Endocrinology (Dr. J.

Carnegie)

1. Describe the features of the endocrine system

1. Distinguish between the endocrine and nervous systems in terms of the

regulation of body function

 Communication system
o NS is rapid, short-lived
o ES is slow, longer lasting

 Components of pathways
o NS: neurons define pathways
o ES: ductless glands – bloodstream or diffusion
 No direct pathway

 Chemical messengers
o NS: neurotransmitters between neurons
o ES hormones bind to target cell receptors

2. Define the following mechanisms of target cell regulation: endocrine,

autocrine, paracrine, neurocrine

Classical endocrine
- Hormone produced by ‘Tissue A’ is released, enter bloodstream to travel to
its target tissue and induce a response

Autocrine
- Hormone produced by ‘Tissue (Cell) A’ binds back to the same ‘Tissue
(Cell) A’ to induce a response
o Self-regulating
o Short distance
 No need for blood stream

Paracrine
- Tissue A produces a hormone and diffuse it to Tissue B (Target cell) that is
in close proximity to Tissue A
 o Short distance
 Short enough for diffusion
 Hormone is released into the extracellular space, travel
to target cell b and induce a response

Neurocrine
- Difference: the initiation
o Instead of hormone producing cell or tissue, hormone producing
neuron is present
o Neurons produces hormone instead of neurotransmitters and
hormones travel via bloodstream to bind to receptors of target cell to
induce a response

3. Define “hormone”; list and distinguish between the 3 chemical classes

of hormones in terms of structure, synthesis and transport giving examples
of for each class

- Hormone
: chemical substance that is secreted in low quantities into the blood by a cell
or grouping of cells and exerts a physiological effect on specific target tissues
(or cells).
- To be more inclusive, change “into the blood” to “into the ECF”.

Exocrine gland vs Endocrine Gland

- Exocrine gland uses ducts to transport wwhatever substance to its
destination
- Endocrine gland does not have ducts. Therefore, product is simply
released into extracellular space and often into bloodstream

3 Chemical Classes of hormones

- Amines
- Protein & Peptide Hormones
- Steroid hormones

Properties Catecholamine Thyroid Peptides Steroids

s (Amines) hormone
(amines)
Solubility Hydrophilic lipophilic hydrophilic lipophilic
structure Tyrosine tyrosine Chains of Cholesterol
derivate derivative specific derivative
amino acids
Synthesis In cytosol In colloid, an In rough Modification
inland endoplasmic of cholesterol
extracellular reticulum: molecule in
site packaged in intracellular
Golgi compartments
complex
Transport Half bound to Mostly bound As free Mostly bound
plasma protein to plasma hormone by plasma
protein proteins
Hormone of Only hormones Only Majority of Hormones
this type from adrenal hormones hormones from the
medulla from thyroid adrenal cortex
follicular cells and gonads

Protein and Peptide Hormones

What is prohormone?
- Produced in an inactive form and part of the molecule is then removed,
converting it to active hormone
o Regulation of blood-glucose
o Pro-insulin is a good example
 when synthesizing insulin, longer peptide chain is made. It
is made longer because two ends of the polypeptide chain
must come together to make bridges between molecules.
Once that happens, parts of amino acid (C-peptide or
shorter peptides) is then removed. It is only
uncut/unremoved peptide molecules are active insulin
hormone
 the reason: you make larger molecule so that you
can remove

Why cell surface receptors?

- Water soluble molecule cannot permeate through plasma membrane
 If water soluble, cannot cross PM. Therefore, it must bind to cell surface
receptor and when it binds to the cell surface receptor, it must tell the cell
that it’s there, which leads to 2nd messengers.

Steroid Hormone
- Produced by adrenal cortex, gonads
o Two other sources of steroid hormones under certain conditions?
 Vitamin D in our skin
 When our skin is exposed to sunlight
 Placenta during pregnancy
 Placenta is an endocrine organ that is present in
female during pregnancy

- What are the consequences of being lipid-soluble?

o They can get across plasma membrane
o Do not need cell surface receptors
o They can get into the nucleus (to find receptors in the nucleus)
o Activate gene transcription
o Can easily travel from one cell to interior of another since PM is
not a barrier

- Two main categories (products) of adrenal cortex

o Glucocorticoids
 Ex: cortisol
 Long term stress hormone
 Profound effects on blood sugar level (glucose level)
o Mineralocorticoids
 Ex: aldosterone
 Salt balance in the body

Lipophilic can easily cross PM and get into nucleus, which means it must be
interacting with DNA in terms of influencing target cell

How are hormones transported in the blood?

A. Peptides, proteins and catecholamines – water soluble

• Peptides and proteins circulate as free hormone
 a) Catecholamines are small - some are bound to plasma
proteins, some are not

B. Steroid & thyroid hormones – not water soluble

- Relies on transport proteins
- free hormone + binding protein = hormone-protein complex
 e.g.
 CBG (cortisol-binding globulin),
 SHBG or TeBG (sex hormone binding globulin),
 TBG (thyroxine binding globulin)

- What is physiologically more important? [bound hormone] or [free

hormone]?
 At the level of target cells, free hormones are what really matters.
 Free hormone is the hormone that come out of circulation and influence what
the target cell is doing
 As long as lipophilic hormone is associated with protein, protein is going to
keep the hormone in the bloodstream, and it won’t be interacting with the
target cell and inducting a response
 Therefore, concentration of free hormone that matters
 Concentration of free hormone in the bloodstream can be
regulated or controlled by regulating binding proteins
 Less binding protein = more free hormones

4. Define hormone “half-life” and justify the different half-lives of

peptides/catecholamines versus steroid/thyroid hormones

- Half life
: the time required for the plasma concentration of a hormone to decrease by
50%

Half-life of peptides/catecholamines = Fast (minutes)

Half-life of steroid/thyroid hormones = slow (hours to days)

WHY? (Justification)
1.5 Outline the body’s approaches to hormone metabolism and excretion
blood concentration of hormone depends on:
• rate of secretion/addition (endocrine cell)
• rate of clearance (liver, kidneys, target cell)

1) liver is the primary metabolism organ & kidneys are ptimary clearance
organs
2) endocytosis of hormone-receptor complexes by targets; receptors recycled
3) peptides & catecholamines can be metabolized by blood-borne enzymes
4) steroid & thyroid hormones bound to proteins are less vulnerable
5) sometimes metabolism activates a hormone (e.g. testosterone 
dihydrotestosterone; also the renin-angiotensin system)

5. Briefly describe the measurement of free hormone concentrations in

biological fluids and distinguish among the following three types of
regulation of hormone secretion, providing an example of each: humoral,
neural, hormonal

- Radioimmunoassay or ELISA
o Measurement of free hormone concentrations
o Used to measure blood hormone concentration

Principle of Radioimmunoassay/ELISA
- Trying to detect the presence of that hormone and measure how much
is there

- 3 types of regulations of hormone secretion

o Humoral regulation
 hormone secretions occur in response to: changes in plasma levels
of minerals or organic nutrients are

ex. Blood level of glucose

  when plasma glucose concentration level rises, some of the
glucose molecules go straight to pancreatic beta cells and directly
stimulates the release of insulin  this released insulin acts on
different target cells and bring the plasma glucose levels down
 appx. 1-2hr process
 once the glucose level is back down in range, insulin level backs
down also due to less demand of it  therefore, glucose-insulin,
acts both as regulator and stimulus for the release of the hormone
that’s going to regulate its levels

Ex. Regulation of blood calcium levels

 Parathyroid gland stimulates various responses in the body
(thyroid and parathyroid glands)
 levels of calcium in the blood stream that are too low is the
stimulus  triggers Parathyroid hormone (PTH)  regulates levels
of calcium

o Neural regulation
 Neurons are stimulating hormones producing cells to release a
product

Ex. Sympathetic nervous system acting at the level of adrenal

medulla to increase the rate of release of catecholamines
(epinephrine and norepinephrine)

o Hormonal regulation
3 parts: Hypothalamic pituitary thyroid access / Hypothalamic
pituitary adrenal access / Hypothalamic pituitary testicular (ovarian)
access

neurohormones are released from hypothalamus  stimulates the

release of more typical hormones by the anterior pituitary gland to
secrete hormones that travel via the blood stream to specific target
cells to stimulate responses

6. Compare and contrast the mechanisms of action of peptide/protein

hormones versus steroid/thyroid hormones; explain the concept of
amplification with regard to hormone action

Peptide/Protein Hormones & catecholamines (hydrophilic)

- Peptide and protein hormones are water-soluble and cannot pass through
cell membranes, so they bind to receptors on the cell surface. Once bound,
they activate second messenger systems within the cell that ultimately lead to
changes in gene expression and cellular activity by regulating enzyme activity
- no latent period

Steroid Hormones & Thyroid Hormones (Lipophilic)

- Steroid and thyroid hormones, on the other hand, are lipophilic (fat-soluble)
and can pass through cell membranes. They bind to receptors within the cell
(intracellular receptors), typically in the nucleus, and directly affect gene
expression by regulating gene transcription
- latent period

Amplification refers to the fact that a small number of hormone molecules can
activate a large number of intracellular signaling pathways, resulting in a large
response.
- Occurs through a process called ‘cascading’
: binding of a hormone to its receptor leads to the activation of a series of
intracellular signaling molecules, each of which then activates the next in
the series : amplifying the initial signal and allows for a greater response to
a small amount of hormone
 Fig. example of implication
- Activation of 10 adenylyl cyclase leads to production of 1000 cAMP as
each adenylyl cyclase activates 100 cAMP.
- Protein kinase activated by cAMP at 1:1 ratio  no amplification
- Each activated protein kinase (1000 units) phosphorylate 100 target
protein molecules to activate.
- Illustrates how hormone from a single target cell can bring out a strong
response

MECHANISM OF ACTION OF HYDROPHILIC HORMONES

[Peptide/Protein Hormones & catecholamines (hydrophilic)]

• Cyclic AMP (cAMP) second messenger system

• IP3-Ca2+ & DAG second messenger pathways

• Both second messenger systems are used by water soluble

hormones that begin the process by binding with cell surface
receptor
• Requires cell surface receptors that can specifically recognize
particular water soluble hormones

Cyclic AMP (cAMP) second messenger system

1) Binding of extracellular messenger to receptor activates a G protein, the a-
subunit of which shuttles to and activates adenylyl cyclase
a. G protein: G stands for GTP/ GTP binding protein
2) adenylyl cyclase converts ATP to cAMP
a. cAMP acts as second messenger for the hormone bounded to
receptor
b. rise in cAMP level provides information to inside of the cell that
hormone is bound to its receptor
c. ATP  cAMP +2 Pi
3) cAMP activates protein kinase A
4) Protein kinase A is an enzyme that phosphorylates inactive target protein,
activating it
a. Phosphorylation changes protein’s activity
b. Occurs in 1:1 ratio (1 specific seat available on the bus)
 i. Molecule of cAMP binds to a molecule of protein kinase A,
activating it
ii. Once Protein kinase A is activated, this enzyme can
repeatedly phosphorylate target proteins
5) Active target protein brings desired response

Deactivation
1) The cellular response diminishes rapidly when hormone is not bound to
the receptor
2) G protein hydrolyze their bound GTP to GDP, returning them to inactive
state and dissociate from adenylyl cyclase
3) This ends cAMP production
4) Existing cAMP is degraded by enzyme phosphodiesterase
a. Phosphodiesterase is present in cytoplasm
b. ATP converts to cAMP with the help of adenylyl cyclase. cAMP
converts to AMP (degraded cAMP) with the help of
phosphodiesterase
5) As cAMP concentration level returns to resting level, protein kinase
inactivates, preventing protein phosphorylation
6) Target cells retunrs to pre-stimulus condition, ready to respond to future
hormone signals

Summary
Signal of water-soluble hormone binds to receptor on plasma membrane. It
is then amplified by activation of many G-proteins and generation of even
more cAMP. cAMP activates many protein kinases, which affect many
intracellular proteins, all shaping target cells’ response. Response of many
target cells produce homeostatic and regulatory effects controlled by
endocrine system

IP3-Ca2+ & DAG second messenger pathways

1) binding of extra cellular messenger to receptor activates G protein

a. a subunit of which shuttles to and activates phospholipase C
(effector protein)
2) phospholipase C converts PIP2 to IP3 and DAG
a. IP3 and DAG act as second messenger
 i. IP3 goes into the cytoplasm
ii. DAG stays associated within plasma membrane

IP3
3a) IP3 mobilizes intracellular Ca2+
4a) Ca2+ activates calmodulin (calcium binding protein)
5a) Ca2+ - calmodulin complex activates Ca2+ - calmodulin – dependent
protein kinase (CaM kinase)
6a) CaM kinase phosphorylates inactive target protein, activating it
7a) Active target protein brings about desired change

DAG
3b) DAG activates protein kinase C
4b) protein kinase C phosphorylates inactive protein activating it
5b) active target protein brings about desired response

concept of amplification with regard to hormone action

- Second messenger provides a way of informing inside of the cell that a
hormone is bound to cell surface receptor and provides means to
activate and amplify a cellular response

MECHANISM OF ACTION OF LIPID-SOLUBLE HORMONES IN NUCLEUS

[Steroid Hormones & Thyroid Hormones (Lipophilic)

 Lipophilic hormones can permeate directly through plasma membrane

and bind to receptors in [cytoplasm/nucleus]  Once, bound to receptor,
hormone travels and binds to specific binding site at a specific gene in the
DNA molecule.  This binding at hormone response element allows for
production of mRNA required for a desired response  mRNA leaves
nucleus and leads to protein synthesis to bring out a response
- Specific binding site for the hormone = hormone response element
- do not require cell surface receptors
- May or may not be binding proteins or receptors in the cytoplasm
(inside PM) to convey hormones into the nucleus
7. Distinguish between the roles of positive and negative feedback in the
endocrine regulation of physiological processes

Q) What is the ultimate goal of negative feedback? What is a

physiological example?

: To maintain [concentration] or [rate] within a certain range

 ex) Product, Thyroid-Stimulating-Hormone, is made from anterior
pituitary and stimulates T3 and T4 from thyroid gland. As level of thyroid
hormone rise in circulation, some of the thyroid hormone will provide a
feedback at the anterior pituitary to limit the release of THS to maintain
or perhaps decrease the thyroid hormone level

Q) What is the ultimate goal of negative feedback? What is a

physiological example?

: To keep stimulating a response

Ex1) labour and delivery (hypothalamic pituitary axis)

Ex2) milk letdown axis

 Stimulation of pressoreceptors in nupples by suckling infant sends
neuropathway (efferent impulse) to the hypothalamus  hypothalamus
send the impulse to posterior pituitary where oxytocin is stored  oxytocin
is released from the posterior putiruirary and stimulates specific cells of
breasts to contract  alveolar glands respond by releasing milk
2. Describe the role of the hypothalamic-pituitary axis in the hormonal
regulation of body function

 Regulates the release of hormones from the pituitary gland and other
endocrine glands in response to changes in the body.

- The hypothalamus, located just above the brainstem, produces and

releases a number of hormones that regulate the activity of the pituitary
gland, including releasing hormones and inhibiting hormones. These
hormones travel through the hypothalamic-hypophysial portal system, a
set of blood vessels that connect the hypothalamus to the pituitary
gland, and bind to receptors on the pituitary cells, thus triggering the
release of pituitary hormone

- The pituitary gland, located at the base of the brain, produces and
releases several hormones that regulate the activity of other endocrine
glands, including the thyroid, adrenal, and gonadal glands.
i) These hormones include growth hormone, follicle-stimulating
hormone, luteinizing hormone, thyroid-stimulating hormone,
adrenocorticotropic hormone, and prolactin

1. Describe the endocrine function of the posterior pituitary gland

Posterior pituitary gland:

- Neural tissue composed of axonal terminals of neurons
- originate in the supraoptic & paraventricular nucleus (SON & PVN)
i) Not a place where hormones are produced
- Hormone produced in (SON & PVN)
ii) A place for hormone storage
- Stimulation of the neurons lead to the release of hormone stored from
the posterior pituitary gland

o Two products:
a. Oxytocin
 Primarily paraventricular nucleus (PVN)
o Uterine contraction
o Milk let-down (nursing)
 b. Vasopressin / antidiuretic hormone (ADH)
 Water conservation at the level of the kidney
 Primarily supraoptic (SON)

What are neurophysins I and II?

- Neurophysins are small peptide hormones that are co-transported with
neuropeptide hormones, such as oxytocin and vasopressin, from the
hypothalamus to the posterior pituitary gland for storage and release.

- Neurophysins are components of oxytocin (I) & ADH (II) precursor

molecules
- neurons of paraventricular and supraoptic neurons produce precursor
molecules that consist of hormone plus its neurophysins
- packaged into vesicles for transport to posterior pituitary
- endopeptidases cleave precursor – hormone stays with neurophysin
carrier until hormone release by axonal terminals is stimulated
(depolarization + Ca++ influx)
- neurophysins serve combined roles of structural component of hormone
precursor molecules and carrier proteins during axonal transit
i) Provides protective structure as hormones travel down the long
axon to be released at posterior pituitary gland
- Neurophysin I is associated with the transport of oxytocin
- neurophysin II is associated with the transport of vasopressin.

1. Define “neuroendocrine loop” and “positive feedback” using oxytocin as

an example

Ex) oxytocin during labor as an example of both a neuroendocrine loop &

positive feedback to achieve a goal

What is neural stimulus?

- Pressure of the baby’s head on cervix activates oxytocin secretion
Therefore, neural stimulus is the pressure of baby’s head on cervix

What is endocrine response?

 - Oxytocin travels via bloodstream to get to uterus to stimulate stronger
contraction by the smooth muscle in the uterus
i) at the same time oxytocin is stimulating as hormone, contracting
smooth muscles, it also stimulates prostaglandins, which also aid
in uterine contraction

How does this involve in positive feedback?

- Stronger contraction pushes the head of the infant against the wall of
uterus, which in turn stimulates the release of oxytocin, which
stimulates uterine contraction and so forth.
- More neurostimulation, more oxytocin, more contraction
i) Keeps going until baby is delivered

EX) ADH (Vasopressin)

• ADH has two effects that both act to increase blood pressure:
• vasoconstriction of blood vessels
• water conservation by kidney
• Targets kidney to stimulate kidney to store as much water

• release of ADH results in

• low urine flow rate & production of a concentrated urine
• less water going into the urine  decreased volume in urine,
increased concentration
 Q) What is the effect of alcohol on ADH secretion?
• “Drink one beer, pee out two”
• Effect of alcohol at the level of posterior pituitary gland has an
inhibitory effect of ADH release
• Less ADH release, lose more water at the kidney

Q) What is diabetes insipidus?

• Type of diabetes where the release of ADH is not a normal rate
• Inability to release normal amount of ADH
• Cannot conserve water at kidney

Q) Why is it called diabetes?

• general term for diseases associated with excess loss of fluid

2. Describe the hypothalamic regulation of anterior pituitary hormone

secretion

Stimulatory perspective
- hypothalamus produces a product that directly travels via portal system
to stimulate secretion of product by anterior pituitary
i) Product 1 (from hypothalamus) stimulates secretion of hormone
#2 (from anterior pituitary). Hormone #2 goes to third target,
(endocrine gland (thyroid/adrenal gland)) and third hormone is
released

The six classical anterior pituitary hormones

1) LH & FSH: gonadotropins involved in reproduction (egg & sperm

development and stimulation of sex hormone production)
2) TSH: thyroid stimulating hormone
NB: LH, FSH & TSH are glycoproteins consisting of an  chain & a 
chain -  chain is common to all 3; only  chain is specific
1) ACTH: adrenocorticotropic hormone – linear 39-a.a. hormone that
increases cortisol production
2) GH: Growth hormone – also called somatotropin (~200 a.a.)
3) Prolactin: mammary gland development & milk production
3. Summarize the regulation of growth hormone secretion, the
physiological effects of growth hormone and the consequences of
excessive or deficient growth hormone secretion

Growth hormone
- Anabolic hormone
- Stimulates synthetic type processes
i) Protein synthesis
ii) promotes cell growth and building of muscle tissues
- Major target
i) Bone & Skeleton muscles increased muscle tissue mass

effects
- Increased stimulation of protein synthesis in bone and muscle to allow
for increased length of long bones and muscle tissue mass
- In soft tissues, increases both cell number (hyperplasia) and cell size
(hypertrophy)
- Increase the use of fats for fuel, thereby conserving glucose
i) Anabolic; but some effects are anti-insulin
- Growth promoting effects of growth hormone is mediated by
somatomedins
i) Key somatomedin that is produced by liver is stimulated by GH
: IGF-1 (Insulin like growth factor-1)
 Control of GH (and IGF-1) Secretion

3. Describe the role of the thyroid gland in the regulation of body

metabolism as well as body growth and development

1. Describe the synthesis of thyroid hormones; differentiate between T3

and T4 in terms of production and biologic activity

T4: tetraiodothyronine (thyroxine)

T3: triiodothyronine

- T3 and T4 are two hormones produced by thyroid gland

- Primary hormone released and produced by thyroid gland are T4

(~90%)
- T3 is more active than T4
i) T4 converts to T3 because…
- T3 binds more actively to thyroid hormone receptors inside
target cells
- 10 times more active
- Conversion aided by deiodinases

- Target cells contain deiodinases

i) Deiodinases removes iodine to convert T4 to T3
synthesis of thyroid hormones

1) Formation of Thyroglobulin
a. Addition of iodine tp tyrosine residues inside of the thyroglobulin
molecule.
b. Must join two tyrosine residues with iodine’s attached to make
two possible products (monoiodotyrosine or diiodotyrosine, MIT
or DIT)
i. If two diiodotyrosine join, T4 is formed
ii. If one diiodotyrosine and one monoiodotyrosine join, T3 is
formed
c. Thyroglobulin is released into the lumen of the follicle to
contribute to colloid
2) iodide trapping in follicular cells
a. Must move as much into colloid to add the iodine to tyrosine
residues
b. Moving against [gradient]
i. Na-K pump keeps sodium in and potassium out and as
sodium goes in, Iodide is picked up (secondary active
transport)
 ii. secondary active transport of iodide (I-) into cells where it is
oxidized to form iodine (I0; highly reactive) by
thyroperoxidase (TPO)
3) Iodination of tyrosine in thyroglobulin
a. Iodine (I0) adds to tyrosine residues in thyroglobulin to make MIT
and DIT
b. Occurs at apical follicle cell colloid junction
4) Coupling of MIT & DIT
a. T4 = 2 DITs
b. T3 = 1 MIT+ 1 DIT
5) Thyroglobulin molecule is taken up by endocytosis which will fuse with
lysosome to cleave out T3 and T4 from larger protein molecule
a. Hormones are released by the follicle cells into the circulatory
system

Q) Where do we get T3?

- Deiodination
i) When T4 gets into target tissue it converts toT3
ii) Mainly happens in liver
iii) T4 is deiodinated by enzyme called ‘Type 1 deiodinase (D1)’ to
convert T4 to T3

Q) What characteristic of T3 makes it a more active hormone than T4?

- Structurally, T3 has one less iodine than T4
- T3 has higher affinity for thyroid hormone receptor in the nucleus
compared to T4

Q) If you were to administer hormone to someone who was thyroid

hormone deficient, would you give T3 or T4?
- T4 (~90%)
- T3 has shorter half life in the circulation
- T4 will get to its target cells and be converted to T3 with the help of
deiodinase enzyme that is associated in the target cell
2. Summarize the regulation of thyroid hormone secretion

- Follows the three-tier system pattern

i) Hypothalamus, anterior pituitary, thyroid gland
Ex) stress inhibits / cold temp increases - thyroid hormone production
i) Hypothalamus produces TRH.
ii) TRH travels via portal system to Anterior pituitary to stimulate the
release of TSH
iii) TSH travels via circulation system to arrive at thyroid gland to
stimulate the increased synthesis and release of T3 and T4

• TSH stimulates:
o secretion of T4 & T3
o follicular cell protein synthesis
o hypertrophy of follicular cells (increase size)
o what is goiter?
: enlarged thyroid gland. More colloid than normal. Excessive TSH
stimulation.

Q) Why is it important that body responses associated with pregnancy override

the normal negative feedback associated with thyroid hormone secretion?

- We want to boost metabolism; therefore, we must override the normal

feedback to allow the set point to be set a little bit higher
- Like a reset
- to ensure that the necessary hormones are produced for the healthy
development of the fetus.

3. Briefly describe how thyroid hormones are transported in the blood

: Thyroid Hormones must be bound to transport protein

 - less than 1% is free hormone / 99% is bound
- T4 binds more tightly than T3
- T3 is more readily broken down

Plasma % in
Binding Circulation
Conc.
Protein
(mg/dl) T4 T3
TBG 2 67 42
TBPA 15 20 1
Albumin 3500 13 53

- Binding to protein keeps that hormone in the circulation for the longer
period of time (increased half life)

Half-lives of thyroid-related hormones:

TSH: ~60 min
T4: 4-7 days
T3: 1.5 days

- Half-life of T4 > T3 because T4 has higher binding affinity

4. Summarize the influences of thyroid hormones on basal metabolic rate,

body temperature and growth & development

• TH activates transcription of a variety of genes associated with growth,

development and the use of food nutrients for ATP production
• TH receptors are widespread in the body
• TH effects kick in slowly (several hours to days), but are long-lasting

A. METABOLIC RATE, INTERMEDIARY METABOLISM & HEAT

PRODUCTION
• Increases oxygen consumption and energy expenditure under resting
conditions (BMR); stimulates mobilization of fats to support that increase
• Increased metabolic activity means increased heat production – known as
the calorigenic effect of TH
 • Influences rates of synthesis and degradation of carbs and proteins;
direction of effect depends on TH levels:
• lower levels stimulate synthesis
• higher levels stimulate degradation

B. SYMPATHOMIMETIC EFFECT & THE CARDIOVASCULAR SYSTEM

• Up-regulates -adrenergic receptors, esp. in heart & nervous system - this
is a permissive action of TH wrt catecholamines – increased TH can cause
individuals with normal catecholamine levels to display signs of excessive
sympathetic nervous system activity
• anxiety and nervousness
• racing heart

C. GROWTH & DEVELOPMENT OF NERVOUS & MSK SYSTEMS

• TH needed for normal production of GH and also IGF-1 by liver
• TH critical for normal development of nervous system in fetus (formation of
axonal terminals, dendrites, myelin sheathes, synapses)
• TH supports muscle growth (protein synthesis) and proper muscle
functioning (calcium uptake by SR, increased max shortening velocity)
• TH needed in adult life needed for proper nerve/muscle reflexes & normal
cognition

5. Discuss thyroid hormone dysfunction during fetal development/early

childhood and in the adult

A) Hypothyroidism
In adults (I,.e. Hashimoto diseases)
- can be due to autoimmune thyroiditis
i) attack on thyroid gland by your own immune system
ii) not producing enough thyroid hormone
- Deficits in TSH or TRH secretion
i) Can’t stimulate thyroid gland strong enough
- Inadequate intake of dietary iodine, thyroidectomy
i) Doesn’t matter how much thyroglobulin is being produced,
without iodination of the tyrosine residues, you cannot make
hormones
 - Lack of iodine
i) Results in goiter
ii) Follicle cell continue to produce thyroglobulin but cannot iodinate
it
- TSH continues to stimulate gland
- Goiter is reversible with iodine supplement

B) In Fetus/Infant (congenital iodine deficiency syndrome):

• can be due to genetic deficiency in fetal thyroid gland or inadequate

intake of iodine by mother during pregnancy
• thyroid hormones essential for development of nervous and skeletal
systems; if lacking, don’t get proper body growth or development of CNS
• affected individuals are short, body is disproportionate & there are
levels of intellectual disability
• during childhood, TH essential for myelination of axons, dendritic
arborization and formation of synapses
• if caught early enough, effects can be reversed at least to a certain
extent by hormone therapy

C) Hyperthyroidism
Autoimmune (i.e. Grave’s Disease)
: patients have developed antibodies that mimic TSH (LATS = Long Acting
Thyroid Stimulator) bind to follicle cells and continuously stimulate output
of thyroid hormones

Q) Why does TSH continue to stimulate the thyroid gland if someone is lacking
iodine?
• Because there is no negative feedback in the form of thyroid hormone coming
from thyroid gland to tone down the secretion of TSH and TRH

Q) Why does ingested radioactive iodine destroy only cells of the thyroid gland?
• That’s the only place it goes to be concentrated

Q) Why would TSH level be low in someone with Grave’s disease

• Graves disease: antibody constantly stimulates secretion/output of increased
level of thyroid hormone (T3 and T4)  increased level of negative feedback
 by decreasing the production of TSH since TSH is responsible for
simulating the thyroid gland to produce more hormones, a low evel of TSH
insdicated that the thyroid is producing more hormones that is needed, which
is a characteristic of hyperthyroidism (incl. Grave’s disease)

Q) how can goiter be a symptom of both hypo- and hyper- thyroidism

• Hypothyroidism:
the thyroid gland is unable to produce enough thyroid hormones, causing the
gland to enlarge in an attempt to produce more hormones

• hyperthyroidism:
the thyroid gland produces too many hormones, leading to an overgrowth of
the gland. Both conditions can lead to the development of a goiter

4. Summarize the roles of the major hormones involved in calcium

homeostasis

The major hormones involved in calcium homeostasis are:

Hormones that increase bone deposition

• insulin
• growth hormone
• IGF-1
• Estrogen, testosterone
• Calcitonin (during childhood)
- Calcitonin is produced by the thyroid gland and decreases the levels of
calcium in the blood by inhibiting the release of calcium from bone and
promoting the excretion of calcium by the kidneys

• Vitamin D
- Vitamin D, which is produced in the skin when exposed to sunlight, promotes
the absorption of calcium from the gut and the reabsorption of calcium by the
kidneys
Hormones that increase bone resorption

• Parathyroid hormone (PTH)

– PTH is produced by the parathyroid glands and increases the levels of
calcium in the blood by promoting the release of calcium from bone and the
reabsorption of calcium by the kidneys
• Cortisol
• T3 and T4

Receptors
• Calcium sensing receptor (CaSR)
- The CaSR is a protein found in the parathyroid glands, kidneys, and other
tissues that senses changes in calcium levels in the blood and regulates PTH
and Vitamin D production in response

Definitions
Osteoblasts
- Adds to bone tissue
- Derived from bone marrow stromal cell
- Active when there’s an increase in size or density of the bone
- deposit calcium in bone

Osteocytes
- Retired osteoblasts
- Osteoblasts get surrounded by boney matrix and get trapped
- Maintains bone tissue
i) Doesn’t add

Osteoclasts
- Bone digesting cells
- digests bone to release calcium into the circulation
- Derived from macrophages

Facts
• Bone is seen as a bank of calcium by the body
 • Bone is constantly remodeled via the actions of osteoblasts and
osteoclasts
• Constantly added on and stripped away
• Mechanical stress also encourages bone deposition
• Of the 1% of calcium remaining (not in bones or teeth), 90% of it is inside
cells, leaving only 0.1% of body calcium available in the ECF
• Of the 0.1% in ECF, half is bound to proteins or phosphate

• 0.05% of total body calcium is free calcium available for essential functions
such as:
o neuromuscular excitability (influences Na+ permeability)
o excitation-contraction coupling in cardiac and smooth muscle
o stimulus-secretion coupling
o maintenance of tight junctions
o blood clotting

1. Distinguish between bone deposition and bone resorption and list those
hormones that stimulate each of these events; define “osteoporosis”

Osteoporosis
• reduced bone density
- Loss of matrix and minerals, especially in response to aging
• More common in women because . . .
- Loss of protective action of estrogen when a woman goes through
menopause
• Treatment
: (anti-osteoclast drugs, including calcitonin (nasal spray) & SERMS (selective
estrogen receptor modulators); newer drugs look at promoting osteoblasts
rather than simply interfering with osteoclasts – possibly statins, also another
type of estrogen signaling molecule

Bisphosphonates (drug)
• Bisphosphonates are taken into osteoclasts
• deposited in the bone tissue along with calcium
- stimulates induce apoptosis of osteoclasts
 q decreases osteoclast activity

2. List the three target organs of parathyroid hormone (PTH) and describe
the effects of PTH on each of these target organs

What stimulates the secretion of PTH?

o Decrease in blood calcium level

Three target organs

• Bone
o Stimulates resorption
 Chew up the bone a little and release the calcium into the
bloodstream
o Fastest response

• GI tract
o Stimulates calcium absorption

• Kidney
o Increases tubular calcium reabsorption

3. Justify the term “humoral” to refer to the regulation of secretion of PTH

by the parathyroid glands
[Left figure]
- Stimulus of the release of parathyroid hormone is reduction in blood
calcium level
- Once calcium level decrease, this will act directly at parathyroid gland
to increase the relate rate of PTH
- PTH reaches to all three of the target organs to collectively work to
restore calcium hoeostasis
i) Mainly bone first,
- PTH reaches bone to increase resorption
ii) Kidneys
- Slows down the loss rate of calcium
- Increased production and activation of vitamin D in skin
cells
iii) bone resorption moves both calcium and phosphate into the
bloodstream. This has the potential to be self defeating.
iv) PTH deals with this by increasing phosphate excretion at the
level of the kidneys so that the calcium remains as free calcium,
available to various target cells.

[Right Figure]: regulation of osteoclasts / what estrogen does before

women goes through menopause to help maintain their bone density
- Osteoblasts can secrete two factors

i) RANK ligand (RANKL)

- Binds to RANK receptor on macrophages or osteoclasts to
produce more osteoclasts
 If macrophage, turns into osteoclast
 If osteoclast already, suppression of apoptosis
- More osteoclast activity (osteoclast action > osteoblast
action)
 Reduces bone mass
 Restores calcium level

ii) Osteoprotegerin (OPG)

- Binds to RANK ligand and take away its ability to bind to
RANK receptor
 Inhibits the ability of RANK ligand to stimulate all of
the positive things about osteoclasts
- Decreased osteoclast action (osteoblast action >
osteoclast action)
 Less bone chewing activity
 Increased or maintained bone mass
iii) Estrogen activates gene responsible for OPG production
- D

- If body has to choose between maintaining blood calcium level vs bone

density, maintaining blood calcium level wins every time

Vitamin D
- Once enters blood circulation from dietary or sunlight, Vitamin D3
travels to Liver
i) Once in liver, Vitamin D3 catalyzed to 25 OH-D
ii) 25OHD is sent to kidney
- With the help of parathyroid hormone (PTH), breaks 25 OH
D further to send to GI tract where calcium and phosphate
is absorbed
4. Summarize the role of calcitonin in calcium homeostasis

- Secreted by thyroid parafollicular cells (thyroid gland)

i) in response to elevated blood calcium
- Inhibits osteoclasts
i) Calcium phosphate salts deposited in the bones have better
chance of survival and not self deprive since osteoclasts activity
is inhibited
- Important during childhood growth
- Not a key player in the day-to-day regulation of bone density in adults

5. Describe the endocrine functions of the adrenal glands and their

regulation

1. Distinguish between the adrenal medulla and the adrenal cortex in terms of
structure and hormone biosynthesis

• The adrenal glands are located on top of each kidney and consist of two main
regions: the adrenal medulla and the adrenal cortex.

• The adrenal medulla

• the innermost part of the adrenal gland
• Consists of neural tissue
• responsible for the production of catecholamines, such as epinephrine
and norepinephrine.

• The adrenal cortex

• the outer layer of the adrenal gland
• responsible for the production of steroid hormones, such as cortisol,
aldosterone, and androgens.
• Organized in distinct layers
o Each layer secretes different steroid hormone
- Zona glomerulosa layer (top) secretes mineralocorticoids
(ex. aldosterone)
 - Zona fasciculata layer (2nd top) secretes glucocorticoids
(ex. Cortisol)
- Zona reticularis layer (above medulla) secretes sex
steroids (ex. primarily dehydroepiandrosterone)
• The hormone production in the adrenal cortex is regulated by the
hypothalamic-pituitary-adrenal (HPA) axis, which controls the release of
cortisol in response to stress and other physiological stimuli

In terms of structure,

• adrenal medulla
• composed of clusters of cells called chromaffin cells

• adrenal cortex
• composed of three distinct layers of cells, each of which produces a
different class of steroid hormones. The outermost layer, called the
zona glomerulosa, produces aldosterone, the middle layer, called the
zona fasciculata, produces cortisol, and the innermost layer, called the
zona reticularis, produces androgens

2. Describe the regulation of aldosterone secretion; summarize the role of this

hormone in salt/water balance in the body

Zona glomerulosa – Mineralocorticoids

• hormones involved in balance of salts (Na+, K+) & water in body
o if sodium moves in certain directions, pathways of water to follow
opens
• primary (95%) mineralocorticoid is aldosterone
aldosterone
o stimulates reabsorption of Na+ by kidney tubules
 (K+ out for Na+ in)
o increases Na+ reabsorption from sweat, saliva, gastric juice
o water follows Na+ if water channels are open
 (Responsible hormone: ADH)
• Conditions that increase aldosterone release
o increased blood K+
 o low blood Na+
o low blood volume/pressure

Mechanisms regulating aldosterone secretion:

• renin-angiotensin system
• plasma Na+/K+
• ACTH
• plasma ANF (atrial natriuretic factor)

q renin-angiotensin system
- major regulator of aldosterone secretion

- Two-step process
i) Renin
- enzyme that converts plasma protein, angiotensinogen, to
angiotensin I
ii) Angiotensin I & II: products
- Angiotensin I is converted to angiotensin II with the help of
converting enzyme, ACE (Angiotensin Converting Enzyme)
- To kickstart, cells must convince kidney to produce and release Renin
i) Sympathetic stimulation, low blood pressure/volume, decreased
sodium delivery will activate the release of Renin
ii) Renin catalyzes step 1 of the process (angiotensinogen 
angiotensin I).
iii) Angiotensin I is converted to angiotensin II with the help of ACE
to produce active Angiotensin II
iv) Angiotensin II released into bloodstream, travel to adrenal cortex,
specifically Zona glomerulosa, to stimulate release of aldosterone
v) Aldosterone goes back to kidney to stimulate pulling back of
sodium into the bloodstream at the expense of potassium
vi) At the same time, if blood volume is low or water deprived,
increase ADH release to open water channels to allow pull back
water with soidum
 q Plasma [Na+] or [K+]
o Low Na+ or high K+ stimulates aldosterone secretion
o Direct stimulating effect

q ACTH
o Very minor player
o comes into effect if individual severely stressed
o High level of stress = high level of ACTH
 ACTH regulates cortisol secretion
 High level of ACTH stimulate release of aldosterone

q Atrial Natriuretic Factor (ANF)

o Released by heart when blood pressure rises
o ANF effects on aldosterone secretion is inhibitory
 Goal: decrease blood pressure by allowing Na+ and water
to leave body via urine

3. Explain why cortisol is essential to the body for the management of long-term
stress

• When the body is under stress, the hypothalamus releases corticotropin-

releasing hormone (CRH), which stimulates the pituitary gland to release
adrenocorticotropic hormone (ACTH). ACTH then travels to the adrenal
glands and triggers the release of cortisol.
• Main function
o increase blood sugar levels by stimulating the liver to convert stored
glycogen into glucose. This provides the body with an immediate
source of energy to respond to the stressor.
o Anti--inflammatory effects, which can help to reduce inflammation in
the body caused by stress.
o impacts the brain by stimulating the release of neurotransmitters that
help regulate mood and emotion, such as dopamine and serotonin.

Zona Fasciculata - Glucocorticoids

 o essential to life - help body cope with stress

Regulation of cortisol secretion:

a) CRH  ACTH  cortisol -- (typical negative feedback)
b) acute stress: sympathetic nervous system overrides usual negative
feedback and triggers CRH release
c) physiological conditions also influence cortisol levels:
» Levels highest just after we rise in AM
» Levels lowest in evening just before and shortly after fall asleep

Physiological Effects of Cortisol:

a) primary effect is to stimulate gluconeogenesis (up to 10x – what allows it to
do this so effectively? By stimulating protein breakdown as stated in (b))
a) gluconeogenesis: synthesis of glucose from molecules that are not
carbohydrate (amino acid, glyceryl molecules)
b) stimulates metabolism of stored proteins to provide amino acids for repair,
synthesis of enzymes, but also for synthesis of glucose
c) increases use of fatty acids by other tissues (spare glucose for CNS)
d) enhances vasoconstriction in response to E (permissive action) »»
increased blood pressure & distribution of needed nutrients
e) anti-inflammatory/immunosuppressive (stabilizes cell membranes,
prevents lysosome rupture); decreases lymphocytes » leaving body
susceptible to infection

Transport of cortisol in blood:

- 80% CBG – corticosteroid binding globulin
- 15% - albumin
- 5% - free (**physiologically active**)

Summary: Cortisol and Metabolism:

Liver:
- Increases gluconeogenesis
Skeletal Muscle:
- Decreases protein synthesis
- Increases protein degradation
- Decreases glucose uptake
Adipose Tissue:
 - Decreases glucose uptake
- Increases lipid mobilization

Long-Term Stress Response

Glucocorticoids
1. Proteins & fats converted to glucose or used for energy
2. Increased blood sugar
3. Suppression of immune response

Mineralocorticoids
1. Retention of sodium & water by the kidneys
2. Increased blood volume and blood pressure

4. Summarize the role of the adrenal cortex in androgen production

• Adrenal cortex plays a role in the production of androgens, a group of

hormones that includes testosterone.
• The adrenal cortex, Zona Reticularis, produces small amounts of androgens,
primarily dehydroepiandrosterone (DHEA)
• These hormones can be converted into testosterone by other tissues in the
body, including the gonads and adipose tissue.
• The androgen production in the adrenal cortex is regulated by the
hypothalamic-pituitary-adrenal axis.

Zona Reticularis
• Primary products – androgens
• Amounts are insignificant compared to gonadal production of these steroids
from late puberty on
Functions of these sex steroids
- Onset of puberty
- Important source of estrogens post-menopause (osteoporosis)
- Boosts female sex hormone
i) During puberty, upregulation of androgen release from adrenal
cortex occurs.
ii) Androgen is taken up by adipose to convert to estrogen which is
then released back into the circulation to boos sex hormone
5. Explain the physiological basis of Cushing’s syndrome and Addison’s disease

Addison’s Disease
- an autoimmune disease characterized by severe hyposecretion of the
adrenal cortex

why do these individuals appear tanned?

- Not sufficient secretion of cortisol
- Cortisol exerts negative feedback at the rate of CRH release, therefore
ACTH coming from anterior pituitary.
- With hyposecretion, negative feedback is not exerted
- Compensate by increasing the rate at which ACTH is stimulated
and synthesized
- Levels of melanocytes stimulating hormone increase
- MSH travels to skin and increase melanin to appear tann

Cushing’s syndrome
- group of clinical symptoms due (primarily) to hypersecretion of cortisol:
(i) cortisol-secreting tumor in adrenal gland (androgens normal)
(ii) excessive release of ACTH from pituitary (excess androgens as well)
(iii) production of ACTH by tumor elsewhere in body (e.g. oat cell carcinoma
of lung; excess androgens as well)

6. Briefly outline the clinical use of adrenal steroid hormones

• most commonly, corticosteroids prescribed to:

(i) replace hormones in patients deficient in their secretion
(ii) suppress inflammatory reactions, manage autoimmune diseases
(iii) minimize immune response in cases of allergy/following organ transplant

(1) Want to reduce inflammation in someone with functioning mineralocorticoid

production? Give prednisone or hydrocortisone – targets primarily the cortisol
receptor
 (2) Want to replace normal hormone levels in an individual with inadequate
adrenal function? Give prednisone or hydrocortisone plus fludrocortisone to
replace both glucocorticoid and mineralocorticoid function

6. Describe the endocrine functions of the pancreas and the physiological

dysfunctions of diabetes mellitus

pancreas
- a gland that produces both digestive enzymes and hormones (insulin and
glucagon)
- plays critical roles in regulating glucose metabolism.
- Insulin, a hormone secreted by the beta cells of the pancreas,
promotes the uptake and storage of glucose by cells
- glucagon, secreted by the alpha cells, raises blood glucose
levels by stimulating the liver to release stored glucose

diabetes mellitus
- a chronic disorder characterized by high blood sugar levels due to defects
in insulin production, insulin action, or both.
- Type 1 diabetes, (insulin-dependent diabetes)
- results from the destruction of the beta cells of the pancreas, leading
to a lack of insulin production.
- the body is unable to produce insulin, which leads to high blood
sugar levels, this can be treated with insulin therapy
- Type 2 diabetes, (non-insulin dependent diabetes)
- occurs when the body becomes resistant to the effects of insulin or
when the pancreas cannot produce enough insulin to meet the body'
needs
- the body may produce enough insulin, but the cells do not respond
to it properly, which leads to high blood sugar levels, this can be
treated with lifestyle changes, medications, and in some cases
insulin therapy
1. Outline the structure and function of the endocrine pancreas

2 regions:
(a) exocrine (80%)
: acini → produce & secrete digestive enzymes & bicarbonate into a
system of ducts
- ducts are used to convey the product to the destination

(b) endocrine (~1% weight of pancreas)

- Endocrine pancreases a.k.a islets of Langerhans
- ~2 million islets of Langerhans

: 4 types of cells which secrete their products directly into the bloodstream

i. alpha (α) cells (20%)

i. produce and secrete glucagon
: acts to increase blood glucose

ii. beta cells (70%)

i. produce and secrete insulin
: acts to lower blood glucose

iii. delta cells (5-10%)

i. produce and secrete somatostatin
- inhibits release of insulin & glucagon
- slows digestive tract activity
- inhibits growth hormone secretion

iv. F cells (1-2%)

i. produce and secrete pancreatic polypeptide
: regulatory role in secretory activity of exocrine pancreas &
inhibits bile release by gallbladder

2. Summarize the role of insulin in regulating metabolic events during the

absorptive state of metabolism
 Absorptive state
- starts when you eat a meal ~ up to 4hr after eating
- Anabolic processes (storage)
- actively breaking down the meal and releasing a whole bunch of
building blocks to be used in synthesis of protein, glycogen, fats
- hormone regulation: insulin

Insulin is…
- synthesized as a biologically inactive precursor, proinsulin, a single
polypeptide chain with 3 disulfide bonds
- active insulin formed when middle portion (C-peptide) of proinsulin
removed; 2 of disulfide bonds hold the 2 chains together
- insulin is the only known hormone that reduces blood glucose levels!!

Regulation of insulin release:

Major player
- During the absorptive state, insulin promotes the uptake of glucose by cells
by stimulating the translocation of glucose transporters (GLUTs) to the cell
membrane. This allows glucose to enter the cell, where it can be used for
energy or stored as glycogen in the liver and muscle tissue
- Insulin also stimulates the synthesis of glycogen, fat, and proteins in the
liver, muscles and adipose tissue. In the liver, insulin activates glycogen
synthase, an enzyme that converts glucose into glycogen. Insulin also
promotes the synthesis of fatty acids by stimulating the activity of
lipoprotein lipase, an enzyme that breaks down triglycerides in adipose
tissue
- regulated primarily by blood glucose level
- secretion stimulated by a rise in blood glucose immediately after
ingestion of a meal
- ATP – sensitive K+ channels  depolarization  Ca+ channel
opens  insulin released

i. As blood glucose level rises, some of the glucose enters beta cell via
GLUT 2 transporter
 ii. Once inside the beta cell, slightly elevated level of glucose will go
through glycolysis with production of ATP
iii. This ATP from glycolysis closes ATP sensitive potassium channels
iv. normally potassium goes out of the cell but as a result of closing of the
channels, potassium is retained inside the cell
v. leads to depolarization that opens voltage gated calcium channels
vi. calcium rushes in and stimulates the movement of vesicles that contain
already made insulin to the periphery of the cell and releasing the
product outside

Minor players
- A rise blood amino acids also stimulates insulin release
- Fats stimulate insulin release very weakly
- can also act indirectly by stimulating release of GI hormones
(secretin, CCK, gastrin, GIP) - these then stimulate insulin release

Major metabolic thrust: Major Liver metabolism:

anabolism and energy energy fuel: Amino acids deaminated
storage glucose and used for energy or
(dietary) stored as fat
Amino Gycerol & Glucose Glucose Amino acids
Acids FA

Keto Acids
Proteins Tri- Glycogen CO2 + H2O
glycerides + ATP
Fats CO2 + H2O + ATP
 Start at GI tract
- GI tract digests meal into glucose, fats (triglycerides) and amino acids

- Glucose travels into liver cells to be converted to glycogen

- If glucose tops the storage capacity of liver, glucose breaks down to
be building blocks for fats (triglyceride) which travels to adipose
tissue to be stored there
- Some glucose goes into muscle tissue to replace/restock glycogen
- Left over glucose travels to adipose tissue to be converted for
building blocks for fats (triglyceride)

- Amino acids synthesizes protein if there is a need

- Rest of amino acids enter the liver to be deaminate (removal of
amine from amino acid) into urea and alpha-ketoacids
- Ketoacids are either burned for energy or used to make fats
(triglycerides)

- Fats (triglyceride) goes straight into adipose tissue and stored as fats there

Effects/goals of insulin
- To increase cellular uptake of glucose by insulin-dependent target tissues
 o Target tissues: skeletal muscle, adipose tissue
o 15-20x within seconds to minutes
- Insulin acts by stimulating movement of glucose transporters into the
plasma membrane

Which tissues require insulin for uptake of glucose?

: Skeletal muscle and adipose tissue
- Insulin stimulates glucose transport by skeletal muscle & adipose tissue
(adipose tissue + skeletal muscle = up to 65% body weight)
- Insulin does not increase glucose transport into brain, RBCs, leukocytes,
intestinal mucosa, kidney epithelium, hepatocytes

Different types of glucose transporters

TRANSPORTER DISTRIBUTION FEATURES
GLUT-4 adipose tissue, muscle insulin-dependent

GLUT-2 liver cells, pancreatic  cells - lower affinity for glucose

- not insulin dependent
GLUT-1 Most other body cells, not insulin-dependent
including neurons

Metabolic effects of insulin:

What insulin stimulates/inhibits

3. Summarize the principal metabolic pathways of the postabsorptive state of

metabolism and their hormonal regulation

Postabsorptive state
- After 4hr from eating
- Catabolic processes (using reserves)
- hormone regulation: glucagon

Major metabolic thrust: Major energy fuels: Liver

catabolism and glucose metabolism:
replacement of fuels in (glycogenolysis and amino acids
blood gluconeogenesis), converted to
FA and ketones glucose
Protein TGs Glycogen Glucose FA & Amino acids
ketones
Keto acids

amino gycerol glucose Glucose

acids & FA CO2 + H2O + ATP

- encourage organs and tissues to use fats for fuel to spare glucose for the
brain
- breaking down protein to amino acids
- breaking down fats (triglycerides) into glycerol and fatty acids
- breaking down of glycogen to get glucose (beginning
-fastest/easiest)

- begin where materials are stored

- almost all arrows lead towards glucose
- start at liver
- glycogen is broken into glucose
- glucose travels into bloodstream, problem solved
- need different strategies bc lack of glycogen
- glycogen presents in skeletal muscle
- hard to extract glucose from skeletal muscle glycogen because
muscle cells made their glycogen so when glycogen breaks down,
muscle cells can hang onto their glucose
- breakdown of glycogen in skeletal muscle leads to glucose-6-
phosphate
- to move glucose into bloodstream, phosphate must be
removed
- muscle cells do not have enzymes to remove phosphate
- therefore, it enters glycolysis to produce lactate or pyruvate,
whether it’s aerobic or anaerobic
- lactate and pyruvate can come out of muscle cells and
enters liver cells to be used as building blocks of
glucose

- Breakdown of fats result in fatty acid (used for ATP production) and
glycerol (used for gluconeogenesis)
- Can’t use fatty acids for gluconeogenesis because they only have
carbons and hydrogens and no oxygen

- Nervous tissues use glucose as energy source

- Other tissues use fatty acids and ketone bodies
- Ketone bodies come from metabolism of fatty acids
- If glucose is plentiful,
- we burn the fat and take it through kreb’s cycle and ETC
to yield ATP
- if glucose is limited
- kreb’s cycle won’t work efficiently
- fatty acids burn instead of carbohydrates to yield
ATP
- if kreb’s cycle is not available
- burn through beta oxidation to yield ketones
4. Physiology of Glucagon

Glucagon:
- hormone of the postabsorptive state
- potent hyperglycemic agent
o can often stimulate processes that increase blood sugar level

A. secretion of glucagon is stimulated by decrease in blood glucose

concentration

- stimulus: drop in glucose

- pancreatic islet alpha cells, responsible for making glucagon, stimulate
increase glucagon secretion
- rise in glucagon in blood will mainly target liver cells to stimulate the
following processes: glycogenolysis, gluconeogenesis, ketone synthesis
o ALSO mobilizes fats from adipose tissue
 If post absorption period is going on for a long period of time
and there’s a shortage on glycogen, increased production of
ketone bodies
 As the person is in the post-absorption state and the state
continues, the person can continue to maintain glucose levels
and may start to accumulate ketone bodies

B. secretion is also stimulated by increase in blood amino acid concentration

- Under what conditions would this be very helpful?

(hint: When could amino acid levels be high and glucose levels low and
insulin present?)

- Important to have glucagon present to maintain the blood sugar levels

 - Stimulated by rise in amino acid: Consumption of high protein meal with
little carbohydrates or if you are well into post absorption and state are
starting to run out of glucose in the bloodstream, protein begins to be
broken down and leads to amino acid levels
- Amino acid enters bloodstream from GI tract, but minimum movement of
carbs into the bloodstream
o As amino acid concentration increase, beta cells and alpha cells are
stimulated to release their products
 Beta cells  insulin
 Alpha cells  glucagon

 Insulin
 stimulates skeletal muscle and adipose tissue to take up
glucose
 inhibits hormones associated with liver that break down
glycogen or gluconeogenesis to raise blood sugar levels
 lowers blood sugar level
o leads to hypoglycaemia

 Glucagon
 Glucagon stimulates processes in the liver to raise blood
sugar level
 Leads to hyperglycaemia

 Battle between insulin and glucagon

 Insulin inhibiting glycogenolysis and gluconeogenesis
 Glucagon stimulating glycogenolysis and gluconeogenesis
 Effects balance out
o Stops you into going into hypo/hyperglycaemia
when

5. Describe how the body maintains fairly constant blood glucose levels
regardless of frequency/composition of food intake

• Fasting state: blood glucose 3.33-5.56 mmol/L;

• rises to 6.67-7.78 mmol/L after a meal
• should return to normal range ~2 h later and we need that level to be
maintained

Why is it important to maintain blood glucose levels???

- Glucose is the only nutrient that can provide reasonable energy to brain
and tissues (retina)
- At least 50% of all glucose formed by gluconeogenesis during the
postabsorptive state is used by the brain

q As you enter post-absorption state and as glucagon level start to increase in

bloodstream, there are different ways to stimulate processes to maintain
blood sugar level
o (A) Making glucose available to the blood:

1) Glycogenolysis in liver:
o liver has ~100 g of glycogen reserves
 enough to maintain blood glucose ~4-6 h during
postabsorptive state

2) Glycogenolysis in skeletal muscle

o another 100 g (4-6 h) of glycogen reserves
 2-step process, involving liver in second step, to release
glucose to blood
 Not as easy, why?
 Begins the breakdown of glycogen in muscle tissue but
cannot release the glucose because of phosphate.
Must be broken down into pyruvate, lactate

3) Lipolysis in adipose tissue, liver:

o products are glycerol and fatty acids
 glycerol can be used for gluconeogenesis
 realize, breakdown of triglyceride produces one
molecule of glycerol and three long chain fatty acids.
o You need two glycerol to make a single glucose
 Therefore, breaking down triglyceride will not generate huge
amount of substrates to be used in gluconeogenesis
  Fatty acids cannot be used for gluconeogenesis
o Fatty acids only consist of carbon and hydrogens
and no oxygen
o We can chop them into 2-carbon fragments to
produce acetyl CoA
 cannot be converted to glucose but do
provide an alternate energy source via
Krebs cycle

4) Catabolism of protein to produce amino acids for gluconeogenesis:

used if fasting is prolonged & other options becoming exhausted
o

q If all of the tissues use the glucose, good chance glucose will run out shortly.
Therefore, most tissues stimulate to use lipids
o (B) Glucose sparing:
: most tissues are stimulated to use noncarbohydrates (lipids) to spare
glucose for brain
- will use fatty acids & ketone bodies for ATP production

q Back up hormones/systems for glucagon

1. Sympathetic Nervous System
- fight or flight system
- kicks in response to injury, anxiety, anger
o stimulates sudden drop in blood glucose due to sudden increase in
usage of glucose
- adipose tissue is well-supplied with sympathetic nerve fibers
- adrenal medulla also releases epinephrine in response to sympathetic
stimulation
(a) mobilizes fats
(b) stimulates glycogenolysis
(c) stimulates gluconeogenesis

2. Cortisol
- cortisol secretion increased by long-term stressors,
eg. hemorrhage, surgery, infections, physical or emotional trauma,
vigorous exercise, . . .
 cortisol stimulates…
(a) mobilizes fats
(b) stimulates gluconeogenesis
(c) stimulates protein catabolism

***one thing cortisol does if stress is long term that glucagon, epinephrine
don’t is cortisol stimulate enzymes associated with protein breakdowns***
o allows us to have amino acids, substrates, we use for
gluconeogenesis.

Cortisol disease
Cushing’s syndrome:
- syndrome presents high blood cortisol all the time, as opposed to only
when going through long term stress (tumor, excess exogenous cortisol)
o as a result of high circulating level of cortisol, a symptom is
persistent hyperglycemia
 persistent hyperglycemia
:blood sugar level is being raised to higher than normal levels
by the actions of cortisol all of the time even when
unnecessary
 over long term, this can put a person at risk of
developing type 2 diabetes
how?
 if you are constantly raising blood sugar levels, that’s
constantly going to stimulate the release of insulin from
pancreatic beta cells
 if you repeat this over time, eventually, beta cells will exhaust
and be less capable of responding to rise in blood glucose
level to release insulin

Addison’s disease:
- autoimmune destruction of steroid hormone producing cells in adrenal
cortex
o hypoglycemia is a symptom andmust go under cortisol replacement
therapy maintain appropriate levels blood sugar levels when going
through long term stress
3. Growth hormone / Thyroid hormone

- minor players in the day-to-day regulation of metabolism.

- They have other very important primary actions but influence some
aspects of metabolism as a result of those primary actions.
o Growth hormone stimulates body growth in targe
o Thyroid hormone to regulate Basal Metabolic Rate (BMR) in target
tissues

o As a result, they have influence on blood glucose level, metabolism

of other nutrient molecules like lipids or proteins

Growth Hormone (anterior pituitary)

- primarily an anabolic hormone

o stimulates synthetic processes
but also:
a) mobilizes fats to provide energy for body growth
b) reduces glucose uptake by muscles to leave enough glucose in the
bloodstream to support body growth
c) stimulates protein synthesis and inhibits protein degradation

Thyroid Hormone
• primary role is to increase BMR
• mixture of insulin-like and glucagon-like actions
a) stimulates glucose oxidation to provide energy during absorption state
b) mobilizes fats
c) stimulates uptake of amino acids to promote protein synthesis
6. Explain why diabetes mellitus is described as “famine in the midst of plenty”

- ‘Midst of plenty’ refers to the fact that there’s plenty of glucose present in
bloodstream
- ‘famine’ refers to the absence of insulin

• A metabolic disorder due to lack/absence of insulin, insulin resistance,

or both. As a consequence, glucose cannot be used properly, leading
to altered metabolism of fats & proteins.

Two main types of diabetes mellitus: Type I and II

Type 1
- insulin-dependent diabetes mellitus (IDDM)
 o Autoimmune disease: complete loss of beta cells that are
responsible for producing insulin
- 10% of cases
- primarily a result of -cell destruction
o prone to ketoacidosis
- plasma insulin level decreases as -cell are destroyed
o responds poorly or not at all to rise in glucose
- -cell destruction; islet cell antibodies (ICAs)
o Evidence immune system has been activated to destroy -cell
o viruses often suspected trigger
 onset often after infections - autoimmune response extends to
-cells
o absolute deficiency of insulin  hyperglycemia, enhanced lipolysis &
protein catabolism; individuals prone to ketoacidosis; require insulin

Type 2
- non-insulin-dependent diabetes mellitus (NIDDM)
- adult-onset, usually after age 30; 70-80% of patients are obese
o ~80% of cases correlated with a positive family history
- insulin production at birth but also a level of insulin resistance
- insulin resistance initially overcome by increased insulin secretion; finally,
-cells begin to become exhausted
o primary problem is with insulin resistance, therefore injecting more
insulin will not work because their structure of the receptor is
defective
- not prone to ketoacidosis
o because while -cells are exhausted, they are still able to produce,
just at slower rate
o usually do not require insulin – but may require other medications to
reduce gluconeogenesis, address insulin resistance
7. Describe the laboratory tests used to diagnose diabetes mellitus

A. Fasting Plasma Glucose (FPG)

- goal: to measure blood-glucose level when the individual is well into post-
absorptive state
- up to 1998, cut-off was 7.8 mmol/L (signaled ~40% of diabetic cases)
- measure early AM, at least 8 h after last meal
- cut-off level of 6.67 mmol/L (120 mg/dL) is more sensitive and agrees
more closely with OGTT results (second step for all patients > 6.67 mol/L)

B. Oral Glucose Tolerance Test (OGTT)

Underlying principle
: a nondiabetic can absorb a given amount of glucose from blood faster
than a diabetic
- To observe how well beta cell insulin production responds to injection of
glucose

Oral glucose load:

a) 75 g/ 2 h test
b) 100 g/ 3 h test
- levels should peak, then return to normal within 2-3 h;
- urine should remain free of glucose

C. Glycosylated Hemoglobin:
- glycosylated Hb = hemoglobin A1c (Hb1c)
- formed slowly & irreversibly during the120-day lifespan of RBC
- levels usually <5% of Hb – that is normal
 - amount of Hb1c increases in response to elevated [blood sugar]
- good diabetic control should maintain level < 6%
- test provides information on control of blood glucose over an interval of
time, rather than blood glucose levels measured on a particular day
- will differentiate between poor control during preceding few months and
an acute illness which has elevated blood glucose

7. Briefly explain the physiological bases for the clinical signs and complications
associated with diabetes mellitus

A. Basic Clinical Signs:

3 “polys” are key signs common to diabetics:
 polyuria
- excess glucose in filtrate prevents water reabsorption by kidneys
 excess urine production also associated with loss of Na+ and K+ as body
strives to get rid of excess, negatively charged ketone bodies

 polydipsia
- dehydration (water loss in urine) stimulates hypothalamic thirst centers
- unable to storage the water because water takes up all the solutes

 polyphagia
- excessive hunger & food consumption because person is actually starving
- unable to use ingested carbohydrates
- feminine in the midst of plenty
o Type 1

- DM also characterized by weight loss & weakness; at risk for infections

(hyperglycemia interferes with neutrophil function)

Acute Complications of Diabetes Mellitus:

1) Diabetic Ketoacidosis
- Consequence of type 1 diabetes
- Serious lack of insulin
2) Hyperglycemic, hyperosmolar, nonketotic (HHNK) Coma
- type 2 diabetes
- sufficient insulin that ketone body accumulation is not a concern
- extreme dehydration due to excessive gluconeogenesis
- often seen in elderly type 2 diabetics who may be going through a
stress of longer duration (recovery from surgery, bad bout of the
flu, . . . )

3) Insulin Reaction
- hypoglycemia occurs often as a consequence of insulin therapy, etc.
1) insulin overdose
2) inadequate food intake
3) increased amount of exercise
4) nutritional/fluid imbalances due to nausea/vomiting
* The key issue is glucose deprivation to the brain