metabolic diseases (diabets, porphyria, gauchers, taysahs Flashcards
where is the majority of haem made? WHAT does it use it for?
80% haem made in the liver
used for p450 cytochrome synthesis which aids in detoxification
ethryocytes will use it to make Hb
why is VitB6 important in haem biosynthesis?
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
what are the symptoms of porphoryia
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
what causes porphoryia
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
how can we treat porphyria
glucose infusions
inject haem which can increase haem levels and then feedback inhibit ALA synthase reducing accumulation of toxin intermediates
what do lysosomes do?
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
what are gangliosides. where are they found?
group of glycolipids found in the neuronal tissue
made up of ceramide and oligosaccharide
what is gauchers disease
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
what influences the disease severity of gaucehrs disease
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
how can you treat gauchers disease
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
what is tay sachs disease
another autosomal recessive diease where there is accumualtion of gangliosides but rarer thatn gauchers
most common in infants and incurable
what is hunters disease
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
What is the diffece between a O- and an N- glycosidic bond in glycoproteins?
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
why is type 3 gauchers disease less severe than type 2?
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
what is Mucopolysaccharidosis?
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
what is enzyme replacement therapy
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
what is substrate reduction therapy?
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
where does haem biosynthesis take place?
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
describe postive and negative regulators of ALA-synthase (haem biosynthesis)?
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
where are GLUT4 receptors found? how do they get activated?
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
which of these tissues do not glut3 receptors? a brain b liver c skeletal muscle d nerves
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
which hormones are involved in glucose homeostasis?
insulin - high BSL and will lower it, promotes glycolysis
glucagon - low BSL will increase it by promoting glycogenolysis and lipolysis
which organs does gluconeogenesis occur?
liver and kidneys!
gluconeogenesis usually kicks off in the late post-absorptive stage when the glycogen stores are depleted
describe the different types of type 1 diabetes
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
explain how a low insulin level results in hyperglycaemia in T1D
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
explain how diabetes leads to polyuria?
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
how can we detect type1A diabetes
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
why does ketoacidosis occur in T1D but not T2D?
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
HOW CAN WE TREAT TYPE 1 DIABEETS?
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
how does maturity onset of diabetes of young (MODY) differ from T1D
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
name some points of error in insulin secretion for those with MODY?
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
why does a mother in pregnancy have transient insulin resistance?
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
describe the role of TNF-alpha in pregnancy?
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
describe the link between adiponectin and diabetes
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
how does exercise help to reduce insulin resisitnace?
helps because it can increase expression of GLUT4 transporters allowing skeletal muscle to utilize the glucose
and this will help to reduce insulin resistance
how can T2D lead to beta cell failure?
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
describe link between obesity and diabetes`
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
how does hyperglycaemia relate to hypertension
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
what is HONK? # diabetes
acute complication of T2D
hyperomolar nonketogenic coma
results in extreme dehydration as BSL is very high (hyperosmotic)
