Biochemical & Clinical

consequences of altered
hormone action with particular
emphasis on NIDDM, IDDM,
and other endocrine disorder
relevant to clinical practice

What is hormone
Definition- hormone is a messenger substance that
convey information signal relevant to cell functions.
Type of hormone
Peptide hormone (water soluble hormone)
Steroid hormone ( lipid soluble hormone)
Amino acid derived hormone (T3 lipid soluble
hormone, cathecolamine water soluble hormone)

Lipid Soluble and Water

Soluble

Case scenario
Zainab who is 48 years old & has type 2 DM
She is breathless, anxious & sweating
She rushing to dental clinic because shes
late for her appointment
Diabetes Mellitus type 1, destruction of B cells (autoimmune)
Diabetes Melitus type 2, the body produces insulin but the target
cells become resistant and unresponsive to it. Diabetes can also
be caused by the body not producing enough insulin. The glucose
does not enter the muscle and liver cells like it should and it
builds up in the blood causing complications.

Type of Diabetes Mellitus

Insulin is a
water soluble
hormone

Insulin synthesis

Insulin secretion
GLUT 2, Glucose sensitive
receptor
High concentration of
Glucose
B cell takes up glucose
through GLUT 2, glucose
phosphorylated by
glucokinase
ATP generated by glycolysis
Closes ATP sensitive
potassium channels,
depolarises cell,
Cause influx of calcium via
voltage sensitive channel
Stimulates release of insulin

Insulin receptor, protein kinase and

protein phosphory

Glucose transporters
Transport
er

Tissue Distribution

Special Properties

GLUT 1

Red blood cells, brain

microvessels, kidney, colon
and other cells

May limit glucose

transport into brain

GLUT 2

Liver pancreatic B cells,

basolateral surface of small
intestine

High capasity, low

affinity

GLUT 3

Neurons, placenta, testes

Low K possibly 1mM

GLUT 4

Fat, skeletal muscle and heart

Mediates insulin
stimulated glucose
uptake

GLUT 5

Small intestine, testes and

sperm.
Lower level in kidney, Skeletal

Fructose transporter

Hormone sensitive lipase

In the Liver
Insulin stimulates
Gycolysis and
Glycogen synthesis
Inhibit lipolysis and
Gluconeogenesis
It stimulates
synthesis of Fatty
Acid and
Triacylglycerols
Promotes lipid
transport from the
liver to peripheral
tissues
Induces endothelial
Lipoprotein, an
enzyme that
liberates

In the Muscle
It stimulates
Glucose transport
via Glut 2
transporter
Glycolysis activated
= ATP + Piruvate
and Glycogen
synthesis
It increase cellular
uptake of amino
acid and stimulates
protein synthesis

In Adipose Tissue
Stimulates Triglyceride synthesis from Glycerol-3-phosphate
and Fatty Acid
And Glycolysis

Glycogen synthase (liver &

muscle)

Metabolism in fed state

How adrenalin and glucagon

appose insulin action

Insulin receptor
activation
activates off
switches in this
case

Case Scenario

Zainab DM is due to insulin resistance

Shes taking oral hypoglycaemic to assist
insulin release
How things happen to her???

Type 2 diabetes induction

Obesity

Decrease insulin receptors in

Type 2
Decreased level of insulin
receptors on the cell
surface will decrease the
responsiveness of the cell
to insulin and therefore
insulin resistance
Insulin resistant could
be caused by a defect
at several levels
Compromised insulin
binding to its receptor
mutation of insulin
receptor gene
Antireceptor
autoantibodies
Defects in the insulin
signaling pathways

Decrease insulin secretion

Elevated Fatty Acid contributed to insulin

resistance by inhibiting peripheral glucose
disposal, enhancing hepatic glucose output
and damaging B-cell function.

Type 2 diabetes with diet

Decreased ability
of tissues to use
glucose
Hyperglycemia is
caused by the
combined effect of
impaired
peripheral glucose
uptake and
increased liver
gluconeogenesis
Excess of FA
available to liver
with less efficient
TCA cycle due to
oxaloacetate being
use in
gluconeogenesis,
result in
accumulation of

 Serious electrolyte losses also

occur as the body rids itself of
excess ketones.
Ketones are negatively
charged and carry positive
ions out with them.
Sodium and potassium are
also lost from the body;
because of the electrolyte
imbalance, the person get
abdominal pains and
may vomit, and the
stress reaction
spirals even higher.

Chronic high level blood glucose

Advance Glycation End Products (AGEs) formation in high

glucose concentration
Spontaneous formation of a covalent bond with proteins
Happens in blood and in cells that do not have Glut 4 transporters
E.g apolipoproteins and LDL receptors (import cholesterol into the
cells) alter cholesterol metabolism and lead to increased BP and
heart problem due to artherosclerosis
BV walls endothelium bind to AGE R lead to oxidative stress
loss of tissue perfusion =inflammatory reaction
Intracellular proteins where glucose uptake does not need insulin
Red Blood cell HGBA1c
Nervous system neuropathy
Kidney decreased perfusion

Case scenario

Nieta has a dental visit. On waiting she is

extremely anxious about her visit to the
dentist.

NIETA IN STRESS

Hormones that involved in this

situations

Adrenalin
Glucagon
Cortisol

Anti- insulin
hormone

All of this hormones also involve during fasting,

and not only occur during fight and flight
reaction but also in trauma, burns surgery and
infection.

Adrenaline is a
water soluble
hormone

Adrenaline
Synthesis
Produced by amino acid tyrosine
Most source from dietary intake
Some of tyrosine form from phenylalanine

Adrenaline
adrenalin is
synthesis &
then stored in
secretory
granules ready
for rapid
release
Adrenalin
stored in
vesicle adrenal
chromaffin
cell- medulla
Activation of
sympathetic
induces
adrenalin
Transport into catecholamine secreting neurons & adrenal
medullary cell
release
by concentration mechanism
Since epinephrine is a water soluble hormone, after release its free to
travel in blood until reach a cell that has a receptor they can bind to.

Receptor water soluble

ligands
3 main classes
Ion-channel coupled receptors
Enzyme coupled receptors
G-protein coupled receptors
Adrenalin acts through G-protein coupled
receptors

MO
A

Types of -adrenergic
receptor
-adrenergic receptors respond particularly to epinephrine and to such
blocking agents as propranolol.
There are three known types of beta receptor, designated 1, 2 and
3.
1-Adrenergic receptors are located mainly in the heart.
2-Adrenergic receptors are located mainly in the lungs, gastrointestinal
tract, liver, uterus, vascular smooth muscle, and skeletal muscle.
3-receptors are located in fat cells

Acting on - receptor

- Acting on - receptor
- Transmit signal to adenylate cyslase via
activated G protein.
This process will increase cAMP & activate
protein kinase
Activated protein will lead to open ion
channel and activates enzyme

Types of -adrenergic
receptor
-adrenergic receptors are adrenergic receptors that respond to
norepinephrine and epinephrine to such blocking agents as
phenoxybenzamine.
They are subdivided into two types:
1, found in smooth muscle, heart, and liver, with effects including
vasoconstriction, intestinal relaxation, uterine contraction and pupillary
dilation,
2, found in platelets, vascular smooth muscle, nerve termini, and
pancreatic islets, with effects including platelet aggregation,
vasoconstriction, and inhibition of norepinephrine release and of insulin
secretion.

Acting on -receptor
Signal transfer from epinephrine receptor to PLC
via activated G protein.
PLC hydrolyzes IP2 to form DAG & IP3
IP3 stimulate release ca2+ from endoplasmic
Reticulum
Ca2+ & DAG activated PKC
Amount of calcium binding protein (calmodulin)
increase
Colmudulin will activate enzyme

Nieta is so anxious
Her BP,HR increase
Sweating
She is ready to fight or flight
This condition needs lots of energy

Fight or Flight Response

Cellular response to
adrenaline
The metabolic effect of adrenaline are similar to glucagon inhibit
glycolisis and lipogenesis. Responsible for hyperglycemia in
response to stress.
Adipose tissue release of free fatty acid (ffa) via
hormone sensitive lipase
Liver
- increase ffa utilized & ketone bodies synthesis
- increase gylcogenolysis via activation glycogen
phosphorylase & inactivation glycogen synthetase
- increase gluconeogenesis via pyruvate carboxylase from
3 glycerol, alanine and lactate

Muscle- increase ffa utilization via beta

oxidation and by decrease glucose uptake
- increase gylcogenolysis via activation
glycogen phosphorylase & inhibition
glycogen
synthetase

Degradation
Half life in
minutes
Once stimulus is
finished rapidly
return to basal
state.

Case scenario

Haziq 25 years old with hyperthyrodism

he appear anxious & sweating

Thyroid is a
lipid soluble
hormone

Major source of
iodine
Thyroid hormones are unique biological molecules in that
they incorporate iodine in their structure.
Thus, adequate iodine intake either through diet or water
is required for normal thyroid hormone production.
Major sources of iodine are:
- iodized salt

- iodated bread

- dairy products

- shellfish
Minimum requirement(RDA): 75 micrograms/day
US intake: 200 - 500 micrograms/day

Thyrosine synthesis
Iodide absorb from diet
by bloodstream to thyroid
gland. pump into the cell
in response to TSH
Tyrosine residue in
thyroglobulin iodinated
with the free iodide
within the follicle lumen
Iodinated thyroglobulin
degraded in the lysosome
Thyroid hormone release
by passive diffusion to
the bloodstream
Thyroid hormone bind to
carrier protein &
distributed through out
the body
Transport via carrier
protein thyrosine-(TBG)

T4/T3 plasma
concentrations

T3 has much greater biological activity than T4.

A large amount of T4 (25%) is converted to T3 in peripheral
tissues.
This conversion takes place mainly in the liver and kidneys. The
T3 formed is then released to the blood stream.

Moa thyroid hormon

Thyroid hormone in oral

health

Case presentation
Sarimah 58 years old come to dental clinic with
complaint of
Burning mouth sensation bilateral and affects
the tongue, lips, palate, gingival, and areas of
denture support
dryness of mouth
eating disorders
On examination, oral mucosal changes,
salivation reduce, osteoporosis

Estrogens
Present in both men and women
Promote development of female secondary
sex characteristics
Stimulate endometrial and uterine growth
Reduce bone resorption, increase bone
formation

Estrogens
Three major types of natural estrogens

Estrogen Synthesis
Estrogen is produced primarily by developing follicles in the
ovaries, the corpus luteum, and the placenta
Follicle-stimulating hormone (FSH) and luteinizing hormone
(LH) stimulate the production of estrogen in the ovaries
Some estrogens are also produced in smaller amounts by
other tissues such as the liver, adrenal glands, and the breasts
The ovaries are the principal source of circulating estrogen in
premenopausal women, with estradiol being the main
secretory product
In postmenopausal women, the principal circulating estrogen
estrone, which is synthesized from dehydroepiandrosterone
and secreted by the adrenals

Regulation of Secretion
Daily secretion: 10 to 100 mg
per day starts from graffian
follicle under influence of FSH
Depends on phase of cycle
increases with FSH in surge
preovulatory
Continue to secrete by corpus
luteum after ovulation
During pregnancy large
quantity by placenta upto 30
mg per day
Post menopausal: 2 10 mg
per day only

 The most potent naturally occurring estrogen in humans for

both the Estrogen Receptor alpha- and beta-mediated actions
is 17beta-estradiol, followed by estrone and estriol
Each estrogen contains a phenolic A ring with a hydroxyl
group at carbon 3 and a beta-OH or ketone in position 17 of
ring D
The phenolic A ring is the principal structural feature
responsible for selective, high-affinity binding to both
receptors
Synthesis of estrogen begins from the synthesis of
androstenedione from cholesterol
Androstenedione crosses the basal membrane into
surrounding granulosa cells, where its converted to estrone or
estradiol wither immediately or through testosterone
The conversion is catalyzed by aromatase

Bio-pathway of Estrogen

This figure shows the major

metabolic intermediates in the
usual synthesis of estrogen,
starting with cholesterol,
proceeding to pregnenolone, an
androgen, and then estrogen.

Estrogen Receptors
Estrogens act as signaling molecules by interacting
with specific target cells.
Include tissues of the breast, uterus, brain, heart,
liver, and bone.
These target cells have estrogen receptors.
There are two estrogen receptors that are normally
found in the cells nucleus: ER and ER .
The receptor undergoes dimerization in order for it
to have increased affinity for DNA.

 This estrogen-receptor complex can now

bind to specific DNA sites, called estrogen
response elements (EREs).
Genes are activated to produce messenger
RNA, which guide the synthesis of new
proteins, determined by the cell type.

Actions of Estrogen
On sexual organs (primary and secondary sexual characteristics)
Brings about pubertal changes in vagina, fallopian tube and uterus
growth
Vagina: cornification of epithelial cells with thickening and stratification
of epithelium
Endometrium: Proliferation of endometrium preovulatory (progeterone)
Absence of progesterone anovulatory cycles withdrawal of estrogen
menstruation
Continued estrogen without progesterone delayed menstruation (but
breakthrough bleeding)
Normal event progesterone withdrawal cannot be suppressed by
estrogen
Secondary Sex Characters: Also acne
Metabolic effects: Anabolic but weaker than testosterone pubertal
growth
Continued exposure fusion of epiphyses

 Bone: Important for maintaining bone mass

increased expression of bone mass proteins
(osteonectin, collagen, osteocalcin, alkaline
phosphatase)
Reduce the maturation and activity of osteoclasts
by modifying regulatory cytokines from osteoblasts
Generation of vit.D3 induction of renal hydroxylase
enzyme
Edema salt and water retention
Decreased LDL and Increased HDL level HDL:LDL
ration increased

Menopause
Transition period in a woman's life when her
ovaries stop producing eggs, her body
produces less estrogen and progesterone,
and menstruation becomes less frequent
Symptoms are mood swings, hot flashes and
vaginal dryness

Oral manifestation
Burning mouth syndrome represents a common
oral abnormality that manifests as intense pain
and spontaneous burning sensation affecting
various areas of the oral cavity in the absence
of any identifiable organic abnormalities.
xerostomia or dryness of mouth is yet another
symptom frequently further implicate
decreased salivary flow as a cause for
increased incidence of root caries, oral
discomfort, taste alterations, oral candidiasis,
and periodontal disease in menopausal women.

 The oral mucosal changes may thus range from a

condition referred to as menopausal
gingivostomatitis to an atrophic pale appearing
mucosa Menopausal gingivostomatitis is characterized
by gingiva that bleed readily, with an abnormally pale
dry/shiny erythematous appearance
Susceptibility to progressive periodontitis and
osteoporosis. The exact pathogenesis remains unclear
although increased accumulation of bacterial plaque
and estrogen/serum osteocalcin deficiency have been
suggested as etiological factors. Systemic osteoporosis
leading to generalized bone loss may make the jaws
susceptible to advanced alveolar bone loss, decreased
bone mineral density (BMD) of alveolar
crest/subcrestal alveolar bone and to a smaller extent
ligamentous attachment loss.

 Diabetes / Insulin (2015,2014,2013,2012,2011)

1. Different type 1 & 2 diabetes
2. What is the mechanism of insulin secretion and how is insulin
secretion controlled?
3. Metabolic effect on liver, muscle and adipose tissue?
4. What biochemical changes occur in absence of insulin?
5. Relationship between diabetes & periodontitis?
6. Outline normal metabolism of cholesterol focussing on the role
of VLDLs, LDLs, and HDLs. Then explain how cholesterol
metabolism can be altered in Type 2 diabetes leading to
atherosclerosis.
7. How do the liver, muscle and adipose tissue respond to fast?
(2014)
8. What is the key hormone that is release during the initial
phase of the fast? (2014)
9. During this crash diet he becomes deficient in micronutrients.
What are the oral manifestations of vitamin deficiencies?
(2014)

 Hormone / Adrenaline (2015, 2014,2013)

1. Describe the general features or water
soluble hormones including time of action,
synthesis, release, transport & mechanisms
of action with target cells
2. Outline the effect of adrenaline on liver,
muscle, and adipose tissue.
3. Describe 3 types of cell surface receptor &
signal
transduction mechanisms that each of
these type receptors use to cause specific
cellular responses.

 Hormone/ Thyroid (2014, 2011)

1. What are the general characteristics of
lipid soluble hormones?
2. How is thyroid hormone synthesised and
secreted?
3. What are the physiological effects of high
level of thyroid hormone?
4. How does thyroid hormone normally affect
carbohydrate, lipid and protein
metabolism?
5. What are the biochemical consequences
of a lack
of thyroid hormone? And how
could this affect oral health?

 Estrogen (2012,2010)
1. Discuss their synthesis, secretion, transport,
mechanism of action and normal feedback control
mechanisms that alter their concentration in blood.
2. What class estrogen belongs to? What are
biochemical charaecteristics of this class of
hormone?
3. How can estrogen deficiency lead to changes in
bone density? Does menopause have an effect on
dental health?