Pathology of Diabetes Mellitis and its Complications Flashcards
What is the normal strucutre of the pancreas?
Normal pancreas – lobules of glandular tissue surrounded by fat
What is normal insulin secretion in the pancreas done by?
2/3 of islet cells are what?
2/3 of islet cells = B cells
what do B cells secrete?
insulin
What stimulates the release of insulin and where is it secreted into?
Intake of food – converted to glucose = stimulates insulin
Insulin - secreted into blood in capillaries
does insulin act on just one tissue type?
no
e.g. muscle, fat
what happens when insulin binds to its receptors on adipocytes?
Insulin binds its receptor and drives glucose into adipocytes (= fat cells)
hwat is the basic glucose and insulin pathway?
what is the aetiology of type I diabetes mellitus?
not entirely known
What are genes found so far that may be the aetiology of type I diabetes mellitus and their effect
Molecules that help T cells recognise self from non-self = Human Leukocyte Antigen (HLA) molecules
And in type 1 diabetes they cannot distinguish own cells from other cells = autoimmune attack on pancreatic B cells
Autoimmune attack on islet cells – lymphocyte infiltration of islets (insulitis) – destruction of B cells
what does destruction of islets cause?
decreased insulin
It is thought that environemtnal tirggers may play a part in causing type 1 diabetes
What are some environmental tirggers that may be involved in causing type 1 diabetes?
Chemicals
Bacteria in gut altered in infancy - People with different bacteria in their gut when their 6 months old may have an increased chance of having type 1 diabetes
Viral infection - Molecules on viral surface mimic molecules on outside of B cells
Genes + Environment ——– > Destruction of _____
B cells
Destruction of B cells _______ insulin and _________ Glc
decreased
increased
what is the aetiology of type II diabetes mellitus?
Not entirely known
Combination of:
- 1) reduced tissue sensitivity to insulin (insulin resistance) and
- 2) inability to secrete very high levels of insulin
Another way of putting it = a failure of the B cells to meet an increased demand for insulin in the body
What environment is the aetiology of type II diabetes mellitus?
Expanded upper body visceral fat mass (pot belly)
central adiposity = accumulation of fat in the lower torso around the abdominal area
Expanded upper body fat mass is due to increased intake of food + lack of exercise (genes relatively unimportant)
What does expanded upper body visceral fat mass (pot belly) result in?
Expanded upper body visceral fat mass (pot belly) results in increased free fatty acids in blood (Note - patient is not yet diabetic)
because ‘overweight’ adipocytes are probably ‘stressed’ and release fatty acids
Expanded upper body visceral fat mass leads to increased free fatty acids which leads to what?
decreased insulin receptor sensitivity
Expanded upper body visceral fat mass leads to increased free fatty acids which leads to decreased insulin receptor sensitivity
why?
not clear why the fatty acids interfere with the insulin receptor pathway
What happens now someone has insulin receptors that do not work very efficiently due to the central adiposity?
Some glucose (Glc) gets into cells but some does not
Not working very well so one glucose gets in and one doesn’t and then more insulin in blood as there is excess glucose and you need more insulin to make that glucose go into cells
Now need more insulin to get same amount of glucose into cells so the pancreas needs to secrete more insulin to move glucose into cells
So pancreas needs to secrete more insulin to move glucose into cells in person with _____ ______
central adiposity
Decreased insulin receptor sensitivity in central adiposity – why?
not clear why the fatty acids interfere with the insulin receptor pathway
Expanded upper body visceral fat mass leads to decreased insulin receptor sensitivity which then causes _________________________
decreased removal of glucose from blood
Decreased removal of glucose from blood
leads to raised glucose, and insulin levels then have to markedly ___________ to make glucose go back to ___________
increase
normal levels
This is what is happening in people with central adiposity so they have high insulin but not yet diabetic as they have enough intact cells to be able to produce more insulin
central adiposity leads to what?
hyperinsulinaemia
if you were to measure the levels in someone with central adiposity who is not diabetic they would have increased insulin levels due to having to secreate more in order to compensate for the increased glucose in the blood
expanded upper body visceral fat mass leads to peripheral insulin resistance
So need _______ insulin to cope with _______ tissue sensitivity to insulin
No diabetes will occur if can _______ insulin substantially
increased
decreased
increased
If peripheral insulin resistance is present how do we keep glucose levels normal?
Need pancreas that produces more and more insulin
Which genes control insulin secretion in pancreas?
Many different genes
Some of these genes control whether you can secrete very large amounts of insulin or not
What may a persons insulin secretion genes in the pancreas look like if they have type 2 diabetes?
If gene is a variant it may promote insulin production at low levels but not high levels
Implicated genes are for poor B cell ‘high end’ insulin secretion
So if you have only a few genes abnormal you will be able to secrete lots of insulin but if you have many gene variants for lower insulin secretion then you cannot produce large amounts of insulin
this is bad in a person with increasing central adiposity meaning they will have peripheral insulin resistance and therefore require more insulin to keep the level of glucose at normal levels
A
normal glucose
B
Type 1 diabetes
C
Normal glucose
D
type 2 diabetes
So in type II diabetes insulin secretion does not _________ enough to counteract insulin _________ caused by ___________________
So in type II diabetes insulin secretion does not increase enough to counteract insulin resistance caused by central adiposity
Can a slim person get type 2 diabetes?
Yes
Slim person who puts on a small amount of weight may get type II diabetes if they have very high dosage of genes resulting in inability to even modestly raise insulin
what are the genes involved that cause type 2 diabetes?
Multiple genes involved in causing inadequate ‘high level’ insulin secretion by B cells
Not HLA genes
Not adiposity genes
A multiple gene defect of pancreatic B cell insulin production which is unmasked by central adiposity
What part of type 2 diabetes is reversible
not genes
central adiposity is reversible and by loosing this it will decrease the need for lots of insulin to be needed
What is the annual mortality of diabetes
Annual mortality is 5.4% - double the rate of non-diabetics
How does DM affect life expectancy?
Life expectancy is decreased by 5-10 years
what is the commonest cause of death due to DM
Myocardial infarction is the commonest cause of death
Do the long term complications only happen in DM due to certain causes? and what are they caused by?
Occur regardless of the cause of the DM
Result from prolonged poor glycaemic control
Main complication of DM is damage to vessels but what ones?
- Large vessel disease - Arteries
- Small vessel disease - Arterioles and Capillaries
What are large vessel (‘macrovascular’) complications of DM?
DM accelerates atherosclerosis
Doesn’t cause it, it just accelerates it
DM accelerates atherosclerosis and what does this put someone more at this of and by how many times?
- Coronary heart disease 2-20x
- Myocardial infarction 2-5x
- Atherothrombotic stroke 2-3x
How is atherosclerosis accelerated?
many mechanisms
How is atherosclerosis accelerated?
Name one eg of a mechanism
Glucoses attach to low density lipoprotein
Glucose molecules stop low density lipoprotein from binding its receptor (on liver cells) tightly
Low density lipoprotein is not removed by liver cells = lipoprotein and lipid stay in blood = Hyperlipidaemia
Hyperlipidaemia = Atherosclerosis
Small vessel (‘microvascular’) disease - Arterioles
In the photo which is normal and which is not
left is normal
right is abnormal
What is this showing the structure of?
(lumen is the space in the middle)
arteriole
Endothelial cell lines lumen, so the arteriole lining = several endothelial cells
Endothelial cells that line the arterile make what to sit on?
basal lamina (collagens) to ‘sit on’
Between basal lamina and endothelial cell is what?
a potential space
What happens in the space between the basal lamina and endothelial cell
Molecules flux into and out from this subendothelial ‘space’
what is found around the basal lamina in an arteriole
smooth muscle cells
What happens in arterioles in DM?
molecules flux into subendothelial space but find it hard to flux back to blood
Which leads to a build up of ‘trapped’ molecules under endothelial cell
In DM, what also happens to the basal lamina in arterioles?
Basal lamina also becomes thickened
histology image showing ateriole in DM
Arteriolar disease is also called ___________
hyaline change
arterilar disease is a process that occurs throughout the ____
body
Narrow arteriole = poor blood flow = __________
ischaemia
where is arteriolar disease very damaging?
Very damaging in kidney, peripheral tissues (foot), eyes and in arterioles supplying nerves
what is the relative risk of morbidity is arteriolar disease?
- Amputation 40x
- End stage renal disease 25x
- Blindness 20x
how does small vessel disease affect capillaries?
Increased connective tissue around capillaries – eg. Glomerulus in kidney
how many ways can small vessel disease happen?
2
Collagen is glycosylated
Proteins are cross-linked
Explain how collagen is glycosylated causes small vessel disease?
Collagen is in normal basal lamina
Albumin can sometimes get into subendothelial space and normal collagen does not bind albumin
albumin fluxes out of space - no accumulation of albumin in subendothelial space of arterioles
But glycosylated collagen does bind albumin leading to accumulation of albumin in subendothelial space of arterioles
Albumin is trapped in subendothelial space
what does this image show?
Accumulation of albumin in subendothelial space of arterioles
How does cross linking proteins cause small vessel disease?
Many normal basal lamina proteins do not crosslink and can be removed easily
But glycosylated proteins bind their neighbouring proteins
Rigid, cross-linked protein cannot easily be removed
Persistence of proteins in arteriole walls even if return to normoglycaemia
Glycosylation leads to what things?
Accumulation of trapped plasma proteins
+
Accumulation of cross-linked basal lamina proteins
Arteriole with hyaline change, less compliant, doesn’t open as easy and doesn’t squeeze as easy
Large and small vessel disease in DM is:
Typically __________ when established
Occurs in setting of _________, ____ diabetic control
irreversible
prolonged, poor
