Pathology of Diabetes Mellitis and its Complications

Question 1

What is the normal strucutre of the pancreas?

Answer 1

Normal pancreas – lobules of glandular tissue surrounded by fat

Question 2

What is normal insulin secretion in the pancreas done by?

Answer 2

Question 3

2/3 of islet cells are what?

Answer 3

2/3 of islet cells = B cells

Question 4

what do B cells secrete?

Answer 4

insulin

Question 5

What stimulates the release of insulin and where is it secreted into?

Answer 5

Intake of food – converted to glucose = stimulates insulin

Insulin - secreted into blood in capillaries

Question 6

does insulin act on just one tissue type?

Answer 6

no

e.g. muscle, fat

Question 7

what happens when insulin binds to its receptors on adipocytes?

Answer 7

Insulin binds its receptor and drives glucose into adipocytes (= fat cells)

Question 8

hwat is the basic glucose and insulin pathway?

Answer 8

Question 9

what is the aetiology of type I diabetes mellitus?

Answer 9

not entirely known

Question 10

What are genes found so far that may be the aetiology of type I diabetes mellitus and their effect

Answer 10

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

Question 11

what does destruction of islets cause?

Answer 11

decreased insulin

Question 12

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?

Answer 12

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

Question 13

Genes + Environment ——– > Destruction of _____

Answer 13

B cells

Question 14

Destruction of B cells _______ insulin and _________ Glc

Answer 14

decreased

increased

Question 15

what is the aetiology of type II diabetes mellitus?

Answer 15

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

Question 16

What environment is the aetiology of type II diabetes mellitus?

Answer 16

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)

Question 17

What does expanded upper body visceral fat mass (pot belly) result in?

Answer 17

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

Question 18

Expanded upper body visceral fat mass leads to increased free fatty acids which leads to what?

Answer 18

decreased insulin receptor sensitivity

Question 19

Expanded upper body visceral fat mass leads to increased free fatty acids which leads to decreased insulin receptor sensitivity

why?

Answer 19

not clear why the fatty acids interfere with the insulin receptor pathway

Question 20

What happens now someone has insulin receptors that do not work very efficiently due to the central adiposity?

Answer 20

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

Question 21

So pancreas needs to secrete more insulin to move glucose into cells in person with _____ ______

Answer 21

central adiposity

Question 22

Decreased insulin receptor sensitivity in central adiposity – why?

Answer 22

not clear why the fatty acids interfere with the insulin receptor pathway

Question 23

Expanded upper body visceral fat mass leads to decreased insulin receptor sensitivity which then causes _________________________

Answer 23

decreased removal of glucose from blood

Question 24

Decreased removal of glucose from blood
leads to raised glucose, and insulin levels then have to markedly ___________ to make glucose go back to ___________

Answer 24

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

Question 25

central adiposity leads to what?

Answer 25

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

Question 26

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

Answer 26

increased decreased increased

Question 27

If peripheral insulin resistance is present how do we keep glucose levels normal?

Answer 27

Need pancreas that produces more and more insulin

Question 28

Which genes control insulin secretion in pancreas?

Answer 28

Many different genes Some of these genes control whether you can secrete very large amounts of insulin or not

Question 29

What may a persons insulin secretion genes in the pancreas look like if they have type 2 diabetes?

Answer 29

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

Question 30

A

Answer 30

normal glucose

Question 31

B

Answer 31

Type 1 diabetes

Question 32

C

Answer 32

Normal glucose

Question 33

D

Answer 33

type 2 diabetes

Question 34

So in type II diabetes insulin secretion does not _________ enough to counteract insulin _________ caused by \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Answer 34

So in type II diabetes insulin secretion does not **_increase_** enough to counteract insulin **_resistance_** caused by **_central adiposity_**

Question 35

Can a slim person get type 2 diabetes?

Answer 35

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

Question 36

what are the genes involved that cause type 2 diabetes?

Answer 36

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

Question 37

What part of type 2 diabetes is reversible

Answer 37

not genes central adiposity is reversible and by loosing this it will decrease the need for lots of insulin to be needed

Question 38

What is the annual mortality of diabetes

Answer 38

Annual mortality is 5.4% - double the rate of non-diabetics

Question 39

How does DM affect life expectancy?

Answer 39

Life expectancy is decreased by 5-10 years

Question 40

what is the commonest cause of death due to DM

Answer 40

Myocardial infarction is the commonest cause of death

Question 41

Do the long term complications only happen in DM due to certain causes? and what are they caused by?

Answer 41

Occur regardless of the cause of the DM Result from prolonged poor glycaemic control

Question 42

Main complication of DM is damage to vessels but what ones?

Answer 42

* Large vessel disease - Arteries * Small vessel disease - Arterioles and Capillaries

Question 43

What are large vessel (‘macrovascular’) complications of DM?

Answer 43

DM accelerates atherosclerosis Doesn’t cause it, it just accelerates it

Question 44

DM accelerates atherosclerosis and what does this put someone more at this of and by how many times?

Answer 44

* Coronary heart disease 2-20x * Myocardial infarction 2-5x * Atherothrombotic stroke 2-3x

Question 45

How is atherosclerosis accelerated?

Answer 45

many mechanisms

Question 46

How is atherosclerosis accelerated? Name one eg of a mechanism

Answer 46

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

Question 47

Small vessel (‘microvascular’) disease - Arterioles In the photo which is normal and which is not

Answer 47

left is normal right is abnormal

Question 48

What is this showing the structure of? | (lumen is the space in the middle)

Answer 48

arteriole Endothelial cell lines lumen, so the arteriole lining = several endothelial cells

Question 49

Endothelial cells that line the arterile make what to sit on?

Answer 49

basal lamina (collagens) to ‘sit on’

Question 50

Between basal lamina and endothelial cell is what?

Answer 50

a potential space

Question 51

What happens in the space between the basal lamina and endothelial cell

Answer 51

Molecules flux into and out from this subendothelial ‘space’

Question 52

what is found around the basal lamina in an arteriole

Answer 52

smooth muscle cells

Question 53

What happens in arterioles in DM?

Answer 53

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

Question 54

In DM, what also happens to the basal lamina in arterioles?

Answer 54

Basal lamina also becomes thickened

Question 55

histology image showing ateriole in DM

Question 56

Arteriolar disease is also called \_\_\_\_\_\_\_\_\_\_\_

Answer 56

hyaline change

Question 57

arterilar disease is a process that occurs throughout the \_\_\_\_

Answer 57

body

Question 58

Narrow arteriole = poor blood flow = \_\_\_\_\_\_\_\_\_\_

Answer 58

ischaemia

Question 59

where is arteriolar disease very damaging?

Answer 59

Very damaging in kidney, peripheral tissues (foot), eyes and in arterioles supplying nerves

Question 60

what is the relative risk of morbidity is arteriolar disease?

Answer 60

- Amputation 40x - End stage renal disease 25x - Blindness 20x

Question 61

how does small vessel disease affect capillaries?

Answer 61

Increased connective tissue around capillaries – eg. Glomerulus in kidney

Question 62

how many ways can small vessel disease happen?

Answer 62

2 Collagen is glycosylated Proteins are cross-linked

Question 63

Explain how collagen is glycosylated causes small vessel disease?

Answer 63

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

Question 64

what does this image show?

Answer 64

Accumulation of albumin in subendothelial space of arterioles

Question 65

How does cross linking proteins cause small vessel disease?

Answer 65

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

Question 66

Glycosylation leads to what things?

Answer 66

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

Question 67

Large and small vessel disease in DM is: Typically __________ when established Occurs in setting of \_\_\_\_\_\_\_\_\_, ____ diabetic control

Answer 67

irreversible prolonged, poor