MP322 Master Set

What does MIT stand for (thyroid)?

• monoiodotyrosine

What does DIT stand for (thyroid)?

• diiodotyrosine

How is T4 → T3 conversion done?

• via deiodination

What are examples of antithyroid drugs?

• carbimazole and propylthiouracil

How do antithyroid drugs work?

• they work by inhibiting the enzyme thyorid peroxidase which converts tyrosine into MIT and DIT (through addition of iodine)

• this prevents the synthesis of T3 and T4

What is active form of carbimazole?

• methimazole

What are the adrenal glands made up of?

• adrenal cortex and adrenal medulla

What are mineral corticosteroids?

Where are these produced?

• e.g aldosterone

• involved in sodium resorption and potassium excretion in kidneys

• the adrenal cortex

What are glucorticorticosteroids?

Where made?

• e.g. cortisol

• regulates body’s response to stress

• adrenal cortex

What does the adrenal medulla make?

• 80% adrenaline

• 20% noradrenaline

What are cellular actions of cortisol?

• increases blood glucose levels

• maintains the responsiveness of blood vessels to vasoconstrictive stimuli

• has effects on immune system, nervous system and kidneys

• anti-inflammatory and immunosuppressant

How is cortisol secreted?

What causes Addison’s disease?

When does onset of disease occur?

• due to dysfunction/ destruction of adrenal cortex

• when 90%+ of both adrenal cortices are destroyed

What are symptoms of Addison’s disease?

• hyperpigmentation

• extreme fatigue

• weight loss

• decreased appetite

• low BP causing light headedness and dizziness

• GI disturbance

• salt cravings

• low blood glucose

What causes Addison’s disease?

• autoimmune destruction of the adrenal gland

• infections

• invasion

• haemorrhage

What is treatment for Addison’s disease?

• hydrocortisone (Glucocorticosteroids)

• fludrocortisone (mineral corticosteroid)

• treatment is lifelong

What is adrenal crisis?

• sudden severe pain in lower back, abdomen or legs

• severe vomiting and diarrhoea

• dehydration

• low BP

• loss of consciousness

• can result in death

What is Cushing’s syndrome?

• hypersecretion of cortisol

What are signs and symptoms of Cushing’s syndrome?

• moon face

• thin skin, legs and arms

• fat pads

• high BP

• poor wound healing

• red striation

• bruisability

What are causes of Cushing’s syndrome?

• pituitary tumour leading to increased secretion of ACTH (most common)

• adrenocortical tumours

• tumours near hypothalamus-pituitary-adrenal gland pathway

What is ACTH dependent Cushing’s?

• body makes too much ACTH because of tumour

What is ACTH independent Cushing’s?

• ACTH level is low

• adrenal glands are making too much cortisol due to adrenal tumour

What is a thyroid follicle?

What is colloid?

• specialised cell located in thyroid that is circular

• located in lumen of follicle and is where thyroid precursors are stored and then synthesised and released from

What are key elements of thyroid synthesis?

• iodine and tyrosine

How does thyroid synthesis occur?

• iodine is transported through the blood using sodium

• diffuses into follicle cell

• iodine is then transported to the colloid where it is attached to rings of tyrosine in thyroglobulin

• iodine is either added to MIT or DIT

• the iodine rings then join together (MIT + DIT or DIT + DIT)

  • forms T4 or T3

• the T3/T4 is then endocytosed back into the blood

What is the active form of thyroxine?

• T3

How is T4 converted to T3?

• Via deiodination

How do T3/T4 travel in the blood?

• using plasma proteins TBG and TTR

How is thyroid hormone secreted (hint: hypothalamus)?

What is euthyroid, hypothyroid and hyperthyroid?

• euthyroid = normal secretion of thyroid hormones

• hypothyroid = subnormal secretion

• hyperthyroid = excessive secretion

What does thyroid stimulating hormone (TSH) do?

• stimulates production of T3 and T4

• also increases DNA replication, cell division and follicular cell protein synthesis

What happens when TSH conc is excessive?

• leads to rapid cell division of thyroid cells → enlargement of thyroid gland (goitre)

What do T3 and T4 do?

• increase basal metabolic rate and maintain it

• increase in heat production

• increase response to sympathetic output

• permits normal growth and development

What is cretinism?

What does it result in?

• extreme iodine deficiency

  • mental retardation

  • stunted growth

  • deaf-mutism

What is salt now fortified with?

• salt

What do results with thyroid function test coincide with?

What is the most common cause of primary hypothyroidism?

• Hashimoto’s thyroiditis

• autoimmune disorder where body produces antibodies against thyroid peroxidase

• more prevalent in women

• T4 decreases and TSH increases

• can result in goitre

What are adverse effects of levothyroxine?

• hair loss first months of treatment

• headaches

• insomnia

• nervousness

• fever

• hot flashes

• sweating

• pounding heart beat

• appetite changes

• weight changes

What is secondary hypothyroidism?

• problem with anterior pituitary or hypothalamus not producing enough TSH or TRH so low levels of TSH and T4

Why are TSH levels low in hyperthyroidism and T4 levels are high?

• T4 high causes -ve feedback loop on TSH so low levels of TSH

What is myxoedema coma?

What are symptoms?

• end result of untreated hypothyroidism

• hypothermia

• progressive weakness → loss of consciousness

• seizures and respiratory depression

• can lead to death if untreated quickly

What drugs affect thyroid function?

• corticosteroids

  • can decrease basal production of TRH and TSH → less T4 and T3

• lithium

  • inhibits release of T4 and T3 and interferes with peripheral deiodination

• amiodarone

  • can cause hypo and hyperthyroidism

• cholestyramine

  • reduces the absorption of T3

What are signs and symptoms of hyperthyroidism?

• heat intolerance

• palpitations

• weight loss even when appetite is increased

• restlessness

• nervousness

• fatigue

• increased sweating

• frequent bowel movements

• goitre

What is most common cause of hyperthyroidism?

How does this disease come about?

• Grave’s disease

• autoimmune disease caused by TSI (thyroid stimulating immunoglobulins)

• TSI activates TSH receptors on thyroid follicular cells causing an increase in secretion of T4 and T3

What are treatments for hyperthyroidism?

• surgery

• radioactive iodine (emits radiation that acts on cells responsible for causing hyperthyroidism)

• thioamides

  • carbimazole and propylthiouracil

How do thioamides work?

• carbimazole and propylthiouracil

• inhibits thyroid peroxidase (enzyme responsible for iodination of tyrosine) and prevents T4 and T3 synthesis

• slow onset (4-6 weeks)

• generally safe but may cause agranulocytosis (reduction in neutrophils) so increases risk of infection

What is one potential problem of thioamides?

• may cause agranulocytosis which is the reduction in neutrophils which increases risk of infection

What does thyroid peroxidase do?

• is the enzyme responsible for iodination of tyrosine (MIT and DIT)

What is metformin MOA?

• reduces hepatic gluconeogenesis

What are S/E to metformin?

• GI upset (why patients start with a lower dose to try and avoid)

• vit B12 deficiency

What is MOA for sulfonylreas?

• stimulate insulin secretion from pancreatic beta cells

• glucose = ATP:ADP ratio increase = ATP sensitive K+ channels close = depolarisation = voltage gated calcium ion channels open = influx of intracellular calcium = insulin secretion

What is SGLT2 MOA?

• act by inhibiting glucose transporter SGLT2 which mediates glucose reabsorption

What are examples of incretins?

What do incretins do?

• GLP-1 and GIP

• incretins are hormones that are released after eating that increase release of insulin from pancreatic beta cells, and suppress glucagon release in alpha cells

• incretins slow digestion by increasing the time it takes for food to leave the body and gives a feeling of being full

How do DDP4 gliptins work?

• inhibit DDP4 enzyme which is an enzyme that degrades incretins (GLP and GIP)

• this causes incretins to remain active allowing for insulin release and glucagon suppression

Does metformin follow Lipinski Rule of 5 ?

• no, but is still orally available

What is the difference between T1D and T2D?

• type 1 = loss of insulin production

• type 2 = receptors are resistant to insulin or insufficient secretion of insulin

Where is insulin produced?

Where is glucagon produced?

• insulin = pancreatic beta cells

• glucagon = pancreatic alpha cells

What are causes of hyperglycaemia?

• loss insulin-stimulated glucose uptake (so build-up of glucose in blood)

• loss of insulin repression of gluconeogenesis

• loss of insulin repression of glycogen breakdown

How does insulin repress gluconeogenesis and glycogen breakdown?

• acts as a off switch for these processes

What percentage of diabetes are type 1?

• 5-10%

Why do T1D produces no/little insulin?

• due to pancreatic beta cells being destroyed by immune system = autoimmune disorder

How do T2D cells respond to insulin?

• cells are in an insulin-resistant state

How do beta cells try to compensate for insulin resistance in T2D?

What are drawbacks?

• produce more insulin

• once beta cells can no longer produce enough insulin to combat the resistance = T2D

What are factors that increase likelihood of developing T2D?

• obesity

• lack of exercise

• diet

• genetic factors (increase likelihood of parent, sibling or child has T2D)

When are T1D symptoms made apparent?

• rapid onset of symptoms

• typically severe e.g. ketoacidosis which requires hospitalisation for treatment

What percentage of women develop gestational diabetes?

When does it typically develop?

When does it disappear?

• 25% women

• during 2nd trimester

• after birth of child (so temporary condition)

What are tests used to diagnose diabetes?

• fasting glucose test

  • no food or drink (except water) for 8-10 hrs then test blood glucose

• random glucose test

• glucose tolerance test

• HBA1c test

How is a glucose tolerance test conducted?

• patient fasts for at least 8 hrs

• blood glucose measured immediately before and after drinking 75g of glucose dissolved in water

What are the values for fasting/ random glucose test?

• normal = 3.9-5.9mmol/L

• prediabetes = 5.5 - 6.9 mmol/L

• diabetic = >7mmol/L

What are the values for the glucose tolerance test?

• 11.1 mmol/L indicates diabetes

• 7.9-11.1 indicates impaired glucose tolerance

What is HBA1c?

What does this help to measure?

What does it help to diagnose?

• glycated blood that is the binding of haemoglobin A and glucose

• measures the average blood glucose levels over the last 3 months (average RBC life span)

• T2D, T1D develops quickly (normally quicker than 3 months so might not catch in a HBA1c test)

What are values for HBA1c test?

• >48mmol/mol indicates diabetes

• 42-48mmol/mol indicates risk of developing diabetes

What is BP goal for diabetics?

What is HBA1c goal for diabetics?

What is total cholesterol level goal for diabetics?

• <130/80mmHg

• 48

• no greater than 5

What are symptoms of diabetes (more acute)?

• dehydration

• frequent urination

• fatigue

• nausea and vomiting

• polyphagia (increased hunger)

• weight loss (T1D)

• UTI and thrush (glucose in urine)

• poor wound healing

• blurry vision

How does Diabetic ketoacidosis (DKA) occur?

• due to glucose being unavailable body uses fat as an energy source

• free fatty acids are converted to ketones by the liver → energy source

• ketones cause blood to become more acidic

• life threatening

When should T1D ketone levels be checked?

• at time of diagnosis

• during an illness (when patient is ill)

• during a growth spurt

• when insulin is taken incorrectly

What are symptoms of DKA?

• extreme thirst

• frequent urination

• nausea

• vomiting

• confusion

• irritability

• loss of consciousness → coma → death

What indicates DKA?

• ketones present in urine

• high blood glucose levels

• fruity smelling breath

What is treatment for DKA?

• fluid replacement, insulin and mineral replacement

What are chronic complications of Diabetes?

• vascular damage

• high BP

• neuropathy

• nephropathy

• retinopathy

• increased risk of CV risk

What are regular checks diabetics should do?

• regular eye, kidney, BP, foot checks

When should a diabetic be put on a primary prevention statin?

• if >40 y/old or been diagnosed for 10+ years

How does diabetic foot occur?

• due to either nerve damage leading to sensation loss in peripherals or due to poor blood flow to feet

• patient cant feel cuts so go unnoticed - infection

• no blood flowing - area cant heal

If a mother has poorly controlled diabetes, what are risks in pregnancy?

• increased risk of miscarriage, stillbirth and birth defects

How are blood glucose levels regulated?

• regulated by insulin secretion

• > glucose in blood = greater insulin secretion

How is insulin secreted (process)?

• increase in glucose in beta cells leads to an increase in ATP:ADP ratio

• this increase in ratio leads to ATP-sensitive K+ channels to close and membrane depolarisation occurs

• depolarisation causes voltage gated Ca2+ ion channels to open

• increase in intracellular calcium promotes the secretion of insulin

• insulin secreted via a vesicle that exits cell through exocytosis

What is the insulin signalling pathway?

• IR binds to insulin causing autophosphorylation of the receptor

• the phosphorylates residues on IR act as binding sites for IRS

• IR phosphorylates 4 tyrosine residues on IRS

• phosphoinositide-3-kinase binds to the phosphorylated tyrosines, converting PIP2 → PIP3

• PIP3 activates PDK1 which phosphorylates and activates PKB

• activated protein kinase B then diffuses through the cell and activates processes such as glucose transport and glycogen synthesis

How does glucose uptake into adipocytes and muscles occur?

• GLUT4 transporter protein contained inside the cell

• protein AS160 holds the GLUT4 inside the cell

• PKB phosphorylates AS160 deactivating it

• this allows GLUT4 to fuse with cell membrane causing increased glucose uptake into muscle and adipocytes

What is Fox01?

What does Fox01 do?

• a transcription factor

• regulates gene expression that mediates gluconeogenesis

What does insulin do to Fox01?

How does insulin go about doing this?

• prevents Fox01 moving to the nucleus (stopping gene expression, which prevent gluconeogenesis)

• insulin signalling pathway occurs, resulting in PKB

• PKB phosphorylates Fox01 stopping it from entering the nucleus → no longer can regulate gene expression and mediate gluconeogenesis

What autoantibodies being present increase risk of developing T1D?

• autoantibodies against these proteins;

  • GAD-65

  • Insulin

  • IA-2

  • ZnT8

What is treatment of T1D?

• subcutaneous injections of insulin that are required lifelong

How often should T1D monitor blood glucose levels?

• before meals, before bed, before driving, before and after exercise, when ill etc.

When a T1D is about to drive what must their blood glucose level be minimum?

What should they do if blood glucose is not at the correct level?

• 5 to drive (or at risk of hypo on the road)

• 15g of fast acting cards, wait 15 mins and then re-check blood glucose levels

What inhibits insulin signalling pathway?

• PTP1B (protein tyrosine phosphatase 1B)

• phosphorylation of serine residues by PKC

How does PTP1B inhibit insulin signalling pathway?

Why does obesity increase PTP1B expression?

• dephosphorylates IR, means IRS an no longer bind = inhibits pathway

• causes pro-inflammatory cytokine e.g TNFalpha, these express PTP1B

How does phosphorylation of serine cause inhibition of insulin signalling pathway?

• serine being phosphorylated by PKC results in inhibition as tyrosine on IRS can no longer be phosphorylated

How does obesity and excess fat affect insulin signalling pathway?

• fatty acids produce 2 intermediates (DAG and ceramide)

• DAG produces PKC = serine phosphorylation instead of tyrosine phosphorylation (inhibition)

• Ceramide causes PKB inhibition

What is adiponectin and what does it do?

• secreted from adipocytes and promotes insulin sensitivity in cells

When is less adiponectin secreted?

• in obesity, less adiponectin is secreted = insulin resistance