insulin and thyroid revision

what is the main hormone involved in glucose metabolism

insulin

what is the only hormone that can bring glucose levels down

insulin

what other control is insulin important for 

the control of supply storage of fats and proteins

what type of hormone is insulin

peptide hormone

what does insulin structurally consist of

• 2 chains- alpha and beta

• linked by disulphide bridges 

where does insulin act at 

tyrosine kinase receptors 

where is insulin secreted from 

beta-cells in the islets of langerhans in the endocrine pancreas into the hepatic portal vein

what is the most abundant cell type in the islets 

beta cells 

where is insulin synthesised

synthesised as pro-peptide by ribosomes on the RER

what does insulin processing involve

• folding and formation of disulphide bonds 

• removal of the C peptide (31 amino acids) to give 2 chains (A-21 aa and B-31 aa)

where does the C peptide remain

• within the secretory vesicle

• therefore when insulin is secreted the C peptide is secreted 

why is plasma C peptide level a measure of insulin secretion

• C peptide has a longer half life than insulin

• therefore it is not cleared from the blood rapidly

what is the major control factor for insulin secretion

levels of blood glucose 

what is the major control of insulin secretion known as

a simple negative feedback pathway 

what is the general outline of how to control insulin secretion

• after a mela glucose concentration increases

• glucose diffuses into the pancreatic beta-cell (via GLUT-2)

• increased glucose concentration. in the cell causes secretion of insulin

• insulin causes a decrease in blood glucose

• decreased glucose in the beta-cell decreases insulin secretion

what are other factors that can influence insulin secretion

• some amino acids (leucine and arginine)

• autonomic nervous system (parasympathetic increases, sympathetic decreases)

• some gut hormone (incretins)- secreted in GI tract in response to food e.g. GLP1

what is the detailed outline of insulin secretion

1. glucose enters the cell via a GLUT-2 transporter, which mediates facilitated diffusion of glucose into the cell

2. the increased glucose influx, stimulates glucose metabolism, leading to an increase in [ATP]

3. the increased [ATP] inhibits an ATP-sensitive K+ channel 

4. inhibition of this channel causes cell membrane to become more positive (depolarisation)

5. the depolarisation activates a voltage-gated Ca2+ channel in the plasma membrane 

6. the activation of this Ca2+ channel promotes Ca2+ influx, and thus increases [Ca2+], which also evokes Ca2+-induced Caa2+ release

7. the elevated [Ca2+] leads to exocytosis and release into the blood of insulin contained within the secretory granules 

what are the other pathways that other modulators of secretion act via 

• adenyllate-cyclase- cAMP- protein kinase A pathway 

• phospholipase C-phosphoinositide pathway 

when is insulin secreted

• following a meal

• due to increased blood glucose

how does insulin decrease blood glucose

by increasing the uptake into cells and the utilisation of glucose 

what does insulin promote

promotes the storage of fuel molecules

what are the major target organs of insulin

• liver

• skeletal muscles 

• adipose tissue

where is insulin secreted into

• into the hepatic portal vein 

• transporting directly into the liver 

how much insulin does the liver remove before it enters the systemic circulation

60%

how does insulin lower blood glucose

• increase In glucose uptake into cells (skeletal muscle and adipose tissue)

• increased gluconeogenesis in the liver and the skeletal muscle

• decreased glycogenolysis

• decreased gluconeogenesis 

• increased glycolysis 

what is increased uptake of glucose mediated by 

mediated by the insulin-dependent facilitated glucose transporter, GLUT-4

what is the mechanism of uptake of glucose 

1. glucose requires a transporter to move through the plasma membrane 

2. GLUT transporters allow facilitated diffusion of glucose down its conc. gradient 

3. in the presence of insulin, GLUT-4 moves from inside the cell to the cell membrane and therefore increases the uptake of glucose

4. GLUT-4 is abundant in skeletal muscle and adipose tissue 

how does insulin lower blood fatty acids and increase triglyceride synthesis 

• increase in fatty acid uptake into adipose tissue 

• increased uptake of glucose into adipose cells where it is used for de novo synthesis of fatty acids and glycerol

• decreased lipolysis 

how does insulin lower blood amino acids and increase protein synthesis 

• increased uptake of amino acids into cells

• increased protein synthesis 

• decreased protein degradation

what is IRS

insulin receptor substrate

what does the insulin receptor phosphorylate

• IRS 

• via the SH2 domain proteins

overview of the thyroid gland

• thyroid endocrine gland located below the larynx wrapping around the trachea

• secreted hormones involved in growth and development 

what is the function of the thyroid

• secretes hormones: Thyroid hormone- contains iodine: Thyroxine (T4), Tri-iodothronine (T3)

• calcitonin- role in calcium metabolism, which is unrelated to other thyroid hormones

thyroid structure

• major thyroid hormone-secreting cells are organised into colloid-filled follicles

where are thyroid hormones synthesised and stored

• synthesised in the follicular (epithelial) cells

• stored in the extracellular colloid (lumen) of the follicles of the thyroid gland

is the thyroid hormone essential for life

• no

• but imbalances cause sever problems

what does the thyroid hormone increase

• increases basal metabolic rate

• increases heat production

• increases cell responsiveness to catecholamines

what cells does the thyroid hormone act on

acts on nearly every cell in the body

what does the thyroid hormone influence

influences synthesis and degradation of major fuels in the body

what does the thyroid hormone stimulate

stimulates GH and IGF-1 secretion so essential for normal growth

what is the thyroid hormone essential for 

development and activity of CNS 

what do the numbers 3 and 4 denote on the thyroid hormones (T4 and T3)

3 and 4 denote number of iodine atoms incorporated

how are T3 and T4 synthesised

synthesised by the iodination of tyrosine

what is the ratio of T4 to T3 secretion

10:1

what is thyroxine converted to

T3 in the target tissue

what is tyrosine synthesised by

the body (non-essential amino acid)

iodine derived from the diet

• iodised salt (not in uk)

• sea fish, shellfish, some cereals 

• dairy foods, eggs, fruit to lesser extent

• varied diet should provide sufficient amounts 

what is the required amount of iodine for adults

• 0.15mg 

• more needed during pregnancy (0.25mg)

what are some iodine deficiencies 

• loss of energy due to hypothyroidism 

• some brain damage

• cretinism 

what can be taken for radiation sickness for the thyroid

potassium iodide tablets 

potassium iodide tablets

• iodine directly absorbed by thyroids

• prevents radioactive I being absorbed into thyroid

• best taken before exposure

• distributed to all citizens of the Republic of Ireland in 2002

• prevented increase in thyroid cancer in Poland after Chernobyl 

synthesis of thyroid hormones

• iodide ions are actively transported into the follicle cells from the blood by the Na+I- co-transporter

• iodide ions are oxidised to iodine by thyroid peroxidase

• thyroglobulin is large glycoprotein forming th colloid in the follicle lumen- contains large amount of tyrosine (115 residues)

• iodine is attached to the tyrosine residues of thyroglobulin- MIT- DIT

• 2 tyrosine molecules join to form T3 and T4

what is MIT and DIT

• monoiodotyrosine

• diiodotyrosine

what is the synthesis of T3 and T4 controlled by

• TSH (tyrosine stimulating hormone)

• secreted from anterior pituitary

where does TSH bind for the control of synthesis of thyroid hormones

cAMP-coupled receptors on epithelial cells

what does the binding of TSH stimulate in the control of synthesis of thyroid hormones 

I- uptake (increased synthesis)

what also controls synthesis of thyroid hormones

• plasma iodine levels 

• increase in [I-] means an increase in T3 and T$ and a decrease in TSH release

• decrease in [I-] means a decrease in T3 and T4 and an increase in TSH release

what is the release of T3 and T4 also controlled by 

• TSH 

• secreted from the anterior pituitary 

• TSH binds to cAMP coupled receptors on epithelial cells

what does the binding of TSH stimulate in the release of T3 and T4

• stimulates uptake of thyroglobulin into the epithelial cells by endocytosis

• endocytotic vesicle fuses with lysosome- proteases

• T3 and T4 are released

are thyroid hormones hydrophobic or hydrophilic and what does this mean for transport of thyroid hormones

• hydrophobic

• require a transporter in the plasma- thyroxine binding globulin (TBG)

• also binds to albumin and transthyretin

what are the plasma concentration of T4 and T3 and the percentages of free T3 and T4

• T4 1 × 10^-7M - 0.02% free

• T3 2 × 10^-9M - 0.2% free

are most cells sensitive to thyroid hormones

yes

what are T3 receptors

• transcription factors (nuclear receptors)

• a1, a2, b1, b2

what does stimulation of T3 receptors result in

• change in transcription of responsive genes- genes important in control of metabolic activity

• e.g. respiratory enzymes, glucaoneogenic enzymes, beta- receptors

what symptoms happen when there is action of thyroid hormones on target cells

• increased body temperature

• increased cardiac output

• increased oxygen consumption

• increased breakdown of energy stores (CHO, fats, proteins)

what are the main thyroid diseases

• hyperthyroidism (hyper secretion/excess of thyroid hormones)

• hypothyroidism (hyposecretion/lack of thyroid hormones)

• thyroid cancer

thyroid cancer

• approx. 3800 cases/year in uk

• more common in females (35-39)

• in males, usually diagnosed later (70s)

what are the different types of thyroid cancer

• follicular

• papillary 

• medullary etc. 

what are the risk factors of thyroid cancer

benign disease, increased weight, radiation exposure, genetic 

treatment for thyroid cancer

• surgery

• thyroid hormone therapy

• radiotherapy (radioactive iodine or external)

what is the prevalence of hyperthyroidism in the UK 

• 2%

• patients between 30-60 years 

what is primary thyroidism and what does it account for 

• failure of thyroid gland 

• accounts for 95% of adult cases

• 20% due to treatment for hyperthyroidism

• can be drug-induced

what is hashmito’s thyroiditis

• autoimmune disease

• antibodies against thyroglobulin (causes goitre due to excess TSH secretion)

secondary hypothyroidism 

hypopituitarism 

tertiary hypothyroidism

hypothalamus

peripheral hypothyroidism

tissue insensitivity to thyroid hormones

what is a cause of hypothyroidism 

lack of dietary iodine 

hypothyroidism clinical manifestations and diagnosis 

• low metabolic rate

• weakness

• slow speech

• cold intolerance

• memory loss

• weight gain

• dry skin

• bradycardia 

• growth failure in children 

• myxoedema coma 

• diagnosed by blood tests for TSH, free T4 or T3 and thyroid antibodies 

treatment for hypothyroidism

• replacement therapy

• thyroxine (given orally)- levothyroxine (T4)

• liothyronine (T3)- faster onset but shorter duration of action 

• need to monitor and control treatment to avoid risk of hyperthyroidism 

• iodine (if hypothyroidism caused by lack of iodine)

what is the most common cause of hyperthyroidism in the western world 

• graves disease (80-90%)

• most patients between 30-60 years of age

• females are 10x more likely to develop graves disease than males 

• in uk - 20/1000 females, 2/1000 males

examples of hyperthyroidism

• graves disease

• toxic nodular goitre

• thyroid adenomas

• drug-induced

• over medication of thyroxine (to treat hypothyroidism)

Grave’s disease

• thyroid stimulating antibodies

• mimics TSH to stimulate TSH receptor in the thyroid gland 

• familial- genetic predisposition

toxic nodular goitre

• lumps around the neck 

• new follicle formation that increases thyroid hormone secretion (develop into nodules)

thyroid adenomas

benign tumours secreting thyroid hormones

hyperthyroidism clinical manifestations

• symptoms associated with increased sympathetic activity (e.g. palpitations, sweating, tremor, anxiety, weight loss)

• goitre and exophthalmos

• other eye signs- swelling of eyelids, irritation, lid retraction, ophthalmoplegia (weakness of eye movement muscles), diplopia (double vision

hyperthyroidism treatment 

• anti-thyroid drugs

• surgery 

• radioiodine (I131)

surgery for hyperthyroidism

• need to stabilise with drugs before surgery

• can lead to hypothyroidismm, hypoparathyroidism 

• hyperthyroidism can recur 

radioiodine (I131)

• selectively taken up by thyroid gland

• emits beta-particles (short range) and gamma-rays

• kills thyroid cells 

• T1/2 is 8 days- after 2 months activity is minimal 

• effect delayed by 1-2 months- maximal effect at 4 months 

anti-thyroid drugs

• thioureylenes

• e.g. carbimazole, methimazole, propylthiouracil- given orally 

mechanism of action for anti-thyroid drugs

• inhibit synthesis of thyroid hormones (inhibits thyroperoxidase hence iodination of tyrosine) 

• takes 2-3 weeks to take effect 

• propylthiouracil also inhibits T4 to T3 conversion in target tissues 

unwanted actions of anti-thyroid drugs

• rashes

• agranulocytosis (rare but life-threatening)- depletion of neutrophils 

iodine/iodide

• can be given as aqueous iodine/iodide oral solution

• high doses temporarily inhibit release of thyroid hormones

• symptoms subside after 1-2 days

• maximal effect at 10-15 days then decreases

• preparation of hyperthyroid patients for surgery and acute thyrotoxic crisis (thyroid storm)

what other drugs are used in the treatment of hyperthyroidism

beta blockersw

hat do beta blockers do in the treatment of hyperthyroidism

• reduce sympathetic mediated symptoms e.g. tachycardia, tremor, sweating, anxiety)

• it is NOT an anti-thyroid agent

• used initially while ant-thyroid drugs are taking effect and in preparation for surgery

• simple anxiolytics