Unit 9
Endocrine System
Session 32
Introduction to the Endocrine System
Session Outline
Introduction
32.1 Organs of the endocrine system
32.2 Features of hormones
32.3 Types of hormones and their modes of action
32.4 Stimulation of hormone secretion
Summary
Learning Outcomes
Introduction
The physiological activities of the body are maintained only if the internal environment of the
body is kept constant. This is maintained only with the help of two major regulating systems in
the body. They are the endocrine system and the nervous system.
Compared with other organs of the body, the endocrine organs are small. Endocrine organs are
widely scattered throughout the body. Endocrine glands are also called ductless glands as they
produce hormones and release it to the blood stream without ducts. They release their hormones
into the surrounding tissue fluid or the blood (endo = within; crine = to secrete). The endocrine
organ generally has a rich vascular and lymphatic drainage that receives the secreted hormones.
Homeostasis (constancy) of the internal environment is maintained by two systems. They are the
endocrine system and the autonomic nervous system. The autonomic nervous system brings
about very rapid changes, while the endocrine system brings about slow and more precise
changes
The endocrine system, interacts with the nervous system to coordinate and integrate the activity
of body cells. The endocrine system influences the metabolic activities of the body by
secretions known as hormones . (The word ‘hormone’ is known to have the meaning ‘to excite’
in Greek). Hormones are secreted by several glands of the body.
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32.1 Organs of the Endocrine system
There are many organs and tissues associated with endocrine function. The hypothalamus is
associated with endocrine function and is also a major regulator of the pituitary gland. Hence it
will be discussed with the pituitary gland in the next session.
The major endocrine organs and their secretions are listed in the table below
Endocrine organ
Pituitary gland
Thyroid gland
Hormones secreted
Growth hormone, Thyroid Stimulating
hormone,
Adreno cortico tropic hormone. Follicular
stimulating Hormone, Leutinizing
hormone, Prolactin,
Thyroxine, tri iodo thyronine
parathyroid glands
Parathormone
adrenal (suprarenal) glands
pancreatic islets (islets of Langerhans)
pineal gland or body
thymus gland
ovaries in the female
testes in the male.
Gastro intestinal tract hormone
Epinephrine, nor epinephrine, o
Insulin, glucogon, sommatostatin.
Melatonin
Oestrogen, progesterone,
testosterone
Gastrin, cholecystokinin pancreozymin,
secretin
These organs are all shown in the diagram below. Figure 32.1
2
Figure 32.1 Endocrine organs of the body
32.1
Self Assessment Questions
Can you explain the importance of the endocrine system
Can you list the organs of the endocrine system?
Can you list the hormones secreted by each endocrine glandsf
32.2 Features of Hormones
Hormones are chemical messengers. They have several features. They are briefly explained
below.
•
Hormones are released into the blood and are transported throughout the body.
Hormones which are released into the blood have their action in a site away from the
point of secretion. Endocrine glands consist of a group of secretory cells surrounded
by capillaries.
•
•
At various tissues where the hormones act, the target cells contain specific hormone
binding sites within its cellular organelles.
When a hormone binds to a hormone binding site in a cell, it stimulates specific
responses in a cell. These initiated responses can go on for a few seconds to even days.
Therefore the responses activated by the endocrine system are much slower in action. The
actions of hormones continue to go on for a prolonged period than those activated by the
nervous system.
3
•
32.2
•
•
Can you briefly outline the main functions of hormones?
What are the retroperitoneal organs in the body ?
Self Assessment Questions
32.3 Types of hormones and their modes of action
There are several types of hormones and they are steroids, peptides and amino acids.
Steroid hormones are cortisol, aldosterone and testosterone. Parathormone and insulin are
peptides and thyroxine is an amino acid.
When hormones reach the target cell via the blood circulation it will only act on cells which have
receptors to bind the hormone. Therefore when a hormone reaches a target cell it binds to the
hormone receptor.
Hormone binding receptors are located in three major sites in a cell. These binding sites are the
cell membrane, the cytoplasm and the nucleus. When the hormone binds to the receptor it
stimulates a specific physiological action in the target cell.
The hormones stimulate several physiological mechanisms within the cell. These are listed
below.
A hormonal stimulus typically produces one or more of the following changes:
1. Alters the permeability of the cell membrane or the potential of the cell membrane, or
both, by opening or closing ion channels
2. Stimulates synthesis of proteins or regulatory molecules such as enzymes within the cell
3. Activates or deactivates enzymes
4. stimulates secretory activity
5. Stimulates mitosis by activating genes
The endocrine glands include the pituitary, thyroid, parathyroid, adrenal, pineal, and thymus
glands. The hypothalamus, along with its neural functions, produces and releases hormones, so
we can consider the hypothalamus as a neuroendocrine organ. In addition, several organs contain
specific areas of endocrine tissue and produce hormones as well as exocrine products. Such
organs, (eg pancreas, gonads (ovaries and testes)), are also major endocrine glands.
32.3
Self Assessment Questions
Can you list the changes that occur in a cell when it is stimulated by a hormone?
Stimulation of hormone secretion:
Secretion of hormones can be stimulated by three main mechanisms. They are the humoral
stimulus, the neural stimulus, and the hormonal stimulus. They are outlined below.
4
(a) Humoral stimulus: Low blood calcium levels triggers the parathyroid glands. The
parathyroid gland releases parathyroid hormone. This hormone causes blood Ca2+ levels to rise
by stimulating release of Ca2+ from bone (Figure 32.2). In this case the humoral substance is
Ca2+.
Figure 32.2 Release of hormones by humoral stimulus
(b) Neural stimulus: Stimulation by nerve fibers can trigger the release of hormones. As an
example when the sympathetic nervous system fibers stimulate the adrenal medullary cells it
stimulates the release of catecholamines ( epinephrine and norepinephrine) into the blood ( figure
32.3).
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Figure 32.3 Release of hormones by neural stimulus (c) Hormonal stimulus: In this method of
hormone release a hormone from one endocrine organ stimulates the release of several hormones
from several target organs. As an example, hormones released by the hypothalamus stimulate the
anterior pituitary to release hormones that stimulate other endocrine organs to secrete hormones
(figure 32.4)
Figure 32.3 Release of hormones by hormonal stimulus
The synthesis and secretion of most hormones are controlled by the hypothalamus and / or the
anterior pituitary gland. Therefore the next session will first discuss the hypothalamus and the
pituitary gland.
32.4
Self Assessment Questions
List the stimuli that activate the secretion of a hormone
Can you list an example for each type of secretion?
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Positive feed back mechanism and negative feed back inhibition- Regulation of secretion of
hormones
The hormones released by the hypothalamus, pituitary and the target endocrine organ are
regulated by negative and positive feed back mechanisms. That is hormones from the
hypothalamus may stimulate or may inhibit the secretions from the anterior pituitary gland. The
anterior pituitary gland secretes tropic hormones which stimulate the target endocrine glands.
Hormones secreted by the target endocrine gland may in turn inhibit the secretions from the
anterior pituitary gland and this is called negative feedback mechanism. When hormones from
the target organs further stimulate the pituitary gland to secrete even further it is called a positive
feed back mechanism.
Hormonal rhythms
Most endocrine secretions occur in rhythms. When these rhythms of secretion are timed within a
24 hour cycle it is known as a circadian (or diurnal) rhythm. Some of the circadian rhythms
known are the sleep wake cycle to time with day and night time, and the secretion of cortisol in
the body.
32.5
Self Assessment Questions
What is meant by hormonal rhythms?
What is the link between the hypothalamus and the pituitary?
Can you explain a positive feed back mechanism and a negative feed back mechanism with mples?
Summary
In this session you learnt about the importance of endocrine glands and their secretions in
maintaining homeostasis. Hormones are released into the blood and are transported throughout
the body.
They have their action in a site away from the point of secretion. Therefore
endocrine glands consist of a group of secretory cells surrounded by a rich net work of
capillaries. The tissues where a hormone acts is known as the target cell. Target cells contain
specific hormone binding sites within its cell. When a hormone binds to a hormone binding site
in a cell, it stimulates specific responses in a cell. These stimulated responses can last only for a
few seconds or go on for even days.
The responses activated by the endocrine system are much slower in action than nervous
responses.
A hormonal stimulus typically produces several changes in the cell. They alter the permeability
of the cell membrane or the potential of the cell membrane, stimulate synthesisof proteins or
enzymes, activates or deactivates enzymes, stimulate secretions or stimulate mitosis. The major
stimuli that activate secretion of hormones are humoral stimuli, nervous stimuli and endocrine
stimuli.
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Learning outcomes
After studying this section you should be able to;
Briefly explain the features of a hormone
List the endocrine organs in the body and their secretions
List the types of hormones and their modes of action
Briefly explain the stimuli that bring about secretion of hormones
Explain the changes that occur in the target cell when the hormone receptor complex binds to the
target cell
Briefly explain the negative feed back mechanism and the positive feed back mechanisms that
regulate the secretion of hormones with examples
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Session 33
HypothaIamus and Pituitary gland
Session Outline
Introduction
33.1 Organs of the urinary system
33.2 Basic structure of the urinary system
33.3 Blood and nerve supply
33.4 Functions of the urinary system
33.5 Regulation of the functions of the urinary system
Summary
Learning Outcomes
Introduction
The pituitary gland secretes the largest number of hormones in the body. The Hypothalamus and
the pituitary gland together form a special axis which regulates the functions of several endocrine
glands in the body. Some of the organs that are regulated by the pituitary are the thyroid gland,
the ovary, the testis, and the adrenal gland.
Figure 33.1 The structure of the Hypothalamus and the Pituitary gland
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The hypothalamus and the pituitary gland (hypophysis) both act as one unit. These glands
together have the ability to regulate the activity of most of the other endocrine glands.
The hypothalamus lies above the pituitary gland and connects to the pituitary gland by a stalk.
The pituitary gland is about the size of a pea and lies in the hypophyseal fossa of the sphenoid
bone. It is located below the hypothalamus and is attached to the hypothalamus by a stalk.
It has three separate parts and each part has its own different type of cells. The anterior
Pituitary (adenohypophysis) is composed of glandular epithelium, the posterior
Pituitary (neurohypophysis) is composed of nervous tissue from the brain. There is a network of
nerve fibres in between the anterior and posterior pituitary is known as the intermediate lobe.
The hypothalamus influences the secretion of the pituitary gland by two methods. They are
briefly outlined below.
The influence of the hypothalamus on the anterior pituitary -The hypothalamus
communicated with the anterior pituitary is supplied indirectly with arterial blood that comes
from a capillary network in the hypothalamus. This network of blood vessels forms part of the
pituitary portal system. The releasing and inhibiting hormones secreted by the hypothalamus
respectively stimulate or inhibit the secretions from the anterior pituitary gland.
The posterior pituitary- This is formed from nervous tissue. It is composed of nerve cells
communicating downwards from the hypothalamic nuclei. These neurone axons form the
hypothalamohypophyseal tract. The posterior pituitary hormones are produced in the
hypothalamic nerve cells, they are transported along the axons and then stored in vesicles within
the axon terminals to be released when required.
33.2
Self Assessment Questions
Can you explain the link between the hypothalamus and the pituitary gland?
Can you explain the pituitary portal system?
What is meant by the hypothalamo hypophyseal tract?
Pituitary hormones are secreted by the pituitary gland. They are secreted by the anterior and
posterior pituitary gland. The pituitary gland is connected to the hypothalamus by the pituitary
stalk (Figure 1.1)
1. Anterior pituitary
The hypothalamus secretes releasing hormones that act on the anterior pituitary. The releasing
hormones stimulate or inhibit pituitary hormone secretion.
The hypothalamus and the anterior pituitary gland are connected by the
hypothalamohypophyseal portal system. The hypothalamus secretes the following hormones:
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•
•
•
•
•
•
•
Thyrotropin releasing hormone -TRH
Corticotropin releasing hormone- CRH
Gonadotropin releasing hormone -GnRH
Prolactin releasing hormone -PRH
Prolactin inhibitory hormone- PIH
Growth hormone releasing hormone- GRH
Growth hormone inhibiting hormone -GIH
(Somatostatin)
Pituitary hormones may act on target organs or stimulate (or inhibit) endocrine glands to produce
hormones.
Hormones secreted by the anterior pituitary gland and their target endocrine organs /tissues are
listed below:
1. FSH (Follicular stimulating hormone) - gonads
2. LH (Leutinizing hormone)- gonads
3. TSH (Thyroid stimulating hormone - thyroid gland
4. ACTH (Adrenocorticotropic hormone)– adrenal gland
5. GH (Growth hormone – liver and other tissue
6. Prolactin –breast
Hypophysiotropic hormones
The term ‘tropic’, means to stimulate the secretion of hormonally active substances in another
endocrine gland, the liver or other tissues. Many of the pituitary hormones act on specific
endocrine organs bringing about a release of hormones from them. Anterior pituitary hormones
(except prolactin) are tropic hormones.
The functional relationship between the hypothalamus and the anterior pituitary gland is
summarized in the table below.
Hypothalamus
Growth Hormone Releasing Hormone
Pituitary gland
Promotes release of Growth
Hormone
Growth Hormone Inhibiting Hormone Inhibits release of Growth
(Somatostatin)
Hormone
Inhibits release of Thyroid
Stimulating Hormone
Thyroid Releasing Hormone
release
of
Thyroid
Stimulating Hormone
Corticotrophin Releasing Hormone
release
of
AdrenoCorticotrophin
Releasing
Target organ
All body tissues
Organs
Thyroid gland
Thyroid gland
Adrenal gland
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Hormone
Prolactin Releasing Hormone
release of Prolactin
Prolactin Inhibiting Hormone
release of Prolactin
Leutinising
Hormone
Releasing release
of
Follicular
Hormone
Stimulating Hormone
Gonadotrophin Releasing Hormone
release
of
Leuteinising
Hormone
Breast
Breast
Ovary and testis
Ovary and testis
Hypothalamus secretes releasing hormones which stimulate or inhibit hormones in the pituitary.
The anterior pituitary releases hormones which will reach the target organ through the blood
stream and produce its actions.
Anterior Pituitary Hormones
The hormones discussed will be briefly out lined as follows. These are synthesis of hormones,
transport, mechanism of action, physiological actions, regulation of secretion and disordered
physiology of secretion (figure 33.2).
Growth Hormone
Growth Hormone (GH) is a peptide hormone secreted by the cells of the anterior pituitary.
Growth hormone receptors are located on the cell membrane.
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Figure 33.2 The actions of growth hormone
The actions of growth hormone are tabulated in the table above and are briefly described below.
Physiological actions of growth hormone
1. Stimulates growth
The main function of GH is the promotion of linear growth. At the epiphysis of long bones
cartilage formation is increased. The epiphyseal plate widens. It promotes laying down of bone
matrix and increases the length of the bone.
After growth is completed in adulthood, GH
2. Effects on the metabolism
13
GH has effects on metabolism and regulates the carbohydrate, protein and fat metabolism.
GH increase amino acid uptake by cells and protein synthesis in cells.
GH reduces the uptake of glucose into the cells. It increases the release of glucose from the liver.
Therefore it increases blood glucose concentration. This is known as the diabetogenic effect.
GH promotes the use of fat (free fatty acids) to produce energy (energy source). In certain
stressful situations of the body it stimulates the production of energy by these methods. Some of
these stressful states are mental stress, during fasting, and during hypoglycaemia.
3. Calcium balance
GH increases Ca+2 absorption from the gastrointestinal tract and increases Ca+2 excretion from
the kidney. A positive calcium balance which facilitates bone mineralization is the main effect
of GH on bone.
Control of GH secretion
GH secretion is controlled by the hypothalamus. Hypothalamus secretes growth hormone
releasing hormone (GRH) and Somatostatin .
GH impairs glucose uptake into the cells and increases the release of glucose from the liver,
increasing blood glucose concentration. Growth hormone secretion is stimulated in
hypoglycaemia leading to an increase in blood glucose concentration.
GH secretion is increased by various stimuli such as, hypoglycaemia, fasting, exercise and
during sleep. GH secretion is decreased by various stimuli such as glucose, and cortisol,
Disorders of growth hormone secretion
Excess secretion of GH is often due to tumours of the pituitary gland. In children, over secretion
of growth hormone stimulates skeletal and soft tissue growth resulting in gigantism.
Excess secretion (eg. pituitary tumour ) of growth hormone in adults results in acromegaly.
These individuals have enlarged hands and feet prominent protruded jaws, a broad nose, and
bitemporal hemianopia .
FSH, LH and Prolactin are described in the session on reproductive system
2. Posterior pituitary
The hormones vasopressin (ADH) and oxytocin are synthesised by the hypothalamus. As
mentioned earlier the hypothalamus controls the secretion of the posterior pituitary via the
hypothalamohypophyseal tract, a neural pathway.
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Physiological action of oxytocin will be described with the reproductive systemn
Posterior pituitary hormones
Antidiuretic Hormone
This is also called vasopressin. It is a peptide hormone and its is synthesized by the
hypothalamus, transported by axons (hypothalamo –hypophysial tract) to the posterior pituitary
and secreted by the posterior pituitary.
The physiological actions of ADH
ADH is the principal regulator of serum osmolality. Therefore this is one of the important
hormones which play a role in maintaining the internal environment.
1. Retention of water by the kidneys (main physiological action)
ADH promotes the insertion of protein water channels (aquaporin) into the luminal membrane
of the collecting ducts in the kidney. This results in an increase in permeability of collecting
ducts in the kidney to water and a decrease in urine output.
ADH increases water reabsorption in the collecting duct. Unlike aldosterone, ADH does not
increase Na+ reaborption. Therefore retention of water in excess of solutes occurs resulting in a
decrease in plasma osmolality.
2. Vasoconstrictor effect
ADH stimulates vascular smooth muscle contraction, leading to an increase in blood pressure,
e.g: in haemorrhage
Regulation of ADH Secretion
ADH secretion occurs in response to various stimuli.
1. Osmotic stimuli
When plasma osmolality increases,it Increases ADH secretion. The stimulus activates the
osmoreceptors. od occurs in response to an increase in plasma osmolality by stimulating
osmoreceptors, located in the hypothalamus (outside the blood brain barrier). Increase in the
plasma osmolality and effective osmotic pressure above the normal range (285-290 mosm/kg)
increases ADH secretion.
15
When plasma osmolality increases, it stimulates the osmoreceptors in the hypothalamus which
then sends impulses to the hypothalamus resulting in secretion of ADH.
The steps which maintain the normal plasma osmolality when the plasma osmolality increases
are shown in the diagram below (Figure 33.1).
2. Alteration of the ECF Volume
ADH secretion is increased when ECF volume is low and decreased when ECF volume is high.
Hypotension and hypovolaemia increase ADH secretion.
E.g: In haemorrhage
A reduction in ECF volume increases ADH secretion, When the ECF volume increases are
outlined below (Figure 1.6):
3. Angiotensin II
When the ECF volume is low Angiotensin II is secreted. Angiotensin II stimulates ADH
secretion from the hypothalamus.
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Diabetes insipidus
When there is deficiency of ADH secretion or when the renal tubules are not responsive to ADH,
Diabetes insipidus occurs. This condition results in polyuria ( passage of a large volume of
urine ) and polydipsia are seen . Unlike in diabetes mellitus the blood glucose level in these
patients is normal.
The other hormone secreted by the posterior pituitary gland is the hormone Oxytocin. Since it
has major effects on the reproductive system, the important features of oxytocin will be
discussed in the session on female reproductive tract
Objectives
Pituitary Gland
Describe the structure of the hypothalamus and the pituitary gland
Explain the influence of the hypothalamus on the lobes of the pituitary gland
Outline the actions of the hormones secreted by the anterior and posterior lobes of the pituitary
gland.
List the hormones secreted by the Anterior and Posterior Pituitary glands
Explain briefly how the pituitary hormone secretion is regulated by the hypothalamus and the
hormonal feedback mechanisms
Growth Hormone (GH)
Outline briefly the importance of GH
Outline the actions of Growth hormone on the target organs
Explain briefly the physiological basis of signs / symptoms of hypo and hyper secretion of the
hormone in a child and adult
Anti Diuretic Hormone (ADH)
Outline briefly the importance of ADH
List the effects of ADH on the target organs
Outline the role of ADH in regulating the volume and osmolality of ECF
Enumerate the effects of hypo secretion of ADH.
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Session 34
Adrenal gland
Session Outline
Introduction
22.1 Structure of the adrenal gland
22.2 Basic structure of the urinary system
22.3 Blood and nerve supply
22.4 Functions of the urinary system
22.5 Regulation of the functions of the urinary system
Summary
Learning Outcomes
Review Questions
References
Introduction
Adrenal Hormones
The adrenal glands a two pyramid shaped organs lying over the upper part of the kidney. They
have the shape of a pointed hat.
When we are excited, frightened, our heart beat increases, the respiration rate increases, our eyes
open wide and the pupils of the eye dilate, and we are even ready to fight, fright and flight. All
these responses are brought about by the adrenal medulla.
Structures of the adrenal gland
Adrenal gland consists of the cortex and the medulla. The medulla secretes catecholamines and
steroid hormones. The adrenal medulla secretes catecholamines whilst the cortex secretes steroid
hormones, glucocorticoids such as cortisol, mineralocorticoids such as aldosterone and sex
hormones. The figure
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Figure 34 .1 Structure of the adrenal gland
1. Adrenal medulla
The adrenal medulla secretions help one to deal with emergencies.
2. Adrenal cortex
The hormones secreted by the adrenal cortex have different functions:
• Glucocorticoids – play a part in the metabolism of carbohydrates and protein.
• Mineralocorticoids - maintains Na+ balance and ECF volume.
• Adrenal sex hormones - reproductive function
Mineralocorticoids and glucocorticoids are essential for life.
Cortisol binds to alpha globulin in plasma and the fluctuations in protein levels affect transport
as in the case of thyroid hormones.
Physiological actions of glucocorticoids are summarized below:
19
Glucocorticoids have many actions that produce many changes with in cells and all the tissues of
the body. They act by acting on the metabolic pathways and both other means outlined below.
1. Increase protein catabolism in tissues. It produces an increase in concentration of amino acids
in plasma
2. Mobilize and redistribute fat.
3. Inhibit glucose uptake by cells and promotes gluconeogenesis in the liver. This results in an
increase in the level of blood glucose. This is known as the diabetogenic effect.
4. Permissive action
Small amounts of glucocorticoids are essential for many metabolic reactions. Eg For
gluconeogenic action of glucagons and for glucocorticoids to produce its calorigenic effect.
5. Vasoconstriction - help catecholamines to produce vasoconstriction. This action restores
vascular reactivity.
6. Reduction in the number of circulating lymphocyte, eosinophils, basophils
7. Adapt to stress - Glucocorticoids are essential for the body to resist the stress caused by
surgical operations, infections and emotional states.
8. Prevent inflammatory changes in the cell.
9. Decrease bone formation
Regulation of glucocorticoid secretion
Glucocorticoid secretion is regulated mainly by ACTH by a negative feedback inhibitory
process. Stressful situations and Corticotrophin Releasing Hormone stimulate the release of
ACTH. (This is shown in the Figure 34.2)
-++
Releases CRH
Hypothalamus
++
-++
Stimulates anterior pituitary
Release of ACTH
++
Stimulates adrenal cortex
Release of Cortisol
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Regulation of glucocorticoid secretion.
Prolonged treatment with large doses of glucocorticoids inhibits the pituitary gland. This will
inhibit the adrenal cortex, resulting in atrophy of the adrenal cortex which can become not
responsive to ACTH. This is dangerous if this glucocorticoid treatment is stopped suddenly, as
then the cortisol concentration suddenly drops and produces many adverse effects.
Disorders of glucocorticoid secretion
Increased secretion of plasma glucocorticoid produces the disorder known as Cushing’s
syndrome. These effects are in opposite to the normal action of glucocorticoids. They are
summarized below.
•
Increased protein catabolism results in poorly developed muscles, thin skin and
subcutaneous and poor wound healing
•
redistribution of body fat results in thin hands and feet; collection of fat in abdominal
wall (pendulous abdomen), moon face, and buffalo hump ( fat deposition in neck)
•
•
Reddish purple striae due to thin skin of the abdomen
Diabetes mellitus due to increased gluconeogenesis & decreased peripheral utilization.
•
•
Increase in facial hair and acne – due to the excess secretion of androgens
Hypertension- excess glucocorticoids having mineralocorticoid action
Osteoporosis- decreased bone formation and increased bone resorption
Mineralocorticoids:
One
of
the
main
mineralocorticoids
produced
is
aldosterone
Aldosterone
The main function of aldosterone is to regulate mineral metatabolism.
Aldosterone acts on the collecting duct of the kidney. It promotes the absorption of Na+ in
exchange for K+ and H + from the cells of the collecting duct. Thus it increases salt reabsorption.
This mechanism helps to expand the ECF volume. This hormone is most active when the blood
volume is decreased (as in hypovolaemic states) such as haemorrage, diarrhoea, and vomiting
etc.
Aldosterone secretion is increased by:
•
•
•
ACTH from the anterior pituitary
Renin from the kidney via angiotensin II
A rise in plasma K + concentration.
21
Disorders of the aldosterone action
Disease conditions can give rise to excess production of aldosterone or deficiency in the
secretion from the adrenal cortex.
Primary hyperaldosteronism (Conn’s syndrome)
Excess production of aldosterone can occur due to an adrenal cortex lesion. This is known as
primary hyperaldosteronism or Conn’s syndrome
Physiological basis of the signs and symptoms of Conn’s syndrome:
In this disorder there is an excess aldosterone lead to Na+ retention and K+ depletion. This results
in ECF volume expansion and hypertension.
Addison’s disease
Hyposecretion of the adrenal cortical hormones results due to primary adrenal insufficiency is
referred to as Addison’s disease. In this condition there is defection secretion of all three classes
of hormones. Most of the clinical features observed are due to reduction in glucocorticoids and
mineralocoticoids. Decreased adrenal androgen secretion would not be evident due to the
presence of normal testes and ovaries.
Adrenal androgens
Dihydroepiandrosterone and androstenedione are the predominant androgens produced by the
adrenal cortex.
In the female, adrenal androgens are the main source of androgens. This promotes the growth of
pubic and axillary hair.
The effect of adrenal androgens:
• Mascuilinizing effect in the female
• Promotes protein anabolism and growth
Testosterone from the testis is the most active androgen. Adrenal androgens have less than 20%
of activity of testosterone.
Adrenal medulla
Norepinephrine, epinephrine and dopamine are catecholamines secreted by the adrenal medulla.
Apart from the adrenal medulla, norepinephrine is also secreted from the noadrenergic nerve
endings.
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Norepinephrine and epinephrine act via α and β receptors.
Actions of norepinephrine and epinephrine:
•
Glycogenolysis in the liver and skeletal muscle.
•
Mobilization of free fatty acids from adipose tissue.
•
Norepinephrine and epinephrine produce an increase in the basal metabolic rate.
•
Increase in heart rate and force of contraction, mediated via the β 1 receptors.
•
•
Increase in diastolic blood pressure by norepinephrine
In contrast epinephrine dilates the blood vessels in skeletal muscles decreasing diastolic
blood pressure.
Regulation of secretion of epinephrine and norepinephrine
Epinephrine and norepinephrine secretion is increased in stressful conditions such as exposure to
cold, hypoglycaemia, during sever injury to the body, and hypoglycaemia
When the above hormones are secreted in exposure to cold it results in increase in the basal
metabolic rate and heat is produced to control body temperature. In hypoglycaemia these
hormones increase the blood glucose concentration by activating glycogenolysis. During a
stressful situation these hormones provide additional oxygen to tissue by bronchodilation,
increasing myocardial contractility, reducing the urine output, and redistribution of blood to the
vital organs.
Pheochromocytoma
Pheochromocytoma is a tumour in the cells that secrete catecholamines in the adrenal medulla.
Summary
In summary you learnt about the adrenal gland. The gland is divided into the adrenal medulla
and the cortex. The adrenal medulla secretes norepinephrine and the adrenal cortex secretes
cortisol and aldosterone. The main functions of these hormones were discussed. The effects
when these hormones are oversecreted and undersecreted were explained in this session.
23
Objectives
Adrenal Gland
Adrenal Cortex
List the hormones secreted by the adrenal cortex
Outline the synthesis and the regulation of secretion of each hormone
Briefly outline the effects of glucocorticoids / mineralocorticoids on target cell
Organs
Give a short account on the physiological basis of signs / symptoms of hypo and
Hyper secretion of glucocorticoids / mineralocorticoids
Adrenal Medulla
List the hormones secreted by the adrenal medulla
Outline the
•
synthesis and the regulation of secretion of hormones
•
mechanism of action on the target organs
•
effects on target organs
•
signs / symptoms / principles of treatment in pheochromocytoma
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Session 35- Thyroid and parathyroid glands
Session 35
Thyroid and Parathyroid Glands
Session Outline
Introduction
22.1 Organs of the urinary system
22.2 Basic structure of the urinary system
22.3 Blood and nerve supply
22.4 Functions of the urinary system
22.5 Regulation of the functions of the urinary system
Summary
Learning Outcomes
Review Questions
References
In this session you will discuss the main functions and features of an important gland located in
your neck . the thyroid gland. The thyroid gland has a butterfly shape and is located anterior to
the thyroid cartilage in the neck. It is an organ essential for life
Thyroid hormone
The hormones secreted by the thyroid gland are as follows:
Thyroxine (T4)
Tri iodo thyronine (T3)
Functions of thyroid hormone
Thyroid hormones maintain the metabolism in the tissues that is best for their normal function. It
stimulates O2 consumption of most cells, regulates lipid and carbohydrate metabolism and is
necessary for normal growth and maturation.
In infants the thyroid hormone is required for normal development of the central nervous system
and in children for normal growth and maturation.
In adults normal functions of multiple organs and systems occur due to thyroid hormones.
Thyroid hormone is not essential for life. However inadequate production results in
hypothyroidism and an excess production results in hyperthyroidism.
25
The functional unit
The functional unit of the thyroid gland is the thyroid follicle. The thyroid gland is made up of
multiple follicles. Each follicle is lined by a single layer of epithelium. The follicle is filled with
colloid. Inactive follicles are filled with colloid and lined by flat cells. Active follicles are small
and are lined by cuboid columnar cells.
Synthesis of thyroid hormone
T4 and T3 are derived from the iodine containing amino acid tyrosine. The thyroid cells perform
three important functions. Several steps occur in the thyroid follicle during synthesis and
secretion of T4 andT3
Uptake and transport of iodine is followed by the uptake of iodide. Iodide is converted to iodine
by oxidation. The molecule tyrosine is iodinated and coupled to form the biologically active, T 4
and T3.The bond between the tyrosine residues and the thyroglobulin breaks down thT3 and T4
Transport of thyroid hormone
The secreted thyroid hormones are translated and secreted they are bound to plasma proteins.
The plasma proteins that bind thyroid hormones are albumin pre albumin and Thyroxin binding
globulin (TBG)
Thyroid hormones are bound to plasma proteins to maintain a large pool of hormones and for
uniform utilization by the target cells.A small amount of thyroid hormones is found in free form.
The free hormones are physiologically active and inhibit TSH.
Control of thyroid function
Thyroid function is regulated primarily by TSH. TSH influences follicle formation and also
every step in the pathway of synthesis and secretion of thyroid hormone.
Since prolonged TSH stimulation increases the growth of the gland and weight of gland, this
gives rise to an enlargement of thyroid gland causing detectable enlargement. This is referred to
as a goiter.TSH secretion is in turn regulated by Free T3, T4 and TRH. Free T3 and T4
negatively inhibit TSH secretion. TSH secretion is also inhibited by stress.
TRH has a positive feedback effect on TSH secretion.
Mechanism of action of thyroid hormone
Receptors for thyroid hormones are located in the nucleus. The affinity of receptors for T3 is
more than for T4. In order to produce actions the thyroid hormones bind to the receptor and the
hormone receptor complex increases gene transcription.
26
The physiological actions of thyroid hormones are summarized below:
1. Calorigenic action
T3 and T4 increase the oxygen consumption of tissue by increasing the metabolic rate. Body
temperature is slightly increased.
2. Influence on actions of catecholamines
Thyroid hormones increase the number of adrenergic receptors in tissues. It also increases the
affinity of the adrenergic receptors to catecholamines. However, thyroid hormone does not
increase the catecholamine level.
3. Cardiovascular system
The thyroid hormone has actions on the myocardium, SA node and the blood vessels. by an
ionotropic effect. It increases the contractility of the myocardium. A chronotropic effect on
the heart increases the heart rate. The peripheral resistance is reduced by thyroid hormones due
to cutaneous vasodilatation.
4. Nervous system
Thyroid hormone has actions on the central and peripheral nervous systems. The thyroid
hormone produces wakefulness and alertness by activation of the reticular activating system. It
increases the excitability of nerves, affecting the reaction time of the stretch reflex.
5. Growth and development is stimulated by facilitating ossification, influences the linear
growth of bone. Thyroid hormone promotes tooth development and eruption.
6. It is essential for the development of the brain before and after birth (during infancy). It is
required for normal myelination, development of axons, dendrites and synapses mainly during
the infancy period.
7. Increases the rate of Carbohydrate absorption from the gastrointestinal tract.
8. It is essential for normal development and function of reproductive glands.
9. It is essential for normal erythropoiesis.
Clinical features of disordered secretion of thyroid hormone
The effects of thyroid disorders can be explained in terms of disordered physiology. Clinical
features of inadequate or excess production of thyroid hormones are described in the paragraphs
below. The clinical features in these conditions can be explained by an understanding of the
physiological actions of thyroid hormones.
Hyperthyroidism
Clinical features appearing in hyperthyroidism and its pathophysiological basis are as follows.
27
1. Extra heat production - occurs due to the calorigenic action. Body temperature rises.
Cutaneous vasodilation gets rid of the extra heat in the body. leads to warm skin and sweating.
Peripheral resistance is decreased. Muscle weakness occurs due to protein catabolism brought
about due to the calorigenic effect of thyroid hormones.
Ionotropic effect on the myocardium and increases the contractility of the myocardium, the
cardiac output is increased. It has a chronotropic effect on the heart, tachycardia and
palpitations are produced.
Irritability and restlessness are the central nervous system effects
the reaction time of the stretch reflex is shortened.
This hormone is essential for normal development and function of the reproductive system.
Therefore menstrual abnormalities occur in hyperthyroidism.
7. Diarrhoea occurs as a result of increase in frequency of bowel contractions
caused by increased thyroid hormone action on gastrointestinal smooth muscles.
8. Osteoporosis occurs due to bone resorption exceeding bone formation. Bone matrix formation
is decreased due protein catabolism in this condition.
9. Eye signs
Lid retraction - Sclera is seen below the upper eye lid
Exophthalmus - Sclera can be seen above the lower eye lid (Figure 1.10).
Proptosis - Eye balls are pushed forward in hyperthyroidism (Figure 1.11).
Exophthalmus and proptosis are only seen in Graves’ disease.
Hypothyroidism
Reduction in the secretion of the thyroid hormone may occur before or after birth (acquired).
Hypothyroidism occurring before birth is called congenital hypothyroidism and after birth is
called acquired hypothyroidism.
Clinical features in hypothyroidism –
1. Goiter - diffused thyroid enlargement (Figure 1.12).
Deficient thyroid hormone production results in TSH hypersecretion giving rise to a goiter.
2. Physical slowness occurs due to a decrease in basal metabolic rate.
28
3. Syndrome of adult hypothyroidism is called myxedema.
Myxedema occurs due to deposition of mucopolysacharides in the subcutaneous tissues.
Thyroid hormones inhibit the synthesis of mucopolysaccharides. This results in these
complexes accumulating in the subcutaneous tissue - around the eye lids, tongue, vocal cords
and in the interstitial spaces resulting in weight gain.
mucopolysacharides are deposited and produce the following clinical features
Tissue
Clinical feature
Around eye lids Puffy eye lids
Tongue
Large tongue, slurred speech
Vocal cords
Dermis
Around nerves
Interstitial spaces
Low pitch voice
Coarse skin
Deafness, Parasthesia, Carpel tunnel syndrome
Oedema of hands and feet
4. Reduced activity of reticular activating system occurs due to a reduction in the response to
catecholamines. This results in slow mentation, lethargy and sleepiness
5. Actions on the SA node
Since the thyroid hormone has chronotropic effects on the heart, when the
are reduced the heart rate is reduced and bradycardia is produced.
hormone levels
6. Thyroxine is required for the normal menstrual cycle. Menstrual abnormalities such as
menorrhagia (excessive regular menstrual flow) occur therefore in hypothyroidism.
7. Thyroid hormone removes cholesterol from the circulation. In hypothyroidism the cholesterol
concentration is increased leading to an increase risk of ischeamic heart disease.
8. Peripheral nervous system
Since thyroid hormone has an influence on the peripheral nervous system, reduced hormones
decrease the excitability of nerves. Therefore the reaction time of the stretch reflex is
prolonged.
9. Since the thyroid hormone is necessary for normal erythropoesis in hypothyroidism anaemia
occurs due to diminished red blood cell production.
10. Thyroid hormone influences the normal functioning of the smooth muscles as well.
Therefore hypothyroidism results in constipation.
Cretinism
Children who are hypothyroid from birth are called cretins (Figure 1.13). The clinical features
manifest within a few days from birth. This condition can lead to irreversible brain damage, if
untreated and therefore early recognition is important.
29
Pathophysiological basis for the clinical features in cretins as a result of diminished activity of
the thyroid hormones are given in the following Table
Pathophysiological basis for the relevant clinical features in cretinism
Pathophysiological basis
Mucopolysacharides deposition around
eye lids
Mucopolysacharides deposition around
Face
Mucopolysacharides deposition around
Tongue
Mucopolysacharides deposition around
Vocal cords
Mucopolysacharides deposition around
Dermis
Central nervous system
Smooth muscle
Maturation of the enzyme glucuronyl
transferase
Linear growth of bone
Tooth development and eruption
Brain development
Cerebral cortex
Clinical feature
Puffy eye lids
Course ugly features
Large tongue, protruding tongue, noisy
respiration, feeding difficulties
Hoarse cry
Coarse skin
Sleepiness, uninterested in his surrounding
Constipation
Prolonged physiological jaundice
Short stature, Infantile body proportions
Delayed eruption of teeth
Delayed milestones
Mental retardation
Tests of thyroid function are conducted to:
•
•
•
Determine the thyroid state of the patient.
Determine the cause of the alteration in the state, if any
Monitor the progress of the illness with treatment.
The following serum tests to determine thyroid function are often done. They are the level of
Free T3, Free T4 and TSH.
Objectives
Thyroid Hormone
Outline the factors regulating synthesis and secretion of thyroid hormones
Write a brief account on the effects on the target organs
Enumerate the signs / symptoms of hypo and hyper secretion in adults / infants
30
Give an account on the usefulness of thyroid function tests in assessing disordered
function of the gland
Calcium metabolism
Introduction
To sustain life serum calcium concentration has to be within a constant range. Parathyroid
hormone (PTH), Vitamin D (1,25-dihydroxycholecalciferol) and calcitonin play a vital role in
regulating serum calcium.
The average serum calcium concentration is 2.5 mol. / L (9.5 mg/dl).
A certain percentage of serum calcium is bound and another percentage is in the free form. Fifty
percent of the serum calcium is free and 40% bound to protein. 10% is complexed with
substances like citrate. Free calcium is also called ionised calcium and it is the physiologically
active form.
The calcium concentration depends on rate of gastrointestinal absorption, renal calcium
absorption and excretion, bone mineralisation and demineralization (Figure 1.17).
Several physiological processes are dependent on serum calcium. The neuromuscular excitability
depends on the serum calcium concentration. When calcium level drops the neuromuscular
excitability increases. In alkalosis binding of calcium to protein increases. This will lower the
free calcium concentration, producing neuromuscular hyperexcitability. In hyperventilation
neuromuscular excitability increases due to alkalosis.
Calcium is essential for secretion of many hormones and neurotransmitters.
Calcium is essential for clotting of blood in both the intrinsic and extrinsic pathway of clotting.
Intracellular Ca++ is a vital second messenger. Calcium is needed for excitation contraction
coupling of both skeletal and cardiac muscle.
31
Figure 1.17 Physiological functions of calcium.
Therefore in our body serum calcium concentration is regulated accurately.
Parathyroid hormone (PTH), Vitamin D (1,25-dihydroxycholecalciferol) and calcitonin are the
hormones
which
maintain
serum
calcium.
The major organs involved in calcium homeostasis are the gastrointestinal system, kidney and
the bone. In the gastrointestinal tract calcium absorption occurs via the upper small intestine in
the presence of vitamin D. Ninety-eight percent (98%) of the filtered calcium is reabsorbed by
the kidney. This occurs by diffusion and carrier mediated transport in the presence of parathyroid
hormone and vitamin D.
Calcium is also exchanged between bone and plasma; 90% of the calcium is in the skeleton.
Bone is formed of matrix (osteoid tissue) and minerals.
Structure of bone
Bone forming cells are called osteoblasts. Osteoblasts synthesize the bone matrix protein
collagen and osteocalcin. After formation of the bone matrix the osteoblasts help in
mineralization as well. Bone mineralization is done by secreteing alkaline phosphatase by the
osteoblast. This helps in precipitation of calcium in the bone.
Osteoblasts that are buried in bone matrix become osteocytes. These are numerous in mature
bone. Osteocytes are within bone spaces called lacunae. Lacunae are interconnected with each
other via channels called canaliculi. There is an extensive canalicular system connecting the
osteocytes and osteoblasts forming a functional syncytium. The previously formed bone is
eroded by osteoclasts. Bone fluid is found in lacunae and in the canaliculi. The minerals in bone
are exchanged with minerals in ECF. Bone fluid is separated from the extracellular fluid by a
layer of osteoblast.
32
Bone remodelling
The process of bone formation and break down (resorption) is called bone remodelling. Bone
remodelling varies with the age. Until 20 years of age bone formation is more than resorption
and after 30yrs bone formation is less than resorption.
Parathyroid hormone (PTH)
Parathyroid hormone is a polypeptide hormone secreted by four parathyroid glands which are
embedded in the thyroid gland.
Actions of Parathyroid hormone
The main action is to increase the plasma calcium concentration. PTH has direct actions on bone
, kidney and an indirect action on the gastrointestinal tract.
Actions of PTH on bone
PTH acts mainly on the osteoclast and mobilizes Ca++ from bone. It decreases bone fluid Ca++
and increases ECF Ca++. It causes increase in the remodeling process. Initially bone osteoclasts
stimulate resorption and subsequently there is bone formation by osteoblasts.
Actions of PTH on Kidney
PTH increases the Ca++ reabsorption in distal convoluted tubule. PTH also decreases the
reabsorption of phosphate. Therefore it has a phosphaturic action.
Actions of PTH on gastrointestinal system
PTH stimulate the formation of vitamin D. Vitamin D stimulates absorption of Ca++ and
PO43-- in the intestine. Therefore PTH indirectly increases Ca++ absorption from the intestine.
Regulation of secretion (Figure 1.18)
Ionized calcium directly regulates the secretion of parathyroid hormone. Low ionized calcium
stimulates the secretion of PTH. PTH by acting on bone mobilizes calcium from bone. PTH by
acting on the kidney produces absorption of Ca++ from the distal convoluted tubule.
It also synthesises vitamin D giving rise to absorption of Ca++ from the intestine. These effects
will bring the ionized calcium back to normal.
33
Vitamin D (1, 25-dihydroxycholecalciferol)
Vitamin D is a steroid hormone.
Vitamin D is obtained from the diet. It is also synthesised in the skin by 7-dehydrocholesterol.
On exposure of skin to sunlight the 7-Dehydrocholesterol is converted to cholecalciferol
(Vitamin D3).
Vitamin D3 is converted to 25-hydroxycholecalciferol (calcidiol) in the liver. In the kidney 25hydroxyclolecalciferol is converted to the active form 1,25-dihydroxyclolecalciferol.
Actions of vitamin D
This hormone increases the serum calcium concentration. It also facilitates bone mineralization.
Vitamin D act on the gastrointestinal system, kidney and bone.
Actions of vitamin D on gastrointestinal system
This hormone increases calcium and phosphate absorption from the intestine. The intestinal
mucosa contains calcium binding protein called calbindin. Vitamin D increases the synthesis of
this calbindin protein.
Actions of vitamin D on kidney
Vitamin D increases tubular reabsorption of Ca++ and PO4-3.
Actions of vitamin D on bone
It is essential for normal bone mineralization. It activates osteoblasts to mineralize osteoid tissue.
Control of secretion of 1, 25-dihydroxycholecalciferol
When plasma calcium is low, PTH secretion is increased and this in turn will increase the
synthesis of 1,25-dihydroxycholecalciferol. The opposite occurs when the plasma calcium is
high. This is the adaptation of calcium absorption in the intestine.
Oestrogen, prolactin
and
growth
hormone increases
the
circulating 1,25dihydroxycholecalciferol. Hyperthyroidism is associated with decrease in circulating 1,25dihydroxycholecalciferol.
34
Calcium exchange between tissue and plasma.
Calcitonin
Calcitonin is a polypeptide secreted from the parafollicular cells of the thyroid glande. It is a
serum calcium lowering hormone.
Calcitonin hormone stimulate bone osteoblast to mineralize bone.This hormone inhibits bone
osteoclasts. This also inhibits absorption of Ca++ and PO4-3 from renal tubule.
In addition to the above 3 hormones, other hormones also influence the Ca++ homeostasis.
Growth hormone increases excretion of Ca++ in urine. It also increases Ca++ absorption from the
gastrointestinal tract. However the Ca++ absorption from the gastrointestinal tract is more than
the excretion in the urine. Therefore growth hormone produces a positive Ca++ balance.
Glucocorticoids increase bone resorption and decrease bone formation by inhibiting protein
synthesis.
35
They decrease absorption of Ca++ and PO4-3 from the gastrointestinal tract and increase the
renal excretion of Ca++ and PO-34.Therefore Glucocorticoids produce bone osteoporosis.
Oestrogens prevent osteoporosis by inhibiting osteoclasts.
Thyroid hormone tends to produce osteoporosis because of the protein catabolic effect.
Hypocalceamia
Hypocalcaemia results from removal of the parathyroid gland (parathyroidectomy). In this
condition the PTH and the 1,25-dihydroxycholecalciferol concentrations reduces. PTH
deficiency result in reduced renal reabsorption of calcium and 1,25-dihydroxycholecalciferol
deficiency result in reduced gastrointestinal absorption of calcium.
In hyperventilation alkalosis occurs. Binding of calcium to protein will also lower the free
calcium concentration although the total plasma concentration remains normal. Hypocalcaemia
increases neuromuscular excitability. This gives rise to carpopedal spasm.
Tetany occurs as a manifestation of carpopedal spasm. A characteristic form occurs in the upper
limb. Adduction of the thumb, flexion of the metacarpophalangeal joints, extension of the
interphalangeal joints, flexion of the wrist and elbow joints (Figure). This is called Trousseau’s
sign.
The Learner should be able to
•
list the main functions of calcium in the body
•
outline the distribution of calcium in the body
•
name the hormones regulating plasma calcium levels
•
outline the role of each hormone in homeostasis of plasma calcium
enumerate the effects of hypo and hyper parathyroidism on the body
•
compare / contrast osteomalacia / rickets / osteoporosis in relation to their
•
aetiology
•
bony changes
•
signs / symptoms
•
treatment methods
36
Session 37- Endocrine pancreas
Session 37
Endocrine Pancreas
Session Outline
Introduction
22.1 Structure of the endocrine pancreas
22.2 Insulin
22.3 Glucogon
22.4 Somatostatin
22.5 Regulation of the function of the endocrine pancreas
Summary
Learning Outcomes
Review Questions
References
The pancreas gland is closely associated with the gastrointestinal system and has both exocrine
and endocrine functions. The endocrine activity of the pancreas is due to the secretions of a
group of cells known as the islets of Langerhan. These islet cells form only a very small
proportion of the pancreatic gland. A healthy adult has about a million islets in his pancreas.
37.1 The endocrine structure of the pancreatic islets
37.2 The hormones secreted by the Pancreas
Hormones secreted by the islets of Langerhan are insulin, glucagon, somatostatin and pancreatic
polypeptide. All these hormones are peptide hormones.
Insulin
Insulin is an anabolic hormone which causes storage of fatty acids, amino acids and glucose.
Glucagon is a catabolic hormone which mobilizes fatty acids, amino acids, glucose. Therefore
these two hormones are reciprocal in action.
Somatostatin inhibits release of other hormones such as insulin, glucagons, and pancreatic
polypeptide. It also regulates the secretion of islet cells. Pancreatic polypeptide inhibits
gallbladder contraction and pancreatic exocrine secretion.
37
Insulin
Insulin is a polypeptide hormone secreted by the beta () cells of the islets of Langerhans. It
consists of two peptide chains connected by a connecting peptide (C peptide).
Actions of insulin are as follows:
The following actions occur within seconds (rapid):
It increases transport of glucose, amino acids and K+ in to insulin sensitive cells. (Figure 1.22)
There are several glucose transporters in the body. However only the glucose transporter named
GLUT4 is stimulated by insulin. This is present in skeletal muscle, cardiac muscle and adipose
tissue.
Figure 1.22 Insulin dependent entry of substances into tissues.
Insulin does not increase the entry of glucose into:
• Mucosa of the gastrointestinal system
• RBC
• Brain
• Renal tubular cell
The following actions occur within minutes (Intermediate):
Insulin stimulates protein synthesis and inhibits protein degradation in the liver and muscle. It
stimulates synthesis of glycogen and inhibits glygogenolysis in the liver and muscle. It inhibits
gluconeogenesis in the liver. These actions result in decreased glucose output from the liver. It
also activates glycolytic enzymes
The following actions occur within hours (delayed):
38
Insulin activates lipoprotein lipase and inhibits hormone sensitive lipase. It increases lipogenesis
in the liver and adipose tissue.
The above actions of insulin have the following actions in various tissues:
Insulin increases synthesis of lipids, protein, glycogen in the liver and decrease ketogenesis and
gluconeogenesis.
Insulin activates the lipoprotein lipase and inhibits the hormone sensitive lipase enzyme. Insulin
increases synthesis of lipids in the adipose tissue.
Insulin increases synthesis of protein, glycogen in the muscle and decrease protein catabolism
and gluconeogenesis. It increases ketone body uptake in the muscle when necessary.
Regulation of insulin secretion
Glucose is the prime regulator of insulin. When the glucose concentration rises insulin secretion
is increased and vice versa. Arginine, leucine and ketoacids stimulate beta cells of the pancreas.
Glucagon, catecholamines, thyroid hormone, adrenal glucocorticoids and growth hormone
stimulate the secretion of insulin.
Glucagon
Glucagon is a polypeptide secreted by the pancreatic alpha (α) cells, intestine and brain.
Glucagon has the following actions on metabolism:
1. Carbohydrate metabolism
Glucagon increases blood glucose levels by stimulating glycogenolysis in liver (not in muscle).
Glucagon increases gluconeogenesis in liver from amino acids, lactate , and pyruvate.
2. Lipid metabolism
Glucagon increases lipolysis in adipose tissue, because it activates the hormone sensitive lipases.
It increases the FFA and ketone bodies in the circulation.
3. Protein metabolism
Glucagon increases the break down of protein in the liver.
39
Glucose homeostsis
Plasma glucose is maintained at a constant level. Normal plasma glucose concentration is 4.5 5.6 mmol/ L (70 - 110mg/dl). There is a balance between the amount of glucose entering and
leaving the circulation. (Figure 1.23)
Factors that determine the plasma glucose level are dietary intake, rate of entry of glucose into
cells and the glucostatic activity of the liver.
Figure 1.23 Interaction of the liver, pancreas and the intestines in glucose homeostasis.
Hepatic glucostat
Liver functions as a glucostat. It helps to maintain a constant circulating glucose level in fasting
as well as in fed state. (Figure 1.24)
During fasting, liver glycogen is broken down and glucose is added to the blood stream. In
prolonged fasting when glycogen is depleted gluconeogenesis begins by using amino acids and
glycerol as substrates.
During the fed state glucose is converted to glycogen in the liver. A greater percentage of
glucose is converted to fat in the adipose tissue.
40
Figure 1.24 Glucostatic activity of the liver.
.
Diabetes Mellitus
Diabetes mellitus is a disease caused by relative or absolute deficiency of insulin.
The disease has two distinct categories namely type 1 diabetes (insulin dependent diabetes
mellitus) and type 2 diabetes (non insulin dependent diabetes mellitus).
Type I diabetes is common in the younger age group (< 30 years) and results from insulin
deficiency. It is an autoimmune condition.
Type II diabetes is common in the older age group (> 30 years) and results from insulin
resistance.
Pathophysiology of diabetes mellitus
1. One of the actions of insulin is to increase transport of glucose to insulin sensitive cells by
increasing the number and activity of the glucose transporter named GLUT4. In diabetes mellitus
when there is relative or absolute deficiency of insulin, the amount of glucose entering insulin
sensitive cells is reduced.
41
Lack of insulin reduces the peripheral utilization of glucose for glycolysis.
(Figure 1.25)
Reduced uptake of glucose, amino acids and K+ by peripheral tissues in diabetes mellitus.
2. Derangement of glucostatic function of liver
In the liver a relative or absolute deficiency of insulin reduces the formation of glycogen due to
inhibition of the enzyme called glycogen synthase .
Glycogenolysis is increased due to increase in activity of the enzyme phosphorylase.
There is increased gluconeogenesis due to an increase in the gluconeogenic substrates such as
glycerol, fatty acids, amino acids and the unapposed actions of adrenal steroids and growth
hormone.
All of the above leads to derangement of glucostatic function of liver. This results in an increase
in glucose output from liver. (Figure 1.26)
Increase in liberation of glucose from the liver.
42
Therefore due to reduction in peripheral utilization and derangement in the glucostatic function
of liver, hyperglycaemia (increase blood glucose concentration) occurs.
This condition will give rise to a situation where glucose concentration in the extracellular fluid
is more than in the intracellular fluid. The cells are starved in the midst of plenty.
Consequences of hyperglycaemia
1) Polyuria
This refers to excess urine production. Glucose concentration in the renal tubule is increased and
the limit of maximum absorption is exceeded. Then glucose starts appearing in urine. The plasma
concentration at which the glucose begins to appear in urine is called the renal threshold.
When the glucose concentration in the plasma increases the renal tubule glucose concentration
also increases. Since glucose is an osmotically active particle it draws water into the tubule and
increases the urine volume. This is polyuria (Figure 1.28)
.
Figure 1.28 Osmotic diuresis following hyperglycaemia.
43
2) Polydipsia (Figure 1.29)
Polydipsia is excessive drinking of water. This due to activation of the thirst mechanism.
Polyuria gives rise to loss of the ECF volume resulting in hypovolaemia. Also the tonicity of the
ECF will increase.
Figure 1.29 Polydipsia following hyperglycaemia.
When the tonicity increases the hypothalamic osmoreceptors are stimulated which in turn will
act on the thirst centre producing thirst. Due to hypovolaemia the volume receptors acting on the
hypothalamus also produce thirst. Another reason is due to hypovolaemia. Angiotensin II
secretion is stimulated via renin and this also will give rise to an increase of thirst.
3) Glycosylated haemoglobin (HbAIc) formation
Glycocylated haemoglobin is formed by a reaction between the amino acids of beta chain of
haemoglobin and glucose. The glycocylation of haemoglobin is dependent on the blood glucose
concentration. Half life of glycocylated haemoglobin relates to the life span of red cells (120
days) and glycocylated haemoglobin formation is proportionately increased in hyperglycaemia.
44
Therefore HbAIc measurement will indicate the glycaemia of the preceding 4-6 weeks (Figure
1.30).
Figure 1.30 HbAIc measurement indicates the glycaemia of the preceding 4-6 weeks.
2. Effects of intracellular glucose deficiency.
Due to break down of protein or fat for energy requirement, weight loss is seen in diabetic
patients
3. Derangement of protein metabolism
Inhibition of protein synthesis in insulin sensitive cells is due to reduced amino acid entry. There
is stimulation of protein degradation. Gluconeogenic substrates (amino acids are formed due to
break down of proteins).
Increase in gluconeogenesis occurs due to lack of insulin and due to other hormones such as
glucagons and glucocorticoids. Blood amino acids increase in the absence of insulin
4. Derangement of lipid metabolism
•
•
•
Due to decreased activity of the lipoprotein lipase there is decreased clearing of the
VLDL (very low density lipoproteins). Therefore plasma free fatty acid, VLDL and
chylomicron concentration is increased.
Reduced entry of glucose reduces the synthesis of triglyceride.
In the absence of stimulation of hormone sensitive lipase in diabetes, there is break
down of lipids. This results in increase in the FFA level in the circulation. FFA are NEFA, UFA. The FFA in the liver is converted to ketone bodies. Ketone bodies are
anions of strong acids. Metabolic acidosis occurs.
The mechanism of air hunger due to ketone bodies is outlined below:
Hospital admissions in diabetes are a common occurrence due to various reasons. Diabetes
metabolic emergencies occur in few patients and this is due to several causes namely
hyperosmolality in the absence of ketosis and hyperosmolality with ketosis. Both conditions can
lead to coma (unrousable unresponsiveness).
45
Hyperosmolar coma
In intercurrent illnesses or older patients with diabetes mellitus, ECF glucose concentration is
higher than in ICF. Therefore water shifts from brain cells to the extracellular compartment,
leading to coma. Coma occurs when effective plasma osmolality reaches about 340 mosm/l.
Diabetic ketoacidosis occurs when there is hyperglycaemia and formation of ketone bodies
(ketosis). Kussmaul breathing occurs in this condition.
Ketone bodies induce vomiting. Polyuria occurs in both situations due to hyperglycaemia
induced osmotic diuresis.
In hyperosmolar states the fluid and electrolyte depletion is more than in ketoacidosis.The reason
is that in hyperosmolar states due to the absence of ketone bodies and symptoms due to ketone
bodies (vomiting and Kussmaul breathing).
Later in ketosis severe polyuria, nausea, vomiting causes depletion in intravascular volume
decreasing renal blood flow.
Hypoglycaemia
Patients with diabetes mellitus are prone to get hypoglycaemia since these patients use oral
hypoglycaemic drugs. Hypoglycaemia leads to dysfunction of the brain.
The brain extracts glucose slowly since entry is not helped by insulin. This is because brain cells
are very dependent on extracellular glucose, since brain cannot store, synthesize or metabolize
substances other than glucose and ketones (Figure 1.31).
Figure 1.31 The importance of maintaining a constant blood glucose concentration for
functioning of the brain.
46
Therefore several compensatory mechanisms take place to correct hypoglycaemia:
Firstly the hepatic glucose output is increased by an increase in glycogenolysis. Hypoglycaemia
is a stimulus for glucagon and epinephrine secretion. Hence these two hormones produce this
effect.
Main counter regulation is by these hormones,which will warn the patient to seek glucose
replacement.
The effect produced by secretion of epinephrine is summarized below:
•
Increase in heart rate, palpitations, sweating, weakness and
other signs and symptoms due to sympathetic overactivity.
The mechanisms operating to compensate hypoglycaemia are outlined:
Glucagon
hepatic glucose output
Epinephrine
Glycogenolysis
Subsequently growth hormone and cortisol secretion occurs to reduce the utilization of glucose.
Growth Hormone
Utilization of glucose
Cortisol
Since the brain is dependent on ECF glucose secondary to hypoglycaemia there is central
nervous system dysfunction (neuroglycopaenia).There is confusion, headaches and can lead to
coma.
Laboratory findings in diabetes mellitus
Blood glucose testing
Normal fasting plasma glucose value is 4.5 - 5.6 mmol/ L (70 - 110mg/dl.
Plasma or serum levels 10-15% are higher than whole blood glucose level. Plasma or serum level
is measured since they are not affected by the packed cell volume.
Venous blood samples, Capillary blood sample.
Samples should be collected in tubes containing NaF which inhibit glycolysis. The enzymic
method (glucose oxidase) or colorimetric method (α toluidine) can determine blood glucose
concentration.
47
Urine glucose
This does not reflect the actual status of diabetes due to many reasons:
The bladder urine concentration reflects the blood glucose at the time of urine formation not the
time of testing.
After the renal threshold, glucose appears in urine and until that time testing urine for glucose
will not provide an indication of diabetes.
Microalbuminuria
When the microalbumin level is higher than normal it indicates development of renal
involvement of diabetes (diabetic nephropathy).
vi.
Endocrine Pancreas
Glucagon
•
outline the regulation of secretion and the main effects on the
body
Insulin
•
outline the regulation of secretion
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explain the role of insulin in regulating the glucose levels in blood
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explain briefly the physiological basis of the signs / symptoms /
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complications of diabetes mellitus
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list the likely causes of coma in diabetes mellitus
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enumerate the likely acid /base / water / electrolyte / biochemical
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abnormalities in ketoacidosis and the principles of treatment
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