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ENDOCRINE & METABOLISM MODULE SEQ REVIEW
15) Explain the pathophysiological basis in a patient with an
inappropriate ADH secretion having a plasma osmolality of 256
mosmol/kg (normal 258-295) & a urine osmolality of 1200
mosmol/kg(normal 40-1200). (30 marks)

ADH is a peptide hormone which is produced by the
hypothalamus & secreted into blood stream by the
posterior pituitary.
It normally increases the water reabsorption by the kidneys
& in turn reduces the plasma osmolality & increases the
urine osmolality.
So it helps to maintain the osmolality of blood.
In syndrome of inappropriate ADH secretion, there is
unusually high amounts of ADH found in blood.
(This ADH can be secreted by a hypothalamic tumour or due
to ectopic secretion. eg: by lung carcinoma )
Normally ADH secretion is inhibited when plasma osmolality
falls.
But in this condition, as there is no such inhibition
osmolality can fall to very low levels.
ADH acts on cortical collecting duct principal cells via V
2
receptors to increase cellular c-AMP &
increases insertion of aquaporin II water channels into the
plasma membrane of luminal side of cells.
This facilitates the diffusion of water down the
concentration gradient in medulla.
The normally impermeable collecting ducts become
permeable to water.
Water is absorbed into the medullary interstitium & then
into the blood stream.
So the plasma osmolality falls & urine osmolality rises.
So in this situation, there is a continuous water
reabsorption
despite of reduced plasma osmolality, which is a product of
total solute concentration (mainly Na + concentration) over
total water content.
The increased water reabsorption from tubular fluid leads
to increased osmolality in urine which reaches the
maximum concentrating capacity.
High osmolality urine is produced.
The dilution of plasma by water leads to a dilutional
hyponatraemia, reduced Na+ concentration in blood &
expansion of ECF volume.
The expansion of ECF volume leads to an expansion in blood
volume, therefore reduction of stimulation of renal
baroreceptors.
Reduced secretion of renin from juxtaglomerular cells &
Low formation of aldosterone which is responsible for
absorption of Na+ from tubular fluid at DCT & CD.
So there is continuous loss of Na+ in urine which leads to
further reduction of plasma osmolality & low Na+
concentration

16) Give the physiological basis of glycosuria seen in a patient with
acromegaly.

Acromegaly is an endocrine disorder which arises due to
excessive secretion of growth hormone in an adult.
It is usually due to a pituitary adenoma.
GH has widespread activity on many metabolic pathways.
Has a special effect on carbohydrate metabolism.
GH causes increased hepatic output of glucose &
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Reduced glucose uptake in peripheral tissues like muscle &
adipose tissue.
This means it has anti-insulin like activity & therefore
diabetogenic.
So the blood glucose levels are elevated above normal
values by excess GH.
Glucose is normally filtered at a rate of around 100mg/min
( 80 mg/dl in plasma * Glomerular Filtration Rate 125
ml/min) from glomeruli into bowmans space in kidney
tubules
and completely reabsorbed by a IIry active mechanism
along with Na
+
in early portion of proximal tubule
Hence in normal people, only minute amounts appear in
urine
But the transport system has a maximum rate, the
transport maximum (Tm) beyond which it is saturated
Tm for glucose is 375 mg/min in men and 200 mg/min in
women
When there is high amount of glucose in blood, the
transport system is saturated & the filtered glucose is not
100% reabsorbed
Glucose appears in urine. This is known as glycosuria.
This happens after renal threshold (200 mg/dl for arterial
blood & 180 mg/dl for venous blood)
which is the plasma level at which glucose first appears in
urine in more than the normal minute amounts
The actual renal threshold is less than predicted renal
threshold (375/125= 300 mg/dl)
because of the splay deviation since Tm in all tubules is
not identical and all glucose is not reabsorbed from each
tubule when filtered amount is below Tm


17) Briefly describe therapeutic uses of ADH & its analogues. (30
marks)

ADH can be used as replacement therapy when the
hormone secretion is deficient or as pharmacotherapy to
treat various disease conditions.
The available preparations are Vasopressin, Lypressin &
Desmopressin.
Since these are nonapeptides, oral preparations are
available.
Other routes of administration are sublingual, subcutaneous
& intranasal.
Desmopressin (DDAVP) is used to treat cranial diabetes
insipidus,
which occurs due to reduced or absent secretion of ADH
from hypothalamus.
It cannot be used in nephrogenic diabetes insipidus which
occurs due to renal tubules being resistant to normal or
high levels of plasma vasopressin.
Desmopressin has no vasoconstrictor effects.
So does not cause side effects like angina due to coronary
vasoconstriction or abdominal colic due to visceral
vasoconstriction.
Also since duration of action with nasal instillation, spray or
subcutaneous injection is 8-20 h, using it once or twice
daily, patients are not inconvenienced by polyuria or
nocturia
But hyponatraemia can occur during treatment.
Can be prevented by allowing the patient to develop some
polyuria for a short period during each week
Dose may decrease during intercurrent illness
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Childrens nocturnal enuresis can be treated using the same
effect.

The vasoconstrictor effect of ADH can be used for
therapeutic effect. (Terlipressin)
Reduce bleeding in oesophageal varices.
In haemophilia, desmopressin can enhance blood
concentration of factor VIII
When given with local anaesthesia, it reduces the local
circulation & prolongs the action of anaesthetic agent
(Felypressin)


18) Explain how thyrotoxicosis develops in Graves disease. (30
marks)

Graves disease is an autoimmune disease.
There is a production of IgG type antibodies to TSH receptors of
thyroid gland cells.
These antibodies bind to TSH receptors & stimulate the receptor by
mimicking the action of TSH.
TSH acts on thyroid follicular cells and causes the following effects
within minutes
Increase iodide binding ( organification binding of
iodine to tyrosine residues of thyroglobulin)
Synthesis of T
3
and T
4
via coupling of mono & di
iodotyrosines
Synthesis of iodotyrosines
Secretion of thyroglobulin into the colloid
Endocytosis of thyroglobulin
Within hours TSH acts to increase the iodide trapping and the blood
flow to the gland, while
With a longer duration there is hypertrophy and increased weight of
the gland
These actions collectively increase the T
3
and T
4
levels within the
blood
So the above reactions are increased in this condition & there is an
increased release of thyroid hormones into the blood stream
Thyrotoxicosis is a condition where increased levels of thyroid
hormones (T
4
& T
3
) are present in the blood.


19) Explain why adrenergic receptor blockers are used in the
symptomatic treatment of cardiac symptoms of thyrotoxicosis. (40
marks)

Thyrotoxicosis is due to increased release of thyroid hormones into
the blood circulation.
Increased levels of thyroxine have widespread effects on many body
systems, especially cardiovascular system.
Those effects on the cardiovascular system are due to positive
chronotropic & inotropic effects.
They are tachycardia, atrial fibrillation, palpitations, arrhythmias &
even cardiac failure.
These effects are produced mainly by increasing the number &
affinity of receptors to catecholamines in myocardium since
T
3
acts on nuclear receptors present within the cardiac and
enhances the expression of genes for
Alpha myosin heavy chain
Sarcoplasmic reticulum Ca
2+
ATPase
Beta adrenergic receptors
G proteins
Na
+
/K
+
ATPase
Certain K
+
channels
It also inhibits the expression of genes for
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Beta myosin heavy chains
Phospholamban
Two types of adenyl cyclase
T
3
nuclear receptors
Na
+
- Ca
2+
exchanger
Also the increased alpha myosin heavy chain levels in cardiac
myocytes also contribute to this since they increase the speed of
cardiac contraction
Thyroxine can also increase the heart rate directly
Thyroxine has a permissive action on catecholamines that increase
the sensitivity of the body to epinephrine & norepinephrine.
adrenergic receptor blocker is a substance which binds to
receptor & blocks the binding of endogenous ligand (epinephrine) to
that receptor, thus preventing its action.
When adrenergic receptor blockers such as propranolol are given,
the above cardiac symptoms are relieved by blocking epinephrine
getting bound to the receptors.
Also excessive permissive action of thyroxine on catecholamines is
of less use.
So the adrenergic receptor blockers are used in thyrotoxicosis for
the symptomatic relief of cardiac symptoms as an adjuvant therapy.


20) Explain the results that you would expect if you would perform
the following on a patient with primary thyrotoxicosis. (40 marks)

a) Plasma thyroxine T4 & triiodothyronine T3 levels (total &
free) hormones (T4 +T3) due to a problem in the thyroid
gland.

Normally T3 & T4 are excessively bound to plasma proteins (thyroid
binding globulin).
Almost 99.9% is protein bound & only 0.1% remains free, which is
the active component.
When there is increased T3 & T4 production in primary
thyrotoxicosis due to a defect in the thyroid gland, the amount
bound to plasma proteins is increased.
When binding sites are saturated, free T3 & T4 levels are elevated
above the normal levels.
Peripheral conversion of T4 to T3 is also increased, contributing to
increased bound & free plasma T3 level.

b) Plasma TSH response to TRH

The excess of free T3 in blood has a negative feedback inhibition on
the anterior pituitary.
Secretion of TSH is reduced & a low concentration of TSH is found in
blood.
There will be a low level when plasma TSH is measured.


21) Explain the role of PTH in maintaining serum Ca
2+
homeostasis.
(40 marks)

PTH is secreted from chief cells of the parathyroid gland, which
acts to increase serum Ca
2+
levels by acting via membrane
receptors.
PTH has several mechanisms to increase serum Ca
2+
level.
Main mechanism of PTH is that it increases bone resorption
which contributes to increase serum Ca
2+
level.
Rapid phase of bone resorption is due to osteolysis &
Slow phase is due to activation of osteoclasts via osteoblasts &
osteocytes.
PTH also increases Ca
2+
reabsorption, from renal tubules at
distal convoluted tubules.
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PTH increases conversion of 25-hydroxycholecalceferol into 1,25-di
hydroxycholecalceferol (1,25-DHCC) by inducing the hydroxylase
enzyme.
1,25-DHCC increases Ca
2+
absorption in the intestine by increasing
the production of calbindin (Ca
2+
binding globulin) & Ca
2+
/H
+
/ATPase
When serum Ca
2+
level increases, it gives negative feedback effect
on parathyroid gland via cell membrane Ca
2+
receptor to reduce the
PTH secretion.
PTH also causes phosphatiuric action and decreases plasma
phosphate levels
Increased plasma phosphate levels stimulates PTH secretion by
decreasing levels of free Ca
2+
and decreasing the formation of 1,25-
DHCC
In this way PTH contribute to serum Ca
2+
homeostasis.


22) Using a clearly labeled diagram, explain the regulation of
glucocorticoid secretion. (50 marks)

Glucocorticoid secretion is dependent on ACTH secreted from the
anterior pituitary.
ACTH travels through the blood stream & affects the adrenal cortex
in 2 ways. It stimulates the glucocorticoid secretion &
Increases the sensitivity of the cortex to subsequent ACTH levels.
ACTH secretion is stimulated by the CRH secreted by the
hypothalamus.
Hypothalamus receives various inputs from afferent pathways,
which cause changes in CRH secretion.
Emotional stress such as fear, anxiety stimulates the paraventricular
nucleus of the hypothalamus, resulting in stimulation of CRH
secretion.

Baroreceptors NTS Trauma via Nociceptors
(-) Hypothalamus Emotional stress via Limbic
Circadian Rhythm
CRH

(-) Pituitary ACTH Adrenal Cortex
Glucocorticoids
Circadian rhythm is controlled by suprachiasmatic nucleus of
hypothalamus.
ACTH is secreted in irregular bursts.
Plasma cortisol levels also follows these changes.
Bursts are most frequent in early morning (4-10 am) & least
frequent in the evening.
Stressful stimuli such as pain, injury, severe inflammation stimulate
ACTH secretion from anterior pituitary via higher centres.
Inhibitory impulses from the baroreceptors via NTS causes inhibition
of ACTH.
There is a negative feedback effect from the glucocorticoids.
When free glucocorticoids levels increases, it exerts feedback
inhibition on the pituitary & hypothalamus to decrease secretion of
ACTH & CRH.
So glucocorticoids secretion reduces.


23) Explain why prolonged treatment with glucocorticoids should
not be suddenly stopped. (80 marks)

(-)
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Glucocorticoids have negative feedback effect on hypothalamus to
reduce CRH secretion & on anterior pituitary to reduce ACTH
secretion.
In pharmacotherapy glucocorticoids are used in higher doses than
the physiological dose.
Prolonged treatment therefore suppresses hypothalamo-pituitary-
adrenal axis.
So there is no stimulation on adrenal cortex to produce
glucocorticoids, leading to atrophy and unresponsiveness of adrenal
cortex.
Endogenous glucocorticoid secretion is reduced.
Even if responsiveness is restored by injecting ACTH, pituitary may
be unable to secrete normal amounts of ACTH for as long as a
month
Slowly ACTH increases to supranormal levels to increase cortisol
upto normal levels, which via negative feedback inhibition gradually
reduces ACTH to normal levels
This process takes about 6-10 months
Glucocorticoids are necessary to cope with stressful situations.
It has permissive action on glucagon & increase gluconeogenesis in
liver during fasting maintaining the blood glucose level in normal
range.
During fasting, muscle protein breakdown & amino acid uptake by
liver are increased.
So during fasting, patient is liable to hypoglycaemia leading to coma
Glucocorticoids have permissive action on catacholamines to
produce calorigenic, lipolytic & pressor effects.
So in the absence of glucocorticoids, catacholamines cannot exert
their effect, leading to postural hypotension.
Water intoxication can result, as glucocorticoids are necessary to
excrete water load.
Lack of glucocorticoids also causes personality changes.
Glucocorticoids are given as immunosupressants in arthritis,
allergies, asthma, eye diseases, skin diseases like eczema.
Also when the drug is suddenly withdrawn, the disease ( to which
the treatment is given) spreads & aggravates more, leading to
serious consequences.
These effects can be avoided by decreasing the steroid dose slowly
over a long period of time

24) Explain the pathophysiological basis of the following findings in a
patient with Addisons disease.

Serum Na
+
115mmol/l (normal 136-145)
Serum K
+
6.2 mmol/l (3.5-5)
Fasting blood glucose 2.8mmol/l (4.2-6.4)

Addisons disease or primary hypoadrenalism occurs due to
autoimmune destruction of the adrenal cortex, tuberculosis,
surgical removal of the adrenal cortex etc.
As the entire cortex is damaged, secretion & synthesis of all cortical
hormones are affected.
Mainly the mineralocorticoids & glucocorticoids levels are reduced.
Mineralocorticoids mainly aldosterone are important to maintain
the electrolyte balance of the body fluids.
It causes Na
+
absorption & K
+
excretion in the kidney, sweat gland &
salivary gland.
Aldosterone acts on the cells of DCT & CD to increase the ENaCs by
increasing the synthesis (slowly) & insertion (rapidly) of them into
apical membrane.
It also increases the Na
+
/K
+
exchangers in the apical membrane &
Na
+
/K
+
ATPase in the basolateral membrane.
In the absence of Aldosterone those effects are impaired resulting
in Na
+
depletion & K
+
retention.
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So the serum Na
+
reduces & K
+
increases.
Glucocorticoids, mainly cortisol affects the glucose & protein
metabolism.
Glucocorticoids increase gluconeogenesis in liver in several ways.
Activate gluconeogenic enzymes such as glucose-6-phosphatase.
Increases muscle protein breakdown & providess amino acid
substrates for gluconeogenesis.
Increases hepatic uptake of amino acids & increase the activity of
enzymes which convert amino acids to glucose.
Glucocorticoids exert a permissive action on glucagon which is
necessary to increase liver gluconeogenesis in fasting.
Glucocorticoids inhibit glucose utilization in peripheral tissues &
increase blood glucose.
In patients with Addisons disease, as long as they maintain food
intake, blood glucose level is maintained in the normal range.
In fasting state, the main mechanism to maintain blood glucose in
normal level is gluconeogenesis.
But does not take place due to absence of glucocorticoids.
So there is no increase in liver gluconeogenesis, which causes faster
hypoglycaemia.

25) Explain how gluconeogenesis contributes to maintenance of blood
glucose level & ketogenesis spareing glucose in a normal healthy person
during starvation.

Gluconeogenesis is a metabolic process which generates glucose
from non-carbohydrate substrates which helps to maintain blood
glucose levels.
This is prominent when glucose from dietary sources is not
available.
Brain needs a continuous supply of glucose for energy production,
as it cannot utilize fatty acids.
Ketone bodies can cross the blood brain barrier & thus can
supplement energy requirement.
Cells like RBCs, cells of the testes either lack or have inadequate
amounts of mitochondria & their energy production is mainly via
glycolysis, so that they are dependant on glucose.
During starvation, Insulin : Glucagon ratio is low.
Thus c-AMP is increased & c-AMP dependant protein kinases are
activated.
Hormone sensitive lipases (HSL) are activated by reversible
phosphorylation.
TAG are hydrolysed into free fatty acids (FFA) & glycerol by HSL.
FFAs is transported to the liver & oxidized in the mitochondria to
produce energy, which can be used for gluconeogenesis.
In the liver, glycerol is converted to glycerol-3-phosphate by
glycerol kinases & subsequently converted to DHAP by glycerol
phosphate dehydrogenase, thus provides substrates for
gluconeogenesis.
Due to low Insulin:Glucagon ratio, c-AMP is increased & protein
kinases are activated.
By the action of protein kinases PFK & PK enzymes are inactivated
by reversible phosphorylation.
Fructose-2,6-BP is reduced thus, PFK1 inactivated & fructose-1,6-BP
is activated.
Thus gluconeogenic pathway is activated & glucose-6-phosphate is
produced from DHAP.
During starvation, the cortisol level in the blood increases & the
protein breakdown in muscles increase.
Thus the uptake of glucogenic amino acids such as Alanine from the
liver is increased.
These glucogenic amino acids can be converted to pyruvates or
other TCA cycle intermediates.
Pyruvate can be converted to OAA by pyruvate carboxylase.
OAA can be converted to PEP by PEP carboxykinase.
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Thus glucose-6-phosphate is subsequently produced & converted to
glucose by glucose-6-phosphatase & diffused into the blood to
maintain the glucose levels.
Since the oxidation of FAs is extensive, the amount of acetyl CoA
produced is very high.
Availability of OAA for the TCA cycle is reduced because of
gluconeogenesis & they are shifted to ketone body formation.
They are not consumed in the liver & they are converted back to
acetyl CoA in the peripheral tissues & used as an alternative fuel.
Since ketone bodies are water soluble, they can cross the blood
brain barrier, & they can be used as alternative fuel by the brain.
Since the glucose utilization in the brain & other peripheral tissues is
reduced.
Glucose is spared.

26) Explain why same 2 procedures aggravate the disease & cause
ketoacidosis in uncontrolled type 1 DM.

In type 1 DM, pancreatic cells are destroyed & insulin is absent.
Thus insulin has to be given exogenously.
Therefore when insulin is not given, Insulin:Glucagon ratio becomes
very low even during the fed state.
Since the basal insulin secretion is absent, the inhibitory action on
production of glucagon is reduced & glucagon secretion is
unrestrained.
This leads to increased levels of cAMP & activation of protein
kinases in the target tissues.
PFK2 & PK are inactivated by reversible phosphorylation.
Generation of fructose-2,6-BP reduced.
Due to the removal of the allosteric inhibitory effect on F-1,6-BPase
& withdrawal of allosteric stimulatory action on PFK1, glycolysis is
suppressed & gluconeogenesis is increased in the liver, increasing
blood glucose levels in the blood.
Due to unrestrained activation of HSL in adipose tissue, by
reversible phosphorylation, by cAMP dependant protein kinases,
there is an increased production of FFAs & glycerol & their releasing
into the circulation.
Glycerol can be converted to glycerol-3-phosphate & used as
substrate in gluconeogenesis.
FFAs are oxidized in the liver& acetyl CoA is produced.
Pyruvate carboxylase is allosterically activated by acetyl CoA &
gluconeogenesis is increased.
Since high amounts of acetyl CoA are produced, they are converted
to ketone bodies.
These are moderately strong acids (low pKa) & are water soluble.
They cause acidaemia, by liberating their H
+

Buffer systems in the body like HCO
3
-
are overwhelmed due to high
load of ketoacids
Also the glucose excretion causes simultaneous water and solute
excretion via osmotic diuresis leading to dehydration
and further aggravates the acidosis

27) Some biological properties of the lens of the human eye are given
below.
a) Km value for glucose of hexokinase is 0.1mM
b) Km value for glucose of aldose reductase is 200mM
c) Glucose-6-phosphate dehydrogenase reaction is a major source of
NADPH
Taking into consideration above data, state the biochemical basis for
the occurrence of diabetic cataract.

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The Michaelis constant, Km is an indicator of an enzyme affinity
towards a particular substrate.
A low Km reflects high affinity, whereas a high Km reflects low
affinity.
Hexokinase
Glucose Glucose -6-phosphate
Km=0.1mM


Glucose Aldose Reductase Sorbitol
Km=200mM
Km value of hexokinase for glucose, 0.1mM is lower than the Km of
aldose reductase for glucose 200mM.
That is, the affinity of hexokinase for glucose is higher than the
affinity of aldose reductase for glucose
Therefore under normal physiological glucose concentrations in
cells, only hexokinase reaction occurs in an appreciable extent.
In DM, the glucose concentration in blood is high.
Since glucose entry into cells of lens is not regulated by insulin,
glucose freely enters the cell which results in high glucose
concentration within them.

Hexokinase G6PDH
Glucose Glucose-6-phosphate HMP

Aldose NADPH NADPH NADP
+

reductase NADP+

Sorbitol DH
Sorbitol ------------------------

At a high substrate concentration, the rate of aldose reductase
reaction becomes significant, leading to increased sorbitol
production within the lens cells.
The NADPH required for this reaction is supplied by Glucose-6-
phosphate dehydrogenase catalysed reaction of HMP pathway,
which is also accelerated due to increased concentration of its
substrate (glucose-6-phosphate).
The increased glucose-6-phosphate results from increased rate of
hexokinase reaction due to the increase in glucose concentration.
The sorbitol formed this way is trapped within the cell due to
impermeability of the cell membrane.
Lens cells lack the enzyme sorbitol dehydrogenase, which converts
sorbitol to fructose
Therefore sorbitol accumulates within cells.
This increases osmolality within the cell, causing water retention &
cell swelling, leading to cataract.


28) A non-insulin dependant diabetic patient after being on oral
hypoglycaemic drugs for a period of 6 weeks presented with the
following lab investigations.
FBG 100mg/dl
Glycosylated Hb 10.5%
Serum total cholesterol 275mg/dl (normal range 150-250)
Serum triglycerides 180mg/dl(normal range 60 -180)
Comment on the results.

NIDDM is also called the type 2 DM.
In this condition the patient has some amount of insulin secretion
from the pancreas but there is a resistance to its action in the
peripheral tissues.
In an obese person, increased amount of adipose tissue is the main
cause of insulin resistance.
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So the predisposing factors to type 2 DM are high sugar & fat
consumption & decrease in physical activity.
Fasting blood glucose value of a patient gives an idea about the
present state of glycemic control.
This is affected by many factors such as diet, level of exercise, illness
& also by hypoglycemic drugs.
In a DM patient, plasma glucose levels are above 126mg/dl.
But this patient uses oral hypoglycemic drugs for 6 weeks. Oral
hypoglycemic drugs either decrease peripheral insulin resistance
(biguanides), or
Increase insulin secretion (sulphonylureas)
Because of these effects of drugs, the blood glucose level has
become normal.(70-110mg/dl)
Glucose in blood, non-enzymatically & slowly reacts with
hemoglobin to form HbA1c.
The reaction rate is proportionate to the glucose concentration in
blood &
Also once glycosylated it remains so, till the RBC is destroyed.
RBCs have a lifespan of 120 days.
So, by measuring HbA1c levels, we can get an idea about the history
of glucose concentration in blood up to 2-3 months.
Also this measurement is not affected by the present state of
glycemic control.
This patients HbA1c is above normal.
The reason for this is that he has been using drugs only for last 6
weeks & HbA1c represents last 8-12 weeks glucose levels & the
value is still above normal.
Triglycerides & cholesterol levels of this patient is above normal
range.
In a NIDDM patient, there is increased synthesis & output of VLDL in
the liver,
but peripheral clearance by adipose tissue is reduced due to
reduction of lipoprotein lipase activity.
So VLDL & also dietary chylomicrons accumulate in blood.
Since the main components these lipoproteins is triglycerides, the
level in the blood is elevated.
High VLDL level in blood lead to high amount of LDL in blood, so the
total cholesterol level is also above normal value.
These findings show that although the patient is taking the drugs,
he may be having a poor dietary control like excessive consumption
of fatty food.

29) Metabolic changes in the liver, muscle and adipose tissue during
stress

Stressful situations like surgery, burn, injury, infections etc result in
secretion of stress hormones like glucagon, cortisol, adrenaline and
growth hormone
In these circumstances, the cells of the immune system release
proteins like TNF , IL 1 and IL 6
To cope with stressful reactions, body tissues require rapid energy
supply
Blood glucose and free fatty acid levels are elevated thus meaning
that maintenance of blood glucose level is essential
Liver, muscle and adipose tissue act in an integrated manner to do
this
Glucagon and adrenaline act on adipose tissue to increase the
intracellular cAMP level
This results in phosphorylation and activation of hormone sensitive
lipase, which breaks down triglycerides in cells to fatty acids and
glycerol
They are transported to the liver via the bloodstream and are taken
up by hepatocytes
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Glycerol Is used as a substrate for gluconeogenesis and free fatty
acids are oxidized by oxidation to supply the energy requirement
for gluconeogenesis
Cortisol acts on the muscles and the breakdown of muscle protein
results in the release of amino acids, which undergo transamination
and oxidative deamination to produce alanine and glutamine, which
are released into the blood stream
These amino acids are again taken up by the liver and used to
provide carbon skeletons for substrates in gluconeogenesis
Cytokines released during stress cause fever and metabolic changes
in the body
IL 1 activates proteolysis in muscle supporting the role of cortisol
IL 6 stimulates hepatic production of acute phase reactants which
play a role in the defense against injury and infections
TNF inhibits lipoprotein lipase activity in adipose tissue and
inhibits triglyceride hydrolysis
They also inhibit triglyceride synthesis in the adipocytes and
stimulates lipolysis in adipose tissue
TNF also inhibits the release of insulin from the pancreas and
induces a relative insulin deficient state

30) Biochemical basis for occurrence of fasting hypoglycaemia in
alcoholics

In the fasting state there is no supply of glucose from the diet
Therefore the main mechanism responsible for maintaining blood
glucose is gluconeogenesis
It is an energy dependant process which requires non carbohydrate
substrates
When alcohol is consumed it is metabolized in the following way
Alcohol Acetaldehyde Acetate




NAD
+
H
+
+ NADH NAD
+
H
+
+ NADH
Metabolism of alcohol causes a reduction in the NAD
+
level so that
the NAD
+
/NADH ratio is low.
The major substrate in gluconeogenesis is lactate, glycerol and
alanine
In order to divert the above substrates into gluconeogenic
pathways, the availability of the high NAD
+
level is essential.
As NAD
+
is required for the following conversions of lactate to
pyruvate and glycerol phosphate to DHAP
Pyruvate is shunted via Oxaloacetate(OAA) into PEP in
gluconeogenesis
OAA is formed in liver mitochondria which cannot cross the
mitochondrial membrane to enter the cytosol, where
gluconeogenesis takes place
So in mitochondria, OAA is converted into malate which can cross
the mitochondrial membrane

In the cytosol the conversion of malate to OAA requires NAD


+

So the lack of NAD


+
results in the inhibition of the above reaction
and the substrate cannot enter the gluconeogenic pathway

So gluconeogenesis is inhibited resulting in hypoglycaemia


oxidation of free fatty acids is the main source of energy for


gluconeogenesis

NADH and FADH


2
are produced in oxidation supply energy for ATP
production in the Electron transport chain

Production of NADH requires NAD


+
which is lacking in alcohol
consumption

So gluconeogenesis is inhibited resulting in hypoglycaemia





31) Metabolic interrelationships between the liver and the kidney are
blown to maintain acid base homeostasis
Explain how these relationships operate to maintain metabolic
acidosis
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The complete catabolism of positively charged AAs such as Arg, Lys
and Sulphur containing amino acids such as methionine and
cysteine result in the net production of protons
Kidneys play a major role in excreting H
+

The ability to excrete H
+
is increased with the increment of the
buffering capacity in renal tubules
By substances such as ammonia and bicarbonate
Therefore in metabolic acidosis there is a mechanism for sparing
bicarbonate and ammonium and directing them to the kidney
There are two types of hepatocytes which differ in enzyme
distribution
Perivenous Which contains mainly glutamine synthase activity
Periportal mainly contains glutaminase activity and urea cycle
enzymes
This mechanism results in the effective utilization of ammonia and
glutamine and production of urea under normal circumstances
In acidosis glutaminase and urea cycle enzymes are inhibited and
glutamine synthase activity in the liver is stimulated
Preventing the incorporation of ammonia and bicarbonate into urea
and sending them to the kidney by means of glutamine
In the kidney glutamine is broken down into glutamate and
subsequently into alpha ketoglutarate each reaction resulting in the
production of ammonia
Alpha KG is converted to malate via the TCA cycle enzymes and
enters gluconeogenesis and bicarbonate is produced
Bicarbonate and ammonia enter the renal tubule and buffer H
+




32) Explain the role of periportal & perivenous hepatocytes in the
regulation of blood ammonium levels.

Glutamine in the blood circulation is taken up by the periportal
hepatocytes,
Where it is converted to glutamate & NH
3
by glutaminase enzyme.
Glutamate reacts with OAA & produce KG & aspartate.
Produced NH
3
& aspartate enter the urea cycle.
NH
3
in the blood circulation is taken up by the perivenous
hepatocytes,
Glutamate in the perivenous hepatocytes reacts with NH
3
to
produce glutamine, in the presence of glutamine synthase.
Produced glutamine is released to the blood circulation where most
of it is taken up by the periportal hepatocytes.
Some amount of the glutamine produced in the perivenous
hepatocytes is diverted from liver to kidney to be used for
gluconeogenesis.
Amount diverted is more when acidosis occurs.
In the kidney,
glutaminase
Glutamine NH
3
+ Glutamate Glucose + HCO
3
-
+ NH
3