Basic Science Flashcards
Pancreatic islets are the endocrine portion of the pancreas and contain 4 types of cell which are?
Beta cells
Alpha cells
Delta cells
PP cells
Describe the role of delta and PP cells?
They help with modulation and secretion. Delta cells secrete somatostatin and PP cells secrete pancreatic polypeptide
Describe synthesis and structure of insulin?
Insulin is synthesised in the rER of Beta cells as a large single chain preproinsulin that is then cleaved to form insulin
Insulin contains two polypeptide chains linked by disulphide bonds
Connecting (C) peptide a by product of cleavage has no known physiologic function
Describe connecting peptide C?
Byproduct of cleavage of preproinsulin and has no physiologic function
Where is insulin synthesised?
rough endoplasmic reticulum of beta cells
Glucose enters Beta cells through the __1___ glucose transporter and is phosphorylated by ____2_____
1) GLUT 2
2) glucokinase
Define and describe KM of an enzyme
the concentration of substrate which permits the enzyme to achieve half Vmax. An enzyme with a high Km has a low affinity for its substrate, and requires a greater concentration of substrate to achieve Vmax.
Glucokinase’s KM for glucose lies in the ________ range of concentrations so a change of glucose concentration leads to a dramatic change in activity of glucokinase
physiological
Beta cells should only secrete insulin in response to blood glucose rising above …
5 mM
Describe normal secretion of insulin
Glucose enters beta cells through GLUT 2 and is phosphorylated by glucokinase, increased glucose metabolism increases intracellular ATP concentration, ATP inhibits KATP channel which leads to depolarisation of cell membrane resulting in opening of voltage gated Ca channels. An increase in Ca2 concentration leads to fusion of secretory vesicles with the cell membrane and release of insulin.
Release of insulin is _1____ 5% of granules are ____2___ for release and rest ___3____
1) biphasic
2) immediately available for release
3) reverse pool must undergo preparatory reactions to become mobilised and available for release
Those with type 2 diabetes will have a flattened phase1 as they are
always releasing insulin
Describe Glucokinase vs Hexokinase
Hexokinase is found in all tissues of body where cellular metabolism occurs except the liver and pancreatic beta cells. It has high affinity for glucose so when supply is low the reaction can still occur but Vmax is low so isn’t ideal for rapid generation of energy from glucose
Glucokinase is only present in the liver and pancreatic beta cells. The affinity for glucose is lower (higher KM) but has a higher Vmax so rapid conversion of glucose to energy. Useful following a big meal.
KATP channels consists of 2 proteins: ____1_____
___2___ are required for a functional channel
Intracellular ATP inhibits KATP which ____3______
KATP is stimulated by diazoxide which ____4____
1) an inward rectifier subunit Kir6 and a sulphonylurea receptor SUR1
2) both
3) causes insulin release
4) prevents insulin release
What is KATP stimulated by?
Diazoxide
Is insulin an anabolic or catabolic hormone? What does this mean?
Insulin is an anabolic hormone: causes cellular growth through activating anabolic pathways
Name 7 things insulin turns on
1) amino acid uptake in muscle
2) DNA synthesis
3) Protein synthesis
4) Growth responses
5) glucose uptake in muscle and adipose tissue
6) glycogen synthesis in the liver and muscle
7) Lipogenesis in adipose tissue and liver
Name 2 things insulin turns off
Lipolysis and gluconeogenesis in the liver
Describe how insulin acts?
Insulin release is mainly driven by rise in blood glucose levels after a meal. Major action is to stimulate glucose uptake with subsequent manufacture of glycogen and triglycerides by adipose, muscle and liver cells.
Its effects are mediated by a receptor tyrosine kinase. This activates an intracellular pathway that results in translocation of glucose transporter GLUT-4 to plasma membrane of affected cell to facilitate the entry of glucose.
Describe tyrosine kinase
Enzyme that can transfer phosphate from ATP to a protein in a cell.
Of the types of receptors which has the fastest response?
Ligand gated ion channels
Describe the response time of ligand gated ion channels?
Response at cellular level in ms - really fast!
Describe how ligand gated ion channels work?
Hormone binds and initiates chemical change within the receptor altering the structure which allows ion channel to open up.
What is an example of a ligand gated ion channel?
Nicotinic receptors (fast acting cholinoreceptors)
2 examples of GCPRs?
Muscarinic receptors (parasympathetic) Adrenoreceptors (Sympathetic)
G protein coupled receptors consist of __1___ transmembrane alpha helices with an extracellular __2___ and intracellular ___3____
G proteins have an _____4______
1) seven
2) NH2
3) COOH
4) alpha subunit attached to GDP, a beta gamma subunit/ dimer
Describe how GCPRs work?
Agonist e.g. adrenaline activates receptor by causing conformational change so G protein attaches. GDP dissociates from alpha subunit and GTP binds. GTP essentially charges up the alpha subunit to prepare to act on enzyme nearby. Alpha subunit combines with and modifies activity of receptor. The signal is turned off when GTP is hydrolysed and everything returns to initial conformation.
Beta 2 adrenoreceptors are coupled with ___1____
Alpha 2 adrenoreceptors are coupled with __2____
Alpha 1 adrenoreceptors are coupled with __3___
1) Gs
2) Gi
3) Gq
Describe the response time of GCPRs?
Response occurs in seconds- SLOWER than ligand gated
Describe specifically GCPR action in relation to beta 2 receptors?
adenyl cyclase activation > cAMP > PKA > Inhibition of MLCK (enzyme that aids contractility of smooth muscle) > BRONCHODILATION
Describe specifically GCPR action in relation to alpha 2 receptors?
adenyl cyclase is inhibited and beta gamma dimer activates K+ channel > hyperpolarisation > relaxation of the GI tract
Describe specifically GCPR action in relation to alpha 1 receptors?
activation of phospholipase > increased Ca2+ > vasoconstriction
Which receptor allows divergent cellular responses?
Kinase linked receptors/ receptor tyrosine kinase
Describe the action of kinase linked receptors?
The receptor has intra and extracellular components. Agonist will bind and then get phosphorylation of intracellular tyrosine residues. Relay proteins will attach to intracellular residues, different relay proteins for different residues, these will activate different proteins etc. so there is divergent cellular responses.
Describe the response time of kinase linked receptors?
Complex pathway so takes hours
Define autocrine regulation
Chemicals released from the cells bind to receptors on or in the cell that is releasing them
Define paracrine regulation
Chemicals released from the cells bind to adjacent cells
Define endocrine regulation
Chemicals released from the cells are transported via the circulatory system. Secretion into the blood stream means target cells may not be close by but physiological response can still be initiated
Define negative feedback
Primary control mechanism, this opposes change, too much hormone causes it to switch off. Resists physiological deflections away from the body’s set points.
Define positive feedback
Initial stimulus produces a response which exaggerates the change. Seldom encountered except clotting cascades and childbirth.
Define intrinsic regulation
Autocrine and Paracrine signalling
Define extrinsic regulation
Nervous system and endocrine
Describe nuclear receptors?
Steroid hormones use these. They pass through the membrane and bind to the receptor in the cytoplasm where they are shuttled into the nucleus. Activated hormone will bind to specific genes activating them leading to production of key proteins.
Describe the response time of nuclear receptors?
As involves transcription etc these have a longer duration of action- e.g. hours, days maybe even longer
Three structural classes of hormones?
Steroids
Peptides and proteins
Amines
Steroids are derived from…
lipids derived from cholesterol
Synthesis rate of steroid hormones controls amount as ________
once synthesised the hormones are secreted not stored
Steroid hormones are transported in the blood plasma by ___1____ they are biologically active when _____2____
1) carrier proteins
2) they are free/ unbound
Examples of steroid hormones?
Cortisol from adrenal cortex, testosterone, estradiol
Examples of amines?
Catecholamines e.g. adrenaline, dopamine (all produced by adrenal glands) also thryroid hormones are amines but they cross membrane so a bit weird
Amines are derived….
from single amino acid - mainly tyrosine
Amines usually bind to _______
membrane bound receptors that evoke cellular responses
Amines tend to be stored in ___________
vesicles in the cytoplasm until needed
Peptide and protein hormones are _____ and transported ______
hydrophilic and transported unbound or free in the blood plasma
Peptide and protein hormones are secreted by _______
pituitary, parathyroid, heart, stomach, liver and kidneys
Peptide and protein hormones are ___________
synthesised as precursor molecules and stored in secretory vesicles
What is the link between the endocrine and nervous system?
The hypothalamus
In _1__ week the thyroid is midline thickening a the back of ___2__ and stretches downwards. The point of origin persists as the ___3____. It migrates in front of the ___4____ and comes into close proximity with ____5____ Also comes into contact with cells from lower pharynx which will become future __6___ By end of 2nd month ___7____ Thyroglossal duct loses contact in all but __8___ By week 12 the thyroid is responsive to ______9_______ and can _____10_____
1) 4th
2) tongue
3) foramen caecum
4) larynx
5) parathyroid glands
6) c cells which produce calcitonin
7) have 2 lobes and isthmus
8) 15% of people which have a pyramidal lobe
9) TSH
10) concentrate iodine
What is the basic functional unit of the thyroid?
Follicles
Describe thyroid follicles?
Circular shaped lined with follicular cells with colloid with glycoprotein in the middle, c cells are at the side to produce calcitonin
Describe regulation of the thyroid
Thyroid is controlled by TSH from the anterior pituitary which in turn is regulated by TRH from the hypothalamus, T3 predominantly completes the negative feedback loop by suppressing the production of TSH and TRH
Describe six steps or thyroid hormone synthesis
1) Follicular cells exclusively produce thyroglobulin (a tyrosine filled protein)
2) From the blood stream the follicular cells actively transport iodide (I-) and concentrate it
3) As iodide moves across the membrane it is oxidised into iodine so the negative charge is removed
4) Iodine is then transported from follicular cells into colloid and so is thyroglobulin
5) Iodine then starts to attach tyrosine residues on thyroglobulin to form MIT and DIT. One iodine is MIT, two is DIT.
6) Coupling of MIT and DIT. MIT + DIT is T3 and DIT + DIT is T4.
What is the major biologically active thyroid hormone?
T3
Roughly 90% of thyroid hormone secreted is ….
T4
Thyroid hormone travels bound to serum proteins, what 3 and what proportion are they?
70% to thyroxine binding globulin (TBG)
20% to thyroxine binding pre albumin (TBPA)
5% to albumin
Explain if unbound or bound thyroxine enters cells and the clinical implications?
Only unbound hormone enters cells and this is a very small proportion of total concentration. Therefore metabolic state correlates more closely with free than with total concentration.
Describe 8 effects of thyroid hormone?
1) Increases metabolic uptake
2) Increases glucose uptake into cells
3) Increased glycogenolysis and gluconeogenesis
4) Decreased glycogenesis
5) Increased lipolysis and decreased lipogenesis
6) Increased breathing rate, HR, and force of contraction
7) Increased thermogenesis
8) Increased responsiveness of organs to adrenaline and noradrenaline.
What and where can T4 be broken down into active T3?
By D1 in the liver and kidneys
What are trophic hormones?
Hormones that stimulate tissues to secrete something
Most peripheral hormone systems are controlled by the….
hypothalamus and pituitary
Majority of anterior pituitary hormones are under __1___ control by hypothalamic releasing hormones the exception is __2__ which is under ____3_____
1) postive
2) prolactin
3) tonic inhibition by dopamine
PITUITARY GROWTH AXIS
Growth hormone is released into the blood stream by the _____1______ Growth hormone acts on many parts of the body to promote growth in children. In adults it doesn’t cause growth but helps ___2____ It is released in a number of controlled bursts controlled by ___3_____ GH stimulates release of ___4____ which is produced by the ____5___ When levels of GH and ILGF-1 are high this ______6________
1) Anterior pituitary gland
2) maintain normal body structure and metabolism including blood glucose levels
3) growth hormone releasing hormone from the hypothalamus and somatostatin which inhibits that release
4) Insulin like growth factor 1
5) liver and involved in growth
6) stops release of GHRH and stimulates somatostatin
PITUITARY THYROID AXIS
Thyroid stimulating hormone is released into the blood by the __1____ This is controlled by release of ___2____ from the hypothalamus. TSH binds to receptors on thyroid cells causing them to release __3___ which help regulate ___4___ by ___5_____ T4 is ____6___ so needs activated by the __7___ When levels of T3 and 4 increase _____8______
1) anterior pituitary gland
2) thyrotropin releasing hormone
3) T3 and T4
4) metabolic rate
5) By acting as transcription factors that switch genes on and off
6) inactive T3
7) liver
9) inhibits release of TRH and TSH
PITUITARY GONADAL AXIS
_____1____ hormone produced by the hypothalamus controls release of __________2_________ from the anterior pituitary gland. FSH and LH control levels of ____3_____ and are important in controlling the production of sperm in men and menstrual cycle in women. In adults levels of GnRH, LH and FSH levels are controlled by levels of _______4___________
1) Gonadotrophin releasing hormone
2) lutenising hormone and follicle stimulating hormone
3) hormones produced by the testes and ovaries (testosterone, oestradiol and progesterone)
4) testosterone and oestrogens
PROLACTIN AXIS
Prolactin is released by the ______1______ into bloodstream and promotes ____2_____ after birth but has many other functions. It is regulated by the hypothalamus which secretes ___3_____ which ___4___ prolactin production. Prolactin ___5____ the release of dopamine which creates a negative feedback loop
1) anterior pituitary gland
2) milk production
3) dopamine
4) inhibits
5) enhances
PITUITARY ADRENAL AXIS
Adrenocorticotrophic hormone is produced by __1_____ into blood stream and stimulates production of __2___ from _3____ It also increases chemical compounds that trigger __4___ ACTH release is controlled by ___5_____ hormone from the hypothalamus. When cortisol levels rise ____6____ is inhibited
1) anterior pituitary gland
2) cortisol
3) adrenal glands
4) an increase in other hormones such as adrenaline and noradrenaline
5) corticotrophin-releasing hormone
6) corticotrophin-releasing hormone
POSTERIOR PITUITARY AXIS ADH
ADH/ vasopressin is produced by the _____1_____ into the bloodstream. It helps control BP by acting on _____2_____ It helps control fluid volume by _____3_____ Higher levels of ADH also cause blood vessels to ___4___ Release is stimulated by ______5_______
1) posterior pituitary glands
2) kidneys and blood vessels
3) causing water in the kidneys to be reabsorbed concentrating the urine
4) constrict raising BP
5) decrease in blood volume or pressure which may occur during dehydration or haemorrhage or if increase in concentration of salt in the blood
POSTERIOR PITUITARY OXYTOCIN
Oxytocin is from ____1_____ into bloodstream Its two main actions are ___2_____ It is controlled by ___3____ feedback mechanism e.g. ____4____ These processes are self limiting ie. production of oxytocin stops when ___5_____
1) posterior pituitary
2) contraction of uterus during childbirth and lactation
3) positive
4) increasing frequency of contractions in childbirth
5) baby is delivered
What inhibits release growth hormone releasing hormone and is stimulated by high levels of growth hormone and ILGF-1?
Somatostatin
Explain how ADH works?
Posterior pituitary releases ADH, in loop of Henle Na and Cl are actively transported into IF creating concentration gradient, so when ADH recruits AQP2 it easily flows into IF.
Increased ADH= _________ urine = ______ osmolality
small volume of concentrated urine and high osmolality
Aldosterone causes sodium retention in exchange for _____
H+ or K+
Decreased sodium concentration caused by too little sodium will give what symptoms?
LOOK DEHYDRATED low pulse, dry mucous membranes, sunken eyeballs, decreased consciousness, decreased urine, decreased skin turgor
Decreased sodium concentration caused by too little sodium causes? How common?
Uncommon but fatal: sodium loss from adrenals gut or skin
Rare: too little sodium in diet
Treatment of Decreased sodium concentration caused by too little sodium?
Give sodium
Decreased Na conc cause by too much water symptoms…
not very noticeable
Decreased Na conc caused by too much water causes…
SIADH meaning decreased water excretion
Rare to be caused by excessive H2O intake
Decreased Na conc caused by too much water treatment?
Fluid restriction- remove water
Very low and very high sodium?
Very low= 120mmol/L
Very high= 160mmol/L
Too high Na conc caused by too much Na symptoms…
cough, PO, heart pumping less effectively, ascites, SOB, tired
Too high Na conc caused by too much Na causes…
Iv medication, (near drowning and malicious poisoning are rare)
Too high Na conc caused by too much Na treatment?
Remove sodium
Too high Na conc caused by too little water symptoms..
less noticeable
Causes of Too high Na conc caused by too little water? How common?
diabetes insipidus- not that common but can see
Decreased water intake in very old or young - extremely common
Treatment of Too high Na conc caused by too little water?
Give water as dextrose (if you gave pure water RBCs would burst)
