metabolic diseases (diabets, porphyria, gauchers, taysahs

Question 1

where is the majority of haem made? WHAT does it use it for?

Answer 1

80% haem made in the liver
used for p450 cytochrome synthesis which aids in detoxification

ethryocytes will use it to make Hb

Question 2

why is VitB6 important in haem biosynthesis?

Answer 2

ALA synthase is an enzyme that needs B6 as a coofactor to catalyse glycine and succinyl coA to create alanine
> this is the RATE limitng step in haem synthesis

Question 3

what are the symptoms of porphoryia

Answer 3

known as vampire disease, can have skin or neurological symptoms
> red bleeding gums
> garlic and drugs and alchohol can exacerbate the disease as they require p450 to detoxify them
> skin photosensitivty as porphrin builds up in blood and deposits into the skin, reacts with o2 = ROS so there is burning in sunlight

Question 4

what causes porphoryia

Answer 4

its an autosomonial dominant disorder where there is A lack of enzymes in the haem biosynthetic pathway

can be recessive too, more severe if deficient in the liver than in RBC

results in accumulation of TOXIC intermediates of the pathway, particularly alanine which can mimic GABA and create ROS and damage DNA

Question 5

how can we treat porphyria

Answer 5

glucose infusions
inject haem which can increase haem levels and then feedback inhibit ALA synthase reducing accumulation of toxin intermediates

Question 6

what do lysosomes do?

Answer 6

can digest unwanted bio molecules (by fusing with endosomes) and old cell organelles (fusing with autophagosomes) using hydrolytic enzymes and involved in waste removal by exocytosis

involved in the degradation of glycoproteins and glycolipids so any abnormalities in this pathway = accumulation of these in the tissues and urine which leads to disease

Question 7

what are gangliosides. where are they found?

Answer 7

group of glycolipids found in the neuronal tissue

made up of ceramide and oligosaccharide

Question 8

what is gauchers disease

Answer 8

autosomal recessive lysosomal disease due to defect in glucocerebrosidase which normally cleaves sugar residue from the ceramide lipid backbone

if glucoceramide accumulated in cells can lead to anaemia, fatigue, bruising and spleen+hepatomegly

Question 9

what influences the disease severity of gaucehrs disease

Answer 9

compound heterozygous disease so depends on which allelles are inherited:
does it result in 0 or 50% enzyme activity?

is it just a SNP or a frameshift mutation

Question 10

how can you treat gauchers disease

Answer 10

treat with enzyme replacement therapy but noncurative, only delays the accumulation of toxic molecules
harder to treat type2 as its neuronal and enzymes cant cross the BBB
> can only treat non-neuropathic gauchers

substrate reducing therapy by preventing synthesis of glucocerebromide but not that effective

Question 11

what is tay sachs disease

Answer 11

another autosomal recessive diease where there is accumualtion of gangliosides but rarer thatn gauchers

most common in infants and incurable

Question 12

what is hunters disease

Answer 12

xlinked recessive where there is an accumulation in GAG as they are unable to be degraded
> large tongue, head, swollen absomen, stiff joints over time

treat with enxyme replacement

Question 13

What is the diffece between a O- and an N- glycosidic bond in glycoproteins?

Answer 13

Hydroxyl group (OH) of aa Reacting with anomeric carbon - O

Or nitrogen grourp of aa reacting with anomeric carbon - N

This is a condensation reaction removing water. This is also a covalent reaction

Question 14

why is type 3 gauchers disease less severe than type 2?

Answer 14

type3- chronic neuropathic | type2 - acute neuropathic

despite having the same proline to lysine substitution, it has been suggested that there are addtional mutation of the GLUCOCEREBROSIDASE which can DELAY accumulation of toxic glucoceremide in neuronal,liver,bone,spleen tissue

so death by 30 instead of 3yrs old

Question 15

what is Mucopolysaccharidosis?

Answer 15

describes diseases where there is an inability to degrade proteoglycans
so instead they accumulate in body tissues and can result in mental retardation, skeletal abnormalities and death
> an example of a mucopolysaccharidosis is HUNTERS DISEASE

Question 16

what is enzyme replacement therapy

Answer 16

using recombinant analogues of enzymes to replace deficient or defective enzymes
> can be expensive
> merely delays the build up of toxic substrates
but can help manage symptoms of lysosomal diseases

Question 17

what is substrate reduction therapy?

Answer 17

a way to treat lysosomal diseases by reducing the synthesis of the toxic intermediate in the first place
> been shown to be not as effective as ERT

Question 18

where does haem biosynthesis take place?

Answer 18

in the erythroblasts (RBC precursor) and hepatocytes (80% production) for p450 production

so a defect of enzymes in the liver will give a more severe disease than if there is a defect of haem biosynthesis in the RBC

Question 19

describe postive and negative regulators of ALA-synthase (haem biosynthesis)?

Answer 19

if there is a decrease in vitb6 (diet) or an increase in haem or haemin byproduct then enzyme activity will decrease = lack of cofactor or feedback inhibition

if there is an increse in alchol, drugs or garlic or iron there will be an increase in ALA-synthase activity to create haem as p450 cytochromes need it to detoxify these substances

Question 20

where are GLUT4 receptors found? how do they get activated?

Answer 20

so as we eat, our BSL increase
this stimulates insulin release to increase expression of GLUT4 transporters on adipocyte and skeletal tissue (myocytes)
uptakes glucose by facilitaed diffusion

FED STATE of the starve-feed daily cycle

Question 21

which of these tissues do not glut3 receptors?
a brain
b liver
c skeletal muscle
d nerves

Answer 21

liver expresses GLUT2 - high km so can uptake a high amount of glucsoe

GLUT3 - low km so this enables constant glucose uptake to the CNS

skeleton and adipocyte express GLUT4

Question 22

which hormones are involved in glucose homeostasis?

Answer 22

insulin - high BSL and will lower it, promotes glycolysis

glucagon - low BSL will increase it by promoting glycogenolysis and lipolysis

Question 23

which organs does gluconeogenesis occur?

Answer 23

liver and kidneys!

gluconeogenesis usually kicks off in the late post-absorptive stage when the glycogen stores are depleted

Question 24

describe the different types of type 1 diabetes

Answer 24

type 1a - immune mediated/autoimmune (85%)
type 1b - idiopathic (no known evidence of autoimmunity), mainly african and asian populations (15%)

usually affects younglings and leads to a decline in B-cell production so very low insulin levels, unable to take up glucose so hyperglycaemic, very high risk of ketoacidosis and muscle wastage as liver in starvation mode

Question 25

explain how a low insulin level results in hyperglycaemia in T1D

Answer 25

as there is a lack of b-cell/insulin, glycogen synthesis is not stimulated in the liver

so processes of glycolysis and gluconeogenesis and lipolysis continue inappropriately

Question 26

explain how diabetes leads to polyuria?

Answer 26

excess glucose (above 12mMol) can overwhelm kindey and is unable to filter it all
so some glucose remains in the Glomreular filtrate, it will increase osmolarity of the filtrate encouring more water to be retained in the filtrate

so this leads to frequent urination and also glucose in urine // also lead to polydipsia

Question 27

how can we detect type1A diabetes

Answer 27

as its autoimmune, we can detect the presence of autoimmune antibodies against the pancreatic cells + insulin before the clinical consequences are seen

we can use ELISA assay to do this// preventative measure

Question 28

why does ketoacidosis occur in T1D but not T2D?

Answer 28

in starvation conditions, if the glycogen stores are depleted, body will use fat stores to generate ketone bodies as main fuel source
> the brain will switch metabolism to utilise these ketone bodies too

but in diabetes, as there is still highBSL, the brain doesn’t undergo this switch so ketone bodies will build up, reducing the blood pH

but in T2D there is some insulin secretion to prevent this

Question 29

HOW CAN WE TREAT TYPE 1 DIABEETS?

Answer 29

as there is beta cell destruction/ decline, there is low insulin SO NEED INSULIN INJECTION TO TREAT

but there is a risk of hypoglycaemia so this needs to be dose controlled to prevent this

Question 30

how does maturity onset of diabetes of young (MODY) differ from T1D

Answer 30

pancreus isn’t destroyed, instead there is a genetic defect in genes controlling insulin secretion

so there is SOME insulin secretion, but rather slowly = transient hyperglycaemia

Question 31

name some points of error in insulin secretion for those with MODY?

Answer 31

could be defective GLUT2
could be defective glucokinase so glucose is not phosphorylated and trapped in cell

could be potassium and calcium channel defect, meaning AP isnt formed and insulin vesicles isn’t stimulated to fuse with membrane - common in newborns

Question 32

why does a mother in pregnancy have transient insulin resistance?

Answer 32

having insulin resitiacne will increase Maternal BSL
this enables the foetus to have a secure glucose supply and prevent mother from becoming hypoglycaemic if inuslin were to be functioning normally

however, if this I-resistance PERSISTS = gestationalD

Question 33

describe the role of TNF-alpha in pregnancy?

Answer 33

secreted by the placenta and can help increase insulin resistance by prevening activation of insulin receptor = less GLUT4 translocation and glycogen synthesis

also placenta secreted HPL hormone which is involved in increasing lipolysis so will also increase BSL

Question 34

describe the link between adiponectin and diabetes

Answer 34

normal function of adiponectin is to increase glucose uptake by activating signal transduction cascades invovled in glygogenesis, lipogenesis, decrease gluconeogenesis

low adiponectin associated with increase in fat mass
so predisposes to type2 diabetes as increases INSULIN RESISTANCE risk

Question 35

how does exercise help to reduce insulin resisitnace?

Answer 35

helps because it can increase expression of GLUT4 transporters allowing skeletal muscle to utilize the glucose
and this will help to reduce insulin resistance

Question 36

how can T2D lead to beta cell failure?

Answer 36

to compensate for high BSL, pancreus will secrete more insulin = hyperinsulinaemia
but this can put strain on the pancreus and lead to damage and Beta-cell failure

Question 37

describe link between obesity and diabetes`

Answer 37

obesity involves ectopic storage of fat in liver and Skeletal muscle, this can activate inflammatory pathways

there is chronic low level inflammation and a high LDL and low adiponectin which can promote insulin resistance

Question 38

how does hyperglycaemia relate to hypertension

Answer 38

excess glucose cannot be taken up by adipose or SKeletal muscle tissue, taken up by GLUT2+ GLUT3 instead
glucose can be shunted down the polyol pathway glu-sorb- fructose)

this creates ROS and reduces NADPH availability meaning synthesis of NO is reduced // can’t vasodilate
addionally sorbitol cannot cross cell membrane so puts osmotic pressure on cells
» high BP can lead to -pathys if blood vessel burst

Question 39

what is HONK? # diabetes

Answer 39

acute complication of T2D
hyperomolar nonketogenic coma
results in extreme dehydration as BSL is very high (hyperosmotic)