REB Endocrine Flashcards
what are the types of hormones?
- steroid
- amine
- peptide
- protein
what are steroid hormones derived from?
cholesterol
what are amine hormones derived from?
from amino acid modification of tryptophan and tyrosine
what are peptide hormones derived from?
multiple amino acids linked together
what type of hormones need transport proteins?
steroid hormones
steroid hormones arrive at the nucleus with the help of transport proteins. what does the activated receptor bind to?
HREs (hormone response elements) of DNA
what are HREs?
regions of DNA that contain a consensus sequence located upstream to the initiation site and associated with transcription factors
hormone signalling duration is _____ but effect duration is _____
short
long
how is cAMP signalling controlled
negative feedback by pKA
what does pKA activate?
phosphodiesterases
what do phosphodiesterases do?
deactivate cAMP
what substance is activated by G-proteins and cleaves membrane-bound phospholipids
phospholipase C
phospholipase C cleaves membrane-bound proteins into
IP3 and DAG
what causes the phosphorylation cascade?
protein kinases activated by DAG
IP3 increases release of
Ca2+
Ca 2+ acts as a second messenger by binding tp
calmodulin
what does calmodulin do
modulates protein kinase activity within the cells
what is the second messenger of a GPCR dependent reaction?
calcium
what is the second messenger of a GPCR independent reaction?
cGMP
explain a GPCR independent reaction
give an example
involves the conversion of GTP to GMP when ligand binds by membrane-bound receptor guanylate cyclase
eg. ANP –> increase Na excretion –> decrease ECF
explain the binding of insulin
insulin binds
tetramer dimerises and autophosphorylation occurs
the insulin response element is then phosphorylated and hence activates
describe a sandwich elisa
monoclonal antibodies plates –> antigen binds –> sandwiched by second monoclonal antibody modified with enzyme –> colour produced
in a sandwich elisa what is the relationship between colour produced and amount of antigen
colour produced directly proportional to amount of antigen
describe a competitive elisa
antibody incubated with sample –> mixture added to wells coated with the same antigen –> bound to antibodies in mixture washed away ; free antibodies will bind to antigen (2nd antibody is added for colour)
in a competitive elisa what is the relationship between colour produced and amount of antigen
colour produced inversely proportional to amount of antigen
where does the anterior pituitary gland arise from
Rathke’s pouch - epithelioid nature
where does the posterior pituitary gland arise from
neural tissue outgrowth from hypothalamus - glial type
what types of neurons are in the posterior pituitary. where are their cells?
neurosecretory neurons in the hypothalamus
what are the main nuclei in the posterior pit
supraoptic
paraventricular
what hormones are produced by the posterior pit
vasopressin/ADH
oxytocin
what nuclei produces vasopressin
supraoptic mostly
1/6 by the paraventricular
what nuclei produces oxytocin
paraventricular mostly
1/6 by the supraoptic
vasopressin and oxytocin are produced as
prohormones
vasopressin and oxytocin are bound to carrier proteins called
neurophysins
how long does it take to transport vasopressin and oxytocin to go to the posterior pituitary
several days
nervous impulses cause the release of both neurophysins and hormones into the
capillaries (they separate immediately)
Unlike the post pit gland, the anterior pituitary gland synthesises its own hormones. What are these hormones?
- somatotrophs (GH)
- corticotrophs (ACTH)
- Gonadotrophs (FSH and LH)
- Lactotrophs (prolactin)
- Thyrotropes (TSH)
all hormones are trophic except
prolactin
what hormones control the release of anterior pituitary hormones
hypothalamic releasing and inhibitory hormones
the hypothalamus releases hormones which control secretions of the anterior pituitary by the
hypothalamic hypophyseal portal system
where does the hypothalamic hypophyseal portal system begin?
median eminence (base of hypothalamus)
the hypothalamic hormones act on the ________ of the anterior pituitary
glandular cells
anterior pituitary hormones are regulated by
- hypothalamic hypophysiotropic hormones
2. negative feedback
what are the types of feedback loops
- ultrashort
- short
- long
how are ultrashort feedback loops regulated
hypothalamic hormones self-inhibit
how are short feedback loops regulated
pituitary hormones inhibit hypothalamic hormones and other pituitary hormones
how are long feedback loops regulated
hormones from peripheral endocrine glands
PIH is identical to
dopamine (has more than 1 effect)
a hormone may be regulated by more than one hormone. example….
GH by GHRH and GHIH
what is primary hypo/hyper secretion
hypo/hyper secretion of the anterior pit cells
what is secondary hypo/hyper secretion
hypo/hyper secretion of the hypophysiotropic hormones
what is tertiary hypo/hyper secretion
hypo/hyper secretion of endocrine gland
what is panhypopituitarism
decrease in secretion in all anterior pituitary hormones
effect of panhypopituitarism on children
rate of development is decreased and they never go through puberty
effect of panhypopituitarism in adults
become sterile but can be treated with thyroid/ adrenocortical hormones
what illness is characterized by:
- decrease in secretion in all anterior pituitary hormones
- rate of development is decreased and they never go through puberty
panhypopituitarism in children
what illness is characterized by:
- decrease in secretion in all anterior pituitary hormones
- person becomes sterile but can be treated with thyroid/ adrenocortical hormones
panhypopituitarism in adults
what cells produce growth hormone
somatotropes
treatment of panhypopituitarism in adults
thyroid/ adrenocortical hormones
which hormones are closely related to GH and its function
thyroid hormone
sex hormones
what i sthe most abundantly produced ant pit hormone
GH
secretion of GH _____ with age
decreases
is GH secreted after growth has seized
YEP
metabolic effects of GH are triggered by
direct binding to the target hormone
what are the metabolic effects of GH
- metabolization of FA in adipose tissue for energy. this increases FA in the blood and conserves glucose for the brain
- decreased rate of glucose utilization throughout the body (decreases uptake) –> GH induced insulin resistance eg Muscles uptake of glucose decreases
- increased rate of protein synthesis
growth- promoting effects are done by stimulating
somatomedins
somatomedins are structurally and functionally similar to
insulin called insulin-like growth factor (IGF1 or somatomedin C)
where is IGF 1 produced
liver
what is the purpose of IGF?
promotes growth upon stimulation (bone growth and protein synthesis)
bone growth occurs through
thickening of the epiphyseal plate and increase in bine length
regulation of GH
- negative feedback on GHRH and GHIH secretions (short loop)
- diurnal rhythm - GH secretion increases 1hr into sleep
- other factors - low blood glucose (GH conserves glucose), exercise (fat usage instead), high protein (protein synthesis) and decrease in plasma FA (mobilisation)
GH deficiency in children can lead to what conditions/ illnesses?
dwarfism
laron dwarfism
african pygmies
symptoms of Dwarfism
short stature
decrease in development of muscles
increase in subcutaneous fat
cause of laron dwarfism
blood GH normal but GH receptor is abnormal
cause of african pygmies
blood GH normal, receptor normal, lack of IGF 1
symptoms of african pygmies
no growth function but normal metabolism
symptoms of GH deficiency in adults
reduced skeletal muscle mass
increased bone density
increased risk of heart failure
excess GH in children can lead to what conditions/ illnesses?
gigantism
hyperglycemia (GH conserves glucose)
symptoms of GH excess in adults
bones and tissue thicken and proliferate
hyperglycemia
** shows mostly in face
explain the change in glucose level if there is a GH deficiency
normally after a meal, insulin should decrease glucose levels which should trigger GH secretion, allowing glucose to rise again.
if deficient, glucose levels cannot rise again
what test can be done to determine if a person has excess GH secretions
glucose loading test
explain the glucose loading test and its result if GH is excessively secreted
patient given glucose –> increase in glucose –> increased GHIH –> decrease glucose normally
if excess, decrease would not be as significant either due to not enough GHIH or too much GH acting
what does prolactin normally stimulate
proliferation and branching of ducts in the breasts
what does prolactin stimulate in pregnancy
development of lobules of alveoli for milk production
what does prolactin stimulate post partum
milk production and secretion
what effect does prolactin have on immunity
decreases immune responses to accept foetal tissue
prolactin increases during pregnancy until
mother stops breastfeeding
deficiency in prolactin leads to
inability to lactate
how is prolactin regulated
short-loop negative feedback by PRH and PIH or dopamine
how does excess prolactin specifically affect women
infertility, loss of menstruation, inappropriate lactation
how does excess prolactin specifically affect men
decreased testosterone levels, sperm production, breast development
how does excess prolactin generally affect both genders
decreased libido
treatment of excess prolactin
dopaminergic drugs (perform PIH functions)
what stimulates oxytocin secretion
positive feedback when suckling or birth canal stretch
what are the functions of oxytocin
milk ejection
contraction of uterus
what are the functions of vasopressin
enhances retention of water by kidneys
constriction of arterial smooth muscle
what stimulates the release of vasopressin
- osmotic: osmoreceptors increased osmolality and increased firing rate –> ADH secretion
- volume: decreased volume of BP causes release detected by baroreceptors or stretch receptors located in the walls of the left atrium and pulmonary veins
- age: older –> more ADH
- ethanol: suppresses ADH release (this is why you get thirsty)
explain ADH levels after hemorrhage
during low volume
ADH is secreted 50 times more to bring back blood volume
what is a deficiency in vasopressin caused by
diabetes (hyperglycemia –> increased blood osmolarity)
symptoms of vasopressin deficiency
same as the symptoms of diabetes (hyperglycemia, polyuria, polydipsia, nocturia)
symptoms of excess vasopressin
electrolyte disturbance
CNS symptoms from too low osmolarity
source of thyroglobulin
epithelial cells surrounding the colloid space or lumen
where is thyroglobulin stored
lumen
where is parathyroid hormone released from
parathyroid gland
what is the effect of parathyroid hormone of Ca
increases calcium levels
where is calcitonin released from
parafollicular (C) cells
what is the effect of calcitonin of Ca
decreases calcium levels
where are parafollicular (C) cells located?
between follicles in the thyroid gland
what regulates thyroglobulin synthesis
TSH through active transport of Iodine (iodinating tyrosine residues)
steps of thyroid hormone synthesis
- thyroglobulin is synthesised by epithelial cells and transported into the colloid space
- TSH causes cells to actively transport iodine into the cytosol. once inside, they are trapped to prevent escape and oxidised into the active form by peroxide.
- iodine enters the lumen through NIS (sodium, iodide symporter). thyroperoxidase iodinates tyrosine molecule on thyroglobulin forming either 2MITs or 1DIT (# of iodine attacks)
- MIT and DIT –> T3 and 2DIT –> T4
- epithelial cells ingest the colloid by endocytosis and fuses the vesicle with lysosomes where thyroglobulin is cleared releasing 90% T4 and 10% T3.
- since the thyroid hormones, T3 and T4, are lipid soluble, they diffuse across the membrane and into the bloodstream.
what hormone causes cells to actively transport iodine into the cytosol?
TSH
what oxidises iodine in the cytosol?
peroxide
iodine enters the lumen through
NIS
what iodinates tyrosine molecules on thyroglobulin
thyroperoxidase
thyroperoxidase iodinates tyrosine molecule on thyroglobulin forming
either 2MITs or 1DIT
1MIT and 1DIT forms
T3
2DIT forms
T4
of the total TH made, how much is T4 and how much is T3
90% T4 and 10% T3
T4 is a ____ of T3
prohormone
which TH is more biologically active
T3
deiodination of T4 forms
T3 reverse T3 (metabolization of T4)
iodine is converted to ____ by bacteria in the gut
iodide
how is iodide transported in the blood
bound to serum proteins
how does the NIS work in transporting iodine
transfers both iodine and sodium in one direction using gradient of sodium
how is TH regulated
- TRH secretion - stimulated by exposure to cold; inhibited by T3 and T4 levels
- TSH secretion from anterior pituitary by thyrotropes - stimulated by TRH during the day and inhibited by T3 (beta subunit) during the night
what part of the T3 inhibits TSH
Beta subunit
what is the significance of the binding of TH to a transport protein
to prevent free diffusion into random cells
Active TH are _____ and can hence freely diffuse into cells to elicit an action.
unbound
what transport proteins are TH bound to and describe their affinity and capacity
- thyroxine-binding globulins (TBG) - high affinity, low capacity
- albumin - low affinity, high capacity
- thyroxine binding prealbumin (TBPA) - low affinity, high capacity
describe the genomic action of TH
TH are steroid hormones (hydrophobic). they diffuse into the cell and T4–>T3 in the cytoplasm. T3 binds to the thyroid receptor activating it. the receptor then complexes with TRE and Retinoid X receptor).
what stimulates and inhibits TRH secretion
stimulated by exposure to cold; inhibited by T3 and T4 levels
what stimulates and inhibits TSH secretion
stimulated by TRH during the day and inhibited by T3 (beta subunit) during the night
TH increases the body’s sensitivity to
catecholamines (adrenaline and noradrenaline)
temporal effects of TH levels
Daytime - low - anabolic - low metabolic rate - protein and glycogen synthesis
night time - high - catabolic - high metabolic rate - protein and glycogen breakdown
Explain the effects of TH on metabolism
presence of TH --> catabolism increased glucose absorption glycogenolysis gluconeogenesis increased fat mobilization --> increased FA
what is the metabolic function of TH
increases overall BMR
most important regulator of oxygen consumption and energy expenditure
it degrades fats and glycogen but doesn’t affect proteins
what is the calorigenic effect of TH
increases metabolic activity –> increases heat production
what is the effect of TH on the nervous system of children
TH is essential for myelination and CNS development
what is the effect of excess TH on the nervous system of adults
restlessness and hypersensitivity
what is the effect of a TH deficiency on the nervous system
lethargy and mental deficit
what the effect of TH on growth
stimulates GH secretion and increases synthesis of IGF-1 and promotes GH and IGF effects on growth and development
what the effect of TH deficiency on growth in children
stunts growth –> dwarfism (african pygmies)
what is the effect of TH on the cardioresp system
TH increases blood flow and increases sensitivity to catecholamines which increase HR, SV and BP
what is the primary cause of hypothyroidism
Gland tissue
what is the secondary cause of hypothyroidism
anterior pituitary/ hypothalamus
symptoms of hypothyroidism
reduces BMR poor tolerance to cold slow mental response weight gain weak pulse lethargy husky voice dry scalp/skin
what is myxedema
severe hypothyroidism
increased H2O retention of carbs
increases interstitial fluid
clinical presentation of myxedema
edemic appearance (puffy) with bagginess under eyes and face swelling
clinical presentation cretinism
congenital –> since birth
they experience dwarfism (no IGF-1) and mental retardation
**effects may not show before birth as the mother supplies the embryo
cretinism can be caused by hypothyroidism or
can also be due to iodine deficiency
treatment of cretinism
T4 supplements few weeks after birth or permanently
diagnostics of hypothyroidism (test and results)
done by measuring TSH and T4 levels in blood
people with hypothyroidism should have high TSH and low T4 (low negative feedback)
if issue is secondary, then low TSH and TRH
most common cause of hyperthyroidism
grave’s disease
what is grave’s disease
autoimmune disease characterised by the production of LATS that also target TSH receptors (not TH)
growth and secretion continue unchecked
what does grave’s disease stimulate
growth and secretion of thyroid gland
grave’s disease has a similar function to
TSH
** but it is not inhibited by TH
symptoms of grave’s disease
elevated BMR
increased appetite and weight loss
intolerance to heat
degradation of fat, protein and carb stores at an abnormal rate
HR and SV increase significantly –> palpitations
excessive degree of mental awareness –> anxiety
clinical signs of grave’s disease
inflammation and swelling of eye muscles –> eye bulge out and lids cannot close –> irritation
diagnostics of grave’s disease
done by measuring TSH and Thyroxine (TH) in plasma
TSH should be very low (inhibited) but TH levels very high.
what is a goitre
an enlarged thyroid thyroid gland
when are goitres present (in relation to TH release)
they are present in hypo and hyperthyroidism or none
when in hypothyroidism is a goitre present?
issue with thyroid gland or lack of iodine
where there is excessive stimulation of the gland by TSH but no TH is being secreted
when in hyperthyroidism is a goitre present?
- Grave’s disease (PRIMARY) - hypersecretion due to LATS which acts like TSH but has no inhibition (continuous stimulation)
- Secondary defect - excessive TSH secretion due to tumor leads to excessive stimulation –> goitre
when in hypothyroidism is a goitre not present?
when the issue is with hypothalamus or anterior pituitary since there is no TSH secretion –> no stimulation –> no goitre
when in hyperthyroidism is a goitre not present?
when there is excessive secretion without extra stimulation –> thyroid tumor
where is calcium stored
bone reservoir, ECF and cells
disorders of Ca are closely related to disorders of
magnesium
phosphates
what are the functions of calcium
- muscle contraction and nerve excitability. Ca2+ deficit causes hyperexcitability of neurons and excess Ca2+ causes increased contractility
- NT and hormone release into synaptic cleft
- Blood coagulation (essential cofactor for clotting factors)
regulation of calcium is done by
parathyroid hormone released from parathyroid glands –> increases Ca2+
calcitonin released from thyroid gland –> decreases Ca2+
effect of parathyroid hormone on Ca
increases Ca2+
effect of calcitonin on Ca
decreases Ca2+
calcium is absorbed in the ____ but requires ____
small intestine
vitamin D
how is plasma Ca2+ levels controlled by the kidney
regulation of excretion of extra calcium and reabsorption if levels are low
if there is impairment of intestines, parathyroid glands and kidneys, how is plasma Ca2+ maintained
at the expense of bone calcification
what are the functions of PTH
- increases Ca2+ and Mg2+ reabsorption in the kidneys
- increases Ca2+, Mg2+ AND HPO4- uptake from GI tract into blood
- increases activity of osteoclasts –> bone breakdown –> increased Ca2+ levels
- promotes vitamin D formation by increasing Ca2+ absorption in small intestine
PTHrP is structurally similar to
PTH
what are some additional functions of PTHrP (beside those similar to PTH)
mammary gland development
lactation
placental transfer of Ca2+
where is PTHrP secreted from
breast and lung tumors
unlike PTH, PTHrP does not stimulate
vitamin D synthesis
nor calcium absorption (bone decalcification only)
what are the PTH receptors
type 1 - high affinity for both PTH and PTHrP and is a G-protein receptor located in the bone and kidney
type 2 - binds to PTH but low affinity for PTHrP
which PTH receptor has a low affinity for PTHrP
type 2
which PTH receptor has a high affinity for both PTH and PTHrP
type 1
calcitonin is produced by
parafollicular (C) cells
calcitonin binds to a ____ receptor
Calcitonin
where is the calcitonin receptor located
on osteoclasts (inhibiting fxn)
osteoblasts ( promotes fxn)
kidneys
what type of receptor is the calcitonin receptor
GPCR
effect of calcitonin receptor on osteoclasts
inhibits fxn
effect of calcitonin receptor on osteoblasts
stimulates fxn
mRNA in C-cells contain _____ exons which code for _______
4 of 6 exons
pre procalcitonin
calcitonin opposes the fxn of §
PTH
mRNA in CNS contain _____ exons which code for _______
5 of 6 exons
calcitonin-gene related peptide (CGRP)
what is the function of CGRP
potent vasodilator
vitamin d can be obtained through the diet as __ in vegetables and __ in meat
D2
D3
how can vitamin D be obtained other than through the diet
endogenously through UV action on the skin producing Calcitriol
formation of vitamin D
7 dehydrocholesterol –> vitamin D3 – liver (hydroxylation) –> 25 hydroxyvitamin D3 – kidney (hydroxylation) —> Calcitriol (1,25 dihydroxyvitamin D3)
enzyme of last step - 25 hydroxyvitamin 1 alpha hydroxylase
where does 1 alpha hydroxylase work
kidney
____ stimulates 1 alpha hydroxylase
PTH
____ inhibits 1 alpha hydroxylase
vitamin D (calcitriol)
____ inhibits PTH
calcitriol
vitamin D is transported in the blood bound to
vitamin D-binding protein
inactive form of vitamin D is
25-hydroxyvitamin D
active form of vitamin D is
1,25-hydroxyvitamin D (calcitriol)
25-hydroxyvitamin D is from the
liver
1,25-hydroxyvitamin D is from the
kidney
vitamin D has a lower affinity for which form of vitamin D
25-hydroxyvitamin D (inactive)
which form of vitamin D has a longer half life
25-hydroxyvitamin D (inactive)
when vitamin D binds to its receptor, it forms a complex with
RXR (like TH) which then goes onto the vitamin D response element
functions of vitamin D
- increases calcium uptake
- mineralises excretion of Ca2+ from kidney by increasing Ca2+ reabsorption
- stimulates osteoclast activity
** same as PTH
calcium is mostly reabsorbed in the
PCT but some in the loop of henle
the functions of vitamin D are similar to that of
PTH
does vitamin D increase or decrease calcium uptake
increases calcium uptake
____% of Ca2+ in the body is found in the blood
____% is bound to albumin or an anion (inactive)
____% is found in it’s free form (Ca2+ ionised form) (active)
0.1
45
55
changes in albumin alters the ________ of calcium but NOT the ________
total amount
fraction of free ionized Ca+
does changes in H+ alter fraction of free ionized Ca+?
YEP
How does changes in H+ alter fraction of free ionized Ca+?
H+ competes with Ca2+ to bind to anions –> increase H+ –> increase acidity –> increase free ionised Ca2+
describe the effect of alkalosis and acidosis on the fraction of free ionised Ca2+
Alkalosis –> less H+ –> decreased free ionized Ca2+
Acidosis –> more H+ –> increased free ionized Ca2+
what are the different types of cells involved in bone turnover and what is the purpose of each
- osteoclasts - bone forming
- osteoblasts - bone-resorbing cells
- osteocytes - embedded osteoblasts - they regulate concentration if osteoblasts and osteoclasts
what is hyperparathyroidism
excess PTH –> increased bone resorption (break down)
what is osteomalacia and rickets
vitamin D deficiency
osteomalacia - demineralizing of pre-existing bones
rickets - in the children version where there is continued collagen formation but incomplete mineralization
In rickets, there is continued ______ formation but incomplete mineralization.
collagen
what is osteoporosis
disorder of reduced bone matrix
** not a disorder of Ca+ metabolism
osteoporosis resembles _______ but normal plasma Ca2+
osteomalacia
treatment of osteoporosis
treated with calcitonin to increase mineralisation
what is paget’s disease
increased osteoclast activity
there is new bone formation but osteoclasts make it weaker
(easy to fracture)
diagnosis of paget’s disease
increased serum alkaline phosphatase (ALP)
symptoms of hypocalcemia
constipation and arrhythmia
clinical presentation of hypercalcemia
trousseau’s sign (wait sign)
chvostek’s sign (twitch of lip or facial spasm)
symptoms of hypercalcemia
muscle cramps
excess Ca2+ –> increase muscle contraction
insulin is secreted by
B cells of Langerhan in the pancreas
when is insulin released in the blood
when glucose levels in the rise after parasympathetic stimulation
insulin facilitates the uptake of
glucose into the cell
what are the cell types in the islets of langerhans and what do they produce
- alpha cells (20%) - glucagon
- beta cells (75%) - insulin
- delta cells (5%) - somatostatin
somatostatin is inhibits
GH secretion
release of pancreatic and GI hormones
somatostatin is released by
Hypothalamus and delta cells
insulin inhibits
somatostatin and glucagon
somatostatin inhibits
insulin and glucagon
glucagon promotes
insulin and somatostatin
why does glucagon promote insulin production
it is needed for glucose transport
insulin synthesis
- synthesised initially as pre proinsulin with 4 domains (in beta cells)
- removal of N-terminus signal peptide becoming proinsulin with 3 domains. Amino B, Middle C and Carboxyl A.
- removal of C peptide forms mature insulin with only 2 domains linked by alpha sulfide bonds –> mature –> amino B and carboxyl A
what domain is removed from insulin first
N-terminus
what domain is removed from inulin second
C peptide
mature insulin and C-peptide are packaged into secretory vesicles by
Golgi
insulin release is triggered by the
influx of glucose
describe the steps in insulin release
- glucose enters beta cells via facilitated diffusion through the GLUT 2 transporter
- Glucose metabolised by glucokinase into G-6-P trapping it in the cell
- ATP generated via glycolysis for K+ channels
- closure of ATP-sensitive K+ channels –> no K+ influx –> depolarises cell leading to opening of Ca+ channel –> Ca2+ influx
- increased intracellular Ca2+ triggers the release of insulin - containing vesicles/ granules.
the 2 domains left on the mature insulin molecule is linked by
alpha sulfide bonds
insulin release - glucose enters beta cells via facilitated diffusion through the
GLUT 2 transporter
insulin release - Glucose metabolised by _____ into G-6-P trapping it in the cell
glucokinase
insulin release - ATP generated via glycolysis for
K+ channels
insulin release - closure of ATP-sensitive _____ –> depolarises cell leading to opening of _____–>
K+ channels
Ca+ channel
insulin release - increased intracellular Ca2+ triggers the release of _____
insulin - containing vesicles/ granules
hyperinsulinism can be induced by
tumors or by excessive insulin intake
hyperinsulinism can lead to
hypoglycemia which can cause brain damage
regulation of insulin release
- nutrients - glucose and amino acids leucine, isoleucine, alanine, arginine
- pancrine via somatostatin and glucagon (inhibition)
- GI hormones - GIP, glucagon-like peptide (GLP) and catecholamines (noradrenaline and adrenaline)
glycogen is synthesised by
aloha cells
interstitial neuroendocrine L cells (gut) and brain
glucagon is secreted is stimulated by
low glucose
high protein
catecholamine stimulation
glucagon is first synthesized as _____ before undergoing post-translational processing
proglucagon
proglucagon in pancreatic alpha cells is converted to (3)
- glucagon
- GRPP (glicentin related pancreatic peptides)
- major proglucagon fragment (MPF)
proglucagon in pancreatic alpha cells is converted by what hormone
prohormone convertase 2 (PC2)
proglucagon in neuroendocrine or enteroendocrine L cells is converted to
- glicentin
- GLP 1 (glucagon-like peptides) - stimulator of insulin secretion and somatostatin secretion but inhibit glucagon secretion
- GLP 2 - useless
function of glicentin
stimulator of insulin secretion, inhibits secretions of gastric acid, and reduces gut motility
(increases beta secretions)
effect of glicinten on pancreatic cells
increases secretion of B cells
effect of GLP 1 on pancreatic cells
decreases secretion of alpha cells
increased secretion of B and D cells
proglucagon in neuroendocrine or enteroendocrine L cells is converted by
prohormone convertase 1 and 3
what are the immediate effects of insulin
increased transport of glucose, amino acids and K+ into cells
what are the intermediate effects of insulin (4)
increased entry of AA
increases glycolysis and glycogen synthesis
decreased gluconeogenesis and glycogenolysis
decreased protein degredation
what are the delayed effects of insulin
Increase in mRNA for lipogenic enzymes to store glucose in the form of lipids in adipose tissue
the insulin receptor is an RTK receptor which has an ____ subunit extracellularly and a ____ subunit intracellularly
alpha
beta
when insulin binds to its receptor, it causes
auto-phosphorylation of tyrosines in the beta subunit
auto-phosphorylation of tyrosines in the beta subunit allows the receptor to phosphorylate
IRS-1
when insulin binds, the whole receptor moves intracellularly allowing
lysosomes degrade insulin
what glucose transporter is found on muscle and adipose?
do they require insulin?
GLUT 4
YUP
what glucose transporter is found on brain and kidneys? do they require insulin?
GLUT 3
NOPE
what glucose transporter is found on liver and pancreas?
do they require insulin?
GLUT 2
NOPE
what glucose transporter requires insulin
GLUT 4
hypoglycemia is due to
insulinomas or congenital
type 1 diabetes is caused by
immune-mediated B cell destruction –> hyperglycemia
describe the onset of type 1 diabetes
fast
type 1 diabetes may cause
ketoacidosis
type 2 diabetes is caused by
B cell dysfunctional insulin resistance and associated with obesity and sedentary lifestyle
describe the onset of type 2 diabetes
slow
type 2 diabetes may cause
blurred vision
slow healing
diagnosis of type 2 diabetes
hyperglycemia but with normal insulin levels
diabetic ketoacidosis is a symptom of
uncontrolled diabetes
without insulin, the body cannot break down glucose.
what is the new fuel source
break down of fat instead
the break down of fat produces
ketone bodies
a buildup of ketone bodies in the liver after beta oxidation can lead to
keto acidosis
keto acidosis is caused by
a buildup of ketone bodies in the liver after beta oxidation
where does beta oxidation occur
liver
explain the cause of glycosuria
too much glucose –> kidney cannot reabsorb 100% of glucose –> its in piss
therefore, with a high glucose concentration in urine, volume increases and there is more piss
normal glycogen levels in the body is
70-120 mg/dL (3.9-7.1 mmol/L)
glucagon regulates blood glucose levels by
stimulating glycogen breakdown
process of glucagon secretion
- hypoglycemia causes intracellular glucose concentration to fall
- reduction in glycolysis ATP –> K+ channels close
- intracellular K+ concentration rises –> depolarises cell –> Ca2+ channels open –> influx of Ca2+
- influx of Ca2+ causes secretion of glucagon through exocytosis
in glucagon secretion, there is a reduction in glycolysis ATP which causes the closure of the
K+ channels
in glucagon secretion, the influx of ____ causes secretion of glucagon through endocytosis
Ca2+
what factors stimulate glucagon release (3)
- low blood glucose
- protein rich meal (secreted with insulin)
- catecholamines (glucagon levels increase in anticipation for increased glucose use)
what factors inhibit glucagon release (2)
- high blood glucose
2. insulin
metabolic effects promoted by glucagon (3)
glycogenolysis
gluconeogenesis
ketogenesis (liver and adipose tissue)
metabolic effects inhibited by glucagon (2)
glycogenesis
glycolysis
what type of receptor is the glucagon receptor
GPCR
what type of reaction is catalysed by enzymes which are active when phosphorylated
catabolism
what type of reaction is catalysed by enzymes which are active when dephosphorylated
anabolism
what is whipple’s triad
- hypoglycemic symptoms - motor impairment, NSB problems
- blood glucose levels < 50 mg/dL (normal 70-120)
- symptoms resolve after glucose administration
types of hypoglycemia (4)
- insulin-induced
- post-prandial
- fasting
- alcohol-induced
cause of insulin-induced hypoglycemia
self-injection
what is postprandial hypoglycemia
exaggerated insulin release after a meal
how is postprandial hypoglycemia treated
eating less
more frequently
cause of fasting hypoglycemia
insulinoma, adrenal insufficiency (catecholamines stimulate glucagon), liver damage
risk group for alcohol-induced hypoglycemia
alcoholics that take irregular meals
how does alcohol consumption increase the risk of hypoglycemia
metabolism of alcohol –> excess NADH –
> diverts oxaloacetate away from gluconeogenesis –> increased the risk of hypoglycemia
prediabetes is also known as
intermediate hyperglycemia
plasma glucose concentration of prediabetes
6.1-6.4 mmol/L
plasma glucose concentration of diabetes
> = 7 mmol/L
> 125 mg/dL
plasma glucose concentration of acute hyperglycemia
at what glucose concentration is the person symptomatic
> = 8 mmol/L
symptomatic at >= 15 mmol/L
symptoms of hyperglycemia (6)
- decreases glucose entry into tissues and increased hepatic output
- glycosuria
- osmotic diuresis - polyuria and polydipsia (increased thirst)
- polyphagia - (increased appetite since body thinks its hypoglycemic)
- weight loss - excess metabolism of proteins and fats
- increase HbA1C - especially following an episode as diagnostic trace. it is glycated hemoglobin
how does osmotic diuresis affect electrolyte composition
excess loss of Na+ and K+ –> dehydration
diabetic ketoacidosis is caused by
alteration of carb, protein and lipid metabolism
DKA is a hallmark of what type of diabetes
type 1
what causes the increases ketosis in DKA
severe insulin deficiency and/or elevated levels of counter-regulatory hormones
what the counter-regulatory hormones of insulin secretion
glucagon
catecholamines
cortisol
the excess ketone production in DKA is from the breakdown of
fat and protein
excess ketone production by the breakdown of fats and proteins can lead to
metabolic acidosis
what hormone is responsible for the shift of K+ into cells
insulin
explain the effect of insulin deficiency on K+ levels of patients
they can be normal or elevated due to extracellular migration
however, cells are being depleted of K+ –> hypokalemia
what is ketogenesis
it is the enhanced lipolysis of lipids in adipose tissue
ketogenesis leads to the release of ____ into the bloodstream
FA
FA are taken up from the blood by the liver where ______ of FA occurs
B oxidation
the B oxidation of FA occurs in the
liver
the B oxidation of FA results in the production of _____ from acetyl coA
ketone bodies
the B oxidation of FA results in the production of ketone bodies from
acetyl coA
how is acetone produced
spontaneous decarboxylation of acetoacetate
how is acetone eliminated from the body
slowly through urine
what is ketonemia
presence of abnormally high concentrations of ketones in blood
what is ketonuria
excretion of abnormally large amounts of ketone in urine
symptoms of DKA (3)
- dehydration
- fruity breath
- CNS shit
DKA can eventually lead to
coma
shock
death
Diagnosis of DKA give the corresponding values for hyperglycemia ketonemia acidemia anion gap
hyperglycemia >11 mM
ketonemia >3mM
acidemia pH<7.3
anion gap >12 mmol/L
what is an anion gap
difference between measured cations and anions
how is DKA treated
IV fluid replacement
IV insulin
potassium replacement
in the treatment of DKA, what IV fluids are used
isotonic initially
hypotonic when Na concentration is fixed
in the treatment of DKA, when should insulin therapy be started
after fluid replacement
only if K>3.3 mmol/L
if DKA is resolved through treatment, the patient starts to take
subcutaneous insulin
chronic hyperglycemia can be caused by
microvascular and macrovascular complications
microvascular complications involve the formation of ______ caused by prolonged (chronic) hyperglycemia and protein glycation
advanced glycation end-products (AGE)
microvascular complications involves the nonenzymatic binding of
glucose with amino groups ( m- terminal) of proteins
what causes the accumulation of AGEs
binding to structural and functional proteins causes permanent changes (resembles protein denaturation) –> alters fxn of protein
what is the receptor for AGEs
RAGE
effect of binding of AGE to its receptor on endothelial cells
altering intracellular signalling and gene expression which leads to the release of proinflammatory molecules and free radicals –> extracellular matrix degradation
effect of binding of AGE to its receptor on platelets
causing aggregation –> vascular proliferation
effect of binding of AGE to its receptor on vascular smooth muscle cells
uncontrolled proliferation
where in the body are RAGE located
epithelial cells
platelets
vascular smooth muscle
binding of AGE to its receptor on _____ leads to extracellular matrix degradation
epithelial cells
binding of AGE to its receptor on _____ leads to uncontrolled proliferation
vascular smooth muscle
binding of AGE to its receptor on _____ leads to vascular proliferation
platelets
what is the most common cause of chronic kidney failure
diabetic nephropathy
cause of diabetic nephropathy
causes kidney failure –> leads to unhealthy glomerulus where protein spills into urine due to damage at the capillary wall
what is the predictor of diabetic nephropathy
microalbuminuria (albumin in urine)
cause of diabetic retinopathy
changes in vessels of the eye
complication of diabetic retinopathy
exudates (lipoprotein leaks)
microaneurysms
hemorrhage
complications of diabetic retinopathy contribute to ischemia which leads to the activation of
hypoxia-induced factor (HIF)
The activation of HIF in diabetic retinopathy is due to
ischemia by complications of diabetic retinopathy which are:
exudates (lipoprotein leaks)
microaneurysms
hemorrhage
The activation of HIF in diabetic retinopathy leads to the formation of ___
new vessels
how will the new vessels formed by activation of HIF in diabetic retinopathy be affected by AGE
AGE makes them leaky again
symptoms of diabetic retinopathy
sudden and complete loss of vision
discoloured spots
blurred vision
diabetic neuropathy develops as a result of
AGEs leading to ischemia and nerve cell injury (stroke)
what are the 2 types of neuropathy
- peripheral
2. autonomic
what does peripheral neuropathy affect
limbs (numbness, burning, pain)
what complication can arise from peripheral neuropathy
minor skin injuries may lead to serious infections because of the loss of sensation
what is autonomic neuropathy
damage of nerves including myelin degeneration
it affects autonomic function
autonomic neuropathy is the damage to nerves involved in autonomic regulation of
autonomic regulation of BP, cardiac function, respiratory, urinary and GI systems
what does autonomic neuropathy affect
weight loss, erectile dysfunction, no sensations of heart attacks
** it affects autonomic function
how do macrovascular complications contribute to hyperglycemia
damages vascular endothelium, increases platelet aggregation, decreases thrombolysis, making it difficult to restore blood as well as promoting pro-inflammatory responses
how do macrovascular complications affect platelet aggregation
increases platelet aggregation,
how do macrovascular complications affect thrombolysis
decreases thrombolysis
macrovascular complications lead to
heart disease
stroke
peripheral vascular disease
what are the 3 main types of microvascular complications
- diabetic nephropathy
- diabetic retinopathy
- diabetic neuropathy
what are the regions of the adrenal gland
- zona glomerulosa
- zona fasciculata
- zona reticularis
- medulla
what hormone is produced in the zona glomerulosa
mineralocorticoids –> aldosterone
what hormone is produced in the zona fasciculata
glucocorticoids –> cortisol
what hormone is produced in the zona reticularis
androgens –> DHEA
what hormone is produced in the medulla
catecholamines –> adrenaline and noradrenaline
cortisol can be made in the zona fasciculata and the
zona reticularis
androgens can be made in the zona reticularis and the
zona fasciculata
what hormones are produced by the ovaries
estrogens and progesterone
what hormones are produced by the testes
large amounts of androgens
in what part of the cell does steroid hormone synthesis occur
mitochondria
ER
are steroid hormones lipid soluble?
yes
can steroid hormones be stored?
nope
adrenocorticoids are bound to _______ to prevent reentry into the cell
plasma proteins
where is cholesterol synthesised
liver
cholesterol is synthesised in the liver as an _____ molecule
amphiphatic
all steroids are synthesised from
cholesterol
all steroid are synthesised from cholesterol via what process
hydroxylation of steroid nucleus
what is the RLS of steroid synthesis
conversion of cholesterol to pregnenolone catalysed by cytochrome P450
this step requires NADPH and oxygen
what protein controls the uptake of cholesterol into the mitochondria
Star
what enzymes involved in steroid synthesis are found in the ER
3B-OH
delta 5,4 isomerase
17-OH
21-OH
what enzymes involved in steroid synthesis are found in the mitochondria
11B-OH
18-OH
conversion of cholesterol to pregnenolone catalysed by ______ . it also requires ______ and _____
cytochrome P450
this step requires NADPH and oxygen
in steroid synthesis, pregnanalone is converted to
progesterone
conversion of pregnenolone to progesterone is catalysed bv
3B-OH
delta 5,4 isomerase
3B-OH and delta 5,4 isomerase catalyses the conversion of
pregnenolone to progesterone
cytochrome P450 catalyses the conversion of
cholesterol to pregnenolone
describe aldosterone synthesis from progesterone
progesterone –> 11-deoxycorticosterone (21-OH)
11-deoxycorticosterone –> corticosterone (11B-OH)
corticosterone –> aldosterone (18-OH, aldosterone synthase)
describe cortisol synthesis from progesterone
progesterone –> 17 hydroxyprogesterone (alpha 17-OH)
17 hydroxyprogesterone –> 11-deoxycortisol (21-OH)
11-deoxycortisol –> cortisol (11B-OH)
which hormones are used in aldosterone synthesis
21-OH
11B-OH
18-OH, aldosterone synthase
which hormones are used in cortisol synthesis
alpha 17-OH
21-OH
11B-OH
how does hypersecretion of mineralocorticoids affect electrolytes
increases Na in ECF
K depletion
–> hypokalemia and hypertension
mineralocorticoids are released in response to
decreased ECF volume
high K+ concentration
the secretion of mineralocorticoids stimulate the transcription of the Na/K pump by
increasing numbers of sodium pumps on the basolateral membrane of epithelial cells
** facilitates uptake of sodium and water from the tubular lumen
Na+ is reabsorbed in the kidney at the expense of K+ and H+. how does this affect ECF volume and electrolyte concentration
increase in ECF volume (dec BP)
decreased K+
INCREASED Na+
what parts of the nephron does aldosterone act
DCT
collecting ducts
aldosterone is secreted by activation of
RAAS
RAAS activation promotes secretion of
aldosterone
what is the main function of glucocorticoids
inhibit anabolism and stimulate catabolism
how do glucocorticoids inhibit anabolism and stimulate catabolism
reverses insulin functions
breakdown of muscle and aa uptake into liver for gluconeogenesis and lipolysis of adipose tissue
what is congenital adrenal hyperplasia (CAH)
autosomal recessive disorders of cortisol biosynthesis
CAH is caused by deficiency in which hormones
3B-OH
17 alpha-OH
21 alpha-OH
11B-OH
explain the effect of a deficiency of 3B-OH
no conversion of pregnenolone to progesterone and hence the pathway to all steroid hormones are affected –> salt excretion in urine and female-like genitalia
explain the effect of a deficiency of 17 alpha-OH
no conversion of progesterone to 17-hydroxyprogesterone
no androgens or cortisol can be produced but there will be high amounts of aldosterone secretion –> increased fluid retention –> hypertension and hypokalemia
female-like genitalia
explain the effect of a deficiency of 21 alpha-OH
no conversion of progesterone to 11-deoxycorticosterone and 11-deoxycortisol
no mineralocorticoids and no glucocorticoids but there is an increase in androgens –> masculinization of external genitalia in females and early sterilization in men
explain the effect of a deficiency of 11B-OH
no conversion of 11-deoxycorticosterone to corticosterone and 11-deoxycortisol to cortisol
no mineralocorticoids and no glucocorticoids but there is an increase in androgens –> masculinization of external genitalia in females and early sterilization in men
increased production of deoxycorticosterone –> fluid retention (hypertension)
a protein shortage leads to
muscle wasting
poor healing
weakened skeleton
effects of an increase and a decrease of aldosterone
i - hypokalemia; hypertension
d - hyperkalemia; salty urine; decreased BP and volume
effects of an increase and a decrease of cortisol
i - adrenal diabetes; fat digestion; decrease in protein
d - hypoglycemia, increased ACTH, dark skin
effects of an increase and a decrease of androgens
i - male-like genitalia
d - female like genitalia
In CAH, a deficiency in which enzymes cause female-like genitalia
deficiency of 3B-OH
deficiency of 17 alpha-OH
In CAH, a deficiency in which enzymes cause masculinization
deficiency of 11B-OH
deficiency of 21 alpha-OH
In CAH, a deficiency in which enzymes cause hypertension
deficiency of 11B-OH
deficiency of 17 alpha-OH
what is the metabolic function of glucocorticoids
increases glucose concentration at the expense of proteins and lipids
- catabolism
what is the permissive function of glucocorticoids
enhances glucagon and catecholamines
what is the immune function of glucocorticoids
anti-inflammatory, decreases stress, and boosts immune response following tissue injury
- important of transplants
what are the factors which control glucocorticoid secretions (3)
- CRH –> ACTH from corticotropin –> zona fasciculata –> cortisol –> CRH and ACTH (by negative feedback)
- diurnal rhythm which acts on the hypothalamus to vary CRH secretion
- highest in morning, lowest at night - dramatic increases in stress increases CRH release
what is cushing’s syndrome
cortisol hypersecretion
adrenal diabetes is caused by
excessive glucose (hyperglycemia)
clinical features of cushing’s syndrome
extra glucose deposited as fat in face, abdomen and shoulder but thin otherwise
what is the significance of DHEA in males and in females
males - overpowered by testosterone
female - governs androgen-dependent processes (pubic hair, growth spurts, sex drive)
in both sexes, the zona reticularis produces
estrogens
androgens
what controls secretions of the adrenal cortex
ACTH
DHEA inhibits
GRH
the inhibition of GRH by DHEA inhibits
FSH and LH
do adrenal hormones feedback to the axis?
NOPE
hypersecretion of androgens may be caused by
tumour or defect in part of the cortisol pathway.
what is the effect of hypersecretion of androgens in newborn females
male type external genitalia
what is the effect of hypersecretion of androgens in adult females
secondary male characteristics
what is the effect of hypersecretion of androgens in prepubescent boys
early puberty but no sperm production
what is the effect of hypersecretion of androgens in adult males
overpowered by testosterone
If one adrenal gland is non-functional, will there be renal insufficiency? why?
nope
the second one can take over
What is Addison’s disease?
Primary adrenocortical insufficiency where all layers of the adrenal cortex are undersecreting due to an autoimmune disease that destroys cells of the adrenal cortex
There is a decrease in aldosterone and the cortisol
Explain the resultant aldosterone deficiency of Addison’s disease
K retention –> hyperkalaemia –> disturbs cardiac rhythm (smooth muscle contraction)
Na depletion –> excessive urinary loss of sodium –> salty urine
Reduced ECF volume –> reduce in pressure –> hypotension, shock
Explain the resultant cortisol deficiency of Addison’s disease
Poor response to stress
decrease in gluconeogenesis
hyperglycaemia
no ACTH negative feedback therefore increased ACTH release and darkening of skin
What is a secondary adrenocortical insufficiency?
Pituitary or hypothalamic abnormality only cortisol is affected.
What is hormones or affected by a primary adrenocortical insufficiency?
Aldosterone and cortisol
What is hormones or affected by a secondary adrenocortical insufficiency?
Cortisol only
What are chromaffin cells and where are they located?§
Modified sympathetic neurons which are part of the adrenal medulla (modified part of SNS)
What do chromaffin cells produce and how much (%)?
Adrenaline 80% and noradrenaline 20%
Do the axonal fibres of chromaffin cells terminate at the effector organ?
nope
the axonal fibres of chromaffin cells do not terminate at the effector organ. Release of Catecholamines is stimulated by….
Released directly into circulation upon stimulation by preganglionic fibres
Secretions of chemicals by preganglionic fibre is by the __NS
ANS
Adrenaline is produced exclusively by the
Adrenal Medulla
Noradrenaline is produced in far greater quantities by
SNS postganglionic fibers
What is the function of catecholamines?
Involved in the flight or fight response
Effects of catecholamines on heart, GI system and skeletal muscle
Increases stroke volume, heart rate, blood pressure and shifting blood to heart and skeletal muscles (vasodilation) and includes respiration
reduces digestive activity
inhibits insulin and stimulates glucagon secretion
Catecholamines inhibit
Insulin
Catecholamines stimulate
Glucagon
Secretions of the adrenal Medulla are controlled by
Sympathetic input into gland
Now you have to do REB endocrine 2
SHIT!
