Endocrinology Flashcards
Define: Endocrine gland
Cells which secrete ‘messenger’ molecules directly into blood
Define: Endocrinology
Study of endocrine glands and their secretions
Define: Hormone
Bioactive ‘messenger’ molecule secreted by an endocrine gland into blood
Define: Endocrine
Relates to hormone’s action of target cells source
Define: Paracrine
Hormone acts within immediate area around source
Define: Autocrine
Hormone has effect on cell that secreted it
Define: Cryptocrine
Hormone can have an effect within its own cell of production
What is the difference between the endocrine and nervous system?
Endocrine= involves release of chemical hormone, effect on many targets, spread throughout body, will take place over long time
Nervous= involves release of chemical NT, effect restricted to target cells, within milliseconds
List examples of protein/polypeptide hormones by size
Complex polypeptides e.g. LH (200 AA)
Intermediate polypeptides e.g. insulin
Small peptides e.g. TRH (3 AA)
Dipeptides e.g. T4 (derived from 2 iodinated tyrosine residues)
Derived from single AA e.g. catecholamines
How are protein hormones synthesised?
In RER
AA sequence determined by specific mRNA synthesised in nucleus
Ribosomal synthesis of pre-prohormone (larger than active hormone)
What is a prohormone?
Precursor of a hormone
Shortened (processed by proteolytic enzymes) to become mature, active hormone
Where are protein hormones stored?
In secretory granules
For release in exocytosis
Describe ACTH production within a corticotroph cell
NUCLEUS
Specific mRNA synthesised from DNA within cell nucleus
CYTOPLASM
Translation of specific mRNA to prohormone POMC in RER
POMC -> Golgi apparatus for POMC processing
Mature ACTH stored in secretory granules within cytoplasm
What are steroid hormones derived from?
Cholesterol
What 2 groups are steroid hormones divided into?
Intact steroid nucleus (adrenal/gonadal steroids)
Broken steroid nucleus (Vit D and metabolites)
How are precursors of steroid hormones transported?
Passive diffusion across cell membrane from blood stream
How does the precursor molecule produce the steroid hormone?
Action of several enzymes
Describe Cortisol production in an adrenal cortical cell
LDL rich cholesterol transferred into cell by endocytosis (from blood capillary to cytoplasm)
Cholesterol splits from lipoprotein and is esterified and stored in cytoplasmic vacuoles
ACTH stimulation activates cholesterol esterase -> cholesterol release from cholesterol ester depots
StAR protein (steroidogenic acute regulatory protein) mediates transfer of cholesterol from outer to inner mitochondrial membrane
What is the difference between mature steroid hormone and mature protein hormone (regarding cell membrane crossing)?
Steroid hormone can freely cross cell membrane without being packed into secretory granules and actively exocytosed
Where are most hormones secreted?
Systemic circulation
EXCEPT hypothalamus releases into hypophyseal portal system (a rich network of blood vessels that ‘bathe’ the anterior pituitary)
What hormones are water soluble?
Protein/polypeptide (circulate freely within the bloodstream- QUICK, MINS)
What hormones are more insoluble?
Steroid and thyroid hormones (bound to plasma proteins or transport proteins- SLOWER)
How does the bound hormone remain in dynamic equilibrium with a small amount of free hormone?
The transport protein acts as a reservoir
Changes in plasma protein or free hormone are followed by adjustments of secretion rates of the hormone (so free hormone available to tissues remains constant)
How do free hormones function?
Biologically active
Buffer hormones and protect against rapid hormone concentration changes
What is albumin?
A general transport molecule (plasma protein)
Non-selectively transports a variety of low molecular weight hormones
What are TBG, CBG and SHBG?
TBG- thyroxine-binding globulin (Thyroid hormones)
CBG- corticosteroid-binding globulin (Cortisol)
SHBG- sex hormone-binding globulin (Testosterone/Oestradiol)
How is clearance rate (from circulation) affected by binding of proteins?
Greater binding capacity-> slower clearance rate of the hormone
If hormone levels fall, is the forward or backward reaction favoured?
Hormone + plasma protein Protein bound hormone
Back
Endocrine cell increases hormone synthesis and release
If plasma levels increase, is the forward or backward reaction favoured?
Hormone + plasma protein Protein bound hormone
Forward
Endocrine cell increases hormone synthesis and release
Biological response of a hormone target is determined by 3 main factors, these are…
Concentration of hormone in circulation
Concentration of number of receptors
Affinity of hormone-receptor interaction
What concentration of hormones are usually present in circulation?
Very low
10(-9) to 10(-12)M
So need high affinity and high specificity
What is the amount of hormone binding dependent on?
Number of specific receptors on target cell
Because binding of a hormone to receptor is a saturable process
How do peptide/protein and catecholamine hormones act?
Via receptors on cell surface
Binding-> activates effectors system-> IC signal and 2nd messengers
Changes membrane transport, DNA and RNA synthesis, protein synthesis and hormone release
Describe how ACTH acts on an adrenal cortical cell
ACTH binds to the GsPCR
Leads to dissociation of alpha subunit from by subunits
Activated adenylate cyclase (ATP->cAMP)
Need PKA to activate cholesterol esterase (provides free cholesterol from cholesterol esters)
Free cholesterol acted on by steroid synthetase-> StAR protein function (cholesterol from outer to inner mitochondrial membrane)
How do steroid hormones act?
Act via intra-nuclear receptors
Enter most cells by passive diffusion
Hormone binds to specific IC protein receptors within cytoplasm and nucleus
Steroid receptor complex binds to DNA binding sites and response elements (RE) to alter gene transcription and protein synthesis
Leads to stimulation of cell growth, differentiation and regulation of specific proteins
When receptor-hormone complex has interacted with the gene, re-establishment of the unoccupied receptor occurs with elimination of hormone from the cell
Describe how cortisol acts on its target cell
Free cortisol enters cell by passive diffusion
Binds to specific glucocorticoid receptors in cell cytoplasm
Hormone-receptor complex travels to nucleus and binds to DNA binding sites/RE
Leads to changes in transcription rates of specific genes and production of mRNA
Translation of MRNA to protein within endoplasmic reticulum
How is any individual hormone system controlled?
Negative and positive feedback (necessary for normal endocrine homeostasis)
Mostly negative closed loop feedback
E.g. hypothalamus and pituitary with target organs (thyroid, adrenals and gonads)
What is a closed loop feedback system?
Feedback of a substance regulated by its own production
Protect against excessive hormone action
Why is assessment of both stimulatory and peripheral hormones analysis necessary?
Feedback relationship
Need to assess endocrine status
What is another name for the pituitary gland?
Anterior lobe?
Posterior lobe?
Hypophysis
Anterior- adenohypophysis
Posterior- neurohypophysis
Where is the hypophysis?
Lies at base of brain in sella turcica directly under the hypothalamus
Where is the hypothalamus?
Around the 3rd ventricle in the brain
Anterior: optic chiasma lies at front of hypothalamus
Posterior: mammillary body at back of hypothalamus is important in the development of the NS
How does the pituitary gland develop?
Anterior lobe (adenohypophysis)- "grows up" and attach to the base of the brain Posterior lobe (neurohypophysis)- nervous tissue "grows down" and attaches to anterior lobe, consists mainly of nerve axons and nerve terminals
What is in the hypothalamo-adenohypophysial axis?
Hypothalamic nuclei Neurons to median eminence Neurosecretions Adenohypophysis Adenohypophysial hormones
SEE DIAGRAMS OF HYPOTHALAMIC NUCLEI/ MEDIAN EMINENCE
What happens in the hypothalamo-adenohypophysial axis to allow adenohypophysial hormons to be released?
Hypothalamic neurone from hypothalamic nucleus-> activation
- Hypothalamic neurosecretion released into hypothalamo-hypophysial portal system
- Hypothalamic neurosecretion acts on anterior pituitary target cells
- Release of adenohypophysial hormone into general circulation
What are the 6 chief adenohypophyseal hormones?
Somatotrophin (growth hormone)
Prolactin
Thyrotrophin (thyroid stimulating hormone TSH)
LF and FSH (luteinizing hormone, follicle stimulating hormone)
Corticotrophin (adrenocorticotrophic hormone, ACTH)
What hypothalamic hormones control the adenohypophyseal cells?
Somatotrophs produce somatotrophin
Lactotrophs produce prolactin
Thyrotrophs produce thyrotrophin (TSH)
Gonadotrophs produce LF and FSH
Corticotrophs produce corticotrophin (ACTH)
Where are adenohypophyseal hormones stored?
In secretory granules (released by exocytosis)
Give an example of an adenohypophyseal precursor pro-hormone
POMC (ProOpioMelanoCorticotrophin)
POMC-> Corticotrophin +Pro-yMSH + BLPH
Group adenohypophyseal hormones into proteins, glycoproteins and polypeptides
PROTEINS
- Somatotrophin (191 AA)
- Prolactin (199 AA)
GLYCOPROTEINS consisting of a and B sub-units (92AA alpha subunit common to all)
- Thyrotrophin (TSH) (B-subunit 110 AA)
- LH (B-subunit 115 AA)
- FSH (B-subunit 115 AA)
POLYPEPTIDE
- Corticotrophin (ACTH) (39AA)
How is the hypothalamus involved in adenohypophyseal hormones?
Hypothalamic hormones have a direct influence on the release of adenohypophyseal hormones
Which hypothalamic hormones affect which adenohypophyseal hormones?
-> STOMATOTROPHIN
Somatotrophin releasing hormone (SRH or GHRH)- STIM
Somatostatin (SS)- INHIB
-> PROLACTIN
Thyrotrophin releasing factor (TRH)- STIM
Dopamine (DA)- INHIB
-> THYROTROPHIN (TRH)
Thyrotrophin stimulating hormone (TSH)- STIM
-> FSH AND LH
Gonadotrophin releasing hormone (GnRH)- STIM
-> ACTH
Corticotrophin releasing hormone- STIM
*Vasopressin
What are the main target cells of the adenohypophyseal hormones?
Somatotrophin-> general body tissue, especially the liver
Prolactin-> breasts (lactating women)
Thyrotrophin-> thyroid
Gonadotrophins-> testes (men), ovaries (women)
Corticotrophin-> adrenal cortex
What are the principle physiological actions of ACTH?
Targets adrenals
Stimulates the adrenal gland to produce a hormone called cortisol
What are the principle physiological actions of TSH?
Targets thyroid
Stimulates the thyroid gland to secrete thyroxine
What are the principle physiological actions of LH and FSH?
Controls reproductive functioning and sexual characteristics
FEMALES
Stimulates ovaries to produce oestrogen and progesterone and stimulates ovulation
Stimulates final maturation of the oocyte
In follicular stage of menstrual cycle: stimulates production of androgens (androstenedione)
MALES
Stimulates testes to produce testosterone and sperm (spermatogenesis)
LH is also referred to as interstitial cell stimulating hormone (ICSH) in males
Describe the hypothalamo-adenohypophyseal-thyroidal axis?
Consider direct, indirect and short negative feedback loops
Hypothalamus secretes TRH-> stimulates TSH in adenohypophysis-> stimulates thyroid to release T3 (triiodothyronine) or T4 (thyroxine)
DIRECT NEGATIVE FEEDBACK
High T3 or T4-> stimulates own inhibition (inhibits secretion of TSH in adenohypophysis)
INDIRECT NEGATIVE FEEDBACK
High T3 or T4-> stimulates own inhibition (inhibits secretion of TRH in hypothalamus-> less tSH in adenohypophysis)
AUTO (SHORT-LOOP) NEGATIVE FEEDBACK
TSH inhibits production of TRH in hypothalamus
(Adenhypophysial hormones influence their own release by influencing secretion of release-stimulating or release-inhibiting hypothalamic hormones)
Explain the growth promoting and metabolic actions of somatotrophin (growth hormone)
Direct and indirect (via IGFI) effects
Stimulation of AA transport into cells (e.g. muscle)
Stimulation of protein synthesis (genomic)
Increased cartilaginous growth
Stimulation of lipid metabolism leading to increased fatty acid production
Increased blood glucose concentration [decreased glucose utilization (due to increased insulin resistance) and increased gluconeogenesis]
Outline the direct and indirect pathways of somatotrophin leading to growth and development
DIRECT
Adenohypophysis-> somatotrophin-> body tissues (metabolic actions)-> growth and development
INDIRECT
Adenohypophysis-> somatotrophin-> liver-> somatotmedins (IGF I and IGF II)-> body tissues-> growth and development
What stimulates somatotrophin production?
Amino acids Fasting (hypoglycaemia) Exercise Oestrogens Sleep (stages III and IV) Stress
What negative feedback takes places in somatotrophin release?
Somatotrophin and somatomedin release in itself inhibits further somatotrophin production via negative feedback loops
Somatostatin (SS) -> inhibits release
What positive feedback takes places in somatotrophin release?
Somatotrophin releasing hormone (SRH/GHRH)-> stimulates release
List the effects of prolactin
Breast= lactogenesis in post-partum women (secretes large amounts during pregnancy and breast feeding) Pituitary= decreased LH release Hypothalamus= decreased sexual behaviour Testes/ovaries= increased LH receptors Immune system= stimulates T cells
Steroidogenesis?
Renal Na/water reabsorption?
Outline how prolactin release is controlled
Neuroendocrine arc
- Suckling of breast (stimulus)
- Tactile receptors around nipple
- Afferent nerve pathway
- Higher centres
- Hypothalamus (TRH (+) and DA (-))
- Adenohypophysis
- Prolactin
- Milk production in post-partum breast
Neural afferent limb (1, 2, 3 4)
Endocrine efferent limb (5, 6, 7, 8)
Why is hyperprolactinaemia associated with a contraceptive effect?
Excessive prolactin production interferes with hypothalamo-pituitary-gonadal axis
Inhibits reproductive axis because of increased DA (inhibits PL due to short-loop fb)
Men become impotent, lose libido, and become infertile
Women develop amenorrhoea or oligomenorrhoea and may not ovulate
Why are growth charts more useful than signal measurements?
Important to take multiple height measurements over a period of time in order to establish a basis for comparison
A single height measurement is not sufficient
Growth chart must be specific to population individual belongs to
What are various causes of short stature?
Malnutrition
Genetic causes: e.g. Down syndrome, osteochondroplasia, Turner’s syndrome; PraderWilli syndrome
Low levels of somatotrophin (GH)
Low levels of SRH/GHRH
High levels of somatostatin (SS)
High levels of somatomedins (IGF1 and IGF2)
Somatotrophin resistance due to a lack of receptors or dysfunctional receptors
Hypothyroidism
Cushing syndrome: excess glucocorticosteroids
How can you test if the GH axis is functioning correctly?
GH released in large pulses during the day
Patient vigorously exercises (or fasts)
Blood sample before and after
Should see marked rise in hormone
Also, can give insulin-> reduce blood glucose-> patient should release GH
Blood sample before and after
What is the posterior pituitary?
Neurohypophysis
Outgrowth of the hypothalamus and is neural tissue
How are neurones that are associated with the neurohypophysis grouped together?
In the supraoptic and paraventricular nuclei in the hypothalamus
Where do unmyelinated axons of paraventricular and supraoptic nuclei pass through and end?
Pass through infundibulum
End within the posterior pituitary (close to capillaries)
Where do magnocellular neurones pass through and terminate? What are they?
Pass through the median eminence and terminate near capillaries of the neurohypophysis
They are neuroendocrine neurones whose cell bodies are mainly in the supraoptic nucleus and paraventricular nucleus of the hypothalamus.
Where do parvocellular neurones release their neurosecretions and send their axons? What are they?
Release their neurosecretions into the primary capillary plexus in the median eminence
Or send their axons to other parts of the brain
They are small neurones within paraventricular nucleus (PVN) of the hypothalamus.
Where do most posterior pituitary capillaries drain into?
The main bloodstream
Via jugular veins
Carries hormones to heart
What are supraoptic neurones and where do they travel from/through?
Leave hypothalamic supraoptic nuclei
Pass through median eminence
Terminate in neurohypophysis
Either vasopressinergic or oxytocinergic
(NB. Have herring bodies along axon)
What are paraventricular neurones and where do they travel from/through?
Originate in paraventricular nuclei
Some parvocellular neurones pass to other parts of the brain
Majority of neurones are magnocellular (pass to other parts of brain)
Some parvocellular (terminate in median eminence)
Either vasopressinergic or oxytocinergic
What are the 2 principal secretory produces of magnocellular neurones?
Vasopressin (ADH)
Oxytocin
Where are pro-hormones of neurohypophyseal hormones?
Synthesised as pro-hormones in the supraoptic and paraventricular nuclei
Then transported to posterior pituitary
How are pro-hormones converted to hormones?
Cleaved to form hormones and neurophysin proteins (released together)
What are the similarities and differences between the structure of arginine (vasopressin) and oxytocin
Both are nonapeptides (9 AAs) with a 6 AA ring (has 2 cysteines linked by disulphide bonds at positions 1 and 6)
Also have a 3 AA chain
They differ by two AAs
AVP= phenylaline at position 3, arginine at position 8
OXY= isoleucine at position 3, leucine at position 8
How are neurohypophyseal hormones synthesised, stored and released?
- Synthesis occurs in cell bodies of magnocellular neurons in supraoptic and paraventricular nuclei in the hypothalamus
- Initially synthesized as prohormones (pro-vasopressin and pro-oxytocin)
[Exons have vasopressin/ oxytocin sequences, then neurophysins, then glycopeptide (only AVP)] - Molecular complexes incorporated into granules which migrate down nerve axons as a result of axon transport
- During migration= pro-hormone cleaved by basic endopeptidases into the mature hormone and the associated neurophysin
- Granules collect at nerve terminals and in Herring bodies along nerve axons
- Nerve endings lie close to capillaries in posterior lobe of pituitary
- Release associated with APs at nerve endings which depolarise terminal membranes
- Granule contents released into bloodstream by exocytosis (neurophysins released with hormones, but not bound to each other)
What is found in Herring bodies?
Granules containing molecular complexes of pro-hormones
Describe pre-provasopressin-> prohormone-> hormone of vasopressin
Pre-> pro: glycosylation, disulphide bridging, folding
Pro-> hormone: cleavage and exocytosis
Vasopressin + neurophysin + glycopeptide
Describe pre-oxytocin-> prohormone-> hormone of oxytocin
Pre-> pro: glycosylation, disulphide bridging, folding
Pro-> hormone: cleavage and exocytosis
Oxytocin + neurophysin (diff from AVP)
*NB. no glycopeptide
What are the receptors for vasopressin and what IC pathways do they activate?
V1a (IP3 and DAG)
Linked via G proteins to PLC
Which acts on membrane phospholipids to produce inositol triphosphate IP3 (and diacyl glycerol, DAG)
IP3-> increase cytoplasmic [Ca2+] and other IC mediators (PKC)
Produce cellular response
V2 (cAMP)
Linked via G proteins to adenyl cyclase
Which acts on ATP to form cyclic AMP
Which activates PKA
Which in turn activates other IC mediators
Which produce cellular response (aquaporins, AQP2)
Where are vasopressin receptors found?
V1a
Arterial (vasoconstriction)
Hepatocytes (glycogenolysis)
CNS neurones (behaviour and other effects)
V1b (V3) Adenohypophyseal corticotrophs (corticotrophin production)
V2
Collecting duct cells (water reabsorption)
Probably other unidentified sites
Factor VII and von Willbrandt factor
What are the main physiological actions of vasopressin?
In principal cells (renal collecting duct)= stimulates water reabsorption and has antidiuretic effect
Vasoconstriction
Corticotrophin release (together with CRH)
CNS effects
Acting as NT (or hormone) e.g. on aspects of behaviour
Synthesis of blood clotting factors (VIII and Von Willbrandt)
Hepatic glycogenolysis
What are the main physiological actions of oxytocin?
Stimulates contraction of smooth muscle of myometrium during parturition
Stimulates contraction of myoepithelial cells surrounding ducts of lactating mammary glands during lactation
How does vasopressin cause renal water reabsorption?
- Vasopressin binds to V2 receptors on BL membrane of epithelial principal cells and activates the associated G protein
- G protein is exchanges GDP for GTP -> alpha subunit moves from the body of the G protein
- This activates adenylate cyclase, which causes GTP to give up a phosphate to make cAMP from ATP
- cAMP activates PKA
- This causes water channels (aquaporins) (contained in vesicles called aggrephores) to move to apical/luminal membrane
Specifically aquaporin-2 - This causes the water to move through the epithelial cells and into plasma
Water leaves epithelial cells via aq-3 and aq-4 on BL membrane
What stimulates production of vasopressin?
Decreased water amount in blood causes increased plasma osmolality
Decreased blood volume as a result of haemorrhage
Emotional/surgical stress may-> massive vasopressin release
What stimulates production of oxytocin?
Suckling a lactating mother
Stretch receptors in the vagina/uterus
Emotional stress may-> inhibition of lactation
How does increased plasma osmolality increase vasopressin production?
Detected by osmoreceptors in hypothalamus
Sends axons to the cell bodies of supraoptic and paraventricular nuclei in the hypothalamus
Causes release of AVP from neurohypophysis
Causes increased uptake of water from collecting duct
Decreases plasma osmolality
How does decreased blood volume increase vasopressin production?
Decreased circulating volumes activate:
- Low pressure mechanoreceptors in L atria and central veins
- High pressure baroreceptors in carotid sinus and aortic arch
Decreased arterial blood volume -> decreased frequency of APs from these various stretch receptors
Stimulates release of vasopressin by decreasing inhibitory effect normally operated by this baroreceptor reflex pathway
Increased vasopressin causes vasoconstriction
Causes an increase in arterial blood pressure
How does suckling increase oxytocin production?
Tactile receptors in breasts, especially around nipples, initiate APs
APs propagate along afferent nerve fibres through SC and midbrain to the hypothalamus
Oxytocinergic cell bodies in the paraventricular and supraoptic nuclei are stimulated and cause the release of oxytocin
Oxytocin causes myoepithelial cells to contract (in breast) -> milk ejection
How do stretch receptors in the vagina/uterus increase oxytocin production?
Stimulate APs in afferent pathways
Leads to oxytocin release
Causes smooth-muscle cells of myometrium to contract
E.g. in uterus at parturition-> contraction-> deliver baby
What clinical conditions are associated with vasopressin?
DIABETES INSIPIDUS Central DI (no VP) Nephrogenic DI (tissue insensitivity)
SIADH
Syndrome of inappropriate ADH
List common symptoms caused by lack of vasopressin
Unquenchable thirst (wakes up at night)
Urinates frequently
Fasting serum glucose level normal
No glucose detected in urine
What can cause lack of vasopressin?
Genetic disorder
Cranial diabetes insipidus
Hypothalamic disorder affecting vasopressinergic neurons e.g. due to trauma or a tumour
What is DDVAP why is it used (not AVP) for measurements to study neurohypophyseal disorders?
DDAVP stimulates water reabsorption in the principle cells of the renal collecting ducts
Increased water absorption in the renal collecting ducts-> urine osmolality rises
DDAVP is synthetic and lasts longer than AVP (nonapeptide broken down too quickly)
How would a ‘normal’ person’s osmolarity of urine respond during a water deprivation test?
Urine osmolality would increase as high blood glucose level exerts an osmotic pressure
This draws water out of plasma and into renal filtrate
->
Polyuria: increased urine volume
Polydipsia: excessive thirst
How does water reabsorption increase when dehydrated?
- Become dehydrated
- Osmolality increases and detected by osmoreceptors
- Signal sent to vasopressinergic cells (in paraventirular and supraoptic nuclei) to increase vasopressin
- Vasopressin released by magnocellular neurons
- Bind to receptor-> stimulates aquaporin to apical membrane
- Increased water reabsorption
- Plasma osmolality decreases
What happens to osmolarity after administering DDAVP?
Osmolality of urine rises
DDAVP functions like AVP
Why is blood glucose concentration closely regulated?
Glucose is a vital energy substrate
Low glucose (hypoglycaemia (impairs brain function) Lower glucose (unconsciousness, coma, death)
High glucose can -> diabetic coma which can -> death
What are normal blood glucose levels?
4-5mMol
What hormones control glucose level?
Decrease levels= insulin
Increase levels= glucagon, catecholamines (e.g. adrenaline), cortisol and somatotrophin
Which type of diabetes is more common?
Type 2 (85-95%, NB. T1=11%)
Considerable health burden
Defined in terms of glucose but also related to hypertension and dyslipidaemia
How much of the pancreas is associated with exocrine secretions (via duct to small intestine)?
98%
What percentage of pancreatic tissues are small clusters of endocrine cells and what are they called?
2%
Islets of Langerhans
What are the main types of islet cells and what do they secrete?
Alpha= secrete glucagon
Beta 60%= secrete insulin
Delta= secrete somatostatin
F= secretes pancreatic polypeptide (unknown function)
What junctions are present between typical islets of Langerhans?
Gap junctions (allow small molecules to pass directly between cells) Tight junctions (form small intracellular spaces and involve fusion of outer cell membranes)
Describe Islet of Langerhans cell structures (and how a, b, d, f cell differ)
Alpha cells= more numerous and denser concentrations of granules in their cytoplasm than beta cells
Beta cells are generally smaller
Delta cells contain numerous, more uniform granules which are less dense than those of either alpha or beta cells
Type F cells also found on periphery, secrete pancreatic polypeptides
Gap and tight junctions important
Describe blood flow around/in the pancreas?
Blood flows from the periphery to the core of the islets
Portal blood supply allows blood from beta cells to bathe the alpha and delta cells for rapid communication
Arterial blood supply is from the splenic hepatic and superior mesenteric arteries
Venous blood drains directly into portal vein reaching the liver directly
Describe how insulin is synthesised?
- On beta cells within islets of Langerhans
- Initially synthesised as preproinsulin via mRNA translation
- Removal of its signal peptide during insertion into the endoplasmic reticulum generates proinsulin (a single chain polypeptide)
- Proinsulin folds spontaneously upon itself -> forms 2 disulphide bridges
- Proinsulin is incorporated into granules at the Golgi body and the C-peptide is cleaved by proteolysis within the granules
- This forms the mature insulin molecule and the C peptide
Describe how insulin is stored?
Stored within granules
Partly as polymers and partly complexed with zinc
Describe how insulin is released?
Insulin secretion is triggered by rising blood glucose levels (detected by glucokinase)
GLUT2 transporter takes glucose up
Glucose phosphorylated by glucokinase (rate limiting)
Glycolytic phosphorylation of glucose -> rise in ATP:ADP ratio
Rise inactivates the K channel that depolarizes the membrane-> Ca channels open up allowing Ca ions to flow inward
Increased Ca channels-> exocytotic release of insulin from storage granule
How much insulin is degraded in the liver and kidneys?
80%
What are 3 of insulin’s main functions?
Decreases blood glucose concentration (carb metabolism)
Decreases blood AA concentration (protein metabolism)
Decreases blood fatty acid and ketone concentrations (fat metabolism)
How does insulin decrease blood glucose concentration?
Increases uptake of glucose by target cells by directing the insertion of GLUT-4 glucose transporters into cell membranes (as glucose enters cells, blood glucose conc decreases)
Increased glycogenosis and glycolysis (promotes glucose-> glycogen in muscle and liver via enhanced glycogen synthase activity)
Also inhibits glycogenolysis (inhibits glycogen phosphorylase)
Decreases gluconeogenesis by increasing the production of fructose 2,6-biphosphate, so substrate is directed away from formation of glucose
LOW INSULIN TO GLUCAGON RATIO
How does insulin decrease blood amino acid concentration?
Stimulates active transport of AAs into peripheral cells
Stimulates protein synthesis directly
Decreases protein catabolism (proteolysis) (because of increased glucose utilisation, stimulated by protein cortisol)
How does insulin decrease fatty acid and ketone concentrations?
Stimulates cellular uptake and oxidation of glucose by adipose tissue
Stimulates lipogenesis in hepatic and adipose tissues and fat storage
Inhibits lipolysis
Activates lipoprotein lipase of endothelial cells which catalyses hydrolysis of triglycerides bound to lipoproteins and stimulates movement of fatty acids into adipocytes
NB. Low prevalence of ketonuria in T2DM
Which factors regulate the release of insulin to decrease blood glucose?
STIMULATE BETA CELLS Certain AAs Certain GI hormones Alpha cells-> glucagon Parasympathetic activity (B-receptors)
INHIBIT BETA CELLS
Delta cells-> somatostatin
Sympathetic activity (a-receptors)
Stress (associated with sympathetic mediators)
Which factors regulate the release of glucagon to decrease blood glucose?
STIMULATE ALPHA CELLS Certain AAs Certain GI hormones Sympathetic activity Parasympathetic activity
INHIBIT ALPHA CELLS
Beta cells-> insulin
Delta cells-> somatostatin
What does glucagon raise?
Blood glucose concentration
Blood fatty acid concentration
Urea production
How does glucagon increase blood glucose?
Increased AA transport into liver-> increased gluconeogenesis-> increased blood glucose
Increased hepatic glycogenolysis-> increased blood glucose
Increased lipolysis-> increased gluconeogenesis-> increased blood glucose
What is glucokinase?
Glucose sensory, hexokinase IV
Acts as a glucose receptor on pancreatic B cells
How does glucokinase affect insulin synthesis and release?
Glucokinase acts as a glucose receptor on pancreatic beta cells
- When glucose levels rise, glucose enters cell via GLUT2 transporters
- Glucokinase mediates phosphorylation of glucose to glucose-6-phosphate (for glycogen syntehsis and glycolysis)
- Phosphorylation of glucose causes ATP:ADP ratio to rise-> K channels close-> depolarises membrane
- Calcium channels open, Ca influx-> exocytotic release of insulin from its secretory granules
What is GLP-1?
Glucagon like peptide-1
Gut hormone secreted in resonse to nutrients in gut
Transcription product of proglucagon gene (mostly from L cell)
What does GLP-1 do?
Stimulates insulin
Suppresses glucagon
Increase satiety
What is GLP-1 degraded by?
Enzyme= Dipeptidyl peptidase-4 (DPPG-4 inhibitor)
Rapid degeneration, so GLP-1 has a short half life
Describe the structure of the insulin receptor
Tetramer with 2 alpha subunits and 2 beta subunits
a= EC subunits, contain insulin binding sites B= span the membrane, have tyrosine kinase activity
How does insulin binding to the receptor lead to glucose being transported into the cell?
Insulin binds to receptor
TK autophosphorylates the B subunits
Phosphorylated receptor then phosphorylates IC proteins
This initiates a signal transduction cascade which stimulates and actives GLUT4 to tranport glucose into the cell
What colour is urine when it has:
No ketones
Ketones
Lots of ketones?
No ketones= yellow
Ketones= green
Lots of ketones= very green
What is likely to be the diagnosis of a young patient who has rapidly lost weight, drinks up to 3.5L a day (and passes nearly all of it) and very green urine with lots of glucose?
She also has polydipsia and polyuria
Type 1 diabetes mellitus
Will ketones be in urine in Type 1 diabetes, Type 2, neither or both?
T1DM
(Ketones won’t be in urine unless fasting in T2DM as ketone body formation is surpressed by insulin, fat not broken down)
Why is glucose in the urine of a patient with T1DM?
Lack of insulin-> glucose uptake (via Glut 2 and glut 4) stopped glycogenesis does not occur (glucose -> glycogen)
This means glucose remains in the plasma (doesn’t enter cells) and is passed out in the urine
In ABSENCE OF INSULIN, glycogen-> glucose by liver
Protein broken down-> AAs towards gluconeogenesis
Fat broken down-> products go towards making more glucose
Why is so much water passed by a patient with T1DM?
Increased glucose concentration in the urine exerts an increased osmotic pressure
So more water drawn out into the urine (due to increased osmolarity)
Therefore urine volume increases
Why is C peptide a good marker for endogenous insulin?
Longer half life (30 mins not 4) and more stable
In T1DM, what is the concentration of plasma glucose and plasma insulin?
Plasma glucose high
Plasma insulin conc= 0mmol/l
(T1DM- beta islets wiped out by GAD antibodies so no insulin synthesised or secreted0
What is the normal fasting plasma glucose?
Is the fasting plasma glucose for higher or lower in T2DM patients?
Higher
What are common characteristics of a patient with T2DM?
Older
Overweight
Cardiovascular symptoms
What causes T2DM?
Unresponsiveness to insulin
Plasma insulin concentration normal/high
Can’t reduce blood glucose levels (high HGO)
Body tries to compensate increasing insulin secretion, but no effect
What do T2DM diets recommend?
Overall calorie control
Including:
Reduce fat calories
Reduce refined carb calories
Reduce sodium intake Increase soluble fibre Increase complex carb calories
What does energy restriction in T2DM ensure?
Energy restriction will ensure that glucose is taken up into cells as a necessary energy source
Prevents hyperglycaemia
What’s the difference between diabetes insipidus and diabetes mellitus?
Diabetes mellitus is characterized by high levels of sugar in the blood e.g. T1DM, T2DM, gestational.
Involves insulin
Diabetes insipidus (rare) is a disease where kidneys are unable to conserve water Involves vasopressin
List effects of insulin (across intermediary metabolism, not just relating to diabetes)
Glucose (decreases HGO- hepatic glucose output, increases muscle uptake)
Protein (decreases proteolysis)
Lipid (decreases lipolysis and ketogenesis)
Growth
Vascular effects
Ovarian function
Clotting (Pai-1)
Energy expenditure (relation to Leptin)
Where is GLUT-4 expressed?
Muscle and adipose tissues
Lies in vesicles until recruited and enhanced by insulin
What effect does GLUT-4 have on glucose uptake into cells?
7x increase in glucose uptake into cells
What is the structure of GLUT-4?
Hydrophobic outer layer and hydrophilic inside (where glucose goes through)
What are GLUT-2 and GLUT-4?
Glucose transporters
GLUT-2 glucose-stimulated (leads to glucose entry into cell, glucokinase aids this)
GLUT-4 insulin-stimulated transported (recruited and enhanced by insulin)
What stimulates protein synthesis (from AAs)?
Insulin
Growth hormone
IGF1
Relating to proteins, what does insulin inhibit?
Proteolysis
Conversion of oxygen to carbon dioxide
What are the effects of insulin and glucagon on glucose?
INSULIN
Stimulates glycogenesis (glucose->glycogen)
Inhibits gluconeogenesis (glycogen-> glucose)
Decreases hepatic glucose output
GLUCAGON
Increases uptake of gluconeogeneic AAs into cells
Stimulates glycogenolysis and gluconeogenesis
Increases hepatic glucose output
What is the difference between carbohydrates, proteins and fat as fuel stores?
CARBS
Liver and muscle cells: glycogen ->glucose (especially in brain)
Short term source: 16 hrs
PROTEIN
Longer term: 15 days
FAT
Long term source: 30-40 days
Highest energy released per gram
What do insulin and lipoprotein lipase do in fat metabolism?
Insulin and lipoprotein lipase stimulates the breakdown of triglycerides into glycerol and non-esterified fatty acids
Insulin also stimulates uptake of glucose into adipose tissue (via Glut 4 transporter)
What does insulin do within adipose tissue?
Stimulates formation of triglycerides for glycerol-3-phosphate non-esterified fatty acids
Inhibits the breakdown of triglycerides into glycerol and non-esterified fatty acids
What stimulates the breakdown of triglycerides into glycerol and non-esterified fatty acids?
Catecholamines, cortisol and growth hormone
Insulin inhibits this
Describe omental circulation
Via hepatic portal vein:
Heart-> GI tract-> liver-> heart
Adipocytes in GI tract are highly metabolically active
Why is waist circumference a good indicator of heart disease?
Increased circumference means more adipocytes in GI tract
This means increased risk of ischaemic heart disease and death
What is hepatic gluconeogenesis?
Occurs in the liver (hepatocytes)
Glycerol (in blood) taken up into the hepatocytes to form glycerol-3-phosphate
G3P is readily interconverted to triglycerides and to glucose (gluconeogenesis)
Glucose released from the hepatocyte via HGO (into blood)
NB. Ketone bodies and glucose can be used for brain (not fatty acid metabolism)
What % of glucose output (after a 10 hour fast) is released from hepatocytes via HGO?
25%
What happens to fatty acids in the liver?
Non-esterified fatty acids taken up into hepatocytes
NEFAs converted to fatty acyl CoA
Fatty acyl CoA converted to acetyl CoA-> acetoacetate -> acetone and 3 hydroxybutarate
These are then released as ketone bodies (an alternative source of fuel for brain if hypoglycaemia occurs)
What inhibits/stimulates the conversion of fatty acyl CoA (in fatty acid metabolism)
Insulin inhibits
Glycogen stimulates
What do ketones in the urine indicate?
Ketones in urine indicate fasting which has lead to fatty acid metabolism
Elevated glucose and ketones present in urine is abnormal and indicates insulin deficiency
What is hepatic glycogenolysis?
After glucose is taken up into hepatocytes and converted to glucose-6-phosphate-> stored as glycogen
Stimulated by insulin
Inhibited by glucagon and catecholamines (which stimulate the revers)
G6P can also be re-converted to glucose (which can be released from cell via HGO to increase blood glucose levels)
Where are fatty acids taken up into?
Muscle cells
What happens to fatty acids and glucose in muscle cells?
FAs are taken up into muscle cells where they are converted to acetyl CoA (which then enters the Krebs cycle)
Glucose uptake via glut-4
Stimulated by insulin
Inhibited by growth hormones, catecholamines and cortisol
Glucose is then stored as glycogen or converted to acetyl-CoA
Describe the fasted state (and prolonged fasting)
FASTED STATE
Low insulin to glucagon ratio
Blood glucose conc 3.0-5.5 mM
Increased in non-esterified fatty acids within the blood
Decreased in AAs within the blood when prolonged
PROLONGED FASTING
Increase in proteolysis (AAs released from muscles)
Increased lipolysis (adipocytes release glycerol and fatty acids)
Increased HGO from glycogenolysis and gluconeogenesis
Muscles use lipid metabolism as energy store
Brain uses glucose metabolism, followed by ketone bodies
Increased ketogenesis
