Metabolism Sessions 7-11 Flashcards
What methods of communication can be used in a control system?
Action potentials
Endocrine hormones
Paracrine hormones
Autocrine hormones
What is the function of a control centre in a control system?
Determines set point, analyses input and determines response
Which pathway does the receptor of a control system use?
Afferent
Which pathway does the effector of a control system use?
Efferent
What happens in a negative feedback loop?
Effector opposes stimulus
Which feedback regulates most homeostatic systems?
Negative
What is positive feedback?
Stimulus produces response which increases its effects causing rapid catastrophic change which can result in a change in state e.g. blood clotting
What does blood cortisol have to be measured at the same time each day?
Follows a circadian/diurnal rhythm
What controls the biological clock in the body?
Suprchiasmatic nucleus (collection of neurones) in the hypothalamus
Why is the body clock cycle reset by external stimuli?
It is naturally slightly longer the 24 hours
What causes jet lag?
External stimuli and biological clock indicate different times
What is released from the pineal gland as soon as eyes are closed to regulate the light/dark cycle?
Melatonin
Why does melatonin release need optic nerve input?
Pineal gland it is released from is buried right at the centre of the brain
Where is the pituitary gland located?
Hangs down from hypothalamus
How are the parts of the pituitary gland related to its function?
Anterior = endocrine supplied by veins Posterior = neuroendocrine supplied by veins and arteries
What percentage of body mass is water in makes and females respectively?
50-60% males
45-50% females
Why do females have a lower percentage mass of water?
They have more fat
What is osmolality?
Solvent expressed per weight of solvent
What is measured along with sodium ion concentration by osmoreceptors in the hypothalamus?
Osmolality
How does the body counteract and increase in blood plasma osmolality?
Released ADH from posterior pituitary to increase reabsorption of water from urine in collecting ducts
What is the name given to a biologically active signalling chemical?
Hormone
Which organs make up the endocrine system?
Hypothalamus Pituitary gland Parathyroid glands Heart Adrenal glands Kidneys Pineal glands Thyroid glands Stomach Pancreas Intestines Ovaries/testes
What type of responses is the endocrine system good for?
Coordinated multiple
What blood system does the hypothalamus release factors into?
Portal
What is considered as the ‘master gland’ of the endocrine system?
Anterior pituitary
What does the anterior pituitary gland release on stimulation from the hypothalamus?
Trophic (stimulating) hormones
Which axis is the classic stress response?
Hypothalamic-pituitary-adrenal (HPA)
What controls the HPA axis?
-ve feedback
Which hormones are elevated in the classic stress response?
Corticotrophin releasing hormone (CRH)
Adrenocorticotrophin releasing hormone (ACTH)
Cortisol
What is the rate of secretion in the endocrine system usually controlled by?
-ve feedback
Why are hormones very difficult to measure in the body?
Circulate in very low concentrations
What is the solubility of hormones like?
Some peptide and amine are water soluble
Steroid and thyroid are lipid soluble
How are steroid and thyroid hormones carried in the blood?
Steroid by specific steroid binding globulins
Thyroid by thyroid binding globulins (TBG)
What is there between the biologically inactive bound form and biologically active free form of hormone?
Dynamic equilibrium
What is the function of carrier proteins in hormone transport?
Increase solubility in plasma
Increase half-life
Create readily accessible reserve
Why is a readily accessible reserve of hormone provided by carrier proteins important for thyroxine?
It is tightly bound
What are the four classes of human hormones?
Peptide
Glycoprotein
Steroid
Amine
Which is the largest class of human hormones?
Peptide
How many known peptide hormones are there?
~20 but often increases due to new gut discoveries
What are all steroid hormones derived from?
Cholesterol
Which two steroid hormones is there one group difference between?
Testosterone and progesterone
Give some examples of steroid hormones.
Vitamin D Corticosteroids Progestins Androgens Oestrogens
How many major amine hormones are there?
3
What is a main precursor of amine hormones?
Tyrosine
Give two examples of locally acting amine hormones.
Histamine and serotonin
What is the precursor of histamine?
Histidine
What is the precursor of serotonin?
Tryptophan
What is the structure of glycoprotein hormones?
2 polypeptides and a carbohydrate side chain
Where are all glycoprotein hormones released from?
Anterior pituitary gland
Give four examples of glycoprotein hormones.
TSH
FSH
LH
hCG
What does the magnitude of a hormonal response depend on?
Concentration of active hormone at target tissue
Receptor number
Affinity of receptor for hormone
Degree of signal amplification
Which type of hormones can cross the CSM?
Steroid
Where do steroid hormones bind to cellular receptors?
In nucleus or in cytosol (heat shock protein) which moves into the nucleus
What effects do steroid hormones have in the nucleus?
Alters transcription process - either switches on or off enzyme expression to affect enzyme action of cell
What happens upon binding of a hormone that cannot cross the CSM to a receptor on the cell surface?
Activates second messenger whose products affect enzyme action in cell
Can steroid hormones bind to CSM receptors and affect enzyme action in a cell?
New research says yes
What do control systems in the body require?
Communication
Control centre
Receptor
Effector
What controls appetite?
Appetite centre/satiety centre located in the arcuate nucleus in the hypothalamus
How many types of neurones are there in the arcuate nucleus?
2
What is the function of the primary neurones in the arcuate nucleus?
Sense glucose and FA in the blood
Respond to hormones
What is the function of secondary neurones in the arcuate nucleus?
Synthesise input
Coordinate a response
Signal to higher sensors in the brain
Which hormones are excitatory in the control of appetite?
Neuropeptide Y
Agouti-related peptide
Which hormones are inhibitory in the control of appetite?
POMC
Beta-endorphin
Alpha-melanocytes stimulating hormone
What is ghrelin?
Peptide hormone released from stomach wall when empty which is the only known hormone to stimulate appetite
When is ghrelin inhibited?
When stomach is filled
What is cleaved off POMC which suppresses appetite?
Alpha-MSH
Which peptide hormone is released from the wall of the small intestine that suppresses appetite?
PYY
What is released from adipocytes to signal appetite suppression?
Lepton
How does lepton cause excess energy in stores to be dissipated as heat?
Induces uncoupling protein expression
Which peptide hormone is secreted by beta cells in the pancreas to suppress appetite?
Amylin
Which peptide hormone uses the same mechanism as leptin but is less important in its role of suppressing appetite?
Insulin
How does glucagon-like peptide cause weight loss?
Released from gut to enhance insulin release
Which gut hormone causes weight loss and ‘cures’ T2DM?
Oxyntomodulin
What does an injection of leptin into deficient patients treat?
Hyperphagia
What conditions comprise metabolic syndrome?
Insulin resistance
Dyslipidaemia
Impaired glucose tolerance
Hypertension
What three methods of bariatric surgery are available?
Adjustable gastric band
Roux-en-Y gastric bypass
Vertical sleeve gastrectomy
Why is Roux-en-Y gastric bypass the most effective type of bariatric surgery?
Reroutes small intestine so gut hormones no longer act
What benefits can Roux-en-Y gastric bypass have?
Rapid weight loss
Reversal of T2DM due to signalling changes
Reverses infertility caused by obesity
What is gut microbiome composition associated with?
Obesity
T2DM
CVD
Non-alcoholic fatty liver disease
What does the strong association between CHD, hypertension, T2DM (adult disease) and low birth and placenta weight suggest?
Foetal programming
What is foetal programming?
Foetus adapts to conditions in utero –> biochemical adaptations are ‘programmed in’ predisposing to adult diseases
What genetic mechanism explains foetal programming?
Epigentics
What is epigenetics?
Inherited phenotype resulting from change in a chromosome w/out change in the DNA sequence
What changes to histones can cause suppression of gene transcription?
DNA methylation changes histone structure
‘Tails’ on histones affected by surroundings which alters DNA
What is diabetes mellitus?
Hyperglycaemia which over years leads to damage of small and large blood vessels causing premature death from CVD
What is diabetes mellitus characterised by?
Hyperglycaemia but may have other metabolic abnormalities
How can the insulin levels be affected in diabetes mellitus?
Beta-cell failure so not produced
Production is fine but resistance prevents it from working properly
How do patients with diabetes present?
Polyuria Polydipsia Tiredness Weakness Blurring of vision Urinary tract infections Weight loss
What is needed to diagnose diabetes?
Either symptoms and 1 abnormal blood test or asymptomatic with 2 abnormal tests
What blood tests can be used to diagnose diabetes?
Fasting glucose
Oral glucose tolerance test
HbA1C
What is a long term indicator of glycaemic control?
Glycosylated haemoglobin - HbA1C
How is a patient in the impaired glucose tolerance range often treated?
Same as if they were in the diabetic range
What is type I diabetes?
Autoimmune or non-immune deficiency of insulin
How does T2DM differ from T1DM?
Characterised by insulin deficiency and resistance
What can cause T2DM?
Iron overload Pancreactectomy Genetic beta-cell defects Drug induced - steroid, diuretics, beta-blockers Hormone disorders e.g. cortisol Genetic defects of insulin action
How does type I diabetes mellitus present?
Rapid onset Weight loss Polyuria Polydipsia Late presentation --> vomiting from ketoacidosis
Why must identified cases of T1DM be urgently referred?
High risk of ketoacidosis and death
What diagnostic feature can be used to differentiate between T1 and T2 diabetes?
T1 has ketones present in the urine, T2 does not
What are the functions of insulin on fuel metabolism?
Enhance glucose uptake by the liver
Inhibit liver glycogen breakdown
Enhance glucose uptake by muscle and adipose
What effects does insulin have in amino acids?
Inhibits catabolism
Inhibits gluconeogenesis in liver
Stimulates active transportation into cells
What effect does insulin have on FA?
Promotes their clearance
What treatment is given in ketoacidosis?
SC injection of exogenous insulin w/fluids and potassium
What causes diabetic ketoacidosis?
Hyperglycaemia and dehydration lead to production of serum acetone
How does obesity cause hyperglycaemia?
Increases insulin secretion –> pancreatic exhaustion
What occurs in T2DM that can cause beta-cell failure?
Amyloid type deposits
What can be considered as a potentially reversible metabolic disorder which is precipitated by chronic intraorgan fat?
T2DM
How does bariatric surgery or hypocalorific diet cause reversal of T2DM?
Calorific intake falls –> profound change in [fat metabolites] –> fat mobilised first from liver then other ectopic sites rather than subcutaneous –> pancreatic fat content decreases normalising bet-cell function
Which two pathologies must both happen to cause T2DM?
Insulin resistance and relative lack of insulin
Is T2DM caused by genetic or environmental factors?
Both
How do T2DM patients present?
Variably due to slow rise in blood glucose
Polyuria
Polydipsia
Weight loss
Can T2DM patients be asymptomatic?
Yes
In what age group is T2DM usually seen?
40+ but increasingly seen in the young
Why are no ketones seen in the urine in T2DM?
Beta cells still produce some insulin, just not enough
Why do even asymptomatic T2DM patients have to maintain good blood glucose control?
To reduce risk of complications e.g. significant morbidity, mortality
How is T2DM treated?
Change lifestyle factors Metformin Sulphonylureas GLP1 to suppress appetite Insulin as a last resort
What life-long monitoring methods are used in T2DM?
Well being Glucose control - capillary vs urinary glucose testing HbA1C Vascular risk factors Surveillance for chronic complications
How is the function of the pancreas split?
~1% of tissue is endocrine
~99% of tissue is exocrine
What are the exocrine secretions of the pancreas?
Digestive enzymes directly into duodenum
Alkaline secretions through pancreatic duct into duodenum
How does the pancreas develop embryologically?
As an outgrowth of the foregut
What are the five major cell types and their respective functions in the endocrine pancreas?
Alpha - glucagon Beta - insulin Delta - somatostatin F - pancreatic polypeptide Unnamed - ghrelin
What is the combined function of insulin and glucagon?
Regulation of metabolism of carbohydrates, proteins and fats
What are the target tissues of insulin?
Liver
Adipose
Skeletal muscle
What does insulin affect the metabolism of?
Carbohydrates
Lipids
Proteins
Is insulin anabolic or catabolic?
Anabolic
What are the target tissues of glucagon?
Liver
Adipose
What does glucagon affect the metabolism of?
Carbohydrates
Lipids
What would cause swelling/shrinking of cells in the brain, thus causing detrimental damage?
Changes in blood glucose altering osmolarity
What can alter the renal threshold?
Elderly increases
Pregnancy decreases it
How are insulin and glucagon carried in the blood?
Dissolved in plasma
What is the half life of insulin and glucagon?
5 minutes
What happens when glucagon and insulin reach target cells?
Interact w/cell surface receptors and form a complex which can be internalised
Why does insulin have a rigid structure?
Has 2 sulphide bridges
How is insulin mRNA translated?
Single chain precursor called preproinsulin
What happens to preproinsulin on insertion to the ER?
Pre cleaved off
What happens to proinsulin in the ER?
Exposed to specific endopeptidases which excise C peptide
What happens to the mature insulin in the Golgi and cytoplasm?
Insulin and free C peptide packaged in Golgi into secretory granules which accumulate in cytoplasm
What is the process of margination in insulin secretion?
Storage vesicles –> CSM –> exocytosis
Why is rapid turnover of insulin needed?
Short half life
How does [glucose] in beta-cells rise?
Enters by facilitated diffusion through GLUT2
How does increasing [glucose] in beta-cells cause release of insulin?
Allows more ATP to be formed so ATP sensitive potassium channel can function –> membrane depolarised –> V-G calcium channel opens and calcium influx triggers exocytosis of insulin
What effect can metabolic insulin have in GLUT4?
Increases insertion to increase glucose uptake into target cells and increase glycogen synthesis
What is the structure of an insulin receptor?
Alpha-chain on exterior of cell membrane
Beta-chain spans cell membrane in single segment
2 units held together by a disulphide bond
Receptor is a dimer
What causes the insulin receptor to become active tyrosine kinase?
Alpha-chains move together and fold round insulin which moves beta-chains together
What effects does tyrosine kinase activation by insulin have in the cell?
Initiates phosphorylation cascade which results in increased GLUT4 expression so cells can take up more glucose
What causes glucagon secretion?
Low glucose levels within alpha-cells
How is glucagon synthesised?
In RER and transported to Golgi where it is packaged into granules
Why is glucagon more flexible than insulin?
No disulphide bridges
How are granules of glucagon secreted?
Move to cell surface by margination and exocytosis
What is the only case where glucagon is not antagonistic to insulin?
When it increases gluconeogenesis when a protein rich meal is consumed
Is glycolysis and amino acid and glucose uptake into muscle and adipose rapid, intermediate or delayed?
Rapid
What are the delayed effects of insulin and glucagon?
Lipogenesis
Lipolysis
Ketogenesis
What happens initially in insulin resistance in the young?
Beta-cells compensate by increasing insulin production which maintains normal blood glucose but kills beta-cells off
What happens eventually in insulin resistance in the young to cause impaired glucose tolerance?
Beta-cells are unable to maintain increased insulin production
What happens finally in insulin resistance in the young causing overt T2DM?
Beta-cell dysfunction leads to relative insulin deficiency
What is decreased in the adipose tissue in addition to decreased lipogenesis in chronic hyperglycaemia?
Esterification
What are the long-term consequences of chronic hyperglycaemia?
Muscle wasting
Weight loss
Ketosis
Hyperglycaemia
What are chronic long-term microvascular consequences of chronic hyperglycaemia?
Neuropathy
Nephropathy
Retinopathy
What are acute metabolic consequences of choroid hyperglycaemia?
Glycosuria - exceeds renal threshold
Polydipsia
Poolyuria
What are chronic microvascular consequences of chronic hyperglycaemia?
Stroke
Coronary artery disease
Poor peripheral circulation esp. feet
How does the development of the anterior and posterior pituitary gland vary?
Anterior derives from primitive gut tissue
Posterior is brain tissue
Why are tumours seen in the gut and pituitary similar?
Derived from same primitive tissue
What is the link between the endocrine and nervous system?
Hyothalamo-pituitary axis
What is a slower metabolic response than the neurological response to the external environment?
Endocrine response
What characteristic symptom does upward tumour growth in the pituitary gland cause?
Tunnel vision due to optic chiasm disruption
Why does sideways tumour growth in the pituitary gland cause headaches and vision problems?
Cranial nerves disrupted
What hormones does the anterior pituitary gland secrete?
ACTH Prolactin Growth hormone TSH LH FSH
Which hormone released by the anterior pituitary gland is the only one under inhibitory control?
Prolactin
Which two hormones are secreted by the posterior pituitary gland?
Oxytocin
ADH
What stimulates lactation after birth?
Oxytocin
Do correctly managed benign pituitary tumours reduce life expectancy?
No
What are the five anterior pituitary axes?
Growth hormone ACTH LH/FSH TSH Prolactin
Which anterior pituitary axis is abused by athletes/body builders?
Growth hormone
Which growth axis that is important for growth and metabolism increases blood glucose like adrenaline but for longer?
Growth hormone
Which tissues does GH act on?
All
How does the growth hormone axis work?
Via insulin-like growth factor (IGF-1) produced by the liver which on binding to receptor stimulates secondary messenger by dimerisation of receptor
What is secreted by the hypothalamus to increase and suppress growth hormone action?
GRH increases
Somatostatin decreases
Why does somatostatin inhibit lots of hormones, especially gut hormones?
Due to their origin
When is GH normally released?
Few pulses each day, mostly during sleep
What does a high mean GH level cause?
Acromegaly
What are the functions of GH?
Skeletal growth Metabolism Muscle strength Bone density Cardiac function Quality of life
How do the changes seen in growth hormone differ in adults and children?
Changes more subtle in adults than children
Which anterior pituitary axis is the most important to preserve life and why?
Hypothalamo-pituitary-adrenal axis as lack of ACTH is potentially fatal
In what rhythm are CRH and ACTH secreted in?
Circadian
What gives a positive hypothalamic control in the hypothalamo-pituitary-adrenal axis?
CRH
What external factor causes ACTH release?
Stress
How do cortisol deficient patients feel all the time?
Sick and groggy
What is used to treat cortisol deficient patients?
Hydrocortisone
When would you measure cortisol levels in suspected Addison’s and why?
Early in the morning when cortisol level is highest
When would you measure cortisol levels in suspected Cushing’s and why?
Midnight as this is when cortisol levels are at their lowest
Which axis is controlled by the action of LH/FSH?
Hypothalamo-pituitary-gonadal axis
What stimulates LH/FSH release from the pituitary gland?
GnRH
What feedback mechanism do LH/FSH use in men?
Simple -ve feedback
What action do LH and FSH have in men?
LH drives testosterone secretion
FSH drives sperm production
When would you measure LH and FSH levels in men and why?
Highest in morning due to circadian rhythm so measure then
Which method of feedback do LH and FSH use during their mid-cycle surge?
+ve
What does LH cause in the follicular phase in women?
Pulses cause oestrogen release
What do LH pulses cause in the mid-late luteal phase in women?
Progesterone release
Which type of feedback does the hypothalamo-pituitary-thyroid axis use?
Simple -ve
How is production of T3 and T4 stimulated?
TRH stimulates pituitary to secrete TSH which activates follicular cells in thyroid
What is the function of prolactin?
Initiate and maintain lactation
What is the target of the lactotroph axis?
Peripheral tissues with no target gland
What do high levels of prolactin cause?
Lactation and menstrual disturbance - inhibits menstruation
What tonically inhibits prolactin?
Dopamine
What increases prolactin levels?
Minor positive control by TRH
Oestrogen
What pattern of secretion does prolactin follow?
Pulsatile, slightly higher at night
When can you measure prolactin?
Any time of day
What are high levels of prolactin caused by?
5Ps: pregnancy, physiological (stress), pharmacological, pituitary, polycystic ovaries
What is primary gland failure?
Failure of actual organ
What hormone levels are seen in primary gland failure?
End organ hormone low
Pituitary hormone high
What is lost in primary gland failure which results in high pituitary hormone levels?
-ve feedback
Which organ fails in secondary gland failure?
Pituitary
What hormone levels are seen in secondary gland failure?
End organ hormone low
Pituitary hormone low
Why is the thyroid not stimulated in secondary hypothyroidism?
Loss of TSH
What hormone levels are seen in excess hormone production by the primary gland?
End organ hormone high
Pituitary hormone low
What hormone levels are seen in excess hormone production by the pituitary gland?
End organ hormone high
Pituitary hormone high
What controls water retention using osmoreceptors which measure serum osmolality and rising sodium levels before thirst occurs?
Posterior pituitary
When a rise in serum osmolality and sodium is detected, what is released?
ADH
What happens when blood concentration increases?
ADH released –> water recycled into bloodstream
What happens if osmolality decreases?
ADH is switched off –> water is not recycled to the bloodstream
What happens in diabetes insipidus?
Water is not reabsorbed by the kidneys which causes an increase in serum osmolality and decrease in urine osmolality
Why are the symptoms of diabetes insipidus?
Polyuria
Polydipsia
What can cause diabetes insipidus?
ADH deficiency due to disease of hypothalamus or pituitary stalk
ADH resistance
What are the S/S of acromegaly?
Large hand and feet Sweating Headaches Coarse features Hypertension and diabetes
What are the S/S of Cushing’s disease?
Central obesity Striae Easy bruising Rounded moon-shaped face Diabetes and hypertension Proximal myopathy
What are prolactinomas?
Prolactin-secreting pituitary tumours
What are the S/S of prolactinomas?
Infertility
Menstrual disturbances
Glactorrhea
What does a a big tumour squashing the pituitary gland cause?
Decreased hormone levels of all pituitary hormones except prolactin which increases
What are the clinical features of hypopituitarism?
Lethargic
Pallor
Loss of body hair
Poor growth in children
What are gonadotropinomas?
LH/FSH secreting pituitary tumours
What do gonadotropinomas cause?
Increases of sex steroids
Increased LH/FSH
What are basal endocrine tests used in pituitary disease to measure prolactin and testosterone?
Tests carried out at any time of day due to stable hormone levels
What are dynamic endocrine tests in pituitary disease?
Tests where the time of day they are conducted is important due to cyclic or pulsatile hormone release
Which hormones are measured by dynamic endocrine tests?
LH
FSH
GH
ACTH
What do you do to a gland if there is a hormone deficiency or excess in order to identify pituitary disease?
Deficiency - try to stimulate gland into action
Excess - try to suppress gland
What is growth hormone stimulation test used for?
Suspected GH deficiency
What does the GH stimulation test investigate?
Pituitary GH reserve to identify growth disorders in children and pituitary tumours in adults
What is the best test of GH reserve?
Insulin tolerance test
What happens in an insulin tolerance test?
IV insulin –> hypoglycaemia –> somatostatin inhibited so GH is stimulated (testing for deficiency) –> GH doesn’t rise –> unpleasant sensation/hot and sweaty/tachycardia/faint
Why is medical supervision important when conducting an insulin tolerance test?
Positive results from the test can be prolonged
When is the insulin tolerance test not used?
If patient has ischaemic heart disease, epilepsy or unexplained blackouts
When is the growth hormone suppression test used?
Suspected GH excess e.g. Acromegaly
What happens in the GH suppression test?
75 g of oral glucose –> increases somatostatin which should suppress GH –> no suppression of GH = acromegaly
How often are glucose and GH measured in the GH suppression test?
Every 30 mins starting 30 mins prior to oral glucose dose
When is the ACTH stimulation test used?
Suspected ACTH deficiency caused by hypopituitarism or another isolated condition
Wha can be used to conduct an ACTH stimulation test if the patient does not suffer from IHD, epilepsy or unexplained blackouts?
Insulin tolerance test
What happens in an ACTH stimulation test?
Stress –> CRH rises –> ACTH should rise and cause cortisol release to prevent hypoglycaemia –> hypoglycaemia occurs
When is a dexamethasone suppression test used?
Suspected excess ACTH e.g. Cushing’s
What happens in a dexamethasone suppression test?
Dexamethasone should act in hypothalamus to decrease CRH and subsequently decrease cortisol but ACTH remains high so cortisol remains high
What treatments are available for pituitary disease?
Controlled removal of tumour by surgery, radiotherapy or medical therapy
Reduce increased hormone secretion
Replace hormone deficiencies
What are the advantages of using radiotherapy to treat pituitary tumours?
Prevents tumour and protects vision
Can damage gland and increase risk of stroke
What medical therapies can be used to remove pituitary tumours?
GH receptor antagonists
Dopamine (D2) agonists
Somatostatin analogues
What effects do dopamine agonists have in pituitary tumour treatment?
Reduce prolactin
Shrink pituitary tumour enough to prevent need for surgery
Which axis do somatostatin and its analogues act on?
GH
What is given as a monthly injection to treat acromegaly?
Somatostatin and its analogues
How do GH receptor blockers work I treating acromegaly?
Normalise IGF-1 (not GH) levels
What controls are the cortex and medulla of the adrenal gland?
Cortex - endocrine
Medulla - neurological
What is the only source of testosterone in women?
Androgens released from the reticularis of the adrenal cortex
What is the most common enzyme deficiency causing absent mineralocortcoids or glucocorticoids?
21-hydroxylase
What causes a newborn to have indistinguishable sex?
Build up of androgens due to deficiency of 21-hydroxylase
What allows the dramatic change in shape of mediator proteins due to steroid hormone binding?
Alteration of DNA transcription
What happens in mineralocortcoid deficiency?
Decreased sodium
Dehydration
Hyperkalaemia
What happens in mineralocortcoid excess?
Increased sodium
Hypertension
Hypokalaemia
What actions do glucocorticoids have?
Increase glucose production
Breakdown protein
Redistribute fat
What does redistribution of fat due to glucocorticoid action depend on?
Enzyme specific concentration in tissues
Where is fat usually distributed in glucocorticoid excess?
Centrally
Dorso-cervical
Why happens in glucocorticoid excess?
Decreased glucose
Weight loss
Nausea
Hypotension
What happens in glucocorticoid excess?
Increased glucose Weight gain Increased appetite Hypertension Cushingoid
What is aldosterone controlled by?
Rennin-cycle
What gland failure does increased pigment around knuckles, scars and bucchal mucosa indicate?
Primary adrenal
What tumour can cause ectopic ACTH secretion?
Small cell lung
What does a Cushingoid appearance but low ACTH levels indicate?
Autonomous cortisol secretion
What precursor is ACTH secreted as?
POMC
What is POMC broken down into?
Amino terminal fragment –> alpha-MSH
ACTH
Beta-lipoproteins –> meta-MSH and met-enkephalin
What does ACTH stimulate in the adrenal glands?
Production of steroid hormones
What is ACTH broken down into which leads to pigmentation?
Alpha-MSH
CLIP
What can cause corticosteroid excess?
Cushing’s disease
Ectopic ACTH
Primary adrenal tumour
Exogenous steroids
What must be considered when testing the HPA-axis?
Its circadian rhythm
What social factor might alter testing time of the HPA-axis?
Shift work
What test is used for primary adrenal failure?
Synacthen
What happens in a synacthen test that indicates primary adrenal failure?
Primary adrenal failure or disease of adrenal cortex means there is no cortisol response to synthetic ACTH
What test is used in suspected secondary adrenal gland failure?
Insulin tolerance test
How long does there have to be absent pituitary stimulation to cause the adrenal gland to atrophy?
~month
What are two causes of pseudocushing’s?
Alcohol
Psychiatric disease
What tests are used in suspected corticosteroid excess?
24hr urine free cortisol
Dexamethasone suppression test
What is Addison’s disease?
Far endocrine disorder due to auto-immune destruction of adrenal cortex causing a deficiency of all hormones
Why are lymphocytes seen in the adrenal cortex of Addison’s patients?
Causes inflammatory infiltrate in adrenal cortex
What do Addison’s disease patients often also present with?
Other auto-immune diseases
Is Addison’s more common in women or men?
Women
What are the S/S of Addison’s disease?
Weight loss Anorexia Malaise Weakness Fever Depression Impotence Amenorrhea Low libido Abdominal pain Myalgia Arthralgia Nausea
What are the specific clinical features of Addison’s disease?
Pigmentation
Postural hypotension
Salt cravings
What are the biochemical features of Addison’s disease?
Decreased sodium
Increased potassium
Increased urea (due to dehydration)
Decreased glucose
What confirmatory tests can be used in Addison’s disease?
0900 cortisol Short synacthen test ACTH Plasma renin Adrenal antibodies
What can cause primary adrenal failure?
Adrenal leucodystrophy Tuberculosis Surgical removal Meningitis Haemorrhage/infarction
Is acute primary adrenal failure an emergency?
Yes
How is glucocorticoid replacement monitored?
Improvement in clinical symptoms
Restoration of normal weight
Cortisol measurements throughout the day
How is fludrocortisone replacement monitored?
Restoration of serum electrolytes to normal
Blood pressure response to posture
Suppression of plasma renin to normal
How do the S/S of primary and secondary hypoadrenalism compare?
Primary: high ACTH, pigmented, gluco and mineralcorticoids raised
Secondary: low ACTH, pale, glucocorticoids only raised
What results is exogenous steroids cause hypo-adrenal crisis?
Hypotension Hypoglycaemia Hyponatreamia Hyperkalaemia Severe dehydration and death if untreated
Why are long-term steroid use patients at an increased risk of peri-operative hypoadrenal crisis?
Cannot mount an endogenous stress response
What is endogenous Cushing’s syndrome?
Rare endocrine disorder caused by pituitary disorder, adrenal tumour/hyperplasia, ectopic ACTH secretion or abnormal receptors in adrenal cortical cells
What is the main cause of endogenous Cushing’s syndrome?
Pituitary source
What are the clinical features of endogenous Cushing’s syndrome?
Central weight gain Change in appearance Depression Insomnia Menstrual disturbance Poor libido Thin skin Easy bruising Hair growth Acne Muscle weakness Growth arrest in children Back pain Psychosis
What is found on examination in endogenous Cushing’s syndrome?
Moon face Plethora Buffalo hump Striae Central obesity Thin skin Bruising Hypertension Proximal myopathy
What confirmatory tests can be used in endogenous Cushing’s syndrome?
24 hour urinary free cortisol
Midnight cortisol
Adrenal CT or MRI
What happens if endogenous Cushing’s syndrome is left untreated?
High mortality Hypertension MI Infection Heart failure
What is congenital adrenal hyperplasia?
Rare endocrine disorder causing deficiency of an enzyme that causes a block in the cortisol pathway
What are the clinical features of congenital adrenal hypertension?
Virilisation of female baby Neonatal salt-losing crisis Hypotension Hypoglycaemia Hyponatraemia
Why is urgent confirmation of congenital adrenal hypertension needed?
To identify before gender assignment
What is tested for in congenital adrenal hyperplasia?
High 17-hydroxyprogesterone
High androstenedione
High testosterone
High ACTH
How is congenital adrenal hyperplasia treated?
Emergency with steroids
What is the function of the thyroid gland?
Secrete thyroid hormone to maintain energy homeostasis
What is the functional anatomy of the thyroid gland?
Wraps around trachea at base of neck below cricoid cartilage 2 lobes connected by isthmus Ductless Alveolar ~20 g
What is the structure of a thyroid follicle, the secretory unit of the thyroid gland?
Polarised cell thyroid epithelia around colloid filled centre
How are the epithelial cells of the thyroid polarised?
Transporters on side that face colloid are different from the that face interstitium
What accounts for 30% of thyroid mass?
Colloid
What is thyroglobulin?
Large glycoprotein rich in tyrosine that is important in thyroid hormone synthesis and secretion
What type of cells make up the thyroid epithelium?
Cuboidal or columnar
Is there a standard size of thyroid follicle?
Nope
How is blood supplied to the thyroid gland?
Superior and inferior thyroid arteries
How is blood drained from the thyroid?
Superior, middle and inferior thyroid veins
How can the lymphatic system of the thyroid be described?
Rich
What innervation is abundant in the thyroid?
Sympathetic and parasympathetic
What has a minor role in overall regulation of the thyroid gland in comparison to its cascade stimulus?
Sympathetic stimulation
What does TRH binding to Gq receptors on the anterior pituitary cause?
Stimulation of PLC which causes an increase in intracellular calcium levels resulting in exocytosis of TSH
Where are the receptors for TSH located on the thyroid follicular cell?
Basolateral membrane
What does binding of TSH on thyroid receptors cause?
Stimulation of iodine uptake
Acutely: Stimulate synthesis and storage of T3 and T4
Production and release of thyroglobulin
Chronically: hyperplasia and hypertrophy
What electrolytes are found in the fluid that bathes the basolateral membrane of epithelial cells in the thyroid?
Sodium
Potassium
Iodine
What creates a sodium gradient in iodine uptake in the thyroid?
Active pumping of sodium out of follicle
How is iodine moved against its concentration gradient I tot eh third follicles?
Taken with sodium as it moves down its concentration gradient
What happens to the iodine transported into a thyroid follicle on the follicular lumen?
Activated into reactive form by oeroxidase enzyme
What associates with thyroglobulin in thyroid follicles?
Reactive iodine
Why is the storage of thyroglobulin as colloid in the thyroid follicle considered to be an iodide trap?
Follicular cells concentrate iodine to 20-50x the naturally occurring amount
Why is it necessary for the colloid in thyroid follicles to act as an iodide trap?
Thyroid hormones contain large amounts of iodine that is not abundant in the diet
How is thyroglobulin synthesised?
Synthesised on ribosomes –> glycosylated on ER cisternae –> translocated to Golgi for packaging into secretory vesicles of follicular epithelium cells
Are T3 and T4 fat or water soluble?
Fat
Which thyroid hormone is more potent, very biologically active and has a shorter half life?
T3
How is T3 made ineffective?
Deiodinated to T2
What carries T3 and T4 around the circulation?
Thyronine binding globulin
Albumin
Prealbumin
How are T3 and T4 degraded?
Deiodination in the liver and kidney
Which thyroid hormone is produced in larger volume, has a greater affinity for binding proteins and has a longer half life?
T4
Where can T4 be deiodinated?
Liver or peripheral tissues
Which thyroid hormone is given in tablet form as a treatment for hypothyroidism?
T4
Which thyroid hormone can shrink thyroid tumours but is a possible growth factor for adenoma?
T4
How is BMR increased by thyroid hormones?
Increased number and size of mitochondria
Increased oxygen consumption and heat production
Increased nutrient utilisation
What metabolic pathways are stimulated by thyroid hormones?
Lipolysis
Glycolysis
Glycogenolysis
Proteolysis
How do thyroid hormones promote normal growth and development of tissues?
Increase synthesis of specific proteins
What do thyroid hormones increase responsiveness of tissues to?
Sympathetic nervous system
Various metabolic and reproductive hormones
How do thyroid hormones increase functional capacity of the nervous system in adults?
Increased myelination of nerve fibres
Increased development of neurones
Increased speed of reflexes
Increased mental activity - alertness, emotional tone, memory
How do thyroid hormones cause an increase in cardiac output?
Direct effect in heart and increased effect of noradrenaline
Where is increase in turnover of proteins and glycoproteins seen due to action of thyroid hormones?
Skin and subcutaneous tissues
What is seen with hypothyroidism in the neonate?
Irreversible severe mental retardation due to failed CNS development
Coarse features
Protruding tongue
Diminished linear growth due to failure of genetic aging
Delayed sexual development
How soon after birth does hypothyroidism have to be treated in order for it to be reversible?
21 days
What is conducted on neonates to look for hypothyroidism?
Heel price test to assay for TSH
What can hyperthyroidism cause to be early but not elevated in children?
Maturation
Why is hyperthyroidism not usually seen in children?
Exceedingly rare and/or symptoms are not noticeable
What are the S/S or hyperthyroidism?
Heat intolerance, increased perspiration Clammy hands Weight loss (lipid and protein) Tachycardia Increased bowel movements Increased appetite Nervousness, irritability, emotional liability Hyper-reflexive Exophthalmos (anterior bulge of eye)
What is Grave’s disease?
Autoimmune disease which produces antibody that stimulates TSH receptor
How does carbimazole treat Grave’s disease?
Inhibits incorporation of iodine with thyroglobulin
What treatments are available for Grave’s disease?
Carbimazole
Radioactive iodine
Surgery
How does radioactive iodine treat Grave’s disease?
Destroys follicular cells
Are males or females more commonly affected by Grave’s disease?
Females, there is 10/1 ratio
What are the S/S of hypothyroidism?
Cold intolerance Deceased perspiration, cold dry hands Mild weight gain Bradycardia Constipation Mood swings Poor concentration, memory and initiative Oedema and myxoedema Dry skin Brittle nails Hair loss
What is Hashimoto’s disease?
Autoimmune disease that destroys thyroid follicles and produces antibody that blocks TSH receptor and inhibits peroxidase enzyme
Is Hashiomot’s disease more common in men or women?
Women, 10/1 ratio
How is Hashimoto’s disease treated?
Oral T4
How do you know oral T4 treatment of Hashimoto’s disease is effective?
Measure TSH to ensure pituitary function is normal and there will be a loss of s/s with no development of hyperthyroid s/s
How can an ectopic thyroid at the back of the tongue arise?
If it does not migrate down to its position in the neck from the back of the tongue by week 12 of development
Why does an ectopic thyroid gland at the back of the tongue have a reduced function?
Lack of proper blood supply
What subunits form TSH?
Alpha and beta
Which portion of thyroid hormones has any biological affect?
Free concentration
What two features of T3 and T4 form a combined mean which causes the overall activity of the hormones to be slit equally?
Respective half lives and comparative activity
How can the comparative activity of T3 and T4 be explained at the cellular level?
T3 can act directly in mitochondria to increase synthesis of enzymes and structural proteins
T4 must bind to cell membrane receptors
Where are there receptors for both T3 and T4 present in the cell?
Nucleus
What can cause hypothyroid disease?
Autoimmune disease Post-surgery Radioactive iodine treatment Anti-thyroid drug treatment Secondary - due to lack of TSH Congenital Iodine deficiency
What is the most common cause of hypothyroidism in the UK?
Autoimmune disease
What is the most common cause of hypothyroidism worldwide?
Iodine deficiency
What cause of hypothyroidism always triggers goitre formation?
Iodine deficiency
What can cause hyperthyroid disease?
Autoimmune: Grave’s, toxic multinodular goitre, solitary toxic adenoma
Excessive T4 therapy
Thyroid carcinoma
Ectopic thyroid tissue
Excess iodine due to treatment with anti-arrhythmic drug amioderone
Is thyroid disease more common in men or women?
Women
Why are used to diagnose hyper, hypo or euthyroid?
Thyroid function tests
Why are free T4 and TSH both looked at in thyroid function tests rather than just one hormone level?
Individual variation is smaller than population variation so what may be in population range may be unusually for an individual
What are free T4 and TSH levels like in the thyroid function test of euthyroid?
Both normal
What are free T4 and TSH levels like in the thyroid function test of hypothyroid?
Free T4 is low and TSH is elevated
What are free T4 and TSH levels like in the thyroid function test of hyperthyroid?
Free T4 is high and TSH is low
What is the spectrum of hyperthyroidism from most to least severe?
Thyroid storm
Gross hyperthyroidism
Mild hyperthyroidism
Autonomous thyroid function
What is the spectrum of hypothyroidism from least to most severe?
Compensated euthyroidism
Mild hypothyroidism
Gross hypothyroidism
Myxoedema coma
What condition on the spectrum of hypothyroid disease may not require treatment but should be continually monitored?
Compensated euthyroidism
What exacerbates myxoedema coma?
Biological stress
What is sick euthyroid syndrome?
Sick in-patients often have abnormal TFTs despite being euthyroid
What do you need to have in order to carry out a TFT in ill in-patients due to the occurrence of sick euthyroid syndrome?
String clinical suspicion of gross thyroid disease
Will all thyroid disease patients have obvious disease?
No
How is calcium found in the bloodstream?
1.0-1.3 M free and 0.9-1.3 M bound to plasma proteins or complexed w/citrate
Where is most of the calcium in the body stored?
Skeleton
What is calcium needed for in the body?
Signalling Activity of some enzymes and hormone receptors Normal kidney function Blood clotting AP transmission at NMJ Regulate heart rhythm
Where is 99% of calcium found in the adult human?
Hydroxyapatite crystals of bone
Why do we need a calcium store in the skeleton if calcium levels can be regulated by uptake in the GI and excretion in the urine?
This regulation cannot be guaranteed
What is the rapid modulator of calcium levels?
Parathyroid hormone
What is the action of parathyroid hormone?
Stimulate bone resorption and release of calcium into circulation
Stimulate calcium reabsorption in kidney and excretion of phosphate
Stimulate final hydroxylation of vitamin D
What is a long-term modulator of calcium levels?
Dietary vitamin D
What action does dietary vitamin D have?
Increase intestinal absorption of dietary calcium
Increase renal reabsorption of calcium
Increase bone resorption
What is the name of active vitamin D?
Calcitriol
Where is calcitonin produced?
Thyroid gland
What is the action of calcitonin?
Counteracts effects of PTH but is not particularly effective in humans
Typically how many parathyroid glands are there per lobe of the thyroid?
2
Where may extra parathyroid glands be located?
Anywhere in the thorax
What is the appearance of chief cells in the parathyroid?
Round
Clear cytoplasm
Large nucleus
Lots of mitochondria
What is the function of chief cells?
Secrete PTH
What are oxyphil/principle cells of the parathyroid?
Assumed old chief cells that are not associated with PTH secretion
How does the number of mitochondria present differ between chief cells and oxyphil cells?
Oxyphil have less
What cells are found in a parathyroid gland?
Chief
Oxyphil/principle cells of the parathyroid
Adipose
Why does PTH stimulate calcium reabsorption but phosphate excretion in the kidney?
Reduce risk of urinary stones forming
How does PTH act in the small intestine?
Increases calcium absorption by activating vitamin D
What is the structure of PTH?
Straight chain polypeptide
Pre-pro-hormone
What accelerates cleavage of the pre- section of PTH in the liver?
High serum calcium levels
Describe the production and storage of PTH.
Continuously produced but not stored
Broken down immediately if not needed by chief cells
How is the mRNA of PTH affected by serum calcium?
Prolongs its survival
What is the half life of PTH?
4 mins
What effect do low and high serum calcium levels have on PTH synthesis?
Low increases gene transcription
High downregulates production
How is PTH release controlled?
-ve feedback loop - calcium binds to receptor which leads to inhibition of PTH secretion
Is there always a degree of basal PTH?
Yes
How are basal PTH secretions maintained if calcium is within normal limits?
2 secondary messenger pathways are balanced
What is found on cell surface of chief cells, kidney tubule cells and C cells of thyroid gland?
Unique G-protein calcium receptors
What happens to the G-protein receptors when there are high calcium levels present?
Phospholipase is activated which inhibits adenylate cyclase leading to reduce cAMP and reduced PTH release
What other ion levels regulate PTH release?
High phosphate –> increased PTH secretion
High magnesium –> low PTH secretion
Levels of which molecule other than calcium ions are important in chronic kidney disease?
Phosphate
How do osteoclasts cause bone resorption?
Produce acid micro-environment which dissolves hydroxyapatite crystals
How is calcium stored in bone?
Calcium phosphate crystals within collagen fibrils
How do osteoblasts create new bone?
Produce collagen matrix which is mineralised by hydoxyapatite
Which function of bone is its main priority and what is the consequence of this?
Maintaining serum calcium which results in soft bendy bones in order to maintain calcium levels
What is the action of PTH on bone?
1-2 hrs stimulates osteolysis
How does PTH affect osteoblastic cells?
Induces them to synthesise and secrete cytokines on CSM which stimulate differentiation and activity in osteoclasts and prevent them from undergoing apoptosis
Decreases their activity
Which part of the kidneys does PTH affect?
PCT
Loop of Henle
DCT
Where does PTH increase calcium reabsorption in the kidney?
Ascending limb
DCT
How does PTH act on the PCT?
Withdraws phosphate transporters from the surface
How much dietary intake of calcium is absorbed by para cellular uptake when calcium is not limited due to PTH action on the gut?
30%
What significantly increases transcellular uptake of calcium in the gut upon PTH stimulation?
Vitamin D
How is calcium absorbed in the gut?
Carriers in the luminal membrane of the duodenum and jejunum move calcium down concentration gradient extruded across basolateral membrane of epithelial cells
What effect does having secretions from the gut rich in calcium have on the minimum load that must be taken in to the diet to maintain calcium balance?
Additive
What is vitamin D?
Lipid soluble vitamin derived from plants or action of sunlight on cholesterol in skin
How is D3 (cholecalciferol) made?
In skin from dairy product intake and using sunlight
Where is D2 obtained from in the human body?
Ingestion of yeast and fungi which is often added to margarine as a supplement
Do D2 and D3 form calcitriol?
Yes
What can be said about the calcitriol forms from D2 and D3?
Equipotent
What are the intermediates of calcitriol formation?
7-dehydrocholesterol
Precalciferol
Cholecalciferol
Calcitriol
Where does the first hydroxylation reaction of calcitriol take place?
C25 on molecule in the liver
How long can the product of the first hydroxylation reaction in vitamin D activation circulate in plasma for?
15-20 days until it is filtered by the kidneys
Where does the second hydroxylation reaction occur if PTH is present?
At C1 on molecule in PCT of kidneys
What does D3 bind to in the blood?
Transcalciferin
How does the first hydroxylation reaction in vitamin D activation affect the half life of the molecule?
Extends it to ~2 weeks
What enzyme catalyses conversion of calcitriol in the PCT?
1-alpha-hydroxylase a
What is the half life of calcitriol?
0.25 days
Why can the pre-vitamin in vitamin D activation be filtered by the glomerulus?
Bound to carrier small enough
What regulates C1 hydroxylation in vitamin D activation?
Negative feedback from serum calcium levels
What effect does high PTH have on C1 hydroxylation?
Stimulators
What action does calcitriol have in the gut?
Active uptake and extrusion of calcium ions
Transcellular transport
Endocytosis and exocytosis of calcium-CaBP complex
What action does calcitriol have on bone?
Stimulates osteoclast formation from haemopoietic stem cells
What affect does calcitriol have on the kidney?
Stimulates calcium reabsorption
What abolished rickets in the UK during WWII?
Adding calcium carbonate to flour and vitamin D to margarine
What secretes calcitonin?
Sporadic parafollicular cells or C cells of thyroid gland
What is the importance of calcitonin in pregnancy?
May have role in protecting maternal skeleton
Does thyroidectomy in humans demonstrate a marked calcium level affect?
Nope
What are the S/S of hypocalcaemia?
Hyper excitability of NMJ so: Pins and needles Tetany Paralysis Convulsions Death
What is the normal response to hypocalcaemia?
Increase osteoclast activity and increase C1 hydroxylation in vitamin D activation
What is rickets?
Filature to mineralise long bones leading to deformity as skeleton is sacrificed to maintain serum calcium
What are the S/S of rickets?
Head soft spot slow to close Bony necklace Curved long bones Big lumpy joints Bowed legs
What happens in accidental surgical removal of the parathyroid?
PTH deficiency causing life threatening hypocalcaemia with rapid onset as PTH is the rapid modulator of serum calcium levels –> convulsions of respiratory system = death
What are the S/S of hypercalcaemia?
Renal canaliculi Kidney damage Constipation Dehydration Tiredness Depression (Stones, moans and groans)
What is the normal response to hypercalcaemia?
Decrease osteoclast activity
Inhibit transcellular absorption of calcium
Is calcitonin used in the normal response to hypercalcaemia?
No
How is hypercalcaemia treated?
Fluids to restore blood volume
Remove causative tumour (likely benign)
What do you have to do before you can remove a benign tumour of the parathyroid gland?
Find the glands (they can be anywhere in the thorax)
What can cause hypercalcaemia?
Over secretion of PTH from primary hyperoarathyroidism
PTH analogue secreted from various tumours
Is phosphate regulated as tightly as calcium?
No
What normal activity gives the human body a classic stress response?
Exercise
What just the body do in order to adapt to exercise?
Meet acute oxygen append metabolite needs of muscles
Dispose of carbon dioxide and other metabolic waste
Minimise disturbances to other physiological systems
What is the metabolic whole body response to exercise?
Mobilise stored fuels at a rate that matches the increased activity whilst preserving blood glucose levels to protect the brain
What effects the body’s metabolic response to exercise?
Type of exercise - muscles used
Intensity
Duration
Physical condition and nutritional state of individual
Why is a muscle store of glycogen needed in a 100 m sprint?
To help spare blood glucose as extra glucose cannot be delivered fast enough
How is ATP created once phosphate stores have been used up in a 100m sprint?
Anaerobic glycolysis
How is energy supplied in a 1500m race?
40% anaerobic as some oxygen can be delivered but not enough
Aerobic can use FA and glucose
How much energy is needed in total for a 100m sprint, a 1500m race and a marathon respectively?
30 kJ
500 kJ
10,000 kJ
How is energy supplied in a marathon?
At least 95% aerobic
Muscle and liver glycogen and FA
Describe the timeline of energy usage during a marathon.
Muscle glycogen deleted in mins
Glucose from liver glycogen peaks after ~1 hour and steadily declines
After 20-30 mins use FA in addition
What are the very short term stores of energy for muscle contraction?
ATP Creatine phosphate (using creatine kinase)
What does muscle glycogen produce without using ATP which can be metabolised anaerobically?
Glucose-6-phosphate
Why is muscle glycogen available when blood flow is limited?
Located within muscle fibres so doesn’t need to cross CSM
What limits the capacity of FA usage in providing energy for exercise?
Albumin levels in blood
Carnitine shuttle transporting molecules across mitochondrial membrane
Describe the aerobic and anaerobic metabolism balance in exercise > 20 mins.
0-30 s = 95% anaerobic
2-4 mins = 40-50% anaerobic
>20 mins = 5% anaerobic
Describe the phases of response in the initial sprint, long middle section and finishing sprint of running a race.
Initial sprint: ATP and creatine phosphate
Long middle: glycogen and FA by aerobic metabolism
Finishing sprint: glycogen by anaerobic mechanism
What is needed in order to mobilise energy reserves during exercise?
Insulin to increase the number of GLUT4 to move glucose into muscle cells
How does glucagon stimulate glycogenolysis in the liver?
Stimulates glycogen phosphorylase phosphorylation
Remembering that exercise causes a stress response, what other hormone can stimulate glycogenolysis in the liver by the Salem mechanism as glucagon?
Adrenaline
How do hormones change over the course of running a marathon?
Insulin decreases slowly
Glucagon increases
Adrenaline and growth hormone increase rapidly
Cortisol increases slowly
What is the action of rapid increase of growth hormone levels when running a marathon?
Increases lipolysis which mobilises FA
How does cortisol stimulate gluconeogenesis if exercise is long duration?
Increases PEPCK and fructose-1,6-bishopshate activity
What are the benefits of exercise?
Improve muscle sensitivity to insulin - improve glucose tolerance Better balance of lean tissue and fat Lower blood lipids Lower blood pressure Lower HR for given cardiac output
What are the benefits of exercise to skeletal muscle?
More and bigger fibres Better FA oxidation capacity Increased glucose transport capacity More myoglobin for oxygen storage More capillaries Increased glycogen
Why is reorganisation of maternal metabolism in pregnancy necessary?
So there is a higher concentration of energy and raw materials in maternal circulation so they can diffuse passively and via carrier proteins down a concentration gradient to the developing foetus
What is the usually weight gain in pregnancy and how much of this is attributed to energy stores?
8-10 kg of which ~3 kg is energy
When do maternal energy stores accumulate?
First 20 weeks of pregnancy
When are maternal stores at their highest?
Later pregnancy and during lactation
What is the development of maternal stores under?
Reproductive hormones mainly from the placenta w/some contribution from the ovaries until the 12th week of pregnancy
How does the placenta supersede maternal HPA?
Ability to secrete just about every hormone
How is the foetus adapted to take over maternal metabolism to ensure its own survival?
Via the placenta
How are stores built in the first 20 weeks of pregnancy?
Stimulus to appetite (also go off harmful foods)
Increased action of insulin in storage tissues
Decreased action of insulin in tissues which use energy
Describe the hormone balance in the early half and second half of pregnancy.
Early half = insulin dominant
Second half = anti-insulin dominant
How do the reproductive steroids enable energy store building during pregnancy?
High levels increase sensitivity of beta-cells to blood glucose and increase appetite so more glucose is ingested and there is a specific effect on calorific foods
What do the high levels of oestrogens and progesterone sin pregnancy cause in beta-cells?
Hyperplasia
Hypertrophy
Increased basal and stimulated insulin synthesis
What affect do oestrogens and human placental lactogen have in muscle due to their anti-insulin properties?
Make it resistant to insulin
What is oestriol?
Oestrogen in placenta
Where is progesterone secreted from during pregnancy?
Ovary their high quantities by placenta
What happens to blood glucose levels in pregnancy despite the higher insulin levels?
They are higher in average, especially after meals
What is the advantage of having elevated blood glucose during pregnancy?
Increases glucose gradient so it easier to move across placenta as well as driving into adipose tissue for storage
What happens in gestational diabetes?
Beta-cells do not respond regularly to increased insulin secretion and blood glucose is seriously elevated as extra demand for glucose is met but not controlled
How common is gestational diabetes?
Affects 3-10% of pregnancies
What are the consequences of gestational diabetes?
Maternal effects of hyperglycaemia
Macrosomia (fat baby) w/lots of liver and muscle glycogen
Difficult delivery
Why do you always screen a pregnancy after 24 weeks for gestational diabetes?
Takes a while to develop so may present late and could require C-section
What is the treatment for gestational diabetes?
Careful short-term insulin
What are the possible sequelae of gestational diabetes?
Normally corrects after placental delivery
Can result in T2DM
