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maintenance of a constant internal environment with dynamic equilibrium
failure of homeostasis > disease
describe the HPA axis
- = hypothalmic-pituitary-adrenal axis
- hypothalamus releases CRF/CRH
- CRH/CRF acts on the ant. pituitary gland > ACTH release
- ACTH acts on zona fasiculata of adrenal gland > cortisol release and ACTH inhibits CRH/CRF release
- cortisol > inhibition of ACTH and CRH/CRF release
what tissues are dependant on glucose?
- kidney medulla
- lens of the eye
- CNS prefers glucose
what are the key features of glycolysis?
- no loss of CO2
- glucose is oxidised to pyruvate
- net yield of 2 molecules of ATP
- 1,3 bisphosphoglycerate is used by RBCs to make 2,3 bisphosphoglycerate which is an important regulator in the oxygen affinity of haemoglobin
what happens to pyruvate at the end of glycolysis?
- converted to acetyl-CoA by pyruvate dehydrogenase
- PDH is a multi-enzyme complex
- reaction is non-reversible
- very sensitive to vitamin B deficiency
- regulated : inhibited by high ATP and NADH, activated by high ADP and insulin
what is gluconeogenesis?
- happens in the liver and kidney cortex
- formation of glucose from pyruvate, lactate and glycerol, amino acids if their metabolism included pyruvate or TCA cycle intermediates
- used after glycogen has been used to support glucose dependant tissues
- reverse glycolysis by-passing steps 3 and 10 these are also the sites of control
- - PEPCK - oxaloacetate > PEP increased by glycagon and cortisol and decreased by insulin
- - fructose-1,6-bisphosphatase - increased by glycagon and decreased by insulin
what is oxidative stress?
- during oxidative phosphorylation reactive molecules are produced as a by-product
- mitochondria produce super oxide radicals that give rise to reactive oxygen species
- these can be converted to H2O2 and water but some react with nitric oxide and can then cause damage to membranes
- antioxidants such as glutathione, NADPH, Vit E and C react with them and deactivate them
how, where and why do we store glucose?
- we store glucose as glycogen it is stored in the liver and muscles
- we store it as diet glucose supply is intermittent
- glucose is converted to glycogen the regulating enzyme is glycogen synthase it is inhibited by glucagon and adrenaline and activated by insulin
what are the features of glycogen?
- highly branched glucose polymer
- linked by alpha 1,4 ans alpha 1,6 bonds
- large molecule
- stored in granules
- limited storage as it is highly polar and thus attracts water
how do we get glucose back from glucogen?
a small amount is always preserved
the control step involves glycogen phosphorylase which is activated by glucagon and adrenaline and inhibited by insulin
how is glycerol metabolised?
- taken to liver
- glycerol > glycerol kinase > TAG synthesis OR dihydroxyacetone phosphate (this enters glycolysis)
what happens to excess amino acids?
- broken down
- common key steps =
- - removal of amine group > urea > excreted
- - remaining C skeleton > pyruvate/oxaloacetate/alpha-ketoglutarate/succinate/acetyl-CoA
what are the two mechanisms of nitrogen metabolism?
nitrogen can either undergo transamination - converted to other nitrogen compounds OR deamination and is removed from the body
- mainly in liver
- stimulated by cortisol
- uses transaminase /aminotransferase enzymes to convert into other nitrogen compounds
- ALT/AST are used to measure liver function
- happens in the liver and kidneys
- amino acids converted into ketoacids and ammonia
what is PKU?
- inherited disorder
- large amounts of phenylketones produced from phenylalanine
- phenylalanine hydroxylase enzyme is defective
- phenylalanine accumulates in tissues > inhibition of brain development
- treatment = restricted diet
what are the effects of hyperammonaemia?
- blurred vision
- slurred speech
ammonia is produced by many cells but it is toxic so what do we do with it?
- convert it to urea
- in liver catalysed by 5 enzymes
- the enzymes are effected by the amount of protein in the diet must reintroduce slowly
what is the structure of a lipoprotein particle?
- surface coat and hydrophobic core
- coat contains phospholipids and cholesterol and apoproteins
- core contains TAGs and cholesterol esters
what are the ketone bodies?
acetone is volatile and can be excreted via the lungs
synthesised from acetyl CoA > hydroxy-methyl-glutaryl-CoA > ketone body
pathway activated when insulin:glucagon ratio falls otherwise cholesterol is made.
how are fatty acids metabolised?
- converted into many acetyl-CoA molecules
what are the features of glycogen storage diseases?
- in excess storage - tissue damage
- fasting hypoglycaemia
- exercise intolerance
what are the differences between oxidative and substrate level phosphorylation?
- oxidative requires membrane bound complexes/substrate level requires soluble enzymes
- oxidative cannot occur in the absence of O2
- oxidative is a major process for ATP synthesis/ substrate level is minor
what health risks are associated with being overweight?
- gall bladder disease
- heart disease
what are the major tissues that contribute to BMR?
- skeletal muscle
how much energy do we use in a day?
what components make up this usage?
- BMR + voluntary activities + diet induced thermogenesis
what is BMR?
= 100*weight in Kg
affected by gender, environmental/body temp, endocrine status
what is BMI?
- weight in Kg / (height in m)2
what are the human bodies nutritional requirements?
what are the fat soluble vitamins?
A, D, E, K
What are the major minerals?
K, Na, S, Mg, P, Ca
what are the minor minerals?
Fe, Zn, Se, Cu, Mn, F, Cr, Mo
what are the two types of protein deficiency?
marasmus - protein energy malnutrition > muscle wasting, emanciation, loss of fat, NO oedema, thin dry hair, diarrhoea, anaemia
kwasiorkor - protein malnutrition > anaemia, lethargy, oedema, ascities, re - feeding syndrome
what is coupling?
matching the energy needed for endergonic reactions to the energy produced by exergonic reactions
what is creatine phosphate?
where is it found?
quick releasing energy store found in muscle cells
creatine + ATP > creatine phosphate + ADP
the reaction is catalysed be creatine kinase
what is glycolysis?
- central metabolism pathway for all sugars
- 10 steps
- aerobic glycolysis produces 2 molecules of pyruvate, 2ATP, 2NADH, 2H+, 2WATER
- anaerobic glycolysis produces 2 lactate and 2NAD+
which steps limit glycolysis and which is most important?
1, 3, 10
- 3 is most important
- fructose-6-phosphate > fructose-1, 6-bisphosphate
- catalysed by PFK-phosphofructokinase
how is PFK regulated in muscle/liver?
muscle - allosteric regulation inhibited by high ATP, stimulated by high AMP
Liver - hormonal regulation - insulin stimulates and glucagon inhibits
what is the pentose phosphate pathway?
- not all of the glucose-phosphate made in the first step of glycolysis enters the rest of the glycolysis pathway.
- the PPP is important in RBCs, liver and adipose as it produces NADPH and ribose for the synthesis of nucleotides
what enzyme regulates the PPP?
what are the effects of G6PDH deficiency?
low NADPH > disulphide bridge formation > proteins such as Hb become X-linked
in the case of Hb Heinz bodies form and haemolysis occurs
how is lactose metabolised?
digested by lactase > galactose + glucose
galactose metabolised in liver (kidneys and GIT)
what is galactosaemia and what are the two types?
- inability to utilise galactose
kinase deficient - galactose stored in tissue and it is reduced to galacticol > depletion of NADPH > cataract and gluacoma
transferase deficient - galactose and galactose-1-phosphate accumulate > damage to liver, kidneys and brain
what are the FA derivatives?
- fatty acids
what are the hydroxy-methyl-glutaric acid derivatives?
- ketone bodies
- bile acids
- bile salts
what is acetyl - CoA and why is it important?
- produced in the catabolism of FAs, sugars, alcohol and certain amino acids
- it is important in lipid biosynthesis and can be converted into triacylglycerols, phospholipids, ketone bodies and cholestrol
what are ketones?
- synthesised in the liver mitochondria from acetyl-CoA in a pathway involving hydroxy-methyl-glutaryl-CoA
- they are used to fuel the CNS during starvation but can lead to acidosis
how are lipids transported?
- 2% is FAs bound non-covalently to albumin
- 98% is carried as lipoprotein particles.
- - chylomicrons - transport dietary TAGs to tissues
- - VLDLs -transport TAGs synthesised in the liver to adipose tissue for storage
- - LDLs - transport cholesterol synthesised in the liver to the tissues
- - HDLs - transport excess cholesterol to the liver to be deposited as bile salts
describe lipoprotein metabolism
lipoprotein lipase is found on the inner surface of capillaries in adipose and muscle tissues. it acts on chylomicrons and VLDLs. It hydrolyses TAGs into FAs and glycerol. the FAs are then taken up by the tissue and the glycerol goes to the liver.
LCAT (lecithin cholesterol acytltransferase) stabilises the lipoprotein particle after core lipids have been removed by converting membrane lipid to core lipid
tissues get the cholesterol they need by receptor mediated endocytosis
what does LCAT deficiency cause?
what are the types of hyperlipoproteinaemia?
type 1- raised chylomicrons in fasting plasma - defective lipoprotein lipase
type 2a - raised LDLs - FAMILIAL HYPERCHOLESTEROLAEMIA - defective LDL receptor - severe link with CAD
type 2b - raised LDLs and VLDLs - severe link with CAD
type 3 - raised LDLs and chylomicron reminants - defective apoprotein - link with CAD
type 4 - raised VLDLs - link with CAD
type 5 - raised VLDLs and chylomicrons - link with CAD
what is the treatment for hyperlipoproteinaemia?
- lifestyle - remove cholesterol and reduce fat in diet
- drugs = statins - reduce cholesterol synthesis by inhibiting HMG-CoA reductase or bile sequestrants - increase disposal
describe the tricarboxylic cycle
what does it need?
name the intermediates
- occurs in the mitochondria
- requires FAD and NAD+ and oxaloacetate
- main function is to break C-C bonds in acetate and oxidise the C atoms to CO2
- other functions = intermediates used to make essential amino acids, haem, glucose and FAs. and reduces NAD+ to NADH for use in glycolysis and electron transfer (as well as FADH2)
- regulated by the NADH/NAD+ and ATP/ADP ratios
- acetyl-CoA > citrate > alpha-ketoglutarate > succinate > fumarate > malate> oxaloacetate
what is a anaplerotic reaction ?
- replacing the TCA cycle intermediates
- can be from the break down of amino acids to give C4/5 intermediates
- main replacement = oxaloacetate replaced by the acitivity of pyruvate carboxylase
what is oxidative phosphorylation?
what are the two processes?
- electron transport + ATP synthesis
- re-oxidises NADH and FADH2 and produces lots of ATP
Describe electron transport
- occurs in inner mitochondrial membrane
- electrons transferred through a series of carrier molecules to O2 causing a release in energy
- lots of energy is released as heat - maintaining body temp.
- 30% of the released energy is used to move H+ ions across the membrane
what is the proton motive force?
- membrane is impermeable to H+
- As electron transport proceeds H+ ions increase in concentration outside of the inner membrane
- the PMF is the potential difference of protons
describe ATP synthesis
- ATP synthase allows the H+ ions to cross back across the membrane thus using the energy from the PMF to drive ATP synthesis
- the greater the PMF the more ATP is synthesised
how are the electron transport and ATP synthesis reactions coupled?
- regulated by the concentration of mitochondrial ATP
- When [ATP] is high ATP synthase stops
- H+ ions can't cross back
- [H+] increases outside the membrane -prevents more proton being pumped
- electron transport stops
how do uncouplers work in oxidative phosphorylation?
- increase to membrane permeability to protons
- ET continues but ATP synthase is not active
- lots of heat generated
- occurs in brown adipose tissue
what is the reaction that occurs in brown adipose tissue?
- UCP1 - uncoupling protein
- in response to cold NA activate lipase > release of FAs from TAGs
- FAs activate UCP1
- extra heat is generated
what are the characteristics of a control system?
- control centre
negative feedback allows control
describe drug metabolism
- function = deactivate and eliminate
- phase 1 - occurs mainly in the liver, exposing/adding reactive groups - P450 cytochrome enzymes
- phase 2 - still in liver, glucuronidation/sulphate conjugation/glutathione conjugation
what is a hormone?
- chemical messenger
- released by endocrine gland
- travels in blood stream
how are hormones classified?
- PEPTIDE - insulin, glucagon, growth hormone
- GLYCOPROTEIN - LH, FSH, TSH, adrenaline
- STERIOD - (derived from cholesterol) cortisol, aldosterone, testosterone, oestrogen
describe the metabolic response to feeding
- absorption of glucose, aas, and lipids from the GIT raises their blood concentration
- as blood glucose rises the endocrine pancreas releases insulin
describe the metabolic response to fasting
- insulin secretion is depressed
- glucose uptake by muscle and adipose tissue is depressed
- falling blood glucose stimulates glucagon > glycogenolysis + lipolysis
- gluconeogenosis begins to increase
describe the metabolic response to starvation (fasting beyond 10hrs)
- insulin continues to fall
- glucagon, cortisol and growth hormone rise > ketogenesis in the liver
describe the metabolic response to pregnancy
- 1st half - insulin/anti-insulin inc > anabolic state > preparing of stores
- 2nd half - mother switches to FAs increasing glucose availability for the child
failure to meet insulin demand = gestational diabetes
describe the metabolic response to alcohol intake
- inc. lactate
- low pyruvate > lack of gluconeogenesis > fasting hypoglycaemia
- inc acetyl-CoA with low lipoprotein > fatty liver
describe the metabolic response to exercise
marathon - slow changes (insulin down, adrenaline/glucagon/cortisol up) - aerobic
sprint - anaerobic, rapid response to increased adrenaline and NA - high lactate and H+ > fatigue
what are the actions of insulin?
- inc glucogenesis
- dec glucogenolysis
- inc glycolysis
- dec ketogenesis
- dec lipolysis
- inc aa uptake and protein synthesis
- inc glucose transfer
what are the actions of glucagon?
- inc glycogenolysis
- dec glycogenosis
- inc gluconeogenesis
- inc ketogenesis
- inc lipolysis
what is metabolic syndrome?
- pattern of symptoms in obese adults
- insulin resistance
- dyslipidaemia - high cholesterol
- impaired glucose tolerance
how is appetite controlled?
- appetite centre at base of hypothalamus
- 2 types of neurones:
- - primary - sense glucose,FAs and hormones in blood
- - secondary - co-ordinate response
- primary neurones can be excitatory or inhibitory
- excitatory neurones stimulate appetite and inhibitory release either Bendorphins (rewards) or alpha - MSH (suppresses appetite)
- ghrelin - peptide released from walls of empty stomach > stimulates appetite
- PYY - peptide released from SI wall - suppresses appetite
- leptin - released from adipocytes - suppresses appetite (deficiency > gross obesity)
- amylin - released from pancreas beta cells - suppress appetite
describe the pituitary gland
- base of brain below hypothalamus
- produces hormones: TSH, ACTH, LH, FSH, prolactin, growth hormone
describe the adrenal glands
- located on top of kidneys
- have outer cortex and inner medulla
what is cortisol and what are its actions?
- lipophillic steriod hormone
- transported around the body bound to plasma proteins
- important in stress and starvation
- decreases aa uptake and protein synthesis and increases proteolysis
- increases hepatic gluconeogenesis and glycogenesis
- decresases peripheral glucose uptake
- increases lipolysis
its release is controlled by the HPA axis
what is addisons disease?
- low cortisol
- can be caused by destruction of cortex or problem with control
- > low BP, hyperpigmentation of the skin, tiredness, weakness
what is cushing's disease?
- high cortisol
- can be caused be adenoma in the pituitary gland, ectopic ACTH...
- > proximal muscle wasting, rapid weight gain, moon face, hyperglycaemia, hypertension
describe the thyroid gland
- lower larynx
- butterfly shape - two lobes + central isthmus
- produces T3/4 and calcitonin
- calcitonin produced in parafollicular cells, thyroxin and idothyronine produced in follicular cells
hypothalamus releases TRH > pituitary releases TSH > follicular cells release t3/4
what do the thyroid hormones do?
- inc BMR
- normal growth and repair
- GI motility
what happens if thyroid hormones not present at birth?
what is hasimoto's disease?
- autoimmune destruction of follicles
- treat with oral T4
what is graves disease?
- antibodies stimulateproduction of T3/4
- treat with carbamizide
what are the symptoms of hypothyroidism?
- husky voice
- dry skin
- cold intolerance
what are the symptoms of hyperthyroidism?
- weight loss
- tiredness, weakness, SOB#
what are the clinical complications of diabetes?
- macrovascular - inc risk of stroke, MI, poor blood flow to the feet
- microvascular - diabetic eye, neuropathy, nephropathy, diabetic feet
what are the consequences of persistent hyperglycaemia?
excess glucose in peripheral nerves, eyes and kidneys > formation of sorbitol > osmotic damage to cells
HbA1c should be 4-6%
describe type 1 diabetes
- affecting B cells in pancreas
- triad of symptoms : polydipsia, polyuria, weightloss
- treat with insulin
describe type 2 diabetes
- disorder of secretion or resistance
- symptoms: may have triad, tiredness, lack of energy, persistent infections, slow healing, visual problems
- diagnosis = random glucose > 11.1mmol/l or fasting glucose > 7 mmol/l
- management = lifestyle, hypoglycaemia drugs, insulin
what is the cause of hyperparathyroidism?
- malignant - PTHrp - small cell lung cancer - mimicks PTH
- primary - adenoma, hyperplasia,carcinoma
- secondary - low vit D intake, chronic renal failure
- tertiary - after prolonged secondary
what is the cause of hypoparathyroidism?
- primary - autoimmune
- secondary - radiation/surgery
symptoms of primary hypoparathyroidism
- pins and needles
- muscle cramps
what are the causes of hypocalcaemia?
- chronic renal failure (raised phosphate)
- vit d deficiency
what are the symptoms of hypocalcaemia?
what are the causes of hypercalcaemia?
what are the symptoms of hypercalcaemia?
- ab pain
- weight loss
- renal stones
- renal failure
- cardiac arrest
what is involved in maintaining serum calcium?
- 3 organ systems - bone, kidney, GIT
- 3 hormones - calcitriol, calcitonin, PTH
describe the parathyroid glands
- structure - often 4, 2 cell types: cheif cells produce PTH and oxyphil cells
- location - posterior thyroid gland