Endocrine system Flashcards
What happens in the absorptive state?
- Nutrients enter bloodstream from GI tract
- Nutrients support energy requirements of the body
- Excess nutrients stored
What happens in post-absorptive state?
- No nutrients entering blood from GI
- Switch to net catabolism of stores - breakdown of glycogen, fat, protein
- Aims to maintain glucose levels in the absence of absorption from the GI tract (brain normally uses glucose for energy.
How is glucose stored in the body?
- Stored as glycogen in liver, skeletal muscle, can be stored as triglycerides in adipose tissue
Where does gluconeogenesis?
Liver
What type of nutrition is used during the post-absorptive phase?
fatty acids
Which hormone is essential for regulating glucose?
Insulin - normal glucose level in blood is around 5mM
What do alpha and beta islet cells form in the pancreas?
Alpha cells - make glucagon
Beta cells - make insulin
What type of hormones are insulin and glucagon?
Peptide hormones
What happens with the liver when insulin is released in the absorptive state?
- Increased glucose uptake
- Increased glycolysis
- Increased glycogen synthesis
- Inhibited gluconeogenesis
- Inhibition of glycogen breakdown
What happens with the skeletal muscle when insulin is released in the absorptive state?
- Increased glucose uptake
- Increased glycolysis
- Increased glycogen synthesis
- Inhibition of glycogen breakdown
What happens with adipose tissue?
- Increased glucose uptake
- Increased glycolysis
- Increased glycogen synthesis
How does glucose regulate insulin release from pancreatic beta cells?
- Initially the ATP-sensitive Potassium channel detect a rise in ATP levels, which causes the channel to close - this then causes membrane depolarisation and due to the outside being more positive than the inside, the calcium channel voltage gated channel opens, allowing calcium into the cells, and the increase in cytolsolic calcium levels promotes secretion of insulin via exocytosis of insulin granules
What type of hormone is Insulin?
Peptide hormone
What does insulin activate once it targets receptors?
Protein Kinase B
How does Protein Kinase B get activated by Insulin signalling?
Binding of insulin to the insulin receptor (IR) leads to receptor auto-phosphorylation
Phosphorylated residues on the IR act as binding sites for insulin receptor substrates (IRS) proteins, the Insulin receptor phosphorylates IRS proteins
Phosphpoinositide 3-kinase, binds to phosphorylated residues on IRS proteins, which converts PIP2 into PIP3.
Binding of PIP3 activates PDK1, which phosphorylates and activates protein Kinase B
Activated PKB mediates many of the intracellular effects of insulin.
What are the main effects of insulin by target cells?
- Increased glucose uptake
- Increased glycolysis
- Increased glycogen synthesis
- Inhibited gluconeogenesis
- Inhibition of glycogen breakdown
What does insulin do to adipocytes and skeletal muscle?
Stimulates glucose uptake into skeletal muscle and adipocytes,
Does this by increasing amount of specialised GLUT-4 transporters there are at the cell surface
PKB stimulates movement of GLUT4 vesicles to fuse with membrane, and when they do, they get glucose transporting via the membrane
How does GSK affect glycogen synthase?
glycogen synthase, in its active form, is responsible for glycogen synthesis.
GSK phosphoryates and inactivates Glycogen synthase.
Protein Kinase B acts on GSK and phosphorylates it, leading to increased active form of Glycogen synthase.
How does PKB activation by insulin lead to an increase in glycogen synthesis?
Insulin signalling causes activation of PKB
PKB phosphorylates and inactivates GSK
Leads to higher amount of activated form of glycogen synthase
Increased glycogen synthase activity increases glycogen synthesis.
What transcription factor regulates gluconeogenesis?
Fox01 - it is synthesised in the cytosol but moves to the nucleus to perform this function
PKB phosphorylates FOX01, which prevents it from entering the nucleus, turning of expression of gluconeogenic genes.
What is the primary cause of metabolic changes in the post-absorptive state?
Lack of insulin
Which hormone acts to increase glucose levels
Glucagon, released from pancreas when glucose levels fall.
Glucagon, upon binding to its receptor, causes…
elevation in cAMP levels, and activation of protein kinase A
PKA then phosphorylates PK, increasing its activity. PK acts on glycogen phosphorylase, and the phosphorylation of glycogen phosphorylase causes an increase in Glycogen breakdown.
PKA phosphorylates glycogen synthase, decreasing its activity,
How does GLP 1 affect insulin and glucagon?
GLP-1 is produced in response to presence of nutrients. It increases glucose-stimulated insulin release and suppresses glucagon secretion.
Calcium is essential for many different physiological processes
Such as:
Excitation-contraction coupling
Stimulus-secretion coupling
Blood coagulation
And structural component in bone (99% of total body calcium is in the bone)
Phosphate is part of many different components such as
Phospholipids
DNA
ATP
Calcium, and phosphate levels are under hormonal control
By hormones such as PTH and 1,25 dihydroxyvitamin D
Calcitonin?
PTH is a….
peptide hormone, secreted by chief cells of the parathyroid gland in response to low calcium levels in plasma
PTH release is regulated by…
Calcium binds to Calcium-sensing receptor, leads to activation of a signalling pathway and a generation of arachidonic acid (AA). Arachidonic acid inhibits secretion of PTH.
Reduced calcium levels switches off this signalling pathway and allows PTH secretion.
PTH acts on…
Cell surface receptors such as PTHR1 - with the main targets being bone and kidney cells
Effects of PTH on calcium and phosphate
Bone - stimulates calcium and phosphate resorption by indirectly stimulating osteoclast activity
Kidney - enhances reabsorption of Calcium but decreases phosphate reabsorption (thereby increasing phosphate excretion)
Increased absorption - indirect and due to increased synthesis of 1,25 dihydroxyvitamin D
Bones is a connective tissue containing several cell types surrounded by
a protein matrix (called osteoid), mainly containing collagen.
Organ matrix is mineralised by hydroxyapatite, a calcium-phosphate-hydroxide salt.
Osteoclasts and osteoblasts regulate…
bone resorption and bone formation
Osteoblasts mediate
bone formation - by secreting collagen and other proteins such as osteocalcin and osteopontin (collectively called osteoid)
Calcium and phosphate become associated with this new bone matrix - process is called mineralisation.
Osteoblasts become osteocytes upon being embedded in the bone matrix - they can also be removed by apoptosis or become inactive bone-lining cells.
Osteoclasts mediate
bone resorption - they attach tightly to the surface of bone, secrete proteases and hydrogen ions.
H+ ions dissolve the hydroxyapatite crystals and expose the organic matrix, allowing degredation of collagen by proteases (e.g. collagenases)
This results in release of Calcium and phosphate from bone.
How does PTH stimulate bone resorption
PTH does not directly act on osteoclasts as they lack a PTH receptor.
PTH binds to osteoblasts, leading to osteoclastogenesis from osteoblast precursor cells
PTH achieves this by enhanciing expression of RANK ligand and inhibiting expression of osteoprotegrin, which is a decoy receptor for RANKL
Interaction of RANK with RANKL mediates interaction of osteoblasts with osteoclast precursors.
RANK/RANKL interaction is blocked by osteoprotegerin, which binds to RANKL
This leads to activation of signalling pathways that promote differentiation of the precursor cells into mature osteoclasts, which mediates bone resorption.
Bone resorption causes the release of both calcium and phosphate ions from the bone.
When osteoblasts and osteoclast precursors bind together via RANK/RANKL, this leads to…
activation of signalling pathways that promote differentiation of the precursor cells into mature osteoclasts - which mediates bone resorption
How does PTH effect reabsorption of calcium and phosphate in the kidneys?
Calcium reabsorption increases due to PTH stimulation of Ca2+ transporter expression and activity
Phosphate reabsoption decreases due to PTH stimulated internalisation and lysosomal degredation of PO4^3- transporter.
Enhanced excretion of phosphate is important to prevent plasma level of this ion rising as a result of increased resorption from bone and increased absorption from intestine.
How does Vitamin D get synthesised and function?
1,25-dihydroxyvitamin D is…
A steroid hormone - receptor is inside cell - binding to receptor leads to gene expression changes.
What effects does 1,25 dihydroxyvitamin D have?
It affects the intestines as it increases both Calcium absorption and Phosphate absorption - this occurs due to increased expression of calcium and phosphate transport proteins
It also increases reabsorption of calcium by the kidneys due increased expression of transporter protein
1,25 dihydroxyvitamin D protects bone from the actions of PTH by increasing Ca2+ uptake from GI tract, and therefore reducing PTH secretion.
How does 1,25 hydroxyvitamin D regulate Ca2+ absorption?
Enter cells
Activates receptor in the nucleus
Increased transcription/expression of Ca2+ transporter proteins
Leads to increased absorption of Ca2+
Similar manner to how calcium transporters are increased in the kidney.
How much vitamin D does babies upto 1 year old need?
8.5 to 10 micrograms a day.
How much vitamin D do 1year+ and adults require?
10 microgram a day - including pregnant and breastfeeding woman.
Effects of taking too much vitamin D?
Over a long period of time, it can cause hypercalcaemia, which can weaken bones and damage kidneys and heart.
Supplements, when taken with correct dosage, should not cause hypercalcaemia
Not possible to overdose on Vitamin D due to exposure to sunlight.
Calcitonin is responsible for?
Lowering blood calcium and phosphate levels - it is secreted by c-cells of the thyroid gland in response to an elevation in plasma Ca2+ levels
Calcitonin receptor is a GPCR - two main sites of action are osteoclasts in bone and kidney cells.
Calcitonin inhibits…
activity and differentiation of osteoclasts - thus inhibits resorption and promotes deposition
Calcitonin however plays little role in normal regulation of calcium and phosphate balance in humans
May play a role in maintaining skeletal integrity when there is high calcium demand e.g. during pregnancy/ breatfeeding
Both PTH and calcitonin are controlled by…
negative feedback
People at risk of Vitamin D deficiency include…
- Those that don’t go outdoors often
- Those that wear clothes that cover most of skin when outdoors
- Those with darker skin
- Women who are pregnant or breastfeeding - which may also affect bone health of developing baby.
What do cells in the thyroid gland do?
C-cells - secrete calcitonin
Follicular cells secrete thyroid hormone
Within the follicular cells there is colloid which is a glycoprotein.
Which 2 hormones does the thyroid gland produce?
T4 and T3
Difference between T3 and T4?
T4 has an extra iodine on the aromatic ring beside the hydroxyl group
Which element is essential for the synthesis of T3 and T4?
Iodine - this must be taken in to maintain thyroid hormone synthesis - seafish, shellfish, cereals, grains
Explain how T3/T4 synthesis occurs?
From the blood, iodine is carried into thyroid follicular cells via Na/I symporters, which is then able to reach the follicular colloid. The Follicular cells produce thyroglobulin, and is secreted via vesicles, from the endoplasmic reticulum, to the colloid via exocytosis.
Iodine is then oxidised and is then able to iodinate the tyrosine residues via iodination and after the conjugation of adjacent tyrosyl residues to form complete forms of T3 and T4 molecules, the final product is released back to the follicular cells via endocytosis and via proteolysis, the T3 and T4 is broken down and released into the blood stream via transporter proteins.
What is the difference in concentration of the iodine, both in plasma and the follicular cells?
Iodide is 20-50x concentrated in follicular cells than in plasma.
The Na+/I- symporter (co-transporter) transports…
2 sodium ions for every iodide ion.
The Na+ electrochemical gradient provides the energy for secondary active transport of iodide.
Thyroglobulin is a…
Glycoprotein - synthesised by follicular cells and released into the colloid by exocytosis.
How do T3 and T4 get liberated?
The endosomes fuse with lysosomes, causing the thyroglobulin to get degraded, liberating T3 and T4.
Synthesis of T3 and T4 are under control of…
Hypothalamus and Anterior pituitary
What does TSH do as part of the thyroid hormone-release process?
TSH stimulates endocytosis of thyroglobulin into follicular cells and release of thyroid hormone into the bloodstream.
TSH stimulates the synthesis of thyroglobulin and Na/I co-transporter.
Negative feedback is exerted by T3/T4 on…
Both the anterior pituitary and hypothalamus.
How do T3 and T4 travel in the blood?
T3 and T4 have poor solubility in water.
They are associated with specific proteins in blood:
- thyroid hormone-binding globulin
- transthyretin
-albumin
Which hormone is more active - T4 or T3?
Although 10x more T4 is secreted than T3, T3 is more active than T4.
Monodeiodination in target cells can convert much of the secreted T4 to T3, which is an important mechanism for regulating cell sensitivity to thyroid hormone.
Which enzyme regulates the activity of thyroid hormone?
Iodothyronine deiodinases types I, II, and III (D1, D2 and D3, respectively).
Expression of these enzymes affects the response to cells to thyroid hormone by regulating conversion of T4 to either active or inactive T3.
Does thyroid hormone require transporters to enter cells?
Yes, although the hormone activates nuclear receptors and is hydrophobic, it requires transporter proteins to cross plasma membrane.
Hormone acts on Nuclear TR, a hormone-sensitive transcription factor.
What are the metabolic effects of thyroid hormone?
-Increased BMR
-Increased oxygen consumption
-Increased thermogenesis
What are the cardiovascular effects of thyroid hormone?
-Increased cardiac output
-Increased heart rate and stroke volume
What are the neurological effects of thyroid hormone?
-Enhances wakefulness
-Enhances memory
-Enhances alertness
-Enhances reflexes
How does thyroid hormone affect growth and development?
- It is essential for fetal neural and bone development
-Essential for normal bone growth after birth
-Essential for normal tooth development
Hyperthyroidism causes…
increased energy expenditure, shown by weight loss, high heart rate, and blood pressure
Hypothyroidism causes..
reduced energy expenditure and weight gain, lethargy and weakness.
Congenital disorders are…
Present at birth.
Symptoms of congenital hypothyroidism are:
-Jaundice, low body temp, poor muscle tone, excessive sleeping
This can lead to reduced growth and intellectual dysfunction.
For congenital hypothyroidism, where can genetic defects be in:
Thyroglobulin gene TG
gene encoding sodium-iodide symporter (SLCA5)
Gene encoding TSH (TSHB)
Gene encoding TSH receptor (TSHR)
Treatment for congenital hypothyroidism is:
Thyroxine T4, orally and daily.
How are newborns screened for Congenital hypothyroidism:
Blood spot procedure, known as ‘heel prick’ where blood is taken and measured for T4 and TSH
What is allan-herndon-dudley syndrome?
It is a very rare disorder caused by loss-of-function mutation in the MCT8 gene (X-linked)
Symptoms include:
-severe cognitive deficiency
-most affected males never walk
-most never speak
Potential method of treating Allan-Herndon-Dudley-syndrome?
-Diiodothypropionic acid
-Tested in 4 children - some improvement but not neurological
Possible to treat during pregnancy?
What is isolated growth hormone deficiency?
Autosomal recessive, caused by shortage or absence of growth hormone; varies in severity
Most congenital cases are idiopathic, but mutations have been identified in:
GH1 gene encoding growth hormone
GHRHR gene encoding growth releasing hormone receptor
GH deficiency does not have major effect on prenatal growth
Impaired length growth noticed from few months of age, and defects in bone maturation and delayed puberty.
Treatment for isolated growth hormone deficiency?
Can reach normal height if they are treated early
Involves daily injections of GH
What does the adrenal medulla secrete?
Amine hormones such as adrenaline and noradrenaline
What does the adrenal cortex secrete?
Steroid hormones such as aldosterone (mineralcorticoids)
Cortisol and adrenal androgens (glucocorticoids)
Adrenal androgens become detectable from:
Around 6 years of age
Adrenal androgens such as DHEAS are converted to….
More potent androgens such as testosterone and dihydrotestosterone, or to estradiol
In males, peripheral conversion of adrenal androgens…
is less common than the synthesis of active androgens by testes
In females, the adrenal glands contribute about…
50% of the active androgens
Congenital Adrenal Hyperplasia is…
an autosomal recessive disorder caused by a deficiency in enzymes needed to make cortisol and aldosterone
Body produces more androgens as a result
As a result of no feedback inhibition, ACTH levels rise.
Increased ACTH leads to build up of cortisol precursors and enhanced production of androgens. Over-stimulation leads to overgrowth of adrenal gland (hyperplasia).
Which mutation is responsible for most cases of Congenital adrenal hyperplasia?
21-hydroxylase
Mutation prevents conversion of progesterone to deoxycorticosterone and also prevents 17-hydroxyprogesterone being converted to 11-deoxycortisol.
Various different mutations in the DNA sequence of this enzyme have been identified, many of which leave residual activity.
8% of patients have 11B-hydroxylase deficiency.
What are the 3 phenotypes of 21-hydroxylase deficiency?
- Classical salt wasting
-usually diagnosed around 0-6months - Classical simple virilising
Females tend to get diagnosed by 2, males tend to get diagnosed between 2-4. - Non-classical. diagnosed anywhere between childhood and adulthood.
Treatments of Congenital adrenal hyperplasia
Corticosteroids - regulate blood glucose
Mineralcorticoids - regulate salt concentration in blood
Surgery to correct abnormal female genitalia
- reduction clitroplasty
-construction of vaginal opening
