ANDROGENS AND PROSTATE
2. Describe the synthesis, secretion and mechanism of action androgens, and the
therapeutic uses of antiandrogens against prostate cancer.
Synthesis:
Androgens are synthesized from cholesterol in the leydig cells primarily and the
remainder from the adrenal cortex and ovaries. Cholesterol is converted to androgens such as
testosterone through the help of CYP17. Dihydrotestosterone is synthesized from testosterone
with the help of 5a-reductase. Moreover, circulating testosterone converted locally by aromatase
can have oestrogenic actions, as they synthesize estradiol.
Secretion: testosterone is the main circulating androgen. It is mainly secreted from
Leydig cells of the testis. The secretion of testosterone is stimulated by the hypothalamu-
pituitary-testicular axis. The hypothalamus secretes GnRH which stimulates the anterior pituitary
to release FSH and LH. LH release stimulate the testicular release of testosterone from leydig
cells, while FSH stimulates the release of androgen binding protein from sertoli cells. Testicular
function is controlled by the negative feedback loop of the hypothalmo-pituitary-testicular axis.
The release of testosterone has an inhibitory effect on the hypothalamus and the anterior
pituitary, inhibiting the release of GnRH, LH and FSH. moreover, sertoli cells release inhibin and
activin which also has an inhibitory effect on the level of the anterior pituitary, inhibiting the
release of FSH.
Mechanism of action of androgens: Androgens stimulate proliferation and Inhibit apoptosis.
When free testosterone enters prostate cells, 90% is converted by hydroxylation to
dihydrotestosterone (DHT) by the enzyme 5α-[Link] & DHT modify gene
transcription by interacting with nuclear receptors: androgen receptors (AR) intracellular
receptors. The MoA is as follows:
1-Testosterone diffuses into the prostate cell.
2-T is converted into DHT (potent form of T) via 5-alpha reductase.
3-DHT binds to AR (intracellular receptor)
4-Dimerization and phosphorylation of AR and DHT occurs.
5-Allowing it to enter into the nucleus and initiate gene transcription.
6-Resulting in gene activation of growth, survival and increased prostate specific androgen
(PSA).
Therapeutic uses of antiandrogens:
● Abiraterone acetate:
● It inhibits androgen synthesis
● Lowers testosterone levels to nearly undetectable
● Inhibits enzyme CYP17
● Enzalutamide:
● Its a non-steroidal antiandrogen
● It targets 3 stages of AR signalling pathway:
● 1) blocks androgen binding to AR
● 2) inhibits AR nuclear translocation
● 3) impairs AR binding to DNA preventing modulation of gene expression
● Other antiandrogens include Flutamide and cyproterone
● AR antagonists prevent testosterone binding to AR.
● They’re most commonly used as combined androgen blockade (CAB).
Q1. Mr Darewood is a 45-year-old butcher. He lives alone and has no partner or children. He
presents at his GP, complaining of nocturia. He is occasionally sexually active. He is not on any
medication and has no significant past medical history. His mother passed away from ovarian
cancer at age 42. On examination, his prostate feels enlarged with a nodule on the right hand
side. His serum PSA level is 12.8 ng/ml.
a) Describe the most appropriate investigations for this patient. (6 marks)
● Digital rectal examination would be performed (check your prostate for enlargement).
● There would be nodular enlargement, smooth and not craggy prostate for BPH
● Hard and craggy prostate is indicative of prostatic carcinoma
● Urine test. Analyzing a sample of your urine can help rule out an infection or other
conditions that can cause similar symptoms.
● Blood test to check levels of plasma PSA. It is not diagnostic of BPH since elevated
levels of PSA could be due to infections, recent procedures or prostate cancer
b) What is the likely diagnosis, giving reasons for your answer. (4 marks)
Benign prostatic hyperplasia since the patient is complaining from nocturia. This is indicative of
BPH as the prostate is enlarged and causes obstruction of the urine outflow. However, at night
when the patient is laying down the pressure from the prostate is reduced causing dilation of the
urethra resulting in symptoms of nocturia. Additionally, the enlarged nodule on the right hand
side is indicative of BPH as it affects the transitional zone of the prostate.
c) What would an MRI of the prostate reveal? (2 marks)
d) Outline the hypothalamo-pituitary control of testosterone. (4 marks)
The secretion of testosterone is stimulated by the hypothalamic-pituitary-testicular axis. The
hypothalamus secretes GnRH which stimulates the anterior pituitary to release FSH and LH. LH
release stimulates the testicular release of testosterone from leydig cells, while FSH stimulates
the release of androgen binding protein from sertoli cells. Testicular function is controlled by the
negative feedback loop of the hypothalamo-pituitary-testicular axis. The release of testosterone
has an inhibitory effect on the hypothalamus and the anterior pituitary, inhibiting the release of
GnRH, LH and FSH. Moreover, sertoli cells release inhibin and activin which also has an
inhibitory effect on the level of the anterior pituitary, inhibiting the release of FSH.
e) Describe how the hypothalamo-pituitary-testicular axis can be pharmacologically targeted to
treat Mr Darewood. (6 marks)
● Using an antagonist that directly inhibits GnRH receptors for example: Degarelix.
● MoA: antagonize GnRH receptors in the pituitary gland resulting in a significant
reduction in circulating LH and a subsequent decrease in the synthesis of testosterone.
An antagonist directly inhibits GnRH receptors and is not associated with the testosterone flare
or delayed onset of testosterone suppression such as GnRh agonist.
f) Describe the clinical uses of androgens and antiandrogens and their unwanted side-
effects. (6 marks)
Androgens are used in Androgen replacement therapy – TxMale hypogonadism due to pituitary
or testicular Disease as it maintains masculine appearance and preserves bone health.
–E.g Nebido, restandol – + Tx Female sexual dysfunction following ovariectomy.
Unwanted S/E: Masculinizing effects
•‘Feminizing’ effects (gynecomastia)
•Impaired growth in children (via premature fusion of epiphysis)
•Acne
•Decreased GnRH >> resultant infertility
•Salt & water retention >> oedema
•Adenocarcinoma of the liver
Therapeutic uses of antiandrogens:
● Abiraterone acetate:
● It inhibits androgen synthesis
● Lowers testosterone levels to nearly undetectable
● Inhibits enzyme CYP17
● Enzalutamide:
● Its a non-steroidal antiandrogen
● It targets 3 stages of AR signalling pathway:
● 1) blocks androgen binding to AR
● 2) inhibits AR nuclear translocation
● 3) impairs AR binding to DNA preventing modulation of gene expression
● Other antiandrogens include Flutamide and cyproterone
● AR antagonists prevent testosterone binding to AR.
● They’re most commonly used as combined androgen blockade (CAB).
● Finasteride:
-5-alpha reductase inhibitor reducing testosterone conversion into DHT
-Commonly used in BPH
-Resulting in: ↓ prostate gland volume –flow rate and symptom improvement –↓in long
term risk of BPH development reduces symptom progression and acute urinary retention
and BPH Related surgery.
PITUITARY
1- Describe the regulation of growth hormone secretion and the therapeutic
strategies used to treat both over-production and underproduction of growth
hormone.
Regulation of growth hormone secretion:
Changes in GHRH and SST secretion in the hypothalamus regulate the secretion of growth
hormone. GHRH has stimulatory effect on the anterior pituitary, while somatostatins have an
inhibitory effect on the anterior pituitary (reduce cAMP). The balance between GHRH and SS
determines the rate of GH secretion. This includes multiple stimuli such as, metabolic
regulation, dopamine, ghrelin, sleep and thyroid hormones.
Another regulatory mechanism of GH secretion is exercise (^ GH) and somatopause (causes
decline in GH between the ages of 20 – 60)
GH also exerts many of its effects indirectly through IGF-1, in which it stimulates IGF-1
synthesis in the liver and many other organs
There is a negative feedback loop by IGF-1 that inhibits GH release on the level of the
hypothalamus and pituitary, by reducing GHRH levels and increasing SS levels. GH itself has a
short negative feedback loop that inhibits pituitary and hypothalamus. Moreover, GHRH inhibits
its own secretion.
Therapeutic strategies for GH overproduction:
First line treatment is surgery or local irradiation to decrease growth from pituitary as the most
common cause for GH excess is a pituitary adenoma.
Second line treatment is medical therapy (receptor targets) which include:
- Somatostatin receptor agonists
o Somatostatin: has an inhibitory function reducing GH, TSH, glucagon, insulin and
gastrin release but limited therapeutic use
o Octreotide is more commonly used since it has the function but is longer acting
and 45x more potent that SS.
- Growth hormone receptor antagonists
o Binds to GH blocking conformational change, blocking signal transduction. It
normalises IGF-1 levels in most patients
o It does not lower GH levels or reduced tumour size so it’s often used in
combination with SS analogues
- Dopamine agonists
o Activates dopamine D2 receptors which act to suppress the pituitary secretion of
PRL and GH by inhibiting GHRH
Therapeutic strategies for GH underproduction:
Daily injections of recombinant hGH (somatotropin) and regular assessment of glucose
tolerance and thyroid functions test
- Recombinant GH or peptide GHRH analogue
o It acts through the GH receptor and GH to increase the production of IGH-1
o It acts to restore normal growth and metabolic GH effects in GH-deficient
individuals and it increases the final adult height in some children with short
stature not due to GH deficiency
- Recombinant IGF1
o Stimulates IGF1 receptors and improves growth and metabolic effects of IGF1
deficiency due to severe GH resistance
THYROID
Q1. Rachel Kelly, a 40-year-old female patient who is overweight, presents to her GP with
fatigue, weight gain, intolerance to cold and three missed periods. Rachel has puffy facial
features and feet and she also reports difficult bowel movements. Examination identifies no
tenderness in the abdomen and the physical HEENT (head, eyes, ears, nose and throat)
examination is within normal limits. Standard laboratory testing reports a haemoglobin of 10.0
g/dl, and otherwise normal haematological parameters. Both pulse (110 beats/min) and
respiratory rate (30 breaths /min) are slightly elevated. Blood chemistry and serum lipids levels
are within the normal ranges. A follow-up blood test identifies that the thyroid hormone
concentrations are: T3 0.65ng/ml, T4 0.4ng/ml and TSH 54 mIU/L.
Questions (parts a-e below contribute equally to the final grade score for this question):
Normal T4: 0.8-1.8ng/ml Normal T3: 100-200ng/ml Normal TSH: 0.5-5 mIU/L.
(a) What is the likely diagnosis for this patient and which of the factors described
above are the indicators of that diagnosis?
Primary Hypothyroidism
- Decreased metabolic activity cause Weight gain, Fatigue (Anaemia)
- 3 missed periods due Here’s what happens: When your thyroid hormone levels
decrease, your brain’s hypothalamus starts producing extra thyrotropin releasing
hormone (TRH), and your pituitary gland releases extra thyroid stimulating hormone
(TSH) and prolactin, another hormone.
High prolactin levels then suppress production of gonadotropin-releasing hormone
(GnRH) in your hypothalamus. This is a problem, because you need GnRH to produce
follicle-stimulating hormone and luteinizing hormone in your pituitary gland. These
hormones are important for normal ovarian function, and when hypothyroidism leads to a
decrease in their levels, menstrual irregularities may occur
-Myxdeoma: is a condition marked by thickening and swelling of the skin caused by
insufficient production of thyroid hormones by the thyroid gland
-Intolerance to cold: Cause normally the th Hormone increases o2 consumption and heat
production. Low Th means they do not produce enough thyroid hormone to convert
and utilize stored energy effectively.
-Anaemia: The low thyroid hormone levels of hypothyroidism suppress the activity
of bone marrow, the tissue that makes red blood cells. That lowers the production of
red blood cells and triggers anemia
-Moreover, T3 and T4 levels low and TSH level is high
This is indicative of hypothyroidism
(b) Which of the thyroid hormones listed above is more biologically active and
discuss its major biological effects?
-Triiodothyronine (T3) 9% of Th synthesis.
-T3 major biological effects are: supporting brain function, heart function and digestion
and binds to nuclear receptors much more readily than T4.
· The active form of thyroid hormone
T3 binds to nuclear Thyroid
Receptors (TRs) which are usually
bound to co-repressors.
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· Upon T3 binding, the TRs change conformation, release co-repressors and recruit co-
activators to induce gene transcription of target genes
(c) What is the appropriate course of treatment and why?
L-Thyroxine (T4) replacement therapy (Levothyroxine), this is the preferred therapy as the
body converts T4 to T3. Half-life is 7 days and its given once daily.
Note that elderly patients with cardiac disease should be started on very low doses and
titrated up slowly.
If the patient has low iodine levels we give iodine to increase thyroid hormone level.
(d) What additional tests, if any, should be undertaken before beginning treatment
and why?
(1) Test for iodine: Cause iodine deficiency can cause hypothyroidism.
(2) Pregnancy test: If positive we increase the dosage of L-Thyroxine.
(3) Thyroid antibody test.
(e) Should any dietary advice be given to Rachel and if so, what advice would you give?
Avoid fatty food. Gluten free diet
Physical examination reveals a blood pressure of 165/75 mm Hg, a systolic ejection murmur,
and tachycardia, as well as diffuse nontender enlargement of the thyroid, slight resting tremor,
fine hair, separation of the fingernail plate from the nail bed (onchyolysis) and brisk reflexes.
Laboratory tests reveal elevated free plasma thyroxine (T4) and reduced TSH.
0. b) What is the likely diagnosis? Give reasons for your answer. (2 marks)
Primary hyperthyroidism. Due to the elevation of free plasma thyroxine and reduced
TSH very very dangerous.
0. c) Why has this woman experienced weight loss? (4 marks)
Normally, the function of the thyroid hormone is to increase metabolism of carb, fats and
proteins. As seen in this patient the levels of thyroid hormone are increased suggesting
the increase in metabolic rate resulting in weight loss.
0. d) What are the two thyroid hormones and which is more potent? (2
marks)
-Thyroxine T4
-Triiodothyronine (T3) 9% of Th synthesis.
-T3 major biological effects are: supporting brain function, heart function and digestion
and binds to nuclear receptors much more readily than T4.
-Both T4 and T3 circulate in the blood tightly bound to plasma proteins, mainly Thyroxine
binding globulin (TBG)
0. e) How are the thyroid hormones synthesised? (6 marks)
(1) Stress stimulate hypothalamus to release TRH
(2) TRH stimulated anterior pituatry to produce TSH
(3) TSH increase transcription factors for iodine transporters.
(4) Plasma iodide uptake by the follicle cells using NIS.
(5) Oragnification of idodie occurs: In the presence of H2o2 and thyroperoxidase
idodine + tyrosine are converted into MIT and DIT
(6) Coupling and iodination resulting in thyroglobulin entering the follicle cell via
endocytosis
(7) The complex dissociates which results in the secretion of T3 + T4.
0. f) Assuming the plasma levels of catecholamines are normal in this
patient, what explains the tachycardia, tumours, palpitations and
increased pulse pressure? (4 marks)
T3 has direct effect on the cardiovascular system where it enhances the sensitivity of
epinephrine by upregulation of beta adrenergic receptors.
Since it also has a high metabolic rate in the peripheral tissues it increases the cardiac
output and force of cardiac contractions.
0. g) What is the difference between primary, secondary and tertiary
hyperthyroidism and which does this patient have? (4 marks)
The patient has primary hyperthyroidism as seen in the blood results, high T4 and low
TSH (dysfunction in thyroid gland). In secondary hyperthyroidism TSH levels are high
and high T4&T3 (dysfunction in pituitary). In tertiary hyperthyroidism high TRH, High
TSH, High T4&T3 (dysfunction in hypothalamus)
0. h) What therapeutic options are available for this patient? (4 marks)
Slide 15-19
DIABETES
2017 S1 Q1. A middle-aged obese woman presents for a pre-employment physical
examination. She complains of increased thirst and frequent urination. Her non- fasting plasma
glucose level is 275 mg/dL. Both of her parents were overweight, had “sugar problems” and
died of cardiovascular complications.
1. a) Which type of diabetes does this patient most likely have and why? (10 marks)
Type 2 diabetes mellitus. Rationale:
-Age: T2DM is more common in middle [Link] have shown that there is genetic
predisposition in T2D. Additionaly, the patient presented with classical symptoms of
T2DM increased thirst and frequent urination.
-Genetics: Both her parents were overweight and had “sugar problems”. This supports
that genetic predisposition may be the cause. There is a linkage to diabetogenic and
obesity related genes.
-Weight: Obesity is a major risk factor for T2DM. Adipose tissue is considered an
endocrine organ which expands with obesity resulting in adipose tissue hypertrophy.
Adipocytes begin to burst invoking an inflammatory response releasing
adipokines, proinflammatory cytokines, free fatty acids. This results in the adipocytes
being insensitive to insulin creating insulin resistance. Therefore, pancreatic beta cells
try to compensate by increasing insulin secretion leading to failure of beta cells overtime
causing decreased insulin secretion translating to T2DM in the blood glucose levels.
2. b) Outline the different pathologies between type1and type2 diabetes(10 marks)
Type 1 diabetes is an autoimmune disease caused by is gross destruction of pancreatic
beta cells where the pancreas fails to produce insulin. (Talk about autoantibodies). The
pathogenesis is the breakdown in self-tolerance to islet autoantigens. Moreover, it has a
major genetic linkage to MHC class 1 and 2 genes resulting in the pathology of
autoimmune insulitis, beta cell depletion and islet atrophy. It usually presents in
childhood with weight loss preceding the diagnosis and there is progressive decrease in
insulin levels and circulating islet autoantibodies are found. Finally, Type 1 diabetes has
a high risk of DKA in the absence of insulin therapy.
Type 2 diabetes is characterized by insulin resistance in peripheral tissue with failure of
compensation by beta cells. It has multiple obesity associated factors (free fatty acids,
Pro-inflammatory adipocytokines) Linked to the pathogenesis of insulin resistance. The
onset is usually in adulthood but it is increasing now in childhood and adolescents. The
vast majority of patients who present with T2DM are obese. Non-Ketotic hyperosmolar
coma is a high risk for these patients.
The patient returns for a follow-up visit 2 weeks later, when fasting laboratory tests show plasma
glucose of 180 mg/dL, total cholesterol of 250 mg/dL, low- density lipoprotein cholesterol of 175
mg/dL, high-density lipoprotein cholesterol of 30 mg/dL, and a urinalysis reveals
microalbuminuria. The patient is started on metformin. She returns to the clinic 3 months later.
Her HbA1c has decreased from 8.5% to 7.5%.
c) What is HbA1c and what do these results mean? (6 marks)
glycated hemoglobin test shows what a person’s average glucose levels were for the past 3
months. Since it deceased from 8.5 to 7.5%, this means she’s adhering to the medication, but
the microalbuminuria requires urgent intervention.
4. d) Describe the mechanisms of action and side-effects of metformin. (6
marks)
1s line therapy of T2DM is Metformin is usually used in monotherapy and dual therapy.
Metformin targets insulin resistance by reducing glucose absorption from the gut,
inhibiting hepatic gluconeogenesis. The MoA is poorly understood and it has a low
hypoglycaemic risk. However, it causes renal insufficiency causing accumulation of
metformin and increasing risk of lactic acidosis
5. e) What different types of insulin are available? How would you introduce
insulin therapy for this patient? (6 marks)
NPH and Lente. This type of insulin has a longer duration of action due to slower rates of
absorption from subcutaneous tissue this is achieved by reducing solubility at physiological pH
by mixing with NPH or Lente.
Different type of insulin available:
1-Ultra short acting: Lespro , Aspart , Glulicine it enters the bloodstream within minutes and it’s
good for using before food intake. It has less risk of hypoglycaemia compared to other insulins.
2-Short acting (Regular): Soluble insulin it is a clear solution of neutral insulin and suitable for
I.V use in emergencies (For ketoacidosis+Gestational Diabetes).
3-Intermediate Basal: NPH and Lente. Given subcutaneously with onset of 1-3hrs.(Written
above)
4-Long acting: Glargine + Detemir. Given when there is a constant low level of plasma insulin in
the fasting and inter prandial state is essential to maintain the overall glycaemic control. They
also complement the rapid acting insulins at meal times. (Go back to slide 21)
6. f) What new classes of drug are available for treating patients with this type
of diabetes? (6 marks)
DPP-4 and GLP1 agonists.
GLP-1 decrease glucagon secretion reducing appetite and slowing gastric emptying and
promoting beta cell proliferation. GLP-1 is injected once daily and often is given as a second line
therapy with other oral hypoglycaemics. S/E: Headache, Nausea, Diarrhoea.
DPP-4 inhibitors is a serine protease that’s delivered orally and reduces HbA1c levels. It is
weight neutral and its S/E include nausea and headaches.
7. g) Why should this patient be educated about the importance of examining
her feet periodically? (6 marks)
The patient has high cholesterol and that might trigger peripheral artery occlusive
disease due to atherosclerosis (build up of fatty plaques) which alongside diabetic
neuropathy (when hyperglycemia produces oxidative stress on neurons), will lead to the
development of diabetic foot.
2018
Mr. Alan Campbell is a 48-year-old accountant. He has a history of heavy alcohol use but quit
drinking alcohol two years ago. He is asymptomatic and presents to your clinic for a routine
check-up. His height is 1.80 metres and his body mass index (BMI) is 34. You advise lifestyle
modifications to reduce his weight.
a) What is Mr. Campbell’s weight in Kg (kilograms)?
b) List the three main BMI-related weight categories and their BMI score
ranges.
c) Which major chronic disease conditions is Mr. Campbell at risk for developing, and
why?
Two years later the patient returns and has gained weight (BMI=38) and complains of excessive
thirst and urination. Based on the results of diabetes testing, you diagnose him with Type II
Diabetes and commence him on metformin initially. You also add a second therapy at this point
to help control his weight and diabetes.
d) By what biological mechanism(s) is obesity associated with increased risk of Type II
Diabetes?
-Weight: Obesity is a major risk factor for T2DM. Adipose tissue is considered an endocrine
organ which expands with obesity resulting in adipose tissue hypertrophy. Adipocytes begin to
burst invoking an inflammatory response releasing adipokines, proinflammatory cytokines, free
fatty acids. This results in the adipocytes being insensitive to insulin creating insulin resistance.
Therefore, pancreatic beta cells try to compensate by increasing insulin secretion leading to
failure of beta cells overtime causing decreased insulin secretion translating to T2DM in the
blood glucose levels.
e) Describe the differences between being pre-Diabetic to Diabetic in the context of blood
glucose diagnostic tests.
Normal range FPG: 5.6mmol/L (<100mg/dl ) Pre diabetic: 5.6-6.9 (100mg/dl) Diabetic:
>7mmol/L (>126mg/dl)
Glycated Haemoglobin in Normal: <39mmol/L Pre diabetic 39-47mmol/L Diabetic: equals
or>48mmol/L
f) Name the second drug (in addition to metformin) that you added in Mr. Campbell’s
case and describe its mechanism of action.
The dual therapy with metformin would be:
(1)Metformin with GLP-1:
GLP-1 decrease glucagon secretion reducing appetite and slowing gastric emptying and
promoting beta cell proliferation. Therefore, this would be a suitable choice for this patient to
control his weight.
GLP-1 is injected once daily and often is given as a second line therapy with other oral
hypoglycaemics. S/E: Headache, Nausea, Diarrhoea.
Mr. Campbell responds well to medication for 5 years but eventually glucose control
deteriorates, and you commence him on insulin. He accidently takes an overdose of the
prescribed insulin by forgetting to eat after injection and enters a hypoglycemic coma.
g) Describe how you would commence the patient on insulin and describe the different
types of insulin available.
Since the patient has type 2 diabetes we give Basal/intermediate acting insulin:
NPH and Lente. This type of insulin has a longer duration of action due to slower rates of
absorption from subcutaneous tissue this is achieved by reducing solubility at physiological pH
by mixing with NPH or Lente.
Different type of insulin available:
1-Ultra short acting: Lespro , Aspart , Glulicine it enters the bloodstream within minutes and it’s
good for using before food intake. It has less risk of hypoglycaemia compared to other insulins.
2-Short acting (Regular): Soluble insulin it is a clear solution of neutral insulin and suitable for
I.V use in emergencies (For ketoacidosis+Gestational Diabetes).
3-Intermediate Basal: NPH and Lente. Given subcutaneously with onset of 1-3hrs.(Written
above)
4-Long acting: Glargine + Detemir. Given when there is a constant low level of plasma insulin in
the fasting and inter prandial state is essential to maintain the overall glycaemic control. They
also complement the rapid acting insulins at meal times. (Go back to slide 21)
h) How did the overdose of insulin cause hypoglycemia?
Unlike other DM drugs the hypoglycaemic risk is of insulin is [Link] overdose of insulin was
not matched by adequate food intake causing the hypoglycemia.
The function of insulin to lower the blood glucose levels by increasing tissue glucose uptake and
decreasing gluconeogenesis in the liver. Additionally, insulin inhibits lipolysis of adipose tissue
and stimulates glycogen synthesis.
i) What could be a differential cause of coma in this diabetic patient and
describe its pathology?
Adrenal insufficiency - Primary adrenal disease (Addison disease); ACTH deficiency. Growth
hormone deficiency. Hyperinsulinism - Endogenous (genetic, beta-cell tumor); exogenous
insulin administration (GOOGLE)
2019
Q2. James Conroy is a 54-year-old man with diabetes first diagnosed 2 years ago due to a
fasting blood glucose level of 136 mg/dL. Other medical problems include hypothyroidism. He
has a history of heavy alcohol use but quit drinking alcohol 2 years ago.
He presents now for routine follow-up and is noted to have a blood pressure of 168/100 mmHg.
Physical exam reveals a height of 1.73 metres (5 feet, 8 inches), weight of 110kg (243 lb), blood
pressure of 168/100 mmHg, and a regular pulse of 84 beats/min. There is no retinopathy or
thyromegaly. There is no clinical evidence of congestive heart failure or peripheral vascular
disease.
Laboratory evaluation reveals trace protein on urinalysis, blood urea nitrogen of 14 mg/dl
(normal range 7 to 20 mg/dL), serum creatinine of 1.2 mg/dl (0.6 to 1.2 mg/dL male normal
range), random serum glucose of 169 mg/dl, normal electrolytes and normal thyroid-stimulating
hormone levels. A 24-h urine collection reveals a urinary albumin excretion rate of 250 mg/day
(normal range is less than 30 mg/day).
Questions (parts a-e below contribute equally to the final grade score for this question):
Normal range FPG: 5.6mmol/L (<100mg) Pre diabetic: 5.6-6.9 (100mg/dl) Diabetic: >7mmol/L
(>126mg/dl)
(a) What type of diabetes does this patient have? Provide the rationale for your
diagnosis.
Type 2 diabetes mellitus. Rationale:
-Age: T2DM is more common in middle aged. The patient age is above 45. Studies have shown
that there is genetic predisposition in T2D
-Weight: Obesity is a major risk factor for T2DM. Adipose tissue is considered an endocrine
organ which expands with obesity resulting in adipose tissue hypertrophy. Adipocytes begin to
burst invoking an inflammatory response releasing adipokines, proinflammatory cytokines, free
fatty acids. This results in the adipocytes being insensitive to insulin creating insulin resistance.
Therefore, pancreatic beta cells try to compensate by increasing insulin secretion leading to
failure of beta cells overtime causing decreased insulin secretion translating to T2DM in the
blood glucose levels.
HTN: The patient’s Blood pressure is 168/100mmhg and the normal blood pressure is
120/80mmhg suggesting that he
Nephropathy: Clinical hallmarks of diabetic nephropathy include a progressive increase in
urinary albumin excretion which is seen in the patient and a decline in GFR, this is seen in the
creatinine levels of the patient suggesting that it is a beginning that will ultimately lead to ESRD
if not treated. Urinary albumin excretion + GFR reduction both occur in association with high BP
that is also seen in the patient. This is not surprising because DM has microvascular and
macrovascular complications. These renal functional changes develop as a consequence of
structural abnormalities, including glomerular basement membrane thickening, mesangial
expansion with extracellular matrix accumulation, changes in glomerular epithelial cells
(podocytes), including a decrease in number and/or density, podocyte foot process broadening
and effacement, glomerulosclerosis, and tubulointerstitial fibrosis. Robbins 781 Basic.
Additionally, secreting leptin but
-Hypothyroidism: Hypothyroidism can affect glucose metabolism in type 2 diabetes in
different ways. For example, subclinical hypothyroidism can result in insulin resistance due to a
decreased rate of insulin-stimulated glucose transfer induced by a translocation of the GLUT 2
gene.
(b) What is his BMI and what is the relevance of his BMI to his condition? Mention briefly the
major forms of lifestyle management that may help him.
(c) What is a common appropriate first line course of treatment for this diabetes
condition, and what is the proposed mechanism of action of this treatment? Describe
side effects associated with this medication.
1s line therapy of T2DM is Metformin is usually used in monotherapy and dual therapy.
Metformin targets insulin resistance by reducing glucose absorption from the gut, inhibiting
hepatic gluconeogenesis. The MoA is poorly understood and it has a low hypoglycaemic risk.
However, it causes renal insufficiency causing accumulation of metformin and increasing risk of
lactic acidosis. Therefore, it is not indicated in patients with renal insufficiency.
(d) What indicates that James has renal disease? What treatment strategy should be
used?
Hypoalbuminemia urinary albumin excretion rate of 250 mg/day (normal range is less than 30
mg/day) including the high blood pressure which indicates renal disease. The treatment strategy
for this patient is: Dual therapy of metformin and SGLT2 inhibitor.
SGLT2 inhibitor blocks glucose and sodium reabsorption from the proximal renal tubule therby
increasing urinary glucose excretion. It is also associated with weight loss and reduced blood
pressure without effects on heart rate. It is also associated with reduction risk in the risk of
ESRF and cardiovascular risk.
MoA? Pharmtokinetics?
(f) What is the significance of the underactive thyroid in this patient?
Hypothyroidism can affect glucose metabolism in type 2 diabetes in different ways. For
example, subclinical hypothyroidism can result in insulin resistance due to a decreased rate of
insulin-stimulated glucose transfer induced by a translocation of the GLUT 2 gene.
