endocrine basic principles Flashcards
what makes up the diencephalon
thalamus and hypothalamus
what makes up the rhombencephalon (hindbrain)
medulla oblongata
pons
cerebellum
how is the action of a hormone terminated
enzymes
what are the 3 categories of hormones
modified amino acids (amines)
steroid hormones
protein and peptide hormones
adrenaline is an example of what kind of hormone
amine
cortisol is an example of what kind of hormone
steroid
progesterone is an example of what kind of hormone
steroid
melatonin is an example of what kind of hormone
amine
insulin is an example of what kind of hormone
protein/peptide
ACTH is an example of what kind of hormone
protein/peptide
testosterone is an example of what kind of hormone
steroid
ADH is an example of what kind of hormone
protein/peptide
oxytocin is an example of what kind of hormone
protein/peptide
thyroid hormones are an example of what kind of hormone
amine
GH is an example of what kind of hormone
protein/peptide
prolactin is an example of what kind of hormone
protein/peptide
what are amine hormones derived from
tyrosine and tyramine
how/when are amine hormones synthesised
pre-synthesised within cells
how are amine hormones stored?
in vesicles
what causes amine hormones to be released
Ca2+-dependent exocytosis
how are amine hormones transported
free in plasma as they are hydrophilic
except thyroid hormones - they are free and bound
where are the receptors for amine synthesis
on cell membrane
what is the half life of amine hormones
seconds
what are steroid hormones derived from
cholesterol
when are steroid hormones synthesised
synthesised and secreted on demand
how are steroid hormones synthesised
stimuli increases cellular uptake and availability of cholesterol and rate of conversion of cholesterol to pregnenolone
what is the rate limiting step in the synthesis of steroid hormones
rate of conversion of cholesterol to pregnenolone
how are steroid hormones transported
in plasma mainly bound to plasma proteins
are steroid hormones active when bound or free
free
where are the receptors for activating steroid synthesis
within cells
what is the half life of steroid hormones
hours/days
why is the half life of steroid hormones long?
due to extensive binding to proteins that suppress elimination
what are protein/peptide hormones made from
proteins
how are protein/peptide hormones made
pre-synthesised usually from a longer precursor - proteolytic steps by convertases during intracellular transport
how are protein/peptide hormones stored
in vesicles
how are protein/peptide hormones released
in response to stimuli by Ca2+ dependent exocytosis
are protein/peptide hormones hydrophobic or hydrophilic
hydrophilic
how are protein/peptide hormones transported in the blood
free
where are the receptors for peptide synthesis found
on cell membrane
what is the half life of peptide hormones
minutes
in what state can hormones cross the capillary wall to activate receptors in target tissues (biophase)
free
give 3 functions of carrier proteins
increase amount of hormone transported in blood
provide a reservoir/buffer of hormone
extend half life of hormone in circulation
what does albumin bind
many steroids and thyroxine
what does transthyretin bind
some steroids and thyroxine
what does cortisol binding globulin bind
cortisol (and aldosterone) selectively
what does thyroxine binding globulin bind
T4 (and some T3) selectively
what does sex steroid binding globulin bind
mainly testosterone and oestradiol
what happens if free hormones diffuses out of the blood into cells
bound and free hormones in blood are in equilibrium - bound hormone will be freed to replace it
what happens if lots of hormone is suddenly secreted
free carrier proteins are available to bind them
what is the primary determinant of plasma concentration of a hormone
rate of secretion
what is the equation of plasma concentration of a hormone
plasma concentration of hormone = rate of secretion - rate of elimination
what are the 2 broad types of hormone receptors
are the ligands hydrophilic or lipophilic for each?
cell surface receptors - ligand is hydrophilic
intracellular receptors - ligand is lipophilic
what are the 2 types of cell surface receptors
GPCRs
receptor kinases
what hormones activate GPCRs
amines and some peptide/proteins
what hormones activate receptor kinases
some proteins/peptides
what are the 3 types of nuclear receptor (intracellular receptors)
class 1 class 2 hybrid class
what hormones activate class 1 nuclear receptors
many steroid hormones
where are class 1 nuclear receptors located in the absence of an activating ligand and what are they bound to
mainly located in the cytoplasm
bound to inhibitory heat shock proteins
where to class 1 nuclear receptors move when they are activated
to nucleus
what hormones activate class 2 nuclear receptors
lipids
where are class 2 nuclear receptors located
nucleus
what hormones activate the hybrid class
T3 (and others) - similar function to class 1
how does insulin signal
receptor kinases
where does insulin bind to receptor kinases
alpha subunit
what does binding of insulin to the alpha subunit of receptor kinases cause
beta subunits to dimerise and phosphorylate themselves (autophosphorylation)
(autophosphorylation of intracellular tyrosine residues)
what does autophosphorylation of intracellular tyrosine residues cause
recruitment of multiple adapter proteins e.g. IRS1 (insulin receptor substrate 1) that are also tyrosine phosphorylated —> protein kinase B –> metabolic effects/catalytic activity of the receptor
what channels cause glucose entry into cells upon insulin binding
GLUT4
true/false
GLUT4 channels remain in the cell membrane at all times
false - stimulated to move to cell membrane when insulin binds
how do steroid hormones enter cells
diffusion across plasma membrane
what does binding of a steroid hormone to an intracellular nuclear receptor cause
dissociation of inhibitory heat shock proteins (HSP)
in the case of steroid hormones, where is the inactive receptor located
in the cytoplasm
where does the receptor-steroid complex move and what does it do there
moves to the nucleus
forms a dimer
binds to hormone response elements in DNA
what does binding to the hormone response elements cause
transactivation or transrepression
- alter mRNA levels and rate of synthesis of mediator proteins
what is transactivation
transcription of specific genes is switched on
what is transrepression
transcription of specific genes is switched off
how do glucocorticoids cause transactivation
binding of the activated glucocorticoid receptor homodimer to a GRE in a promoter region of steroid sensitive genes
what does binding of the activated glucocorticoid receptor homodimer to a GRE in a promotor region of steroid sensitive genes cause
transcription of genes encoding anti-inflammatory mediators
what does the glucocorticoid-receptor-corticosteroid complex interact with to cause transrepression
large co-activator moleules with intrinsic HAT (histone acetyltransferase) activity which is activated by proinflammatory transcription factors
thus, switching off inflammatory gene expression that are activated by these transcription factors
where is ADH released from
posterior pituitary
what does ADH cause and how
water reabsorption from renal tubules by counter current multiplication
what steroid controls sodium balance
aldosterone mainly (also others e.g. cortisol)
what does aldosterone do to Na conc
Na reabsorption in renal tubules in exchange for K+/H+
increased pulse dry mucous membranes soft/sunken eyeballs decreased skin turgor decreased consciousness decreased urine output postural decrease in BP - all indicate what?
decreased {Na+} / decreased ECF
what can cause decreased Na
increased Na loss
decreased Na intake
decreased water excretion e.g. SIADH
increased water intake
coughing tiredness SOB pulmonary oedema weak heart peripheral oedema ascites pleural effusion - all indicate what?
increased [Na+] - increased ECF
what can cause increased Na
increased Na intake e.g. IV meds, near drowning, malicious
decreased Na loss
increased water loss e.g. diabetes insipidus
decreased water intake
what qualifies as life threatening levels of sodium
< 120 nmol
> 160 nmol
if Na rises or falls rapidly even if to a point in normal range
where would 5% dextrose go
plasma
interstitial fluid
intracellular fluid
where would 0.9% saline go
plasma
interstitial fluid
where would plasma/blood go
plasma
what are some s/s of life threatening hypo/hypernatraemia
altered consciousness
confusion
nausea/vomiting
fitting
what does [Na] reflect
Na loss
what does [K] reflect
K retention
what are some physiological causes of raised prolactin
breast feeding
pregnancy
stress
sleep
what are 5 drugs that cause raised prolactin
dopamine antagonists e.g. metoclopramide antipsychotics e.g. phenthiazines antidepressants e.g. TLA, SSRIs oestrogens cocaine
would hypothyroidism cause raised or lowered prolactin
raised
would a prolactinoma cause raised or lowered prolactin
raised
would a stalk lesion (iatrogenic, RTA) cause raised or lowered prolactin
raised
what does aldosterone do to the blood pressure
raised BP
does aldosterone increase parasympathetic or sympathetic outflow
sympathetic
what effect does aldosterone have on the heart/BVs
increased cardiac collagen
LVH
atheroma
altered endothelial function/increased pressure response
what GPCR do adrenaline, glucagon and CRH signal via
Gs
what does Gs do to the production of cAMP from ATP by adenylyl cyclase
increases it
what does increased cAMP do
stimulates protein kinase A leading to phosphorylation of Ser/Thr residues in target proteins
what GPCR does melatonin signal via
Gi
what does Gi do to the production of cAMP from ATP by adenylyl cyclase
decreases it
what GPCR do angiotensin II, GnRH and TRH signal via
Gq
what does Gq do to the activity of PLC (phosolipase C)
increases it
what is the role of PLC in the Gs pathway
converts PIP2 to DAG and IP3
what does IP3 do
binds to IP3 receptor on the endoplasmic reticulum causing calcium release to cause cellular effects
what does DAG do
stimulates protein kinase C causing phosphorylation of Ser/Thr residues in target proteins leading to cellular effects
what does the kidney release when BP falls
Renin
what does renin do
converts angiotensinogen to angiotensin I
how does angiotensin I get to angiotensin II
ACE
what does angiotensin II do
causes BP to rise
stimulates adrenal gland to produce aldosterone
what does aldosterone do to increase the BP
salt retention
what is released from the hypothalamus to stimulate the anterior pituitary to produce ACTH
CRH
what causes the hypothalamus to release CRH
time of day
stress
illness
where does ACTH act and what does it cause
stimulates adrenal cortex to produce cortisol
what effect does increased cortisol have on CRH and ACTH levels
negative feedback - cortisol goes up, CRH and ACTH go down
how is adrenaline and noradrenaline released from the adrenal gland
direct control by nervous system
where is MSH released and where does it act
anterior pituitary
melanocytes
where are LH and FSH released from and where do they act
anterior pituitary
ovaries and testes
where is ADH released from
posterior pituitary
where is oxytocin released from
posterior pituitary
where does oxytocin act
uterine smooth muscle and mammary glands
smooth muscle in vas deferens and prostate gland
where is PRL released from
anterior pituitary
where does PRL act
mammary glands
where is GH released from
anterior pituitary
where does GH act
liver
also adipose tissue and target tissues
what does GH cause the liver to produce
somatomedins
where do somatomedins work
bone, muscle etc
where is TSH released from
anterior pituitary
what does TSH cause the thyroid to produce
T3 and T4
what does ACTH cause the adrenal gland to produce
glucocorticoids
what gland is under direct control by the nervous system
adrenal gland
what gland is under indirect control through release of regulatory hormones
anterior pituitary
where are oxytocin produced and stored
produced in hypothalamus
stored in posterior pituitary
where is ADH produced and stored
produced in the hypothalamus
stored in posterior pituitary
what hormone from the hypothalamus causes ACTH to be released
CRH
what hormone from the hypothalamus causes TSH to be released
TRH
what hormone from the hypothalamus causes LH/FSH to be released
GnRH
what hormone from the hypothalamus causes GH to be released
GHRH
what hormone from the hypothalamus inhibits prolactin
dopamine (DA)
what hormone from the hypothalamus inhibits GH secretion
somatostatin (SS)
what does GH cause the liver to produce
IGF-1
where does IGF-1 act
target tissues
what does GH cause adipose tissue to produce
leptin and free fatty acids
what effect do free fatty acids have on hypothalamus
negative feedback
what effect does leptin have on the hypothalamus
positive feedback
what kinds of things stimulate the hypothalamus to produce GHRH
ghrelin sleep exercise stress amino acids sex hormones
what effect does IGF1 have on the anterior pituitary and hypothalamus
negative feedback
what effect does GH have on the hypothalamus
negative feedback
what feedback does PRL have on the hypothalamus
positive feedback
what feedback does PRL have on the anterior pituitary
negative feedback
what kind of signalling does PRL show at the breast tissue
paracrine/autocrine
what stimulates the hypothalamus to cause ADH release from the posterior pituitary
fall in BP
what does V1 do
constricts blood vessels to increase systemic vascular resistance and increase blood pressure
what does V2 do
causes fluid reabsorption in the kidneys to increase blood volume and increase blood pressure
how is glucose taken up into pancreatic beta cells
GLUT2 transporter
what happens after the uptake of glucose into pancreatic beta cells
glucose is phosphorylated by glucokinase
how are the Katp channels inhibited in the pancreatic Beta cells and how does this eventually lead to insulin release
phosphorylation of glucose by glucokinase increases intracellular ATP which inhibits Katp channels. This causes depolarisation of the cell membrane which leads to opening of voltage gated Ca2+ channels
increase in Ca2+ conc. leads to fusion of secretory vesicles with the cell membrane and release of insulin
what is released by pancreatic alpha cells
glucagon
what is released by pancreatic delta cells
somatostatin
what is released by pancreatic PP cells
pancreatic polypeptide
how and where is insulin synthesised
in the RER of pancreatic beta cells as a larger single chain preprohormone - preproinsulin which is cleaved to form insulin
what is the structure of insulin
2 polypeptide chains linked by disulfide bones
what is a biproduct of insulin formation
C-protein
how is the release of insulin described
biphasic
what % of insulin is from a readily releasable pool
5%
what happens to the curve of insulin secretion in poorly controlled type 2 diabetes
curve flattens and weakens
at what blood glucose should B cells produce insulin
over 5mM
what happens in type 1 diabetes
destruction of beta cells
what is glucokinases Km for glucose
within the physiological range of concentration - change in glucose conc leads to a dramatic change in glucokinase activity
how do beta cells lose ability to sense changes in glucose in other types of diabetes
hyperglycaemia takes glucose conc. outwith the Km of glucokinase, mitochondrial exhaustion
the Katp channel is a ____ complex and consists of 2 proteins - pore subunit and regulatory subunit
octomeric complex
consists of 2 proteins
what makes up the pore subunit
4 potassium inward rectifier 6.2 subunits
Kir6.2
what makes up the regulatory subunit
4 sulphonylurea receptor 1 subunits
SUR1
what does the tetramer of Kir6.2 subunits form
K selective ion channel
what happens to the Katp channel when extracellular glucose is high
ATP binding to each of the Kir6.2 subunits closes the channel causing depolarisation of the beta cell and insulin release
what happens to the Katp channel when extracellular glucose is low
ADP-Mg2+ binding to the SUR1 subunits opens the channel maintaining the resting potential of the beta cell and inhibiting the secretion of insulin
what does diazoxide do to the Katp channel
stimulates the Katp channel inhibiting insulin release
what can some mutations in Kir6.2 lead to and how
neonatal diabetes
constitutively activated Katp channels or increase in Katp numbers
what may some cases of neonatal diabetes respond to
sulfonylureas e.g. tolbutamide
what else could a Kir6.2 mutation lead to
congenital hyperinsulinism
trafficking or inhibiting mutations
what could be used to treat congenital hyperinsulinism
diazoxide
what does insulin do to amino acid uptake in muscle
increases
what does insulin do to DNA synthesis
increases
what does insulin do to protein synthesis
increases
what does insulin do to lipolysis
inhibits
what does insulin do to gluconeogenesis in liver
inhibits
what does insulin do to glycogen synthesis in liver and muscle
increases
what does insulin do to glucose uptake in muscle and adipose tissue
increases
what does insulin do to lipogenesis in adipose tissue and liver
increases
what is another name for donotive syndrome
leprechaunism
what is the inheritance pattern of leprechaunism
autosomal recessive
where is the mutation in donotive syndrome and what does it cause
mutation in gene for insulin receptor
defects in insulin binding/insulin receptor signalling
—> severe insulin resistance
what are some features of leprechaunism
elfin facial appearance
growth retardation
absence of SC fat
decreased muscle mass
what is the inheritance pattern of Rabson Mendenhall syndrome
autosomal recessive
what is the issue in rabson mendenhall syndrome
severe insulin resistance, hyperglycaemia and compensatory hyperinsulinaemia
what are some features of RMS
developmental abnormalities
acanthosis nigricans
DKA
severe cases of RMS are linked to mutations in what
insulin receptor that reduces sensitivity
where are ketone bodies formed and where do they go
liver mitochondria
diffuse into blood stream and into peripheral tissues
what are ketone bodies derived from
acetyl-coA
where is acetyl-coA from
beta oxidation of fats / fatty acid oxidation
how are ketones used for energy metabolism
converted back to acetyl co-A which enters the TCA cycle
how does insulin prevent ketone body overload
prevents lipolysis
how does DKA occur in T1DM
if insulin is missed –> break down of fats
when might acetyl coA be converted to ketones
if supply of oxaloacetate is limited e.g. no glycolysis
why are ketones formed in glucose limiting conditions e.g. DMT1, starvation
increased lipolysis
oxaloacetate used for gluconeogenesis so crebs cycle inhibited
acetyl coA goes to ketones
