are

synthe-sized in the zona fasciculata and zona reticularis of the

ad-renal cortex.

4 The mineralocorticoid aldosterone is synthesized in the

zona glomerulosa of the adrenal cortex.

5 Cholesterol, used in the synthesis of the adrenal cortical

hormones, comes from cholesterol esters stored in the

cells Stored cholesterol is derived mainly from

low-den-sity lipoprotein particles circulating in the blood, but it can

also be synthesized de novo from acetate within the

adre-nal gland.

6 The conversion of cholesterol to pregnenolone in

mito-chondria is the common first step in the synthesis of all

ad-renal steroids and occurs in all three zones of the cortex.

7 The liver is the main site for the metabolism of adrenal

steroids, which are conjugated to glucuronic acid and

ex-creted in the urine.

8 ACTH increases glucocorticoid and androgen synthesis in

adrenal cortical cells in the zona fasciculata and zona

retic-ularis by increasing intracellular cAMP ACTH also has a trophic effect on these cells.

9 Angiotensin II and angiotensin III stimulate aldosterone synthesis in the cells of the zona glomerulosa by increas- ing cytosolic calcium and activating protein kinase C.

10 Glucocorticoids bind to glucocorticoid receptors in the tosol of target cells The glucocorticoid-bound receptor translocates to the nucleus and then binds to glucocorti- coid response elements in the DNA to increase or decrease the transcription of specific genes.

cy-11 Glucocorticoids are essential to the adaptation of the body

to fasting, injury, and stress.

12 The catecholamines epinephrine and norepinephrine are synthesized and secreted by the chromaffin cells of the ad- renal medulla.

13 Catecholamines interact with four adrenergic receptors ( ␣ 1 ,

␣ 2 , ␤ 1 , and ␤ 2 ) that mediate the cellular effects of the mones.

hor-14 Stimuli such as injury, anger, pain, cold, strenuous cise, and hypoglycemia generate impulses in the choliner- gic preganglionic fibers innervating the chromaffin cells, resulting in the secretion of catecholamines.

exer-15 To counteract hypoglycemia, catecholamines stimulate glucose production in the liver, lactate release from mus- cle, and lipolysis in adipose tissue.

K E Y C O N C E P T S

607

when fed a normal diet, an adrenalectomized animal

typi-cally loses body sodium and water over time, and

eventu-ally dies of circulatory collapse Its death is caused by a lack

of certain steroid hormones that are produced and secreted

by the cortex of the adrenal gland

The glucocorticoid hormones, cortisol and

corticos-terone, play essential roles in adjusting the metabolism of

carbohydrates, lipids, and proteins in liver, muscle, and

adi-pose tissues during fasting, which assures an adequate

sup-ply of glucose and fatty acids for energy metabolism

de-spite the absence of food The mineralocorticoid hormone

aldosterone, another steroid hormone produced by the

ad-renal cortex, stimulates the kidneys to conserve sodium

and, hence, body fluid volume

The glucocorticoids also enable the body to cope with

physical and emotional traumas or stresses The physiological

importance of this action of the glucocorticoids is

empha-sized by the fact that adrenalectomized animals lose their

ability to cope with physical or emotional stresses Even when

given an appropriate diet to prevent blood glucose and body

sodium depletion, an adrenalectomized animal may die when

exposed to traumas that are not fatal to normal animals

Hormones produced by the other endocrine component

of the adrenal gland, the medulla, are also involved in

com-pensatory reactions of the body to trauma or

life-threaten-ing situations These hormones are the catecholamines,

ep-inephrine and norepep-inephrine, which have widespread

effects on the cardiovascular system and muscular system

and on carbohydrate and lipid metabolism in liver, muscle,

and adipose tissues

FUNCTIONAL ANATOMY OF THE

ADRENAL GLAND

The human adrenal glands are paired, pyramid-shaped

or-gans located on the upper poles of each kidney The

ad-renal gland is actually a composite of two separate

en-docrine organs, one inside the other, each secreting

separate hormones and each regulated by different

mech-anisms The outer portion or cortex of the adrenal gland

completely surrounds the inner portion or medulla and

makes up most of the gland During embryonic

develop-ment, the cortex forms from mesoderm; the medulla arises

from neural ectoderm

The Adrenal Cortex Consists of

Three Distinct Zones

In the adult human, the adrenal cortex consists of three

his-tologically distinct zones or layers (Fig 34.1) The outer

zone, which lies immediately under the capsule of the

gland, is called the zona glomerulosa and consists of small

clumps of cells that produce the mineralocorticoid

aldos-terone The zona fasciculata is the middle and thickest

layer of the cortex and consists of cords of cells oriented

ra-dial to the center of the gland The inner layer is comprised

of interlaced strands of cells called the zona reticularis.

The zona fasciculata and zona reticularis both produce the

physiologically important glucocorticoids, cortisol and

corticosterone These layers of the cortex also produce the

androgen dehydroepiandrosterone, which is related ically to the male sex hormone testosterone The molecu-

chem-lar structures of these hormones are shown in Figure 34.2.Like all endocrine organs, the adrenal cortex is highlyvascularized Many small arteries branch from the aorta andrenal arteries and enter the cortex These vessels give rise tocapillaries that course radially through the cortex and ter-minate in venous sinuses in the zona reticularis and adrenalmedulla; therefore, the hormones produced by the cells ofthe cortex have ready access to the circulation

The cells of the adrenal cortex contain abundant lipiddroplets This stored lipid is functionally significant be-cause cholesterol esters present in the droplets are an im-portant source of the cholesterol used as a precursor for thesynthesis of steroid hormones

The Adrenal Medulla Is a Modified Sympathetic Ganglion

The adrenal medulla can be considered a modified thetic ganglion The medulla consists of clumps and strands

sympa-of chromaffin cells interspersed with venous sinuses

Chro-maffin cells, like the modified postganglionic neurons thatreceive sympathetic preganglionic cholinergic innervationfrom the splanchnic nerves, produce catecholamine hor-mones, principally epinephrine and norepinephrine Epi-nephrine and NE are stored in granules in chromaffin cellsand discharged into venous sinuses of the adrenal medullawhen the adrenal branches of splanchnic nerves are stimu-lated (see Fig 6.5)

HORMONES OF THE ADRENAL CORTEX

Only small amounts of the glucocorticoids, aldosterone,and adrenal androgens are found in adrenal cortical cells at

Aldosterone Cortisol Androgens Catecholamines

Medulla: 10–20%

Cortex: 80–90% Zona reticularis

Zona fasciculata Zona glomerulosa

The three zones of the adrenal cortex and corresponding hormone secretion

FIGURE 34.1

a given time because those cells produce and secrete these

hormones on demand, rather than storing them Table 34.1

shows the daily production of adrenal cortex hormones in

a healthy adult under resting (unstimulated) conditions

Be-cause the molecular weights of these substances do not vary

greatly, comparing the amounts secreted indicates the

rel-ative number of molecules of each hormone produced

daily Humans secrete about 10 times more cortisol than

corticosterone during an average day, and corticosterone

has only one fifth of the glucocorticoid activity of cortisol

(Table 34.2) Cortisol is considered the physiologically

im-portant glucocorticoid in humans Compared with the

glu-cocorticoids, a much smaller amount of aldosterone is

se-creted each day

Because of similarities in their structures, the

glucocorti-coids and aldosterone have overlapping actions For

exam-ple, cortisol and corticosterone have some coid activity; conversely, aldosterone has some glucocorti-coid activity However, given the amounts of these hor-mones secreted under normal circumstances and theirrelative activities, glucocorticoids are not physiologicallyimportant mineralocorticoids, nor does aldosterone func-tion physiologically as a glucocorticoid

mineralocorti-As discussed in detail later, the amounts of coids and aldosterone secreted by an individual can varygreatly from those given in Table 34.1 The amount se-creted depends on the person’s physiological state For ex-ample, in an individual subjected to severe physical or emo-tional trauma, the rate of cortisol secretion may be 10 timesgreater than the resting rate shown in Table 34.1 Certaindiseases of the adrenal cortex that involve steroid hormonebiosynthesis can significantly increase or decrease theamount of hormones produced

glucocorti-The adrenal cortex also produces and secretes tial amounts of androgenic steroids Dehydroepiandros-terone (DHEA) in both the free form and the sulfated form(DHEAS) is the main androgen secreted by the adrenalcortex of both men and women (see Table 34.1) Lesseramounts of other androgens are also produced The adrenalcortex is the main source of androgens in the blood in hu-man females In the human male, however, androgens pro-duced by the testes and adrenal cortex contribute to themale sex hormones circulating in the blood Adrenal an-drogens normally have little physiological effect other than

substan-a role in development before the stsubstan-art of puberty in bothgirls and boys This is because the male sex hormone activ-ity of the adrenal androgens is weak Exceptions occur inindividuals who produce inappropriately large amounts ofcertain adrenal androgens as a result of diseases affectingthe pathways of steroid biosynthesis in the adrenal cortex

Adrenal Steroid Hormones Are Synthesized From Cholesterol

Cholesterol is the starting material for the synthesis ofsteroid hormones A cholesterol molecule consists of fourinterconnected rings of carbon atoms and a side chain ofeight carbon atoms extending from one ring (Fig 34.3) Inall, there are 27 carbon atoms in cholesterol, numbered asshown in the figure

Sources of Cholesterol. The immediate source of terol used in the biosynthesis of steroid hormones is theabundant lipid droplets in adrenal cortical cells The cho-

choles-Aldosterone

Cortisol Corticosterone

Dehydroepiandrosterone

Zona glomerulosa

Zona fasciculata and zona reticularis

Molecular structures of the important mones secreted by the adrenal cortex

hor-FIGURE 34.2

TABLE 34.1 The Average Daily Production of

Hor-mones by the Adrenal Cortex

Hormone Amount Produced (mg/day)

Cortisol 20

Corticosterone 2

Aldosterone 0.1

Dehydroepiandrosterone 30

TABLE 34.2 Comparison of Shared Activities of

Adrenal Cortical Hormones

Glucocorticoid Mineralocorticoid Hormone Activitya Activityb

Cortisol 100 0.25 Corticosterone 20 0.5 Aldosterone 10 100

aPercentage activity, with cortisol being 100%

bPercentage activity, with aldosterone being 100%

lesterol present in these lipid droplets is mainly in the form

of cholesterol esters, single molecules of cholesterol

ester-ified to single fatty acid molecules The free cholesterol

used in steroid biosynthesis is generated from these

choles-terol esters by the action of cholescholes-terol esterase

(choles-terol ester hydrolase [CEH]), which hydrolyzes the ester

bond The free cholesterol generated by that cleavage

en-ters mitochondria located in close proximity to the lipid

droplet The process of remodeling the cholesterol

mole-cule into steroid hormones is then initiated

The cholesterol that has been removed from the lipid

droplets for steroid hormone biosynthesis is replenished in

two ways (Fig 34.4) Most of the cholesterol converted to

steroid hormones by the human adrenal gland comes from

cholesterol esters contained in low-density lipoprotein

(LDL) particles circulating in the blood The LDL particles

consist of a core of cholesterol esters surrounded by a coat

of cholesterol and phospholipids A 400-kDa protein

mol-ecule called apoprotein B 100is also present on the surface

of the LDL particle; it is recognized by LDL receptors

lo-calized to coated pits on the plasma membrane of adrenal

cortical cells (see Fig 34.4) The apoprotein binds to the

LDL receptor, and both the LDL particle and the receptor

are taken up by the cell through endocytosis The cytic vesicle containing the LDL particles fuses with a lyso-some and the particle is degraded The cholesterol esters inthe core of the particle are hydrolyzed to free cholesteroland fatty acid by the action of CEH

endo-Any cholesterol not immediately used by the cell is verted again to cholesterol esters by the action of the en-

con-zyme acyl-CoA:cholesterol acyltransferase (ACAT) The

esters are then stored in the lipid droplets of the cell to beused later

When steroid biosynthesis is proceeding at a high rate,cholesterol delivered to the adrenal cell may be diverted di-rectly to mitochondria for steroid production rather thanreesterified and stored Accumulating evidence suggests

that high-density lipoprotein (HDL) cholesterol may also

be used as a substrate for adrenal steroidogenesis

In humans, cholesterol that has been synthesized de novo

from acetate by the adrenal glands is a significant but minorsource of cholesterol for steroid hormone formation Therate-limiting step in this process is catalyzed by the enzyme

3-hydroxy-3-methylglutaryl CoA reductase (HMG CoA reductase) The newly synthesized cholesterol is then in-

corporated into cellular structures, such as membranes, or

O

O HO

18 12 21

9

8

DB

A

C

14 13

17 16

OH

The formation of pregnenolone from lesterol by the action of cholesterol side- chain cleavage enzyme (CYP11A1) Note the chemical struc-

cho-ture of cholesterol, how the four rings are lettered (A to D), and

how the carbons are numbered The hydrogen atoms on the

car-bons composing the rings are omitted from the figure.

FIGURE 34.3

CEH

Lipid droplet

HMG CoA reductase Acetate

Cholesterol ester Cholesterol ester

Endocytosis Plasma membrane Blood

Fatty acid ⫹ cholesterol Steroids

Apoprotein

Coated pit

LDL

Adrenal cortical cell

Sources of cholesterol for steroid thesis by the adrenal cortex Most choles- terol comes from low-density lipoprotein (LDL) particles in the blood, which bind to receptors in the plasma membrane and are taken up by endocytosis The cholesterol in the LDL particle is used directly for steroidogenesis or stored in lipid droplets for later use Some cholesterol is synthesized directly from acetate CEH, cholesterol ester hydrolase; ACAT, acyl-CoA:cholesterol acyltransferase; HMG, 3-hydroxy-3-methylglutaryl.

biosyn-FIGURE 34.4

converted to cholesterol esters through the action of

ACAT and stored in lipid droplets (see Fig 34.4)

Pathways for the Synthesis of Steroid Hormones.

Adrenal steroid hormones are synthesized by four CYP

enzymes The CYPs are a large family of oxidative

en-zymes with a 450 nm absorbance maximum when

com-plexed with carbon monoxide; hence, these molecules

were once referred to as cytochrome P450 enzymes The

adrenal CYPs are more commonly known by their trivial

names, which denote their function in steroid

biosynthe-sis (see Table 34.3)

The conversion of cholesterol into steroid hormones

be-gins with the formation of free cholesterol from the

cho-lesterol esters stored in intracellular lipid droplets Free

cholesterol molecules enter the mitochondria, which are

located close to the lipid droplets, by a mechanism that is

not well understood Evidence indicates that free

choles-terol associates with a small protein called scholes-terol carrier

protein 2, which facilitates its entry into the

mitochon-drion in some manner Several other proteins, as well as

cAMP, appear to be involved in cholesterol transport into

mitochondria, but the process is still unclear

Once inside a mitochondrion, single cholesterol

mole-cules bind to the cholesterol side-chain cleavage enzyme

(CYP11A1), embedded in the inner mitochondrial

mem-brane This enzyme catalyzes the first and rate-limiting

re-action in steroidogenesis, which remodels the cholesterol

molecule into a 21-carbon steroid intermediate called

preg-nenolone The reaction occurs in three steps, as shown in

Figure 34.3 The first two steps consist of the hydroxylation

of carbons 20 and 22 by cholesterol side-chain cleavage

en-zyme Then the enzyme cleaves the side chain of

choles-terol between carbons 20 and 22, yielding pregnenolone

and isocaproic acid.

Once formed, pregnenolone molecules dissociate from

cholesterol side-chain cleavage enzyme, leave the

mito-chondrion, and enter the smooth ER nearby This

mecha-nism is not understood At this point, the further

remodel-ing of pregnenolone into steroid hormones can vary,

depending on whether the process occurs in the zona

fas-ciculata and zona reticularis or the zona glomerulosa We

first consider what occurs in the zona fasciculata and zona

reticularis These biosynthetic events are summarized in

Figure 34.5

In cells of the zona fasciculata and zona reticularis, most

of the pregnenolone is converted to cortisol and the mainadrenal androgen dehydroepiandrosterone (DHEA) Preg-

nenolone molecules bind to the enzyme 17 ␣-hydroxylase

(CYP17), embedded in the ER membrane, which

hydroxy-lates pregnenolone at carbon 17 The product formed by

this reaction is 17 ␣-hydroxypregnenolone (see Fig 34.5).

The 17␣-hydroxylase has an additional enzymatic tion that becomes important at this step in the steroido-genic process Once the enzyme has hydroxylated carbon

ac-17 of pregnenolone to form ac-17␣-hydroxypregnenolone,

it has the ability to lyse or cleave the carbon 20–21 sidechain from the steroid structure Some molecules of 17␣-hydroxypregnenolone undergo this reaction and are con-verted to the 19-carbon steroid DHEA This action of

17␣-hydroxylase is essential for the formation of gens (19 carbon steroids) and estrogens (18 carbonsteroids), which lack the carbon 20–21 side chain There-

andro-fore, this lyase activity of 17␣-hydroxylase is important inthe gonads, where androgens and estrogens are primarilymade 17␣-hydroxylase does not exert significant lyaseactivity in children before age 7 or 8 As a result, youngboys and girls do not secrete significant amounts of adre-nal androgens The appearance of significant adrenal an-drogen secretion in children of both sexes is termed

adrenarche It is not related to the onset of puberty, since

it normally occurs before the activation of the mic-pituitary-gonad axis, which initiates puberty The ad-renal androgens produced as a result of adrenarche are astimulus for the growth of pubic and axillary hair.Those molecules of 17␣-hydroxypregnenolone that dis-sociate as such from 17␣-hydroxylase bind next to another

hypothala-ER enzyme, 3 ␤-hydroxysteroid dehydrogenase (3␤-HSD II) This enzyme acts on 17␣-hydroxypregnenolone to iso-merize the double bond in ring B to ring A and to dehydro-genate the 3␤-hydroxy group, forming a 3-keto group The

product formed is 17 ␣-hydroxyprogesterone (see Fig 34.5) This intermediate then binds to another enzyme, 21-hy-

droxylase (CYP21A2), which hydroxylates it at carbon 21.

The mechanism of this hydroxylation is similar to that formed by the 17␣-hydroxylase The product formed is 11-

per-deoxycortisol, which is the immediate precursor for cortisol.

To be converted to cortisol, 11-deoxycortisol moleculesmust be transferred back into the mitochondrion to be

acted on by 11 ␤-hydroxylase (CYP11B1) embedded in the

inner mitochondrial membrane This enzyme hydroxylates11-deoxycortisol on carbon 11, converting it into cortisol.The 11␤-hydroxyl group is the molecular feature that con-fers glucocorticoid activity on the steroid Cortisol is thensecreted into the bloodstream

Some of the pregnenolone molecules generated in cells

of the zona fasciculata and zona reticularis first bind to 3hydroxysteroid dehydrogenase when they enter the endo-

␤-plasmic reticulum As a result, they are converted to

prog-esterone Some of these progesterone molecules are

hydroxylated by 21-hydroxylase to form the

mineralocor-ticoid 11-deoxycorticosterone (DOC) (see Fig 34.5) The

11-deoxycorticosterone formed may be either secreted ortransferred back into the mitochondrion There it is acted

on by 11␤-hydroxylase to form corticosterone, which isthen secreted into the circulation

TABLE 34.3 Nomenclature for the Steroidogenic

En-zymes

Previous Current Common Name Form Form Gene

Cholesterol side-chain P450 SCC CYP11A1 CYP11A1

cleavage enzyme

3 ␤-Hydroxysteroid 3 ␤-HSD 3 ␤-HSD II HSD3B2

dehydrogenase

17 ␣-Hydroxylase P450 C17 CYP17 CYP17

21-Hydroxylase P450 C21 CYP21A2 CYP21A2

11 ␤-Hydroxylase P450 C11 CYP11B1 CYP11B1

Aldosterone synthase P450 C11AS CYP11B2 CYP11B2

Progesterone may also undergo 17␣-hydroxylation in

the zona fasciculata and zona reticularis It is then

con-verted to either cortisol or the adrenal androgen

an-drostenedione.

The 17␣-hydroxylase is not present in cells of the zona

glomerulosa; therefore, pregnenolone does not undergo

17␣-hydroxylation in these cells, and cortisol and adrenalandrogens are not formed by these cells Instead, the enzy-matic pathway leading to the formation of aldosterone isfollowed (see Fig 34.5) Pregnenolone is converted by en-zymes in the endoplasmic reticulum to progesterone and11-deoxycorticosterone The latter compound then moves

C O CH3

17 α-Hydroxylase (CYP17)

17 α-Hydroxylase (CYP17)

17 α-Hydroxylase (CYP17)

3 β-Hydroxysteroid dehydrogenase (3 β-HSD II)

3 β-Hydroxysteroid dehydrogenase (3 β-HSD II)

21-Hydroxylase (CYP21A2)

11 β-Hydroxylase (CYPIIBI)

Aldosterone synthase (CYPIIB2)

The synthesis of steroids in the adrenal cortex

FIGURE 34.5

into the mitochondrion, where it is converted to

aldos-terone This conversion involves three steps: the

hydroxy-lation of carbon 11 to form corticosterone, the

hydroxyla-tion of carbon 18 to form 18-hydroxycorticosterone, and

the oxidation of the 18-hydroxymethyl group to form

al-dosterone In humans, these three reactions are catalyzed

by a single enzyme, aldosterone synthase (CYP11B2), an

isozyme of 11␤-hydroxylase (CYP11B1), expressed only in

glomerulosa cells The 11␤-hydroxylase enzyme, which is

expressed in the zona fasciculata and zona reticularis,

al-though closely related to aldosterone synthase, cannot

cat-alyze all three reactions involved in the conversion of

11-deoxycorticosterone to aldosterone; therefore, aldosterone

is not synthesized in the zona fasciculata and zona

reticu-laris of the adrenal cortex

Genetic Defects in Adrenal Steroidogenesis. Inherited

genetic defects can cause relative or absolute deficiencies in

the enzymes involved in the steroid hormone biosynthetic

pathways The immediate consequences of these defects

are changes in the types and amounts of steroid hormones

secreted by the adrenal cortex The end result is disease

Most of the genetic defects affecting the steroidogenic

enzymes impair the formation of cortisol As discussed in

Chapter 32, a drop in cortisol concentration in the blood

stimulates the secretion of adrenocorticotropic hormone

(ACTH) by the anterior pituitary The consequent rise in

ACTH in the blood exerts a trophic (growth-promoting)

effect on the adrenal cortex, resulting in adrenal

hypertro-phy Because of this mechanism, individuals with genetic

defects affecting adrenal steroidogenesis usually have

hy-pertrophied adrenal glands These diseases are collectively

called congenital adrenal hyperplasia.

In humans, inherited genetic defects occur that affect

cholesterol side-chain cleavage enzyme, 17␣-hydroxylase,

3␤-hydroxysteroid dehydrogenase, 21-hydroxylase,

11␤-hydroxylase, and aldosterone synthase The most common

defect involves mutations in the gene for 21-hydroxylase

and occurs in 1 of 7,000 people The gene for

21-hydroxy-lase may be deleted entirely, or mutant genes may code for

forms of 21-hydroxylase with impaired enzyme activity

The consequent reduction in the amount of active

21-hy-droxylase in the adrenal cortex interferes with the

forma-tion of cortisol, corticosterone, and aldosterone, all of

which are hydroxylated at carbon 21 Because of the

re-duction of cortisol (and corticosterone) secretion in these

individuals, ACTH secretion is stimulated This, in turn,

causes hypertrophy of the adrenal glands and stimulates the

glands to produce steroids

Because 21-hydroxylation is impaired, the ACTH

stim-ulus causes pregnenolone to be converted to adrenal

an-drogens in inappropriately high amounts Thus, women

af-flicted with 21-hydroxylase deficiency exhibit virilization

from the masculinizing effects of excessive adrenal

andro-gen secretion In severe cases, the deficiency in aldosterone

production can lead to sodium depletion, dehydration,

vas-cular collapse, and death, if appropriate hormone therapy is

not given

Addison’s Disease. Glucocorticoid and aldosterone

defi-ciency also occur as a result of pathological destruction of the

adrenal glands by microorganisms or autoimmune disease

This disorder is called Addison’s disease If sufficient adrenal

cortical tissue is lost, the resulting decrease in aldosteroneproduction can lead to vascular collapse and death, unlesshormone therapy is given (see Clinical Focus Box 34.1)

Transport of Adrenal Steroids in Blood. As noted earlier,steroid hormones are not stored to any extent by cells of theadrenal cortex but are continually synthesized and secreted.The rate of secretion may change dramatically, however, de-pending on stimuli received by the adrenal cortical cells Theprocess by which steroid hormones are secreted is not wellstudied It has been assumed that the accumulation of the fi-nal products of the steroidogenic pathways creates a con-centration gradient for steroid hormone between cells andblood This gradient is thought to be the driving force fordiffusion of the lipid-soluble steroids through cellular mem-branes and into the circulation

A large fraction of the adrenal steroids that enter thebloodstream become bound noncovalently to certain

plasma proteins One of these is corticosteroid-binding

globulin (CBG), a glycoprotein produced by the liver.

CBG binds glucocorticoids and aldosterone, but has a

greater affinity for the glucocorticoids Serum albumin also

binds steroid molecules Albumin has a high capacity forbinding steroids, but its interaction with steroids is weak.The binding of a steroid hormone to a circulating proteinmolecule prevents it from being taken up by cells or beingexcreted in the urine

Circulating steroid hormone molecules not bound toplasma proteins are free to interact with receptors on cellsand, therefore, are cleared from the blood As this occurs,bound hormone dissociates from its binding protein and re-plenishes the circulating pool of free hormone Because ofthis process, adrenal steroid hormones have long half-lives

in the body, ranging from many minutes to hours

Metabolism of Adrenal Steroids in the Liver. Adrenalsteroid hormones are eliminated from the body primarily

by excretion in the urine after they have been structurallymodified to destroy their hormone activity and increasetheir water solubility Although many cells are capable ofcarrying out these modifications, they primarily occur inthe liver

The most common structural modifications made in renal steroids involve reduction of the double bond in ring

ad-A and conjugation of the resultant hydroxyl group formed

on carbon 3 with glucuronic acid Figure 34.6 shows howcortisol is modified in this manner to produce a major exc-

retable metabolite, tetrahydrocortisol glucuronide

Corti-sol, and other 21-carbon steroids with a 17␣-hydroxylgroup and a 20-keto group, may undergo lysis of the carbon20–21 side chain as well The resultant metabolite, with a

keto group on carbon 17, appears as one of the

teroids in the urine Adrenal androgens are also

17-ketos-teroids They are usually conjugated with sulfuric acid orglucuronic acid before being excreted and normally com-prise the bulk of the 17-ketosteroids in the urine Before thedevelopment of specific methods to measure androgensand 17␣-hydroxycorticosteroids in body fluids, the amount

of 17-ketosteroids in urine was used clinically as a crude

in-dicator of the production of these substances by the

adre-nal gland

ACTH Regulates the Synthesis of

Adrenal Steroids

Adrenocorticotropic hormone (ACTH) is the

physiologi-cal regulator of the synthesis and secretion of

glucocorti-coids and androgens by the zona fasciculata and zona

retic-ularis It has a very rapid stimulatory effect on

steroidogenesis in these cells, which can result in a great

rise in blood glucocorticoids within seconds It also exerts

several long-term trophic effects on these cells, all directed

toward maintaining the cellular machinery necessary to

carry out steroidogenesis at a high, sustained rate These

actions of ACTH are summarized in Figure 34.7

Role of cAMP. When the level of ACTH in the blood

rises, increased numbers of ACTH molecules interact with

receptors on the plasma membranes of adrenal cortical

cells These ACTH receptors are coupled to the enzyme

adenylyl cyclase by stimulatory guanine

nucleotide-bind-ing proteins (Gsproteins) The production of cAMP from

ATP greatly increases, and the concentration of cAMP rises

in the cell cAMP activates protein kinase A (PKA), whichphosphorylates proteins that regulate steroidogenesis.The rapid rise in cAMP produced by ACTH stimulatesthe mechanism that transfers cholesterol into the inner mi-tochondrial membrane This action provides abundant cho-lesterol for side-chain cleavage enzyme, which carries outthe rate-limiting step in steroidogenesis As a result, the rates

of steroid hormone formation and secretion rise greatly

Gene Expression for Steroidogenic Enzymes. corticotropic hormone maintains the capacity of the cells

Adreno-of the zona fasciculata and zona reticularis to producesteroid hormones by stimulating the transcription of thegenes for many of the enzymes involved in steroidogenesis.For example, transcription of the genes for side-chaincleavage enzyme, 17␣-hydroxylase, 21-hydroxylase, and

11␤-hydroxylase, is increased several hours after adrenalcortical cells have been stimulated by ACTH Because nor-mal individuals are continually exposed to episodes ofACTH secretion (see Fig 32.7), the mRNA for these en-zymes is well maintained in the cells Again, this long-term

or maintenance effect of ACTH is due to its ability to crease cAMP in the cells (see Fig 34.7)

in-The importance of ACTH in gene transcription

be-C L I N I be-C A L F O be-C U S B O X 3 4 1

Primary Adrenal Insufficiency: Addison’s Disease

Adrenal insufficiency may be caused by destruction of the

adrenal cortex (primary adrenal insufficiency), low pituitary

ACTH secretion (secondary adrenal insufficiency), or

defi-cient hypothalamic release of CRH (tertiary adrenal

ciency) Addison’s disease (primary adrenal

insuffi-ciency) results from the destruction of the adrenal gland by

microorganisms or autoimmune disease When Addison’s

first described primary adrenal insufficiency in the

mid-1800s, bilateral adrenal destruction by tuberculosis was the

most common cause of the disease Today, autoimmune

destruction accounts for 70 to 90% of all cases, with the

re-mainder the resulting from infection, cancer, or adrenal

hemorrhage The prevalence of primary adrenal

insuffi-ciency is about 40 to 110 cases per 1 million adults, with an

incidence of about 6 cases per 1 million adults per year.

In primary adrenal insufficiency, all three zones of the

adrenal cortex are usually involved The result is

inade-quate secretion of glucocorticoids, mineralocorticoids, and

androgens Major symptoms are not usually detected until

90% of the gland has been destroyed The initial symptoms

generally have a gradual onset, with only a partial

gluco-corticoid deficiency resulting in inadequate cortisol

in-crease in response to stress Mineralocorticoid deficiency

may only appear as a mild postural hypotension

Progres-sion to complete glucocorticoid deficiency results in a

de-creased sense of well-being and abnormal glucose

metab-olism Lack of mineralocorticoid leads to decreased renal

potassium secretion and reduced sodium retention, the

loss of which results in hypotension and dehydration The

combined lack of glucocorticoid and mineralocorticoid can

lead to vascular collapse, shock, and death Adrenal

an-drogen deficiency is observed in women only (men derive

most of their androgen from the testes) as decreased pubic and axillary hair and decreased libido.

Antibodies that react with all three zones of the adrenal cortex have been identified in autoimmune adrenalitis and are more common in women than in men The presence of antibodies appears to precede the development of adrenal insufficiency by several years Antiadrenal antibodies are mainly directed to the steroidogenic enzymes cholesterol side-chain cleavage enzyme (CYP11A1), 17 ␣-hydroxylase (CYP17) and 21-hydroxylase (CYP21A2), although antibod- ies to other steroidogenic enzymes may also be present In the initial stages of the disease, the adrenal glands may be enlarged with extensive lymphocyte infiltration Genetic susceptibility to autoimmune adrenal insufficiency is strongly linked with the HLA-B8, HLA-DR3, and HLA-DR4 alleles of human leukocyte antigen (HLA) The earliest sign

of adrenal insufficiency is an increase in plasma renin tivity, with a low or normal aldosterone level, which sug- gests that the zona glomerulosa is affected first during dis- ease progression.

ac-Treatment for acute adrenal insufficiency should be rected at reversal of the hypotension and electrolyte ab- normalities Large volumes of 0.9% saline or 5% dextrose

di-in saldi-ine should be di-infused as quickly as possible ethasone or a soluble form of injectable cortisol should also be given Daily glucocorticoid and mineralocorticoid replacement allows the patient to lead a normal active life.

Dexam-Reference

Orth DN, Kovacs WJ The adrenal cortex In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR, eds Williams Text- book of Endocrinology 9th Ed Philadelphia: WB Saun- ders, 1998;517–664.

comes evident in hypophysectomized animals or humans

with ACTH deficiency An example of the latter is a human

treated chronically with large doses of cortisol or related

steroids, which causes prolonged suppression of ACTH

se-cretion by the anterior pituitary The chronic lack of

ACTH decreases the transcription of the genes for

steroidogenic enzymes, causing a deficiency in these

en-zymes in the adrenals As a result, the administration of

ACTH to such an individual does not cause a marked

in-crease in glucocorticoid secretion Chronic exposure to

ACTH is required to restore mRNA levels for the

steroido-genic enzymes and, hence, the enzymes themselves, to

ob-tain normal steroidogenic responses to ACTH A patient

receiving long-term treatment with glucocorticoid may

suf-fer serious glucocorticoid deficiency if hormone therapy is

halted abruptly; withdrawing glucocorticoid therapy

grad-ually allows time for endogenous ACTH to restore

steroidogenic enzyme levels to normal

Effects on Cholesterol Metabolism. ACTH has several

long-term effects on cholesterol metabolism that support

steroidogenesis in the zona fasciculata and zona reticularis

It increases the abundance of LDL receptors and the ity of the enzyme HMG-CoA reductase in these cells.These actions increase the availability of cholesterol forsteroidogenesis It is not clear whether ACTH exerts theseeffects directly The abundance of LDL receptors in theplasma membrane and the activity of HMG-CoA reductase

activ-in most cells are activ-inversely related to the amount of cellularcholesterol By stimulating steroidogenesis, ACTH reducesthe amount of cholesterol in adrenal cells; therefore, the in-creased abundance of LDL receptors and high HMG-CoAreductase activity in ACTH-stimulated cells may merely re-sult from the normal compensatory mechanisms that func-tion to maintain cell cholesterol levels

ACTH also stimulates the activity of cholesterol terase in adrenal cells, which promotes the hydrolysis ofthe cholesterol esters stored in the lipid droplets of thesecells, making free cholesterol available for steroidogenesis.The cholesterol esterase in the adrenal cortex appears to beidentical to hormone-sensitive lipase, which is activatedwhen it is phosphorylated by a cAMP-dependent protein

OH

C O

HO

C O OH

H O

tetrahydro-soluble than cortisol, it is easily excreted in the urine.

FIGURE 34.6

ACTH

Gs

AC ATP

cAMP PKA P proteins

mRNAs

Lipid droplets

Cholesterol Mitochondrion

Steroidogenic enzymes

Pregnenolone

Smooth ER

Androgens Glucocorticoids

steroidogen-G proteins (steroidogen-Gs) cAMP rises in the cells and activates protein nase A (PKA), which then phosphorylates certain proteins (P- Proteins) These proteins presumably initiate steroidogenesis and stimulate the expression of genes for steroidogenic enzymes.

ki-FIGURE 34.7

kinase The rise in cAMP concentration produced by

ACTH might account for its effect on the enzyme

Trophic Action on Adrenal Cortical Cell Size. ACTH

maintains the size of the two inner zones of the adrenal

cor-tex, presumably by stimulating the synthesis of structural

elements of the cells; however, it does not affect the size of

the cells of the zona glomerulosa The trophic effect of

ACTH is clearly evident in states of ACTH deficiency or

excess In hypophysectomized or ACTH-deficient

individ-uals, the cells of the two inner zones atrophy Chronic

stimulation of these cells with ACTH causes them to

hy-pertrophy The mechanisms involved in this trophic action

of ACTH are unclear

ACTH and Aldosterone Production. The cells of the

zona glomerulosa have ACTH receptors, which are

cou-pled to adenylyl cyclase In these cells, cAMP increases in

response to ACTH, resulting in some increase in

aldos-terone secretion However, angiotensin II is the important

physiological regulator of aldosterone secretion, not

ACTH Other factors, such as an increase in serum

potas-sium, can also stimulate aldosterone secretion, but

nor-mally, they play only a secondary role

Formation of Angiotensin II. Angiotensin II is a short

peptide consisting of eight amino acid residues It is

formed in the bloodstream by the proteolysis of the ␣2

-globulin angiotensinogen, which is secreted by the liver.

The formation of angiotensin II occurs in two stages

(Fig 34.8) Angiotensinogen is first cleaved at its

N-ter-minal end by the circulating protease renin, releasing the

inactive decapeptide angiotensin I Renin is produced and

secreted by granular (juxtaglomerular) cells in the kidneys

(see Chapter 23) A dipeptide is then removed from the

C-terminal end of angiotensin I, producing angiotensin II

This cleavage is performed by the protease

angiotensin-converting enzyme present on the endothelial cells lining

the vasculature This step usually occurs as angiotensin I

molecules traverse the pulmonary circulation The

rate-limiting factor for the formation of angiotensin II is the

renin concentration of the blood

Cleavage of the N-terminal aspartate from angiotensin IIresults in the formation of angiotensin III, which circulates

at a concentration of 20% that of angiotensin II giotensin III is as potent a stimulator of aldosterone secre-tion as angiotensin II

An-Action of Angiotensin II on Aldosterone Secretion. giotensin II stimulates aldosterone synthesis by promotingthe rate-limiting step in steroidogenesis (i.e., the move-ment of cholesterol into the inner mitochondrial mem-brane and its conversion to pregnenolone) The primarymechanism is shown in Figure 34.9

An-The stimulation of aldosterone synthesis is initiatedwhen angiotensin II binds to its receptors on the plasmamembranes of zona glomerulosa cells The signal generated

by the interaction of angiotensin II with its receptors istransmitted to phospholipase C (PLC) by a G protein, andthe enzyme becomes activated The PLC then hydrolyzesphosphatidylinositol 4,5 bisphosphate (PIP2) in the plasmamembrane, producing the intracellular second messengersinositol trisphosphate (IP3) and diacylglycerol (DAG) The

IP3mobilizes calcium, which is bound to intracellular tures, increasing the calcium concentration in the cytosol.This increase in intracellular calcium and DAG activatesprotein kinase C (PKC) The rise in intracellular calcium

struc-also activates calmodulin-dependent protein kinase

(CMK) These enzymes phosphorylate proteins, whichthen become involved in initiating steroidogenesis.Signals for Increased Angiotensin II Formation. Al-though angiotensin II is the final mediator in the physio-logical regulation of aldosterone secretion, its formationfrom angiotensinogen is dependent on the secretion ofrenin by the kidneys The rate of renin secretion ultimatelydetermines the rate of aldosterone secretion Renin is se-creted by the granular cells in the walls of the afferent arte-rioles of renal glomeruli These cells are stimulated to se-crete renin by three signals that indicate a possible loss ofbody fluid: a fall in blood pressure in the afferent arterioles

of the glomeruli, a drop in sodium chloride concentration

in renal tubular fluid at the macula densa, and an increase inrenal sympathetic nerve activity (see Chapters 23 and 24)

ASP

ASP Arg Val Tyr Ile His Pro Phe His Leu Leu Val R

The formation of giotensins I, II, and III from angiotensinogen.

an-FIGURE 34.8

Increased renin secretion results in an increase in

an-giotensin II formation in the blood, thereby stimulating

al-dosterone secretion by the zona glomerulosa This series of

events tends to conserve body fluid volume because

aldos-terone stimulates sodium reabsorption by the kidneys

Extracellular Potassium Concentration and Aldosterone

Secretion. Aldosterone secretion is also stimulated by an

increase in the potassium concentration in extracellular

fluid, caused by a direct effect of potassium on zona

glomerulosa cells Glomerulosa cells are sensitive to this

ef-fect of extracellular potassium and, therefore, increase their

rate of aldosterone secretion in response to small increases

in blood and interstitial fluid potassium concentration This

signal for aldosterone secretion is appropriate from a

phys-iological point of view because aldosterone promotes the

renal excretion of potassium (see Chapter 24)

A rise in extracellular potassium depolarizes glomerulosa

cell membranes, activating voltage-dependent calcium

channels in the membranes The consequent rise in lic calcium is thought to stimulate aldosterone synthesis bythe mechanisms described above for the action of an-giotensin II

cytoso-Aldosterone and Sodium Reabsorption by Kidney Tubules. The physiological action of aldosterone is tostimulate sodium reabsorption in the kidneys by the distaltubule and collecting duct of the nephron and to promotethe excretion of potassium and hydrogen ions The mech-anism of action of aldosterone on the kidneys and its role inwater and electrolyte balance are discussed in Chapter 24

Glucocorticoids Play a Role in the Reactions to Fasting, Injury, and Stress

Glucocorticoids widely influence physiological processes Infact, most cells have receptors for glucocorticoids and arepotential targets for their actions Consequently, glucocorti-coids have been used extensively as therapeutic agents, andmuch is known about their pharmacological effects.Actions on Transcription. Unlike many other hor-mones, glucocorticoids influence physiological processesslowly, sometimes taking hours to produce their effects.Glucocorticoids that are free in the blood diffuse throughthe plasma membranes of target cells; once inside, theybind tightly but noncovalently to receptor proteins pres-ent in the cytoplasm The interaction between the gluco-corticoid molecule and its receptor molecule produces anactivated glucocorticoid-receptor complex, whichtranslocates into the nucleus

These complexes then bind to specific regions of DNA

called glucocorticoid response elements (GREs), which

are near glucocorticoid-sensitive target genes The bindingtriggers events that either stimulate or inhibit the transcrip-tion of the target gene As a result of the change in tran-scription, amounts of mRNA for certain proteins are eitherincreased or decreased This, in turn, affects the abundance

of these proteins in the cell, which produces the logical effects of the glucocorticoids The apparent slow-ness of glucocorticoid action is due to the time required bythe mechanism to change the protein composition of a tar-get cell

physio-Glucocorticoids and the Metabolic Response to Fasting.During the fasting periods between food intake in humans,metabolic adaptations prevent hypoglycemia The mainte-nance of sufficient blood glucose is necessary because thebrain depends on glucose for its energy needs Many of theadaptations that prevent hypoglycemia are not fully ex-pressed in the course of daily life because the individualeats before they fully develop Full expression of thesechanges is seen only after many days to weeks of fasting.Glucocorticoids are necessary for the metabolic adaptation

Cholesterol Mitochondrion

tivates phospholipase C (PLC), which is coupled to the

an-giotensin II receptor by G proteins (Gq) PLC hydrolyzes

phosphatidylinositol 4,5 bisphosphate (PIP2) in the plasma

mem-brane, producing inositol trisphosphate (IP3) and diacylglycerol

(DAG) IP3 mobilizes intracellularly bound Ca 2 ⫹ The rise in

Ca 2 ⫹ and DAG activates protein kinase C (PKC) and

calmodulin-dependent protein kinase (CMK) These enzymes phosphorylate

proteins (P-Proteins) involved in initiating aldosterone synthesis.

FIGURE 34.9

level is stabilized by the production of glucose by the body

and the restriction of its use by tissues other than the brain

Although a limited supply of glucose is available from

glycogen stored in the liver, the more important source of

blood glucose during the first days of a fast is

gluconeoge-nesis in the liver and, to some extent, in the kidneys

Gluconeogenesis begins several hours after the start of a

fast Amino acids derived from tissue protein are the main

substrates Fasting results in protein breakdown in the

skeletal muscle and accelerated release of amino acids into

the bloodstream Protein breakdown and protein accretion

in adult humans are regulated by two opposing hormones,

insulin and glucocorticoids During fasting, insulin

secre-tion is suppressed and the inhibitory effect of insulin on

protein breakdown is lost As proteins are broken down,

glucocorticoids inhibit the reuse of amino acids derived

from tissue proteins for new protein synthesis, promoting

the release of these amino acids from the muscle Amino

acids released into the blood by the skeletal muscle are

ex-tracted from the blood at an accelerated rate by the liver

and kidneys The amino acids then undergo metabolic

transformations in these tissues, leading to the synthesis of

glucose The newly synthesized glucose is then delivered

to the bloodstream

The glucocorticoids are essential for the acceleration of

gluconeogenesis during fasting They play a permissive role

in this process by maintaining gene expression and,

there-fore, the intracellular concentrations of many of the

en-zymes needed to carry out gluconeogenesis in the liver and

kidneys For example, glucocorticoids maintain the

amounts of transaminases, pyruvate carboxylase,

phospho-enolpyruvate carboxykinase, fructose-1,6-diphosphatase,

fructose-6-phosphatase, and glucose-6-phosphatase

needed to carry out gluconeogenesis at an accelerated rate

In an untreated, glucocorticoid-deficient individual, the

amounts of these enzymes in the liver are greatly reduced

As a consequence, the individual cannot respond to fastingwith accelerated gluconeogenesis and will die from hypo-glycemia In essence, the glucocorticoids maintain the liverand kidney in a state that enables them to carry out accel-erated gluconeogenesis should the need arise

The other important metabolic adaptation that occursduring fasting involves the mobilization and use of storedfat Within the first few hours of the start of a fast, theconcentration of free fatty acids rises in the blood (seeFig 34.10) This action is due to the acceleration of lipol-

ysis in the fat depots, as a result of the activation of

hor-mone-sensitive lipase (HSL) HSL hydrolyzes the stored

triglyceride to free fatty acids and glycerol, which are leased into the blood

re-HSL is activated when it is phosphorylated by a dependent protein kinase As the level of insulin falls in theblood during fasting, the inhibitory effect of insulin oncAMP accumulation in the fat cell diminishes There is arise in the cellular level of cAMP, and HSL is activated Theglucocorticoids are essential for maintaining fat cells in anenzymatic state that permits lipolysis to occur during a fast.This is evident from the fact that accelerated lipolysis doesnot occur when a glucocorticoid-deficient individual fasts.The abundant fatty acids produced by lipolysis are taken

cAMP-up by many tissues The fatty acids enter mitochondria, dergo␤-oxidation to acetyl CoA, and become the substratefor ATP synthesis The enhanced use of fatty acids for en-ergy metabolism spares the blood glucose supply There isalso significant gluconeogenesis in liver from the glycerolreleased from triglyceride by lipolysis In prolonged fast-ing, when the rate of glucose production from body proteinhas declined, a significant fraction of blood glucose is de-rived from triglyceride glycerol

un-Within a few hours of the start of a fast, the increaseddelivery to and oxidation of fatty acids in the liver results inthe production of the ketone bodies As a result of theseevents in the liver, a gradual rise in ketone bodies occurs inthe blood as a fast continues over many days (Fig 34.10).Ketone bodies become the principal energy source used bythe CNS during the later stages of fasting

The increased use of fatty acids for energy metabolism

by skeletal muscle results in less use of glucose in this tissue,sparing blood glucose for use by the CNS Two productsresulting from the breakdown of fatty acids, acetyl CoAand citrate, inhibit glycolysis As a result, the uptake anduse of glucose from the blood is reduced

In summary, the strategy behind the metabolic tion to fasting is to provide the body with glucose pro-duced primarily from protein until the ketone bodies be-come abundant enough in the blood to be a principalsource of energy for the brain From that point on, thebody uses mainly fat for energy metabolism, and it cansurvive until the fat depots are exhausted Glucocorticoids

adapta-do not trigger the metabolic adaptations to fasting butonly provide the metabolic machinery necessary for theadaptations to occur

Cushing’s Disease. When present in excessive amounts,glucocorticoids can trigger many of the metabolic adapta-

tions to the fasting state Cushing’s disease is the name of

such pathological hypercortisolic states Cushing’s disease

0

Days of fasting ( ⫹)

Metabolic adaptations during fasting This graphs shows the changes in the concentrations

of blood glucose, fatty acids, and ketone bodies and the rate of

glu-coneogenesis during the course of a prolonged fast Only the

direc-tion of change over time is indicated: increase (⫹) or decrease (⫺).

FIGURE 34.10

may be ACTH-dependent or ACTH-independent One

type of ACTH-dependent syndrome (actually called

Cush-ing’s disease) is caused by a corticotroph adenoma, which

secretes excessive ACTH and stimulates the adrenal cortex

to produce large amounts of cortisol ACTH-independent

Cushing’s syndrome is usually due toa result of an

adreno-cortical adenoma that secretes large amounts of cortisol

Whatever the cause, prolonged exposure of the body to

large amounts of glucocorticoids causes the breakdown of

skeletal muscle protein, increased glucose production by

the liver, and mobilization of lipid from the fat depots

De-spite the increased mobilization of lipid, there is also an

ab-normal deposition of fat in the abdominal region, between

the shoulders, and in the face The increased mobilization

of lipid provides abundant fatty acids for metabolism and

the increased oxidation of fatty acids by tissues reduces

their ability to use glucose The underutilization of glucose

by skeletal muscle, coupled with increased glucose

produc-tion by the liver, results in hyperglycemia, which, in turn,

stimulates the pancreas to secrete insulin In this instance,

however, the rise in insulin is not effective in reducing the

blood glucose concentration because glucose uptake and

use are decreased in the skeletal muscle and adipose tissue

Evidence also indicates that excessive glucocorticoids

de-crease the affinity of insulin receptors for insulin The net

result is that the individual becomes insensitive or resistant

to the action of insulin and little glucose is removed from

the blood, despite the high level of circulating insulin The

persisting hyperglycemia continually stimulates the

pan-creas to secrete insulin The result is a form of “diabetes”

similar to Type 2 diabetes mellitus (see Chapter 35)

The opposite situation occurs in the

glucocorticoid-de-ficient individual Little lipid mobilization and use occur, so

there is little restriction on the rate of glucose use by

tis-sues The glucocorticoid-deficient individual is sensitive to

insulin in that a given concentration of blood insulin is

more effective in clearing the blood of glucose than it is in

a healthy person The administration of even small doses of

insulin to such individuals may produce hypoglycemia

The Anti-inflammatory Action of Glucocorticoids.

Tis-sue injury triggers a complex mechanism called

inflamma-tion that precedes the actual repair of damaged tissue A

host of chemical mediators are released into the damaged

area by neighboring cells, adjacent vasculature, and

phago-cytic cells that migrate to the damaged site Mediators

re-leased under these circumstances include prostaglandins,

leukotrienes, kinins, histamine, serotonin, and

lym-phokines These substances exert a multitude of actions at

the site of injury and directly or indirectly promote the

lo-cal vasodilation, increased capillary permeability, and

edema formation that characterize the inflammatory

re-sponse (see Chapter 11)

Because glucocorticoids inhibit the inflammatory

re-sponse to injury, they are used extensively as therapeutic

anti-inflammatory agents; however, the mechanisms are

not clear Their regulation of the production of

prostaglandins and leukotrienes is the best understood

These substances play a major role in mediating the

in-flammatory reaction They are synthesized from the

unsat-urated fatty acid arachidonic acid, which is released from

plasma membrane phospholipids by the hydrolytic action

of phospholipase A 2 Glucocorticoids stimulate the

syn-thesis of a family of proteins called lipocortins in their

tar-get cells Lipocortins inhibit the activity of phospholipase

A2, reducing the amount of arachidonic acid available forconversion to prostaglandins and leukotrienes

Effects on the Immune System. Glucocorticoids havelittle influence on the human immune system under normalphysiological conditions When administered in largedoses over a prolonged period, however, they can suppressantibody formation and interfere with cell-mediated immu-nity Glucocorticoid therapy, therefore, is used to suppressthe rejection of surgically transplanted organs and tissues.Immature T cells in the thymus and immature B cells and

T cells in lymph nodes can be killed by exposure to highconcentrations of glucocorticoids, decreasing the number

of circulating lymphocytes The destruction of immature Tand B cells by glucocorticoids also causes some reduction inthe size of the thymus and lymph nodes

Maintenance of the Vascular Response to Norepinephrine.Glucocorticoids are required for the normal responses of vas-cular smooth muscle to the vasoconstrictor action of norep-inephrine NE is much less active on vascular smooth muscle

in the absence of glucocorticoids and is another example ofthe permissive action of glucocorticoids

Glucocorticoids and Stress. Perhaps the most ing, but least understood, of all glucocorticoid action is theability to protect the body against stress All that is reallyknown is that the body cannot cope successfully with evenmild stresses in the absence of glucocorticoids One mustpresume that the processes that enable the body to defenditself against physical or emotional trauma require gluco-corticoids This, again, emphasizes the permissive role theyplay in physiological processes

interest-Stress stimulates the secretion of ACTH, which creases the secretion of glucocorticoids by the adrenal cor-tex (see Chapter 32) In humans, this increase in glucocor-ticoid secretion during stress appears to be important forthe appropriate defense mechanisms to be put into place It

in-is well known, for example, that glucocorticoid-deficientindividuals receiving replacement therapy require largerdoses of glucocorticoid to maintain their well-being duringperiods of stress

Regulation of Glucocorticoid Secretion. An importantphysiological action of glucocorticoids is the ability to reg-ulate their own secretion This effect is achieved by a neg-ative-feedback mechanism of glucocorticoids on the secre-tion of corticotropin-releasing hormone (CRH) andACTH and on proopiomelanocortin (POMC) gene ex-pression (see Chapter 32)

PRODUCTS OF THE ADRENAL MEDULLA

The catecholamines, epinephrine and norepinephrine, arethe two hormones synthesized by the chromaffin cells ofthe adrenal medulla The human adrenal medulla produces

and secretes about 4 times more epinephrine than

norepi-nephrine Postganglionic sympathetic neurons also

pro-duce and release NE from their nerve terminals but do not

produce epinephrine

Epinephrine and NE are formed in the chromaffin cells

from the amino acid tyrosine The pathway for the

synthe-sis of catecholamines is illustrated in Figure 3.18

Trauma, Exercise, and Hypoglycemia Stimulate

the Medulla to Release Catecholamines

Epinephrine and some NE are released from chromaffin

cells by the fusion of secretory granules with the plasma

membrane The contents of the granules are extruded into

the interstitial fluid The catecholamines diffuse into

capil-laries and are transported in the bloodstream

Neural stimulation of the cholinergic preganglionic

fibers that innervate chromaffin cells triggers the secretion

of catecholamines Stimuli such as injury, anger, anxiety,

pain, cold, strenuous exercise, and hypoglycemia generate

impulses in these fibers, causing a rapid discharge of the

catecholamines into the bloodstream

Catecholamines Have Rapid, Widespread Effects

Most cells of the body have receptors for catecholamines

and, thus, are their target cells There are four structurally

related forms of catecholamine receptors, all of which are

transmembrane proteins: ␣1,␣2,␤1, and ␤2 All can bind

epinephrine or NE, to varying extents (see Chapter 3)

Fight-or-Flight Response. Epinephrine and NE produce

widespread effects on the cardiovascular system, muscular

system, and carbohydrate and lipid metabolism in liver,

muscle, and adipose tissues In response to a sudden rise in

catecholamines in the blood, the heart rate accelerates,

coronary blood vessels dilate, and blood flow to the

skele-tal muscles is increased as a result of vasodilation (but

vaso-constriction occurs in the skin) Smooth muscles in the

air-ways of the lungs, gastrointestinal tract, and urinary

bladder relax Muscles in the hair follicles contract, causing

piloerection Blood glucose level also rises This overall

re-action to the sudden release of catecholamines is known as

the fight-or-flight response (see Chapter 6)

Catecholamines and the Metabolic Response to

Hypo-glycemia. Catecholamines secreted by the adrenal

medulla and NE released from sympathetic postganglionic

nerve terminals are key agents in the body’s defense

against hypoglycemia Catecholamine release usually

starts when the blood glucose concentration falls to the

low end of the physiological range (60 to 70 mg/dL) A

fur-ther decline in blood glucose concentration into the

hy-poglycemic range produces marked catecholamine release

Hypoglycemia can result from a variety of situations, such

as insulin overdosing, catecholamine antagonists, or drugs

that block fatty acid oxidation Hypoglycemia is always a

dangerous condition because the CNS will die of ATP

deprivation in extended cases The length of time

pro-found hypoglycemia can be tolerated depends on its ity and the individual’s sensitivity

sever-When the blood glucose concentration drops towardthe hypoglycemic range, CNS receptors monitoring bloodglucose are activated, stimulating the neural pathway lead-ing to the fibers innervating the chromaffin cells As a re-sult, the adrenal medulla discharges catecholamines Sym-pathetic postganglionic nerve terminals also releasenorepinephrine

Catecholamines act on the liver to stimulate glucoseproduction They activate glycogen phosphorylase, result-ing in the hydrolysis of stored glycogen, and stimulate glu-coneogenesis from lactate and amino acids Cate-cholamines also activate glycogen phosphorylase inskeletal muscle and adipose cells by interacting with ␤ re-ceptors, activating adenylyl cyclase and increasing cAMP

in the cells The elevated cAMP activates glycogen phorylase The glucose 6-phosphate generated in thesecells is metabolized, although glucose is not released intothe blood, since the cells lack glucose-6-phosphatase Theglucose 6-phosphate in muscle is converted by glycolysis

phos-to lactate, much of which is released inphos-to the blood Thelactate taken up by the liver is converted to glucose via glu-coneogenesis and returned to the blood

In adipose cells, the rise in cAMP produced by cholamines activates hormone-sensitive lipase, causing thehydrolysis of triglycerides and the release of fatty acids andglycerol into the bloodstream These fatty acids provide analternative substrate for energy metabolism in other tissues,primarily skeletal muscle, and block the phosphorylationand metabolism of glucose

cate-During profound hypoglycemia, the rapid rise in bloodcatecholamine levels triggers some of the same metabolicadjustments that occur more slowly during fasting Duringfasting, these adjustments are triggered mainly in response

to the gradual rise in the ratio of glucagon to insulin in theblood The ratio also rises during profound hypoglycemia,reinforcing the actions of the catecholamines onglycogenolysis, gluconeogenesis, and lipolysis The cate-cholamines released during hypoglycemia are thought to

be partly responsible for the rise in the glucagon-to-insulinratio by directly influencing the secretion of these hor-mones by the pancreas Catecholamines stimulate the se-cretion of glucagon by the alpha cells and inhibit the se-cretion of insulin by beta cells (see Chapter 35) Thesecatecholamine-mediated responses to hypoglycemia aresummarized in Table 34.4

TABLE 34.4 Catecholamine-Mediated Responses

to Hypoglycemia

Liver Stimulation of glycogenolysis

Stimulation of gluconeogenesis Skeletal muscle Simulation of glycogenolysis Adipose tissue Simulation of glycogenolysis

Stimulation of triglyceride lipolysis Pancreatic islets Inhibition of insulin secretion by beta cells

Stimulation of glucagon secretion by alpha cells

DIRECTIONS: Each of the numbered

items or incomplete statements in this

section is followed by answers or by

completions of the statement Select the

ONE lettered answer or completion that is

the BEST in each case.

1 Which of the following sources of

cholesterol is most important for

sustaining adrenal steroidogenesis

when it occurs at a high rate for a long

(D) Cholesterol in lipid droplets within

adrenal cortical cells

(E) Cholesterol from the endoplasmic

reticulum

(F) Cholesterol in lipid droplets within

adrenal medullary cells

2 A 7-year-old boy comes to the

pediatric endocrine unit for evaluation

of excess body weight Review of his

growth charts indicates substantial

weight gain over the previous 3 years

but little increase in height To

differentiate between the development

of obesity and Cushing’s disease, blood

and urine samples are taken Which of

the following would be most

diagnostic of Cushing’s disease?

(A) Increased serum ACTH, decreased

serum cortisol, and increased urinary

free cortisol

(B) Decreased serum ACTH, increased

serum cortisol, and increased serum

insulin

(C) Increased serum ACTH, increased

serum cortisol, and increased serum

insulin

(D) Increased serum ACTH, decreased

serum cortisol, and decreased serum

insulin

(E) Increased serum ACTH, decreased

serum cortisol, and decreased urinary

free cortisol

(F) Decreased serum ACTH, decreased

serum cortisol, and increased serum

(E) Cushing’s disease

(F) Defects in aldosterone synthase

4 What is the mechanism through which catecholamines stabilize blood glucose concentration in response to

hypoglycemia?

(A) Catecholamines stimulate glycogen phosphorylase to release glucose from muscle

(B) Catecholamines inhibit glycogenolysis in the liver (C) Catecholamines stimulate the release of insulin from the pancreas (D) Catecholamines inhibit the release

of fatty acids from adipose tissue (E) Catecholamines stimulate gluconeogenesis in the liver (F) Catecholamines inhibit the release

of lactate from muscle

5 A patient receiving long-term glucocorticoid therapy plans to undergo hip replacement surgery.

What would the physician recommend prior to surgery and why?

(A) Glucocorticoids should be decreased to prevent serious hypoglycemia during recovery (B) Glucocorticoids should be increased to stimulate immune function and prevent possible infection (C) Glucocorticoids should be decreased to minimize potential interactions with anesthetics (D) Glucocorticoids should be increased to stimulate ACTH secretion during surgery to promote wound healing

(E) Glucocorticoids should be decreased to prevent inadequate vascular response to catecholamines during recovery

(F) Glucocorticoids should be increased to compensate for the increased stress associated with surgery

6 Which of the following is most likely

to result in a decreased rate of aldosterone release?

(A) An increase in renin secretion by the kidney

(B) A rise in serum potassium (C) A fall in blood pressure in the kidney

(D) A decrease in tubule fluid sodium concentration at the macula densa (E) An increase in renal sympathetic nerve activity

(F) A decrease in IP3 in cells of the zona glomerulosa

7 The rate-limiting step in the synthesis

of cortisol is catalyzed by (A) 21-Hydroxylase (B) 3 ␤-Hydroxysteroid dehydrogenase

(C) Cholesterol side-chain cleavage enzyme

(D) 11 ␤-Hydroxylase (E) 3-Hydroxy-3-methylglutaryl CoA reductase

(F) 17 ␣-Hydroxylase

8 A patient complains of generalized weakness and fatigue, anorexia, and weight loss associated with gastrointestinal symptoms (nausea, vomiting) Physical examination notes hyperpigmentation and hypotension Laboratory findings include

hyponatremia (low plasma sodium) and hyperkalemia (high plasma potassium) The most likely diagnosis is

(A) Cushing’s disease (B) Addison’s disease (C) Primary hypoaldosteronism (D) Congenital adrenal hyperplasia (E) Hypopituitarism

(F) Glucocorticoid-suppressible hyperaldosteronism

9 Through what “permissive action” do glucocorticoids accelerate

gluconeogenesis during fasting? (A) Glucocorticoids stimulate the secretion of insulin, which activates gluconeogenic enzymes in the liver (B) Glucocorticoids inhibit the use of glucose by skeletal muscle

(C) Glucocorticoids maintain the vascular response to norepinephrine (D) Glucocorticoids inhibit glycogenolysis

(E) Glucocorticoids maintain the intracellular concentrations of many of the enzymes needed to carry out gluconeogenesis through effects on transcription

(F) Glucocorticoids inhibit the release

of fatty acids from adipose tissue

S U G G E S T E D R E A D I N G

Bornstein SR, Chrousos GP Clinical view 104 Adrenocorticotropin (ACTH)- and non-ACTH-mediated regulation of the adrenal cortex: Neural and immune inputs J Clin Endocrinol Metab 1999;84:1729–1736.

re-Lumbers ER Angiotensin and aldosterone Regul Pept 1999;80:91–100

Miller WL: Early steps in androgen biosynthesis: From cholesterol to DHEA Baillieres Clin Endocrinol Metab 1998;12:67–81.

Nordenstrom A, Thilen A, Hagenfeldt L, Larsson A, Wedell A Genotyping is a valuable diagnostic complement to neonatal screening for congenital adre- nal hyperplasia due to steroid 21-hy- droxylase deficiency J Clin Endocrinol Metab 1999;84:1505–1509.

R E V I E W Q U E S T I O N S

(continued)

Orth DN, Kovacs WJ The adrenal cortex.

In: Wilson JD, Foster DW,

Kronen-berg HM, Larsen PR, eds Williams

Textbook of Endocrinology 9th

Ed Philadelphia: WB Saunders,

1998.

Sapolsky RM, Romero LM, Munck AU.

How do glucocorticoids influence stress responses? Integrating permis- sive, suppressive, stimulatory, and preparative actions Endocr Rev 2000;21:55–89.

Young JB, Landsberg L Catecholamines and the adrenal medulla In: Wilson

JD, Foster DW, Kronenberg

HM, Larsen PR, eds: Williams book of Endocrinology 9th Ed Philadelphia: WB Saunders, 1998.

Text-The Endocrine Pancreas

Daniel E Peavy, Ph.D.

35

C H A P T E R

35

The development of mechanisms for the storage of large

amounts of metabolic fuel was an important adaptation

in the evolution of complex organisms The processes

in-volved in the digestion, storage, and use of fuels require a

high degree of regulation and coordination The pancreas,

which plays a vital role in these processes, consists of two

functionally different groups of cells

Cells of the exocrine pancreas produce and secrete

di-gestive enzymes and fluids into the upper part of the small

intestine The endocrine pancreas, an anatomically small

portion of the pancreas (1 to 2% of the total mass),

pro-duces hormones involved in regulating fuel storage and use

For convenience, functions of the exocrine and

en-docrine portions of the pancreas are usually discussed

sep-arately While this chapter focuses primarily on hormones

of the endocrine pancreas, the overall function of the

pan-creas is to coordinate and direct a wide variety of processes

related to the digestion, uptake, and use of metabolic fuels

SYNTHESIS AND SECRETION OF THE

ISLET HORMONES

The endocrine pancreas consists of numerous discrete

clusters of cells, known as the islets of Langerhans, which

are located throughout the pancreatic mass The isletscontain specific types of cells responsible for the secretion

of the hormones insulin, glucagon, and somatostatin cretion of these hormones is regulated by a variety of cir-culating nutrients

Se-The Islets of Langerhans Are the Functional Units of the Endocrine Pancreas

The islets of Langerhans contain from a few hundred to

sev-eral thousand hormone-secreting endocrine cells The isletsare found throughout the pancreas but are most abundant inthe tail region of the gland The human pancreas contains,

on average, about 1 million islets, which vary in size from 50

to 300 ␮m in diameter Each islet is separated from the rounding acinar tissue by a connective tissue sheath

sur-Islets are composed of four hormone-producing celltypes: insulin-secreting beta cells, glucagon-secreting alphacells, somatostatin-secreting delta cells, and pancreaticpolypeptide-secreting F cells Immunofluorescent stainingtechniques have shown that the four cell types are arranged

in each islet in a pattern suggesting a highly organized lular community, in which paracrine influences may play animportant role in determining hormone secretion rates (Fig 35.1) Further evidence that cell-to-cell communica-

cel-■SYNTHESIS AND SECRETION OF THE ISLET

HORMONES

■METABOLIC EFFECTS OF INSULIN AND GLUCAGON

■DIABETES MELLITUS

C H A P T E R O U T L I N E

1 The relative distribution of alpha, beta, and delta cells

within each islet of Langerhans shows a distinctive pattern

and suggests that there may be some paracrine regulation

of secretion.

2 Plasma glucose is the primary physiological regulator of

insulin and glucagon secretion, but amino acids, fatty

acids, and some GI hormones also play a role.

3 Insulin has anabolic effects on carbohydrate, lipid, and

pro-tein metabolism in its target tissues, where it promotes the

storage of nutrients.

4 Effects of glucagon on carbohydrate, lipid, and protein tabolism occur primarily in the liver and are catabolic in nature.

me-5 Type 1 diabetes mellitus results from the destruction of beta cells, whereas type 2 diabetes often results from a lack of responsiveness to circulating insulin.

6 Diabetes mellitus may produce both acute complications, such as ketoacidosis, and chronic secondary complica- tions, such as peripheral vascular disease, neuropathy, and nephropathy.

K E Y C O N C E P T S

623

tion within the islet may play a role in regulating hormone

secretion comes from the finding that islet cells have both

gap junctions and tight junctions Gap junctions link

dif-ferent cell types in the islets cells and potentially provide a

means for the transfer of ions, nucleotides, or electrical

cur-rent between cells The presence of tight junctions between

outer membrane leaflets of contiguous cells could result in

the formation of microdomains in the interstitial space,

which may also be important for paracrine communication

Although the existence of gap junctions and tight junctions

in pancreatic islets is well documented, their exact function

has not been fully defined

The arrangement of the vascular supply to islets is also

consistent with paracrine involvement in regulating islet

se-cretion Afferent blood vessels penetrate nearly to the

cen-ter of the islet before branching out and returning to the

surface of the islet The innermost cells of the islet,

there-fore, receive arterial blood, while those cells nearer the

sur-face receive blood-containing secretions from inner cells

Since there is a definite anatomical arrangement of cells in

the islet (see Fig 35.1), one cell type could affect the

se-cretion of others In general, the effluent from smaller islets

passes through neighboring pancreatic acinar tissue before

entering into the hepatic portal venous system By contrast,

the effluent from larger islets passes directly into the

ve-nous system without first perfusing adjacent acinar tissue

Therefore, islet hormones arrive in high concentrations insome areas of the exocrine pancreas before reaching pe-ripheral tissues However, the exact physiological signifi-cance of these arrangements is unknown

Neural inputs also influence islet cell hormone secretion.Islet cells receive sympathetic and parasympathetic inner-vation Responses to neural input occur as a result of acti-vation of various adrenergic and cholinergic receptors (de-scribed below) Neuropeptides released together with theneurotransmitters may also be involved in regulating hor-mone secretion

Beta Cells. In the early 1900s, M A Lane established ahistochemical method by which two kinds of islet cellscould be distinguished He found that alcohol-based fixa-tives dissolved the secretory granules in most of the isletcells but preserved them in a small minority of cells Water-based fixatives had the opposite effect.He named cells con-taining alcohol-insoluble granules A cells or alpha cells andthose containing alcohol-soluble granules B cells or betacells Many years later, other investigators used immuno-fluorescence techniques to demonstrate that beta cells pro-duce insulin and alpha cells produce glucagon

Insulin-secreting beta cells are the most numerous cell

type of the islet, comprising 70 to 90% of the endocrinecells Beta cells typically occupy the most central space ofthe islets (see Fig 35.1) They are generally 10 to 15 ␮m

in diameter and contain secretory granules that measure0.25␮m

Alpha Cells. Alpha cells comprise most of the remaining

cells of the islets They are generally located near the riphery, where they form a cortex of cells surrounding themore centrally located beta cells Blood vessels passthrough the outer zone of the islet before extensive branch-ing occurs Inward extensions of the cortex may be presentalong the axes of blood vessels toward the center of theislet, giving the appearance that the islet is subdivided intosmall lobules

pe-Delta Cells. Delta cells are the sites of production of

so-matostatin in the pancreas These cells are typically located

in the periphery of the islet, often between beta cells andthe surrounding mantle of alpha cells Somatostatin pro-duced by pancreatic delta cells is identical to that previ-ously described in a neurotransmitter role (see Chapter 3)and as a hypothalamic hormone that inhibits growth hor-mone secretion by the anterior pituitary (see Chapter 32)

F Cells. F cells are the least abundant of the

hormone-se-creting cells of islets, representing only about 1% of the tal cell population The distribution of F cells is generally

to-similar to that of delta cells F cells secrete pancreatic

Alpha cells

Delta cells

Beta cells

(Glucagon) (Somatostatin) (Insulin)

Major cell types in a typical islet of hans.Note the distinct anatomical arrange- ment of the various cell types (Modified from Orci L, Unger RH.

Langer-Functional subdivision of islets of Langerhans and possible role of

D cells Lancet 1975;2:1243–1244.)

FIGURE 35.1

Proinsulin Synthesis. The gene for insulin is located on

the short arm of chromosome 11 in humans Like other

hormones and secretory proteins, insulin is first

synthe-sized by ribosomes of the rough ER as a larger precursor

peptide that is then converted to the mature hormone prior

to secretion (see Chapter 31)

The insulin gene product is a 110-amino acid peptide,

preproinsulin Proinsulin consists of 86 amino acids

(Fig 35.2); residues 1 to 30 constitute what will form the B

chain of insulin, residues 31 to 65 form the connecting

pep-tide, and residues 66 to 86 constitute the A chain (Note

that “connecting peptide” should not be confused with

“C-peptide.”) In the process of converting proinsulin to insulin,

two pairs of basic amino acid residues are clipped out of the

proinsulin molecule, resulting in the formation of insulin

and C-peptide, which are ultimately secreted from the beta

cell in equimolar amounts

It is of clinical significance that insulin and C-peptide

are co-secreted in equal amounts Measurements of

circu-lating C-peptide levels may sometimes provide important

information regarding beta cell secretory capacity that

could not be obtained by measuring circulating insulin

lev-els alone

Insulin Secretion. Table 35.1 lists the physiologically

relevant regulators of insulin secretion As indicated

previ-ously, an elevated blood glucose level is the most importantregulator of insulin secretion In humans, the thresholdvalue for glucose-stimulated insulin secretion is a plasmaglucose concentration of approximately 100 mg/dL (5.6mmol/L)

Based on studies using isolated animal pancreas

prepara-tions maintained in vitro, it has been determined that insulin

is secreted in a biphasic manner in response to a marked crease in blood glucose An initial burst of insulin secretionmay last 5 to 15 minutes, resulting from the secretion ofpreformed insulin secretory granules This response is fol-lowed by more gradual and sustained insulin secretion thatresults largely from the synthesis of new insulin molecules

in-In addition to glucose, several other factors serve as portant regulators of insulin secretion (see Table 35.1).These include dietary constituents, such as amino acids andfatty acids, as well as hormones and drugs Among theamino acids, arginine is the most potent secretagogue forinsulin Among the fatty acids, long-chain fatty acids (16 to

im-18 carbons) generally are considered the most potent ulators of insulin secretion Several hormones secreted bythe gastrointestinal tract, including gastric inhibitory pep-tide (GIP), gastrin, and secretin, promote insulin secretion

stim-An oral dose of glucose produces a greater increment in sulin secretion than an equivalent intravenous dose becauseoral glucose promotes the secretion of GI hormones that

augment insulin secretion by the pancreas Direct infusion

of acetylcholine into the pancreatic circulation stimulates

insulin secretion, reflecting the role of parasympathetic

in-nervation in regulating insulin secretion Sulfonylureas, a

class of drugs used orally in the treatment of type 2

dia-betes, promote insulin’s action in peripheral tissues but also

directly stimulate insulin secretion

In addition to factors that stimulate insulin secretion,

there are several potent inhibitors Exogenously

adminis-tered somatostatin is a strong inhibitor It is presumed that

pancreatic somatostatin plays a role in regulating insulin

se-cretion, but the importance of this effect has not been fully

established Epinephrine and norepinephrine, the primary

catecholamines, are also potent inhibitors of insulin

secre-tion This response would appear appropriate because

dur-ing periods of stress and high catecholamine secretion, the

desired response is mobilization of glucose and other

nutri-ent stores Insulin generally promotes the opposite

re-sponse, and by inhibiting insulin secretion, the

cate-cholamines produce their full effect without the opposing

actions of insulin

Decreased Blood Glucose Stimulates

the Secretion of Glucagon

Similar to insulin, glucagon is first synthesized as part of a

larger precursor protein Glucagon secretion is regulated by

many of the factors that also regulate insulin secretion In

most cases, however, these factors have the opposite effect

on glucagon secretion

Synthesis of Proglucagon. Glucagon is a simple 29-amino

acid peptide The initial gene product for glucagon,

pre-proglucagon, is a much larger peptide Like other peptide

hormones, the “pre” piece is removed in the ER, and the

pro-hormone is converted into a mature pro-hormone as it is

pack-aged and processed in secretory granules (see Chapter 31)

Secretion of Glucagon. The principal factors that

influ-ence glucagon secretion are listed in Table 35.2 With a few

exceptions, this table is nearly a mirror image of Table 35.1,

the factors that regulate insulin secretion The primary

reg-ulator of glucagon secretion is blood glucose; specifically, a

decrease in blood glucose below about 100 mg/dL

pro-motes glucagon secretion As with insulin, amino acids,

es-pecially arginine, are potent stimulators of glucagon tion Somatostatin inhibits glucagon secretion, as it doesinsulin secretion

secre-Increased Blood Glucose and Glucagon Stimulate the Secretion of Somatostatin

Somatostatin is first synthesized as a larger peptide sor, preprosomatostatin The hypothalamus also producesthis protein, but the regulation of somatostatin secretionfrom the hypothalamus is independent of that from thepancreatic delta cells Upon insertion of preprosomato-statin into the rough ER, it is initially cleaved and converted

precur-to prosomaprecur-tostatin The prohormone is converted inprecur-to tive hormone during packaging and processing in the Golgiapparatus

ac-Factors that stimulate pancreatic somatostatin secretioninclude hyperglycemia, glucagon, and amino acids Glu-cose and glucagon are generally considered the most im-portant regulators of somatostatin secretion

The exact role of somatostatin in regulating islet mone secretion has not been fully established Somato-statin clearly inhibits both glucagon and insulin secretionfrom the alpha and beta cells of the pancreas, respectively,when it is given exogenously The anatomic and vascularrelationships of delta cells to alpha and beta cells furthersuggest that somatostatin may play a role in regulating bothglucagon and insulin secretion Although many of the dataare circumstantial, it is generally accepted that somato-statin plays a paracrine role in regulating insulin andglucagon secretion from the pancreas

hor-METABOLIC EFFECTS OF INSULIN AND GLUCAGON

The endocrine pancreas secretes hormones that direct thestorage and use of fuels during times of nutrient abundance(fed state) and nutrient deficiency (fasting) Insulin is se-creted in the fed state and is called the “hormone of nutri-ent abundance.” By contrast, glucagon is secreted in re-sponse to an overall deficit in nutrient supply These twohormones play an important role in directing the flow ofmetabolic fuels

TABLE 35.1 Factors Regulating Insulin Secretion

from the Pancreas

Stimulatory agents or Hyperglycemia

conditions Amino acids

Fatty acids, especially long-chain Gastrointestinal hormones, especially gastric inhibitory peptide (GIP), gastrin, and secretin

Acetylcholine Sulfonylureas Inhibitory agents or Somatostatin

conditions Norepinephrine

Epinephrine

TABLE 35.2 Factors Regulating Glucagon

Se-cretion From the Pancreas

Stimulatory agents or conditions Hypoglycemia

Amino acids Acetylcholine Norepinephrine Epinephrine Inhibitory agents or conditions Fatty acids

Somatostatin Insulin

Insulin Affects the Metabolism of Carbohydrates,

Lipids, and Proteins in Liver, Muscle, and

Adipose Tissues

The primary targets for insulin are liver, skeletal muscle, and

adipose tissues Insulin has multiple individual actions in

each of these tissues, the net result of which is fuel storage

Mechanism of Insulin Action. Although insulin was one of

the first peptide hormones to be identified, isolated, and

characterized, its exact mechanism of action remains elusive

The insulin receptor is a heterotetramer, consisting of a pair

of␣/␤ subunit complexes held together by disulfide bonds

(Fig 35.3) The ␣ subunit is an extracellular protein

contain-ing the insulin-bindcontain-ing component of the receptor The ␤

subunit is a transmembrane protein that couples the

extra-cellular event of insulin binding to its intraextra-cellular actions

Activation of the ␤ subunit of the insulin receptor results

in autophosphorylation, involving the phosphorylation of

a few selected tyrosine residues in the intracellular portion

of the receptor This event further activates the tyrosine

ki-nase portion of the ␤ subunit, leading to tyrosine

phospho-rylation of specific intracellular substrates A cascade of

events follows, leading to the pleiotropic actions of insulin

in its target cells While tyrosine phosphorylation events

appear to be the early steps in insulin action,

serine/threo-nine phosphorylation or dephosphorylation is involved in

many of the final steps of insulin action

Insulin and Glucose Transport. Perhaps one of the most

important functions of insulin is to promote the uptake of

glucose from blood into cells Glucose uptake into many

cell types is by facilitated diffusion A specific cell

mem-brane carrier is involved but no energy is required, and the

process cannot move glucose against a concentration

gra-dient The carriers shuttle glucose across the membranefaster than would occur by diffusion alone Considerablerecent work has revealed not just one transporter, but afamily of about seven different glucose transporters(GLUT), commonly called GLUT 1 to GLUT 7 Thesetransporters are expressed in different tissues and, in somecases, at different times during fetal development

GLUT 4, the insulin-stimulated glucose transporter, isthe primary form of the transporter present in skeletal mus-cle tissue and adipose tissue It is present in plasma mem-branes and in intracellular vesicles of the smooth ER In tar-get cells, the effect of insulin is to promote thetranslocation of GLUT 4 transporters from the intracellularpool into plasma membranes As a result, more transportersare available in the plasma membrane, and glucose uptake

by target cells is, thereby, increased

Insulin and the Synthesis of Glycogen. Besides ing glucose uptake into target cells, insulin promotes itsstorage Glucose carbon is stored in the body in two pri-mary forms: as glycogen and (by metabolic conversion) astriglycerides Glycogen is a short-term storage form thatplays an important role in maintaining normal blood glu-cose levels The primary glycogen storage sites are the liverand skeletal muscle; other tissues, such as adipose tissue,also store glycogen but in quantitatively small amounts In-sulin promotes glycogen storage primarily through two en-

promot-zymes (Fig 35.4) It activates glycogen synthase by

pro-moting its dephosphorylation and concomitantly

inactivates glycogen phosphorylase, also by promoting its

dephosphorylation The result is that glycogen synthesis ispromoted and glycogen breakdown is inhibited

Insulin and Glycolysis. Insulin also enhances glycolysis

In addition to increasing glucose uptake and providing amass action stimulus for glycolysis, insulin activates the en-zymes glucokinase and hexokinase and phosphofructoki-nase, pyruvate kinase, and pyruvate dehydrogenase of theglycolytic pathway (see Fig 35.4)

Lipogenic and Antilipolytic Effects of Insulin. In adiposetissue and liver tissue, insulin promotes lipogenesis and in-hibits lipolysis (Fig 35.5) Insulin has similar actions inmuscle, but since muscle is not a major site of lipid storage,the discussion here focuses on actions in adipose tissue andthe liver By promoting the flow of intermediates throughglycolysis, insulin promotes the formation of ␣-glycerolphosphate and fatty acids necessary for triglyceride forma-tion In addition, it stimulates fatty acid synthase, leadingdirectly to increased fatty acid synthesis Insulin inhibitsthe breakdown of triglycerides by inhibiting hormone-sen-sitive lipase, which is activated by a variety of counterreg-ulatory hormones, such as epinephrine and adrenal gluco-corticoids By inhibiting this enzyme, insulin promotes theaccumulation of triglycerides in adipose tissue

In addition to promoting de novo fatty acid synthesis in

adipose tissue, insulin increases the activity of lipoproteinlipase, which plays a role in the uptake of fatty acids fromthe blood into adipose tissue As a result, lipoproteins syn-thesized in the liver are taken up by adipose tissue, andfatty acids are ultimately stored as triglycerides

S S

S S

of two extracellular insulin-binding ␣ subunits linked by disulfide

bonds to two transmembrane ␤ subunits The ␤ subunits contain

an intrinsic tyrosine kinase that is activated upon insulin binding

to the ␣ subunit.

FIGURE 35.3

Effects of Insulin on Protein Synthesis and Protein

Degra-dation. Insulin promotes protein accumulation in its

pri-mary target tissues—liver, adipose tissue, and muscle—in

three specific ways (Fig 35.6) First, it stimulates amino acid

uptake Second, it increases the activity of several factors

in-volved in protein synthesis For example, it increases the

ac-tivity of protein synthesis initiation factors, promoting the

start of translation and increasing the efficiency of protein

synthesis Insulin also increases the amount of protein thesis machinery in cells by promoting ribosome synthesis.Third, insulin inhibits protein degradation by reducing lyso-some activity and possibly other mechanisms as well

syn-Glucagon Primarily Affects the Liver Metabolism

of Carbohydrates, Lipids, and Proteins

The primary physiological actions of glucagon are exerted

in the liver Numerous effects of glucagon have been mented in other tissues, primarily adipose tissue, when thehormone has been added at high, nonphysiological con-centrations in experimental situations While these effectsmay play a role in certain abnormal situations, the normaldaily effects of glucagon occur primarily in the liver.Mechanism of Glucagon Action. Glucagon initiates itsbiological effects by interacting with one or more types of

docu-cell membrane receptors Glucagon receptors are coupled

to G proteins and promote increased intracellular cAMP,via the activation of adenylyl cyclase, or elevated cytosoliccalcium as a result of phospholipid breakdown to form IP3.Glucagon and Glycogenolysis. Glucagon is an impor-tant regulator of hepatic glycogen metabolism It produces

a net effect of glycogen breakdown by increasing lular cAMP levels, initiating a cascade of phosphorylationevents that ultimately results in the phosphorylation ofphosphorylase b and its activation by conversion intophosphorylase a Similarly, glucagon promotes the netbreakdown of glycogen by promoting the inactivation ofglycogen synthase (Fig 35.7)

intracel-Glucagon and Gluconeogenesis. In addition to ing hepatic glucose production by stimulating glycogenol-ysis, glucagon stimulates hepatic gluconeogenesis (Fig.35.8) It does this principally by increasing the transcrip-tion of mRNA coding for the enzyme phosphoenolpyru-vate carboxykinase (PEPCK), a key rate-limiting enzyme ingluconeogenesis Glucagon also stimulates amino acid

promot-Glycogen

Glucose 6-phosphate

Citric acid cycle

Glucose

Glucokinase

hexokinase

Glycogen synthase

Glycogen phosphorylase

Insulin stimulation of glycogen synthesis and glucose metabolism Insulin promotes glucose uptake into target tissues, stimulates glycogen synthesis,

and inhibits glycogenolysis In addition it promotes glycolysis in

its target tissues Heavy arrows indicate processes stimulated by

insulin; light arrows indicate processes inhibited by insulin.

Effects of insulin on lipid metabolism in adipocytes.Insulin promotes the accumulation

of lipid (triglycerides) in adipocytes by stimulating the processes

shown by the heavy arrows and inhibiting the processes shown

by the light arrows Similar stimulatory and inhibitory effects

oc-cur in liver cells.

FIGURE 35.5

Amino acids

Amino acids Protein

Protein degradation

Protein synthesis

LIVER CELL, MUSCLE CELL, ADIPOCYTE Effects of insulin on protein synthesis and protein degradation Insulin promotes the ac- cumulation of protein by stimulating (heavy arrows) amino acid uptake and protein synthesis and by inhibiting (light arrows) pro- tein degradation in liver, skeletal muscle, and adipose tissue.

FIGURE 35.6

transport into liver cells and the degradation of hepatic

proteins, helping provide substrates for gluconeogenesis

Glucagon and Ureagenesis. The glucagon-enhanced

conversion of amino acids into glucose leads to increased

formation of ammonia Glucagon assists in the disposal of

ammonia by increasing the activity of the urea cycle

en-zymes in liver cells (see Fig 35.8)

Glucagon and Lipolysis. Glucagon promotes lipolysis in

liver cells (Fig 35.9), although the quantity of lipids stored

in liver is small compared to that in adipose tissue

Glucagon and Ketogenesis. Glucagon promotes esis, the production of ketones, by lowering the levels of mal-onyl CoA, relieving an inhibition of palmitoyl transferaseand allowing fatty acids to enter the mitochondria for oxida-tion to ketones (see Fig 35.9) Ketones are an importantsource of fuel for muscle cells and heart cells during times ofstarvation, sparing blood glucose for other tissues that areobligate glucose users, such as the central nervous system.During prolonged starvation, the brain adapts its metabolism

ketogen-to use keketogen-tones as a fuel source, lessening the overall need forhepatic glucose production (see Chapter 34)

The Insulin-Glucagon Ratio Determines Metabolic Status

In most instances, insulin and glucagon produce opposingeffects Therefore, the net physiological response is deter-mined by the relative levels of both hormones in the blood

plasma, the insulin-glucagon ratio (I/G ratio).

I/G Ratio in the Fed and Fasting States. The I/G ratiomay vary 100-fold or more because the plasma concentra-tion of each hormone can vary considerably in different nu-tritional states In the fed state, the molar I/G ratio is ap-proximately 30 After an overnight fast, it may fall to about

2, and with prolonged fasting, it may fall to as low as 0.5.Inappropriate I/G Ratios in Diabetes. A good example ofthe profound influence of the I/G ratio on metabolic status

is in insulin-deficient diabetes Insulin levels are low, sopathways that insulin stimulates operate at a reduced level

Glycogen synthase

Glycogen phosphorylase Glycogen

LIVER CELL

Glucose phosphate

6-The role of glucagon in glycogenolysis and glucose production in liver cells Heavy ar- rows indicate processes stimulated by glucagon; light arrows indi-

cate processes inhibited by glucagon.

Ammonia

Protein synthesis

Protein degradation Urea

synthesis

genesis

processes inhibited by glucagon.

FIGURE 35.8

LIVER CELL

sensitive lipase

Hormone-Glycerol Ketogenesis

Ketones

Fatty acids

Fatty acids

Glucose

Triglycerides α-Glycerol phosphate

Ketones

Acetyl CoA

The role of glucagon in lipolysis and genesis in liver cells Heavy arrows indicate processes stimulated by glucagon; light arrows indicate processes inhibited by glucagon.

keto-FIGURE 35.9

However, insulin is also necessary for alpha cells to sense

blood glucose appropriately; in the absence of insulin, the

secretion of glucagon is inappropriately elevated The

re-sult is an imbalance in the I/G ratio and an accentuation of

glucagon effects well above what would be seen in normal

states of low insulin, such as in fasting

DIABETES MELLITUS

Diabetes mellitus is a disease of metabolic dysregulation—

most notably a dysregulation of glucose

metabolism—ac-companied by long-term vascular and neurological

complica-tions Diabetes has several clinical forms, each of which has a

distinct etiology, clinical presentation, and course Insights

into diabetes and its complications have been gleaned from

extensive metabolic studies, the use of radioimmunoassays for

insulin and glucagon, and the application of molecular

biol-ogy strategies Diabetes is the most common endocrine

dis-order Some 16 million people may have the disease in the

United States; the exact number is not known because many

people have a borderline, subclinical form of the disorder

Many deaths attributed to cardiovascular disease are in fact

the result of complications from diabetes

Diagnosing diabetes mellitus is not difficult to do

Symptoms usually include frequent urination, increased

thirst, increased food consumption, and weight loss The

standard criterion for a diagnosis of diabetes is an elevated

plasma glucose level after an overnight fast on at least two

separate occasions A glucose value above 126 mg/dL (7.0

mmol/L) is often used as the diagnostic value

Diabetes mellitus is a heterogeneous disorder The

causes, symptoms, and general medical outcomes are

vari-able Generally, the disease takes one of two forms, type 1

diabetes or type 2 diabetes Other forms of diabetes, such

as gestational diabetes, are also well known.

Most Forms of Type 1 Diabetes Mellitus

Involve an Autoimmune Disorder

Type 1 diabetes is characterized by the inability of beta

cells to produce physiologically appropriate amounts of

in-sulin In some instances, this may result from a mutation in

the preproinsulin gene However, the most common form

of type 1 diabetes results from destruction of the pancreatic

beta cells by the immune system The initial pathological

event is insulitis, involving a lymphocytic attack on beta

cells Antibodies to beta cell cell-surface antigens have also

been found in the circulation of many persons with type 1

diabetes, but this is not a primary causative factor and

prob-ably results from the initial cellular damage

Studies of identical twins have provided important

in-formation regarding the genetic basis of type 1 diabetes If

one twin develops type 1 diabetes, the odds that the second

will develop the disease are much higher than for any

ran-dom individual in the population, even when the twins are

raised apart under different socioeconomic conditions In

addition, individuals with certain cell-surface HLA antigens

bear a higher risk for the disease than others

Environmental factors are involved as well because the

development of type 1 diabetes in one twin predicts only a

50% or less chance that the second will develop the ease The specific environmental factors have not beenidentified, although much evidence implicates viruses.Therefore, it appears that a combination of genetics andenvironment are strong contributing factors to the devel-opment of type 1 diabetes

dis-Because the primary defect in type 1 diabetes is the ability of beta cells to secrete adequate amounts of insulin,these patients must be treated with injections of insulin In

in-an attempt to match insulin concentrations in the bloodwith the metabolic requirements of the individual, variousformulations of insulin with different durations of actionhave been developed Patients inject an appropriateamount of these different insulin forms to match their di-etary and lifestyle requirements

The long-term control of type 1 diabetes depends onmaintaining a balance between three factors: insulin, diet,and exercise To strictly control their blood glucose, pa-tients are advised to monitor their diet and level of physicalactivity, as well as their insulin dosage Exercise per se,much like insulin, increases glucose uptake by muscle Dia-betic patients must take this into account and make appro-priate adjustments in diet or insulin whenever general exer-cise levels change dramatically

Type 2 Diabetes Mellitus Primarily Originates

in the Target Tissue

Type 2 diabetes mellitus results primarily from impairedability of target tissues to respond to insulin There aremultiple forms of the disease, each with a different etiol-ogy In some cases, it is a permanent, lifelong disorder; inothers, it results from the secretion of counterregulatoryhormones in a normal (e.g., pregnant) or pathophysio-

logical (e.g., Cushing’s disease) state Gestational

dia-betes occurs in 2 to 5% of all pregnancies but usually

dis-appears after delivery Women who have had gestationaldiabetes have an increased risk of developing type 2 dia-betes later in life

Insulin Resistance in Type 2 Diabetes. In most cases oftype 2 diabetes, normal or higher-than-normal amounts ofinsulin are present in the circulation Therefore, there is noimpairment in the secretory capacity of pancreatic betacells but only in the ability of target cells to respond to in-sulin In some instances, it has been demonstrated that thefundamental defect is in the insulin receptor In most cases,however, receptor function appears normal, and the im-pairment in insulin action is ascribed to a postreceptor de-fect Since the exact mechanism of insulin action has notbeen determined, it is difficult to explore the causes of in-sulin resistance in much greater depth

Genetics, Environment, and Type 2 Diabetes. As withtype 1 diabetes, key information on the influence of genet-ics and environmental factors in type 2 diabetes comesfrom studies of identical twins These studies indicate thatthere is a strong genetic component to the development oftype 2 diabetes and that environmental factors, includingdiet, play a considerably lesser role If one identical twindevelops type 2 diabetes, chances are nearly 100% that the

second will as well, even if they are raised apart under

en-tirely different conditions

Many persons with type 2 diabetes are overweight, and

often the severity of their disease can be lessened simply by

weight loss However, no strict cause-and-effect

relation-ship between these two conditions has been established

Clearly, not all persons with type 2 diabetes are obese, and

not all obese individuals develop diabetes

Treatment Options for Type 2 Diabetes. In milder forms

of type 2 diabetes, dietary restriction leading to weight loss

may be the only treatment necessary Commonly, however,

dietary restriction is supplemented by treatment with one of

several orally active agents, most often of the sulfonylurea

class These drugs appear to act in two ways First, they

pro-mote insulin action in target cells, lessening insulin resistance

in tissues Second, they correct or reverse a somewhat

slug-gish response of pancreatic beta cells often seen in type 2

di-abetes, normalizing insulin secretory responses to glucose

The exact mechanisms of these effects are unknown In some

cases, persons with type 2 diabetes may also be treated with

insulin, although in the most of cases a regimen of oral agents

and dietary manipulation is sufficient

Diabetes Mellitus Complications Present

Major Health Problems

If left untreated or if glycemic control is poor, diabetes

leads to acute complications that may prove fatal

How-ever, even with reasonably good control of blood glucose,

over a period of years, most diabetics develop secondary

complications of the disease that result in tissue damage,

primarily involving the cardiovascular and nervous systems

Acute Complications of Diabetes. The nature of acute

complications that develop in type 1 and type 2 diabetics

differs Persons with poorly controlled type 1 diabetes

of-ten exhibit hyperglycemia, glucosuria, dehydration, and

di-abetic ketoacidosis As blood glucose becomes elevated

above the renal plasma threshold, glucose appears in the

urine As a result of osmotic effects, water follows glucose,

leading to polyuria, excessive loss of fluid from the body,

and dehydration With fluid loss, the circulating blood

vol-ume is reduced, compromising cardiovascular function,

which may lead to circulatory failure

Excessive ketone formation leads to acidosis and

elec-trolyte imbalances in persons with type 1 diabetes If

uncon-trolled, ketones may be elevated in the blood to such an

ex-tent that the odor of acetone (one of the ketones) is

noticeable on the breath Production of the primary ketones,

␤-hydroxybutyric acid and acetoacetic acid, results in the

generation of excess hydrogen ions and a metabolic acidosis

Ketones may accumulate in the blood to such a degree that

they exceed renal transport capacities and appear in the

urine As a result of osmotic effects, water is also lost in the

urine In addition, the pK of ketones is such that, even with

the most acidic urine, a normal kidney can produce about

half of the excreted ketones in the salt (or base) form To

en-sure electrical neutrality, these must be accompanied by a

cation, usually either sodium or potassium The loss of

ke-tones in the urine, therefore, also results in a loss of

impor-tant electrolytes Excessive ketone production in type 1 betes results in acidosis, a loss of cations, and a loss of fluids.Emergency department procedures are directed toward im-mediate correction of these acute problems and usually in-volve the administration of base, fluids, and insulin

dia-The complex sequence of events that can result from controlled type 1 diabetes is shown in Figure 35.10 If leftunchecked, many of these complications can have an addi-tive effect to further the severity of the disease state.Persons with type 2 diabetes are generally not ketoticand do not develop acidosis or the electrolyte imbalancescharacteristic of type 1 diabetes Hyperglycemia leads tofluid loss and dehydration Severe cases may result in hy-perosmolar coma as a result of excessive fluid loss The ini-tial objective of treatment in these individuals is the ad-ministration of fluids to restore fluid volumes to normal andeliminate the hyperosmolar state

un-Chronic Secondary Complications of Diabetes. Withgood control of their disease, most persons with diabetescan avoid the acute complications described above; how-ever, it is rare that they will not suffer from some of thechronic secondary complications of the disease In most in-stances, such complications will ultimately lead to reducedlife expectancy

Most lesions occur in the circulatory system, althoughthe nervous system is also often affected Large vessels of-ten show changes similar to those in atherosclerosis, withthe deposition of large fatty plaques in arteries However,most of the circulatory complications in diabetes occur inmicrovessels The common finding in affected vessels is a

Events resulting from acute deficiency in type 1 diabetes mellitus If left untreated, in- sulin deficiency may lead to several complications, which may have additive or confounding effects that may ultimately result in death.

FIGURE 35.10