Physiology Flashcards
What is the command centre of the endocrine system?
hypothalamus-pituitary complex
What is the function of the hypothalamus-pituitary complex?
The complex secretes several hormones that directly produce responses in target tissues, as well as hormones that regulate the synthesis and secretion of hormones in other glands
What are the hormones produced by the posterior pituitary hormone?
ADH
Oxytocin
What is the target of ADH?
Kidneys, sweat glands, circulatory system
What is the effect of ADH?
Water balance
What is the target of oxytocin?
Female reproductive system
What is the effect of oxytocin?
Triggers uterine contraction during childbirth
What are the anterior pituitary hormones?
LH
FSH
TSH
PRL
GH
ACTH
What is the target of LH?
Reproductive system
What is the target of FSH?
Reproductive system
What is the target of TSH?
Thyroid gland
What is the target of PRL?
Mammary gland
What is the target of GH?
Liver, bone and muscles
What is the target of ACTH?
Adrenal glands
What are the effects of LH?
Stimulates production of sex hormones by gonads
What are the effects of FSH?
Stimulates production of sperm and egg
What are the effects of TSH?
Stimulates the release of thyroid hormone. TH regulates metabolism
What are the effects of PRL?
Promotes milk production
What are the effects of GH?
Induces targets to produce insulin-like growth factors. IGFs stimulate body growth and a higher metabolic rate
What are the effects of ACTH?
Induces targets to produce glucocorticoids which regulate metabolism and the stress ressponse.
How is prolactin secreted?
- The exception is prolactin, which is under tonic inhibition by hypothalamic dopamine (rather than controlled by an activating hormone)
- In a non-pregnant women, prolactin secretion is inhibited by prolactin-inhibiting hormone (PIH), which is actually the neurotransmitter dopamine, and is released from neurons in the hypothalamus
- Only in pregnancy do prolactin levels rise in response to prolactin-releasing hormone (PRH) from the hypothalamus
- Secretion of PRH regulated by a ‘short-loop’ negative feedback
- Effects of PRL mediated by the prolactin receptor
What are the usual pituitary tests?
TSH, fT4, LH, FSH, testosterone, GH, IGF-1, PRL
When is dynamic endocrine testing used?
- Hormone excess - suppression test
- Hormone deficiency - stimulation test
What is the stimulatory test for cortisol levels?
Synacthen (synthetic ATCH)
- Check cortisol at 0, 30 and 60 mins
- Normal: cortisol rises by 150 and reaches 500
What is the stimulatory test of insulin stress or prolonged glucagon?
Insulin stress test or prolonged glucagon test
- Cortisol and GH response every 30 min for 2-3 hours
- Normal cortisol >500
- Normal GH >7ug/l
Describe water deprivation tests
- Check serum and urine osmolarities for 8hr, and then 4hr after giving IM DDAVP
- If Ur/serum osmol ratio >1.9 then it is normal, otherwise DI
What is produced in the zona glomerulosa?
aldosterone
Where is cortisol (glucocorticoids) synthesised?
zona fasciculata
Where is DHEA and androstenedione synthesised and what is it converted to?
DHEA and androstenedione in the zona reticularis which can be converted into testosterone and dihydrotestosterone in the peripheral tissues by 5⍺ reductase
How is cortisol and androgen production regulated?
regulated by hormones produced by hypothalamus and anterior pituitary gland - HPA axis
How is aldosterone regulated?
- regulated by renin-angiotensin-system
- Activated in response to decreased blood pressure
What is the function of aldosterone?
Leads to production of angiotensinogen II which causes direct (vasoconstriction) and indirect (aldosterone) methods of BP elevation
What is the mechanism of action of corticosteroids?
- Bind to intracellular receptors (primarily nuclear)
- Receptor/ligand complex binds DNA to affect transcription
What are the classes of steroid receptors?
- Glucocorticoid
- Mineralocorticoid
- Progestin
- Oestrogen
- Androgen
- Vitamin D
What are the major cortisol actions in the circulatory system?
- ↑ cardiac output
- ↑ blood pressure
- ↑ renal blood flow and GFR
What are the major cortisol actions in the CNS?
- Mood lability
- Euphoria/psychosis (in excess)
- ↓ libido
What are the major cortisol actions in the bone/connective tissue?
- Accelerates osteoporosis
- ↓ serum calcium
- ↓ collagen forming
- ↓ wound healing
What are the major cortisol actions immunologically?
- ↓ capillary dilation/permeability
- ↓ leucocyte migration
- ↓ macrophage activity
- ↓ inflammatory cytokine production
What are the major cortisol actions metabolically?
- Carbohydrate: ↑ blood sugar
- Lipid: ↑ lipolysis, central redistribution
- Protein: ↑ proteolysis
What are the clinical applications of corticosteroids?
- 3 main principles of use:
- Suppress inflammation
- Suppress immune system
- Replace treatment
- Can be given orally, IV, IM and topically
- Role in treatment of:
- Allergic disease - asthma/anaphylaxis
- Inflammatory disease e.g. rheumatoid arthritis, IBD
- Malignant disease
What is the mechanism of action of aldosterone?
Effects via mineralocorticoid receptor - expressed primarily in the kidneys but also in the salivary glands, gut and sweat glands
What are the main actions of aldosterone?
- Sodium/potassium balance
- BP regulation
- Regulation of extracellular volume
What is adrenaline and noradrenaline derived from?
are dopamine derived, which in turn is derived from tyrosine
Describe the insulin peptide structure and its synthesis?
- Synthesized in the RER of pancreatic β-cells as a larger single chain preprohormone - preproinsulin
- The removal of preproinsulin signalling peptide during insertion into the endoplasmic reticulum generates proinsulin
- Proinsulin consists of an A chain, a B chain and a connecting peptide in the middle known as the C peptide
- Within the endoplasmic reticulum, proinsulin is exposed to several specific endopeptidases which excise the C peptide, thereby generating the mature form of insulin
- Mature insulin consists of two polypeptide chains linked by disulfide bonds
- When insulin is secreted into the blood, C peptide is also secreted but has no known physiological function - can be used as a measure of endogenous insulin production
How have synthetic insulin preparations made?
Synthetic insulin preparations have been created by changing the amino acid sequence of endogenous insulin
What are the biological effects of insulin on glucose?
Regulates glucose in the blood - decreases blood glucose concentration
What are other biological effects of insulin?
Increases:
- Amino acid uptake in muscle
- DNA synthesis
- Protein synthesis
- Growth responses
- Glucose uptake in muscle and adipose tissue
- Lipogenesis in adipose tissue and liver
- Glycogen synthesis in liver and muscle
Decreases:
- Lipolysis
- Gluconeogenesis in liver
What is the function of pancreatic beta cell?
- The β-cell is the only cell in the body that makes insulin
- It should only do this in response to blood glucose rising above 5 mmol/l
How is insulin secreted?
- Glucose enters the β-cells through the GLUT2 glucose transporter and is phosphorylated by glucokinase
- Glucokinases’ Km for glucose lies in the physiological range of glucose concentration (glucose 4.5-5.5. mmol/l)
- Acts as a glucose sensor (normally) - a change of glucose concentration leads to a dramatic change in glucokinase activity
- Increased metabolism of glucose leads to an increase in intracellular ATP concentration (36 ATP per glucose)
- ATP inhibits the ATP-sensitive K+ channel KATP
- Depolarisation of the cell membrane results in opening of voltage-gated Ca2+ channels
- An increase in internal Ca2+ concentration leads to fusion of secretory vesicles with the cell membrane and release of insulin
What are the pattern of insulin release?
- Insulin is secreted at a low basal rate which accounts for about 5% of insulin produced
- Post-prandial insulin is secreted in relation to post meal glucose in a biphasic pattern
Why is post-prandial release of insulin biphasic?
- 5% of insulin granules are immediately available for release (RRP - readily releasable pool)
- These are responsible for the first phase which prevents a sharp increase in blood glucose
- Reserve pool must undergo preparatory reactions to be mobilised and available for release - requires signalling processes related to the glucose exposure so this means the second phase is more tuned to the requirement
What are the different islet endocrine cell types? And what are their functions?
- β-cells: secrete insulin, gather close to blood vessels which helps them sense glucose concentration in the blood
- ⍺-cells: secrete glucagon, also gather close to blood vessels
- δ-cells: secrete somatostatin, found on the periphery of the islets
- Other types:
- PP cells: secrete pancreatic polypeptide, found on the periphery of the islets
- ε-cells: secrete ghrelin
Describe systemic glucose homeostasis.
- Insulin drives anabolic pathways in target tissue to promote storage of nutrients and lower blood glucose
- Beta cells respond to numerous nutrients and hormones besides glucose to coordinate insulin secretion
How is T2DM related to insulin sensitivity?
- In normal patients, increased insulin sensitivity will result in a compensatory decrease in insulin secretion (and vice versa)
- In T2DM, there is no compensation for decreased insulin sensitivity or release
- In T2DM the number of secretory granules per β-cell is reduced - degranulation
- Insulin secretion defects observed early in the aetiology of T2DM (pre-diabetes)
- Individuals with T2DM will no longer have a biphasic pattern of insulin secretion
At low glucose levels what occurs in alpha cells?
- Glucose uptake and metabolism low
- KATP channels open
- Voltage-gated sodium channels (NaV) contributes to action potentials
- P/Q type voltage gated calcium channels (CaV) enable calcium influx
- Glucagon exocytosis triggered
At high glucose levels, what occurs in alpha cells?
- Glucose uptake and metabolism high
- KATP channel closed, cell depolarised
- Presence of SGLT2 glucose transporters contributes to non-voltage regulated sodium ion influx
- NaV and CaV channels closed, glucagon not exocytosed
What are the actions of glucagon?
Glucagon acts on the liver to promote hepatic glucose production, raising blood glucose
What is the link between T2DM and alpha cells?
Glucagon secretion is elevated in the fed state in T2DM and contributes to hyperglycaemia
How is islet function regulated?
- Somatostatin 14 is secreted from δ-cells in response to nutrient or hormonal stimulation
- SST14 suppresses beta cell and alpha cell function, in a paracrine manner (signal the functional status of neighboring islet cells and modify a cell’s activity to coordinate its hormone secretion)
- There are numerous bidirectional paracrine circuits within islets
What is the incretin effect?
greater increase in insulin production in response to oral glucose than in response to IV glucose
Where is GLP-1 secreted and what is its function?
- GLP-1, the principle incretin hormone, is secreted by gastrointestinal L-cells following eating
- GLP-1 increases glucose-induced insulin release by β-cells, promotes beta cell proliferation and suppress glucagon secretion at depolarising glucose concentrations
- Does not stimulate insulin secretion in the absence of a depolarising stimulus (e.g. glucose)
- GLP1 signals via a G protein-coupled receptor (second messenger cAMP)
How do incretin drugs work?
- Incretin drugs act via amplifying pathway through the GLP-1/GIP receptor and cAMP to augment insulin secretion when the pathway is triggered
- Therapeutic targeting of the incretin effect achieved via DPP4 inhibition (sitagliptin) or delivery of DPP4-resistant GLP1 analogues (liraglutide, semaglutide)
- As incretin drugs act via the amplifying pathway (glucose-dependent mechanism) there is no risk of hypoglycaemia
Describe the secretion of thyroid hormones?
- Hypothalamus produces TRH
- TRH stimulates anterior pituitary to produce TSH
- TSH binds to TSH receptor on surface of thyroid epithelial cells
- G proteins activated with conversion of GTP to GDP and production of cAMP.
- cAMP increases production and release T3 and T4.
- T3 and T4 circulate in bound and free forms
- On release T3 and T4 bind to receptor in target cells.
- Complexes translocate to the nucleus
- Binds to thyroid response elements on target genes
- Stimulates transcription of these genes → increase BMR
- T3 and T4 complete the negative feedback loop by suppressing the production of TRH and TSH by the hypothalamus and anterior pituitary.
How are thyroid hormones synthesised?
- Thyroglobulin synthesis in follicular cells
- Uptake and concentration of iodine by the follicular cells
- Oxidation of iodine to iodine by the follicular cells which border the colloid.
- Iodine moves into the colloid and attaches to tyrosine residues on thyroglobulin to form DIT and MIT, which couple together to form T3 and T4.
- Secretion of T3 and T4 occurs when colloid is enveloped by microvilli on cell surface to form colloid vesicles which fuse with lysosomes, enzymes break down the lysosomes releasing thyroid hormone.
Describe the make up of the thyroid gland?
- The thyroid gland consists of follicles lined by cuboidal epithelial cells.
- Inside is the colloid (the iodinated glycoprotein thyroglobulin) which is synthesised by the follicular cells
- Each follicle is surrounded by basement membrane, and between them are parafollicular cells containing calcitonin-secreting C-cells
What are the thyroid hormones?
- T3 (triiodothyronine) - accounts for ~10% of thyroid hormones secreted.
- 4x more potent than T3
- Acts at the cellular level - major biologically active thyroid hormones secreted.
- T4 (thyroxine) - accounts for ~90% of thyroid hormones secreted
- Prohormone - converted to T3 by liver and kidney to become biologically active.
How are thyroid hormones transported?
- In plasma, more than 99% of all T4 and T3 is bound to hormone-binding proteins
- Thyroxine binding globulin (70%)
- Thyroxine binding pre-albumin (20%)
- Albumin (5%)
- T3 is not bound very strongly to serum proteins compared to T4 so has a more rapid onset and offset of actions
- Only unbound hormones will enter cells (<1%)
- Metabolic state correlates more closely with the free than with the total concentration of thyroid hormones in the plasma
What can cause alterations in thyroxine binding globulin levels?
- Many drugs and other factors affect TBG; all may result in confusing total T4 levels so most labs will measure free T4 levels
- Examples of states which increase TBG include pregnancy, OCP, chronic active hepatitis and biliary cirrhosis
- Examples of states which decrease TBG include androgens, Cushing’s, severe systemic illness and chronic liver disease
What are the effects of thyroid hormone on target cells?
All cells, especially neurones
- Increase metabolic rate
- Increased glucose uptake
Liver tissue
- Increased glycogenolysis and gluconeogenesis
- Decreased glycogenesis
Adipose connective tissue
- Increased lipolysis
- Decreased lipogenesis
Lungs
- Increased breathing rate
- Along with effects on heart this helps meet increased O2 demand
Heart
- Increased HR
- Increased forced of contraction
- Along with effects on lungs this helps meet increased O2 demand
What is the effect of thyroid hormones on metabolic rate and thermogenesis?
- Thyroid hormones increase basal metabolic rate
- Increase number and size of mitochondria
- Increase oxygen use and rates of ATP hydrolysis
- Increase synthesis of respiratory chain enzymes
- Thyroid hormones increase thermogenesis
- ~30% of temperature regulation is due to thyroid hormone thermogenesis
- Carbohydrate metabolism
- Increased blood glucose due to stimulation of glycogenolysis and gluconeogenesis
- Increased insulin-dependent glucose uptake into cells
- Lipid metabolism
- Mobilised fats from adipose tissues
- Increased fatty acid oxidation in tissues
- Protein metabolism
- Increased protein synthesis
What is the effect of thyroid hormone on growth and development?
Growth
- Growth hormone releasing hormone (GHRH) production and secretion requires thyroid hormones
- Glucocorticoid-induced GHRH release also dependent on thyroid hormones
- GH/somatomedins require presence of thyroid hormone for activity
Development of foetal and neonatal brain
- Myelinogenesis and axonal growth require thyroid hormones
Normal CNS activity
- Hypothyroidism - slow intellectual functions
- Hyperthyroidism - nervousness, hyperkinesis and emotional lability
How are thyroid hormones degraded?
- Key enzymes are de-iodinates
- Type I (D1): found in liver and kidney
- Type II (D2): found in heart, skeletal muscle, fat, thyroid, and pituitary
- Type III (D3): found in foetal tissue, placenta, and brain (except pituitary)
- Breaks down the majority of T3 (into inactive T2) and T4 (into inactive reverse T3)
What are ligand gated ion channels?
- ion channels that can open in response to the binding of a ligand
- only a few ligand-gated ion channels are needed to produce a response within a cell because there is a huge influx of ions through each channel.
What is the structure of ligand gated ion channels?
- membrane-spanning region with a hydrophilic channel through the middle of it
- The channel lets ions to cross the membrane without having to touch the hydrophobic core of the phospholipid bilayer.
What is the mechanism of action of ligand gated ion channels?
- when a ligand binds to the extracellular region of the channel, the protein’s structure changes in such a way that ions of a particular type such as Ca2+ or Cl-, can pass through.
- Includes a depolarisation, or hyperpolarisation, of the cell membrane which changes the activity of other molecules, such as ion-binding enzymes and voltage-sensitive channels, to produce a response.
- Cellular response occurs in milliseconds.
What are examples of ligand gated ion channels?
neurons have ligand-gated channels that are bound by neurotransmitters.
What is the structure of G-protein coupled receptors?
- G-protein coupled receptors are composed of a transmembrane region crossing the lipid bilayer seven times (hence they are also referred to as 7-transmembrane receptors)
- This transmembrane region is coupled with a G-protein.
- GPCRs have no integral enzyme activity or ion channel, therefore all their downstream effects are mediated via their G-protein.
- Cellular response occurs in seconds.
What is the mechanism of action of G-protein coupled receptors?
- Ligands bind to the extracellular portion of the G-protein coupled receptor
- Binding at the extracellular ligand binding site causes aconformational changein the GPCR, allowing the G-protein subunit to bind to the receptor
- GDP is released from the α-subunit of the G-protein and replaced with a GTP
- This activates the G-protein, causing the α-subunit and bound GTP todissociatefrom the transmembrane portion of the GPCR and βγ-subunit
- The α-subunit interacts with its relevant effectors and causedownstream effects, e.g. ion channel opening or enzyme activity regulation
How is activity terminated in G-protein coupled receptors?
- GTPase catalyses the hydrolysis of GTP on the α-subunit into GDP + Pi
- GDP increases the α-subunit’s affinity for the βγ-subunit, allowing reformation of the G-protein complex
- The ligand dissociates from the extracellular portion, and the G-protein then reassociates with the transmembrane receptor, reforming the GPCR for the next ligand binding
What are examples of G-protein coupled receptors?
How is the signal amplified in G protein coupled receptors?
- Despite the fact that one G-protein coupled receptor only contains one α-subunit, this can interact with several secondary messengers, which can in turn activate multiple enzymes and catalyse many reactions
- This creates a cascade response whereby one agonist binding to the GPCR can bring about the catalysis of many reactions - signal amplification
What are kinase-linked receptors?
- Class of enzyme-linked receptors
- A kinase is just a name for an enzyme that transfers phosphate groups to a protein or other target e.g., receptor tyrosine kinase transfers phosphate groups specifically to the amino acid tyrosine
- Cellular response occurs in minutes-hours
What is the mechanism of action for kinase-linked receptors?
- Ligand binds to the extracellular domains of two nearby receptor tyrosine kinases
- The two neighbouring receptors then come together (dimerize)
- The receptors then attach phosphates to tyrosine in each other’s intracellular domains (autophosphorylation)
- Relay proteins attach to the phosphorylated tyrosine residues
- The relay proteins allow a varied cellular response - multifunctional
What are the examples of kinase-linked receptors?
- insulin
- growth hormone
What is autocrine regulation?
- ‘Self-regulation’
- Chemicals (i.e. signalling molecules) released from the cells bind to receptors on the cell that is releasing them
What is paracrine regulation?
Chemicals (i.e. signalling molecules) released from the cells bind to receptors on adjacent cells
What is endocrine regulation?
Chemicals (i.e. hormones) released from secretory cells are usually transported via the circulatory system to target cells
What are hormones?
- Any substance elaborated by one cell to regulate another cell
- May be delivered by autocrine, paracrine or endocrine routes
- The biological response initiated by hormone binding is generally the result of an amplification of a signal transduction cascade
- May hormones can evoke cellular and tissue effects at very low concentrations
- Most hormones have effects on multiple targets in the body
- Hormonal duration of action can vary from seconds to days
Describe the hypothalamic control?
- The hypothalamus provides the highest level of endocrine control
- Integrates activities of nervous and endocrine systems by:
- Secretion of regulatory hormones which control activity of anterior pituitary cells
- Synthesises hormones and transports them to the posterior pituitary via the infundibulum
- Direct neural control function: hypothalamic autonomic centres control secretion of adrenaline and noradrenaline by the adrenal medulla
What is the diurnal control of hormone levels?
- External cues (light/dark) evoke fluctuations in hormone secretions
- Example: cortisol levels follow a circadian rhythm
- Has implications for cortisol blood testing - random cortisol levels are of little value but a 9am cortisol level test may indicate HPA function
- Hormonal levels are also influenced by the rate at which they are eliminated by the body
Give an example of complementary actions of hormones?
sympathetic response and the actions of adrenaline, cortisol and glucagon on blood glucose levels
Give an example of antagonistic actions of hormones?
hormonal control of glucose homeostasis
What are steroids?
- Lipids derived from cholesterol
- Synthesis rate controls amounts
- Once synthesised steroids are secreted, they are not stored
- Steroids are hydrophobic and are transported in the blood plasma by binding to carrier proteins
- ~90% are bound, the 10% of ‘free’ steroids are biologically active (can cross lipid bilayer)
What is the mechanism of action of steroids?
- Steroid hormone passes through plasma membrane
- Steroid hormones are hydrophobic/lipophilic
- Activated hormone-receptor complex forms within the cell
- The complex binds to DNA and activates specific genes → gene activation leads to production of specific genes
What are examples of steroids?
- Cortisol, from adrenal cortex, plays a role in mediating stress responses
- Testosterone and oestradiol secreted from the gonads and placenta, responsible for male and female sexual characteristics
What are amine-derived hormones?
- Most amine-derived hormones are hydrophilic and are transported unbound (‘free’) in blood plasma
- Exception: thyroid amine which are bound to carrier proteins
- Derived from amino acids e.g., tyrosine
- Secreted from thyroid and adrenal medulla
- Amines like adrenaline stored as vesicles in the cytoplasm until needed
What is the mechanism of action of amine-derived hormones?
Amine hormones bind to bound receptors to evoke cellular response
What are examples of amine-derived hormones?
- Adrenaline
- Thyroid hormones
What are peptide hormones?
- Peptide hormones are hydrophilic and are transported unbound (‘free’) in the blood plasma
- Account for the majority of hormones produced
- Secreted by pituitary, parathyroid, heart, stomach, liver, kidneys
- May be composed of a ring structure due to disulfide bonds e.g. somatostatin
- May be composed of 2 chains held together by disulfide bones e.g., insulin
- Amino acid sequence may differ between species (encoded by genes)
What is the mechanism of action of peptide hormones?
- Synthesised as precursor molecules and stored in secretory vesicles
- Different end hormones can be made by cleaving a common precursor with a different enzyme
What are the examples of peptide hormones?
- Oxytocin
- ADH
- Growth hormone
- Insulin
What are the 3 important specific carrier proteins?
- Cortisol-binding globulin (CBG): binds cortisol in a selective manner (also some aldosterone)
- Thyroxine-binding globulin (TBG): binds thyroxine (T4) selectively (also some triiodothyronine T3)
- Sex steroid-binding globulin (SSBG): binds mainly testosterone and oestradiol
How are hormones transported?
- Steroid and thyroid hormones are insoluble in plasma and are transported in the blood via carrier proteins
- Binding to carrier proteins provides:
- Facilitation of hormone transport
- Increased half-life of the hormone
- A reservoir for the hormone
