ENDOCRINE SYSTEM

BIOCHEMISTRY OF HORMONES

[email protected]
 Signaling Molecules and cell
receptors
Communication by extracellular signals usually
involves the following steps:
– Synthesis and release of the signaling molecule by
the signaling cell
– Transport of the signal to the target cell
– Binding of the signal by a specific receptor protein
leading to its activation
– Initiation of one or more intracellular signal-
transduction pathways by the activated receptor
– Specific changes in cellular function, metabolism, or
development
– Removal of the signal, which often terminates the
cellular response.
Signal Transduction And Hormone
Action
• For a coordinated function of cells in a
tissue, tissues in an organ, organs in a
system and systems in the body, cells
need to be able to communicate with
each other.
• Each cell should be capable of sending
chemical signals to other cells and of
receiving chemical signals from other
cells, as well as signals (chemical or
other) from its immediate
environment.
• A cell can communicate signals to
other cells in various ways.
• Autocrine signaling
• Paracrine signaling
• Endocrine signaling
• Direct signaling
• Synaptic signaling
Types of receptors
• Cell-surface receptor Hormones can also categorized
• Intracellular receptor in to two according to their
solubility
1.Hydrophilic
2.Hydrophobic
Shown in the figure…
(A) hydrophilic--unable to
cross the target cell’s plasma
membrane directly; instead,
they bind to cell-surface
receptors, which in turn
generate signals inside the
target cell.
(B) hydrophobic…diffuse
across the plasma membrane
and bind to receptor proteins
inside the target cell (either in
the cytosol or in the nucleus
Two general mechanisms of hormone
action
Signal transduction differs
depending on the chemical
nature of the hormones.
These are;
Peptide and amine hormones
•Fast
•Plasma membrane receptor
•Effectors: intracellular signaling
•Altering the pre-existing
enzymes
•Gene expression

Steroid and thyroid hormones

•Slower
•Enter the cells
•Nuclear receptors: transcription
factor
•Gene expression
Cell-Surface Receptor Fig…simple intracellular
Proteins signaling pathway activated by
an extracellular signal
molecule.

The signal molecule

usually binds to a
receptor protein that is
embedded in the plasma
membrane of the target
cell and activates one or
more intracellular
signaling pathways
mediated by a series of
signaling proteins.
Finally, one or more of
the intracellular signaling
proteins alters the
activity of effector
proteins and thereby
changes the behavior of
Extracellular
signals can act
slowly or rapidly to
change the
behavior of a
target cell.
Types of cell surface
receptor
There are three types of
cell surface receptors
•Channel-linked receptors
•G-protein-
inked (Transmembrane)
•Catalytic-linked (kinases or
bind kinases).
Ion channel receptors:
When a signaling molecule binds to an ion channel
on the outside of the cell, this triggers the change
of the 3D conformation of the protein and the
channel opens, allowing the ions to move in or
out of the cell following their electrical gradients
and thus altering the polarization of the cell
membrane.
Some ion channels respond to non-chemical stimuli
in the same way, including changes in
– Electrical charge
– Mechanical disturbance of the membrane
Enzyme-coupled
Receptors
• Their main features is that the
intracellular domain of the
receptor is a kinase, that is
activated when the hormone
binds to the extracellular
domain.
• Receptor kinase
phosphorylates an amino acid
residue that is present on the
receptor or an associated
protein.
• Message is transmitted Tyrosine Kinase
through signal transducer Receptors
proteins.
G protein-linked receptors
• They are seven-pass trans membrane proteins.

G-protein-coupled receptor (GPCR). The structure of an inactive G protein.

• Activation of a G protein by an
activated GPCR.
• Binding of an extracellular signal to
a GPCR changes the conformation
of the receptor, which in turn alters
the conformation of the G protein.
• The alteration of the α-subunit of
the G protein allows it to exchange
its GDP for GTP, activating both the
α- subunit and the βγ- complex, both
of which can regulate the activity of
target proteins in the plasma
membrane.
• The receptor stays active while the
external signal molecule is bound
to it, and it can therefore catalyze
the activation of many molecules of
G protein, which dissociate from the
receptor once activated .
• In some cases, the α-subunit and
the βγ- complex dissociate from
each other when the G protein is
activated.
 Signal transduction from cell surface
receptor
There are three common types of signal transduction
pathways
1. cAMP mediated transductions
Stimulation of adenylyl
cyclase, a membrane-
bound enzyme, by the
Gs protein then
catalyzes the
conversion of a small
amount of cytoplasmic
adenosine
triphosphate (ATP)
into cAMP inside the
cell.
This then activates cAMP-dependent
protein kinase, which phosphorylates
specific proteins in the cell, triggering
biochemical reactions that ultimately
lead to the cell's response to the
hormone.
 2. IP3 & DAG mediated signal transduction Some hormones
activate
transmembrane
receptors that activate
the enzyme
phospholipase C
attached to the inside
projections of the
receptors.
This enzyme catalyzes
the breakdown of some
phospholipids in the cell
membrane, especially
phosphatidylinositol
biphosphate (PIP2), into
two different second
messenger products:
The IP3 mobilizes calcium ions from mitochondria and the inositol
endoplasmic reticulum, and
triphosphate
the calcium ions then have their own second messenger (IP3effects, such as smooth
) and diacylglycerol
muscle contraction and changes in cell secretion. DAG, the other lipid second
messenger, activates the enzyme protein kinase C (PKC),(DAG).
which then phosphorylates
a large number of proteins, leading to the cell's response. In addition to these effects,
the lipid portion of DAG is arachidonic acid, which is the precursor for the
prostaglandins and other local hormones that cause multiple effects in tissues
throughout the body.
3. Ca++ mediated signal transduction
• Calcium (Ca++) ions serve even more widely than
cAMP as second messengers. Ca++ levels inside
the cytoplasm of a cell are normally very low
while outside the cell and in the endoplasmic
reticulum are quite high.

• Chemically gated calcium channels in the

endoplasmic reticulum membrane act as
switches; when they open, Ca++ rushes into the
cytoplasm and triggers proteins sensitive to Ca++
to initiate a variety of activities. For example, the
efflux of Ca++ from the endoplasmic reticulum
causes skeletal muscle cells to contract and some
endocrine cells to secrete hormones.

• The gated Ca++ channels are opened by a G-

protein linked receptor. In response to signals
from other cells, the receptor activates its G
protein, which in turn activates the enzyme,
phospholipase C. This enzyme catalyzes the
production of inositol trisphosphate (IP3) from
phospholipids in the plasma membrane.

• The IP3 molecules diffuse through the cytoplasm

to the endoplasmic reticulum and bind to the Ca+
+ channels. This opens the channels and allows
Intracellular Receptors
 Intracellular Receptors cont’d…
Many cell signals are lipid-
soluble or very small
molecules that can readily
pass across the plasma
membrane of the target cell
and into the cell, where they
interact with a receptor.
Some bind to protein
receptors located in the
cytoplasm; others pass across
the nuclear membrane as well Basic structure of a gene-
and bind to receptors within regulating intracellular
the nucleus. receptor.
These receptors are located within
These intracellular receptors
may trigger a variety of the cell and function in the
responses in the cell, reception of signals such as
steroid hormones, vitamin D, and
depending on the receptor.
thyroid hormone.
Intracellular receptors that act as gene regulators
• Some intracellular receptors act as regulators of gene transcription such
as the receptors for steroid hormones, such as cortisol, estrogen, and
progesterone, as well as the receptors for a number of other small, lipid
soluble signal molecules, such as vitamin D and thyroid hormone.
• All of these receptors have similar structures; Because of their structural
similarities, they are all part of the intracellular receptor superfamily.
Each of these receptors has a binding site for DNA.
• In its inactive state, the receptor typically cannot bind DNA because an
inhibitor protein occupies the binding site. When the signal molecule
binds to another site on the receptor, the inhibitor is released and the
DNA binding site is exposed. The receptor then binds to a specific
nucleotide sequence on the DNA, which activates (or, in a few instances,
suppresses) a particular gene, usually located adjacent to the regulatory
site.
• The lipid-soluble signal molecules that intracellular receptors recognize
tend to persist in the blood far longer than water-soluble signals. Most
water-soluble hormones break down within minutes, and
neurotransmitters within seconds or even milliseconds.
Cont’d…
• A steroid hormone like cortisol or estrogen, on the other
hand, persists for hours.
• The target cell’s response to a lipid-soluble cell signal can
vary enormously, depending on the nature of the cell.
• This is true even when different target cells have the same
intracellular receptor, for two reasons:
– First, the binding site for the receptor on the target DNA differs from
one cell type to another, so that different genes are affected when the
signal-receptor complex binds to the DNA, and
– second, most eukaryotic genes have complex controls.
• Thus the intracellular receptor interacts with different
signals in different tissues.
• Depending on the cell-specific controls operating in
different tissues, the effect the intracellular receptor
produces when it binds with DNA will vary.
Figure 7.5. How
intracellular receptors
regulate gene
transcription.
In this model, the binding of
the steroid hormone cortisol
to a DNA regulatory protein
causes it to alter its shape.
The inhibitor is released,
exposing the DNA binding
site of the regulatory
protein. The DNA binds to
the site, positioning a
specific nucleotide sequence
over the transcription
activating domain of the
receptor and initiating
transcription.
HORMONE-RECEPTOR
INTERACTIONS

THYROID HORMONES
 THYROID HORMONES
• All are amino acid derivatives (tyrosine), but are
hydrophobic molecules
• Can freely cross the cell membrane
• Transported in circulation bound to specific protein
carriers
• Bind to intracellular receptors on target tissues
• Synthesis accomplished via iodination of tyrosine
residues on thyroglobulin in iodide cycle
􀂄 Maintain metabolic homeostasis by regulating:
􀂄 Intermediary metabolism
􀂄 Body weight
􀂄 Oxygen requirements
􀂄 Body temperature
􀂄 + control of growth, reproduction and differentiation
 Biosynthesis and Secretion
• Thyroid hormones (THs) play
critical roles in differentiation,
• There are two biologically
growth, and metabolism. TH is active thyroid hormones:
required for the normal function of – Tetraiodothyronine (T4;
nearly all tissues, with major usually called thyroxine)
effects on oxygen consumption – Triiodothyronine (T3)
and metabolic rate. • Derived from modification of
• Thyroid gland tissue is composed tyrosine.
of many follicles with a central
glycoprotein core (colloid – stores
thyoid hormones) surrounded by a
cuboidal epithelium of cells
(thyroid follicular cells). Follicular
cells are functionally asymmetric,
with distinct basolateral and apical
membranes. A rich capillary bed
perfuses the follicles near the
basolateral surface.
• Thyroid follicular cells
manufacture thyroid hormones
and thyroglobulin .
Biosynthesis and Secretion
cont’d..
(1) The Iodide Pump:
• Basolateral iodide (I-) uptake from blood into thyroid follicular
cell requires energy(goes against the Igradient). I- uptake
occurs via the Na+/I- symporter (NIS) (energy is provided by
the basolateral Na+/K+ ATPase).
(2) Thyroglobulin Synthesis and Secretion:
• Thyroglobulin is synthesized and glycosylated in follicular cells
secreted into the lumen by exocytosis (thyroglobulin contains
tyrosine residues thyroid hormones).
(3) Iodine Oxidation:
• I- apical efflux into colloid is via pendrin (Cl-/I- transporter).
Iodide (I-) is oxidized to iodine (Io) by TPO and H2O2.
(4) Tyrosine Iodination(organification)*:
• Oxidized iodine (Io) atoms are covalently attached to tyrosine
rings in thyroglobulin via TPO. 1-2 iodine atoms is incorporated
into each tyrosine ring [ monoiodotyrosine (MIT) or
diiodotyrosine (DIT)]. Iodination is inefficient (~20% of the
available tyrosines in thyroglobulin undergo organification).
(5) Coupling and Storage:
• Two iodinated tyrosine rings (still attached to thyroglobulin) are
coupled by TPO. Precursor (storage) form of thyroid hormones
(coupling of two DIT units -----T4 and coupling of MIT and DIT------
T3). Formation of T3 occurs with less frequency. The coupling
reaction is inefficient (~20% of iodinated tyrosines undergo
coupling - each TG molecule produces only 0.5 molecules of T4).
(6) Colloid Reabsorption and Lysozomal Proteolysis:
• When thyroid hormones are needed, colloid is pinched off and
endocytosed into the follicular cell. The endocytotic vesicles
containing organified thyroglobulin fuse with intracellular
lysosomes, and the thyroglobulin undergoes proteolysis release
of mature T4, T3, and the constituent amino acids of thyroglobulin
(MIT and DIT) into the cytosol of the follicular cell.
(7) Secretion and Recycling: T4 and T3 enter the bloodstream
by
• Simple diffusion across the basolateral membrane. DIT and MIT
are deiodinated (by cytosolic thyroid deiodinase) in the thyroid
follicular cell.
Thyroid Hormone Action
• Thyroid hormones are transported into target cells by
plasma membrane carriers.
• Intracellularly, thyroid hormones bind non-histone
protein nuclear receptors and with Thyroid Hormone
Response Elements (TRE) regulates translation of
various downstream targets.
• The response of various tissues to thyroid hormones
vary and are proportional to the amount of nuclear
thyroid hormone receptors present in the specific tissue
– liver responds with large changes in protein synthesis and
enzyme patterns, while the spleen and testis, are not
influenced by thyroid hormones
– myocardial tissue responds to thyroid hormones by increasing
the number of adrenergic receptors and by increased activity
of actomyosin ATPase.
Thyroid Hormone Physiological Function
• Stimulates both anabolic and catabolic pathways of metabolism and
supports a normal balance between them.
• Regulates body weight and basal metabolism as well as oxygen
requirements.
– Thyroid hormone action on protein expression and activity
– Metabolic increase due to increased body temperature
– Catecholamine-dependent up-regulation of β-adrenergic receptors and
changes in expression of G-proteins .
• Regulates oxidative metabolism (↑ basal metabolic rate and ↑O2
comsumption), ↑ rates of anabolic and catabolic processes, ↑
growth and development, ↑ systemic function.
• Enhanced metabolic activity increases the body’s demand for
oxygen consumption  ↑ cardiac output, ↑ respiratory drive, and ↑
production of red blood cells (↑ EPO), ↑ appetite, ↑ GI motility, and
↑ intestinal absorption.
Metabolic fates of thyroid hormones
• In the peripheral tissues, about 33% of the T4 secreted
undergoes 5'-deiodination to give T3, and another 40%
undergoes deiodination of the inner ring to yield the inactive
material rT3.
• The deiodination of T4 is a reductive process catalyzed by a
group of enzymes named iodothyronine deiodinases referred
to as deiodinases and symbolized by D, found in a variety of
cells.
• Three types of deiodinases are currently known and are
distinguished from each other primarily based on their
location, substrate preference, and susceptibility to inhibitors.
• Type I deiodinase is found in liver and kidney and catalyzes
both inner ring and outer ring deiodination (i.e., T4 to T3 and r
T3 to 3,3'-T2).
• Type 11 deiodinase catalyzes mainly outer ring deiodination
(i.e., T4 to T3 and T3 to 3,3'-T2) and is found in brain and the
pituitary.
• Type III deiodinase is the principal source of rT3 and is present
in brain, skin, and placenta.
Metabolism occurs in liver,
kidney, & other tissues in two
ways: outer ring deiodination
by the enzyme 5'-D, which
yields T3, and inner ring
deiodination by the enzyme 5-
D, which yields rT3, for which
there is no known biologic
function.

Degradative metabolism of
the thyroid hormones, apart
from peripheral deiodination,
occurs mainly in the liver,
where both T3 and T4 are
conjugated to form either
glucuronide (mainly T4) or
sulfate (mainly T3) through
the phenolic hydroxyl group.
 Parathyroid Hormone, Calcitonin and Vitamin
D.
Calcium and Phosphate Metabolism
The calcium in the plasma is
present in three forms:
1)About 41% of the calcium is
combined with the plasma
proteins and in this form is
indiffusible thorugh the capillary
membrane
2)About 9% of the calcium is
diffusible through the capillary
membrane but is combined with
anionic substances of the
plasma and interstitial fluid
(such as citrate and phosphate)
3)The remaining 50% of the
calcium in the plasma is both
diffusible and ionized
 Inorganic phosphate in the
extracellular fluids
• About 85% of the body phosphate is found in the
bones; 14-15 % in the cells and less than 1% in
the extracellular fluid
• Inorganic phosphate in the plasma is mainly in
two forms:
• HPO4-
• H2PO4-
• The average total quantity of inorganic
phosphorus for both ions is about 4 mg/dl
Non-bone physiologic effects of altered
calcium and phosphate concentrations
in the body fluids
• Ca ions in extracellular and cellular fluids is
essential to normal function of a most of
biochemical processes
– Neuoromuscular excitability and signal
transduction
– Blood coagulation
– Hormonal secretion
– Enzymatic regulation
– Neuron excitation
Cont’d…
• Calcium label controlled by transfer of Ca among 3 organs:
intestine, bone, kidneys.
• Changing the level of phosphate in the extracellular fluid
from far below normal or two or three times normal does
not cause major immediate effects on the body
• In contrast, even a slight increase or decrease of calcium
ion in the extracellular fluid can cause extreme immediate
physiologic effects.
• Hypocalcemia causes nervous system excitement and
tetany.
– Increased permeability of neurons to sodium ions
• Hypercalcemia depresses nervous system and muscle
activity.
– These effects become marked as the calcium level rises
above 15 mg/dl
Absorption and Excretion of Calcium
and Phosphate
• Approximately 10% (100 mg/day) of the
ingested calcium is excreted in urine
• Normally, the renal tubules reabsorb 99% of the
filtered calcium, and only 100 mg/day is
excreted in urine
• Renal phosphate excretion is controlled by an
over-flow mechanism, when phosphate level is
below 1 mmol/lt, all phosphate in the glomerular
filtrate is reabsorbed.
Regulation of blood calcium level
Three principal
hormones
regulate Ca2+ and
three organs that
function in Ca2+
homeostasis.
Parathyroid
hormone (PTH),
1,25-dihydroxy
Vitamin D3
(Vitamin D3),
and Calcitonin,
regulate Ca2+
resorption,
reabsorption,
absorption and
excretion from
 Vitamin D
• Vitamin D, after its activation to the hormone 1,25-
dihydroxy Vitamin D3 is a principal regulator of Ca2+.
• Increases Ca2+ absorption from the intestine and Ca2+
resorption from the bone .
• Vitamin D3 synthesis occurs in keratinocytes in the
skin.
• 7-dehydrocholesterol is photoconverted to previtamin
D3, then spontaneously converts to vitamin D3.
• Previtamin D3 will become degraded by over
exposure to UV light and thus is not overproduced.
• Also 1,25-dihydroxy-D (the end product of vitamin D
synthesis) feeds back to inhibit its production.
• Vitamin D itself is inactive, it requires modification
to the active metabolite, 1,25-dihydroxy-D.
• The first hydroxylation reaction takes place in the
liver yielding 25-hydroxy D.
• Then 25-hydroxy D is transported to the kidney
where the second hydroxylation reaction takes
place.
• The mitochondrial P450 enzyme 1α-hydroxylase
converts it to 1,25-dihydroxy-D, the most potent
metabolite of Vitamin D.
• The 1α-hydroxylase enzyme is the point of
regulation of D synthesis.
• Feedback regulation by 1,25-dihydroxy D inhibits
this enzyme.
• PTH stimulates 1α-hydroxylase and increases 1,25-
dihydroxy D.
 Regulation of Vitamin D Metabolism
• PTH increases 1-hydroxylase activity, increasing production of
active form.
• This increases calcium absorption from the intestines, increases
calcium release from bone, and decreases loss of calcium through
the kidney.
• Low phosphate concentrations also increase 1-hydroxylase activity
(vitamin D increases phosphate reabsorption from the urine).
PTH

1-hydroxylase

25-hydroxycholecalciferol 1,25-dihydroxycholecalciferol

increase
Low phosphate phosphate
resorption
Mechanism of Action
• The active form of vitamin D binds to intracellular receptors
that then function as transcription factors to modulate gene
expression.
• The vitamin D receptor forms a complex with another
intracellular receptor, the retinoid-X receptor, and that
heterodimer binds to DNA.
• In most cases studied, the effect is to activate transcription,
but situations are also known in which vitamin D suppresses
transcription.
• The vitamin D receptor binds several forms of
cholecalciferol. Its affinity for 1,25-dihydroxycholecalciferol
is roughly 1000 times that for 25-hydroxycholecalciferol,
which explains their relative biological potencies.
• because it is lipid soluble, it travels in the blood bound to
hydroxylated α-globulin.
• There are many target genes for Vitamin D.
 Parathyroid Hormone
• PTH is synthesized and secreted by the parathyroid
gland which lie posterior to the thyroid glands.
• The blood supply to the parathyroid glands is from
the thyroid arteries.
• The Chief Cells in the parathyroid gland are the
principal site of PTH synthesis.
• It is the major hormone of Ca homeostasis in
humans.
• PTH is translated as a pre-prohormone.
• Cleavage of leader and pro-sequences yield a
biologically active peptide of 84 aa.
• Cleavage of C-terminal end yields a biologically
inactive peptide.
Structure of PTH
Synthesis of PTH
 Regulation of PTH secretion

Regulated by the negative feed back of ca++

concentration
• When Ca2+ falls, cAMP rises and PTH is secreted.
• High Ca++ inhibits the secretion of PTH
• 1,25-(OH)2-D inhibits PTH gene expression,
providing another level of feedback control of
PTH.
• Despite close connection between Ca2+ and PO4,
no direct control of PTH is exerted by phosphate
levels
Calcium
regulates
PTH
secretion
 Mechanism of Action of PTH
• PTH binds to a G protein-
coupled receptor.
• Binding of PTH to its
receptor activates 2
signaling pathways:
- increased cyclic AMP
- increased phospholipase
C
• Activation of PKA appears
to be sufficient to decrease
bone mineralization
• Both PKA and PKC activity
appear to be required for
increased resorption of
calcium by the kidneys
 Calcitonin
• Calcitonin is a hormone secreted from the parafolicular of C
cells in the thyroid gland, known to participate in calcium and
phosphorus metabolism.
• Calcitonin is a 32 amino acid peptide cleaved from a larger
prohormone.
• It contains a single disulfide bond, which causes the amino
terminus to assume the shape of a ring.
• Calcitonin plays a role in calcium and phosphorus metabolism.
• Acts on two well-studied target organs:
• Bone:
– Calcitonin suppresses resorption of bone by inhibiting the activity
of osteoclasts, a cell type that "digests" bone matrix, releasing
calcium and phosphorus into blood.
• Kidney:
– Calcium and phosphorus are prevented from being lost in urine
by reabsorption in the kidney tubules.
– Calcitonin inhibits tubular reabsorption of these two ions, leading
to increased rates of their loss in urine.
Control of Calcitonin Secretion
• The most prominent factor controlling calcitonin
secretion is the extracellular concentration of
ionized calcium.
• Elevated blood calcium levels strongly stimulate
calcitonin secretion, and secretion is suppressed
when calcium concentration falls below normal.
 PANCREATIC HORMONES
Three Cell Types secrets the pancreatic hormones
• Alpha cells produce glucagon.
• Beta cells produce insulin. Pancreatic
• Delta cells produce somatostatin.Hormones, Insulin
and Glucagon,
Regulate
Metabolism
 Structure of Insulin

• Insulin is a
polypeptide hormone,
composed of two
chains (A and B)
• Both chains are
derived from
proinsulin, a
prohormone.
• The two chains are
joined by disulfide
bonds.
Roles of Insulin
The Insulin Receptor and Insulin
action
The insulin receptor is composed of two
subunits, and has intrinsic tyrosine kinase
activity.
Activation of the receptor results in a cascade
of phosphorylation events: … Cell Responese
•Increased activity of glucose transporters.
 Moves glucose into cells.
•Activation of glycogen synthetase.
 Converts glucose to glycogen.
•Inhibition of phosphoenolpyruvate
carboxykinase.
 Inhibits gluconeogenesis.
•Activation of acetyl CoA carboxylase.
 Stimulates production of free fatty acids
from acetyl CoA.
•Activation of lipoprotein lipase (increases
breakdown of triacylglycerol in the
circulation).
 Fatty acids are then taken up by adipocytes,
and triacylglycerol is made and stored in the
cell.
 Insulin Action on Cells:
Dominates in Fed State Metabolism
 Regulation of
Insulin
Release
Major stimulus:
increased blood
glucose levels
•After a meal, blood
glucose increases
•In response to
increased glucose,
insulin is release
•Insulin causes uptake
of glucose into tissues,
so blood glucose levels
decrease
•Insulin levels decline
as blood glucose
declines
 Other Factors Regulating Insulin Release
• Amino acids stimulate insulin release (increased
uptake into cells, increased protein synthesis).
• Keto acids stimulate insulin release (increased
glucose uptake to prevent lipid and protein
utilization).
• Insulin release is inhibited by stress-induced
increase in adrenal epinephrine
– epinephrine binds to alpha adrenergic receptors
on beta cells
– maintains blood glucose levels
• Glucagon inhibits insulin secretion (glucagon has
opposite actions).
Structure and Actions of Glucagon
 Peptide hormone, 29 amino acids
 Acts on the liver to cause breakdown of glycogen
(glycogenolysis), releasing glucose into the
bloodstream.
 Inhibits glycolysis
 Increases production of glucose from amino acids
(gluconeogenesis).
 Also increases lipolysis, to free fatty acids for
metabolism.
Result: Maintenance of blood glucose levels during
fasting.
 Mechanism of Action of
Glucagon
• Main target tissues: liver, and adipose
tissue
• Binds to a Gs-coupled receptor, resulting
in increased cyclic AMP and increased
PKA activity.
• Also activates IP3 pathway (increasing
Ca++)
 Glucagon Action on Cells:
Dominates in Fasting State Metabolism
• Glucagon prevents hypoglycemia by  cell
production of glucose
• Liver is primary target to maintain blood
glucose levels
Glucagon Action on Cells: Dominates in
Fasting State Metabolism
 Targets of Glucagon Action
• Activates a phosphorylase, which cleaves off a
glucose 1-phosphate molecule off of glycogen.
• Inactivates glycogen synthase by
phosphorylation (less glycogen synthesis).
• Increases phosphoenolpyruvate
carboxykinase, stimulating gluconeogenesis
• Activates lipases, breaking down triglycerides.
• Inhibits acetyl CoA carboxylase, decreasing
free fatty acid formation from acetyl CoA
• Result: more production of glucose and
substrates for metabolism
 Regulation of Glucagon Release
• Increased blood glucose levels inhibit
glucagon release.
• Amino acids stimulate glucagon release
(high protein, low carbohydrate meal).
• Stress: epinephrine acts on beta-
adrenergic receptors on alpha cells,
increasing glucagon release (increases
availability of glucose for energy).
• Insulin inhibits glucagon secretion.
 Energy Regulation of Pancreas

• Islets of Langerhans contain 3 distinct

cell types:
– α cells:
• Secrete glucagon.
– β cells:
• Secrete insulin.
– δ cells:
• Secrete somatostatin.

