Pathology of Diabetes Mellitus (P.Brown)

Question 1

what is the normal appearance of the pancreas

Answer 1

lobules of glandular tissue surrounded by fat - septae between lobules

Question 2

what are the islets of langerhans

Answer 2

make up the endocrine pancreas - 2/3 of islets cells are B cells that secrete insulin

Question 3

how does insulin act on fat

Answer 3

insulin binds to receptors and drives glucose into adipocytes (fat cells)

Question 4

what is the basic glucose metabolism pathway

Answer 4

increased glucose in plasma = increased insulin = increased glucose uptake by cells = decreased glucose in plasma

Question 5

what is the aetiology of type I DM

Answer 5

• aetiology not entirely known

1. genes + 2. environment = destruction of B cells

Question 6

what are the genes involved in type I

Answer 6

genes that code for molecules that help T cells recognise self from non-self (human leukocyte antigen (HLA) molecules)

Question 7

what happens when there is a faulty gene that then leads to type I

Answer 7

T cells cannot distinguish own cells from other cells - leads to autoimmune attack on pancreatic B cells - destruction of B cells = decreased insulin

Question 8

what kind of environmental triggers are involved in type I

Answer 8

1. ? chemicals

2. ? viral infection - ? molecules on viral surface mimic molecules on outside of B - immune attack

Question 9

what does destruction of B cells cause

Answer 9

decrease in insulin - increase in glucose in plasma

Question 10

what is the aetiology of type 2 DM

Answer 10

• aetiology not entirely known but COMBINATION of:

1. reduced tissue sensitivity to insulin (insulin resistance)
2. inability to secrete very high levels of insulin

ie - failure of B cells to met an increased demand for insulin in the body

Question 11

what type of increased body mass is important in type 2

Answer 11

expanded upper body visceral fat mass (i.e. pot belly) due to increased food intake + lack of exercise (genes not important)

• not just high BMI - specifically weight put on around the abdomen and fat in the momentum inside i.e. doesn’t include the weight many women put on around butt and thighs

Question 12

what does a “pot belly” result in

Answer 12

increased free fatty acids in blood due to “overweight” adipocytes become “stressed” and release fatty acids

(patient not yet diabetic though)

Question 13

what does increased FFA’s in the blood lead to

Answer 13

decreased insulin receptor sensitivity

Question 14

what effect does decreased insulin receptor sensitivity have on the pancreas

Answer 14

Pancreas has to secrete more insulin:
some glucose gets into cells but some does not - needs MORE insulin to get the same amount of glucose into cells

= hyperinsulinaemia (NOT diabetic yet)

Question 15

summarise what happens in hyperinsulinaemia (peripheral insulin resistance) to get blood glucose levels back to normal

Answer 15

decreased insulin receptor sensitivity - decreased removal of glucose from blood - increased glucose levels in blood - increase in section of insulin from pancreas - increased insulin in blood - blood glucose levels return to normal

Question 16

many genes control insulin secretion in the pancreas - what can they determine with regards to this

Answer 16

whether an individual can secrete very large amounts of insulin or not

Question 17

how would a few abnormal genes affect insulin production

Answer 17

can still produce large amounts of insulin

Question 18

how would many abnormal genes affect insulin production

Answer 18

cannot produce large amounts of insulin - implicated genes appear to be or poor B cell “high end” insulin secretion

Question 19

how do many abnormal genes lead to type 2

Answer 19

cannot produce large amounts of insulin - insulin levels not high enough to counteract insulin resistance caused by central adiposity

Question 20

summarise how blood glucose is maintained in people with normal weight

Answer 20

insulin increases - blood glucose deceases - blood glucose normal

Question 21

summarise how type 1 occurs

Answer 21

b cells destroyed - insulin decreases - blood glucose increases - type 1

Question 22

summarise how blood glucose is maintained in people with central adiposity BUT many genes for high end insulin secretion

Answer 22

central adiposity - peripheral insulin resistance - glucose increases - huge increase in insulin - decreases glucose - normal blood glucose

(NOT DIABETIC)

Question 23

summarise how type 2 diabetes occurs

Answer 23

central adiposity + numerous defective genes for high end insulin secretion - glucose increases - insulin levels CANNOT be raised - blood glucose increases - type 2

Question 24

how could a slim person get type 2

Answer 24

many abnormal genes for producing insulin - small weight gain - cannot even modestly raise insulin - type 2

Question 25

what are long term complications of DM

Answer 25

1. life expectancy decreased by 5-10 yrs
2. myocardial infarction commonest cause of death
3. main complications are damage to vessels (large and small)

All arise from poor glycemic control

Question 26

what are large vessel complications of DM

Answer 26

macrovascular - ACCELERATION of atherosclerosis

*does not cause it

Question 27

how does DM accelerate atherosclerosis

Answer 27

causes hyperlipidaemia which leads to atherosclerosis

Question 28

how does hyperlipidaemia come about in DM

Answer 28

increased glucose attaches to low density lipoprotein - stops LDLP from binding to receptor on liver cells - not removed by liver cells - stay in blood = HYPERLIPIDAEMIA

Question 29

what are small vessel complications of DM

Answer 29

microvascular - arteriolar disease (hyaline change), capillary damage

Question 30

what forms the arteriole lining

Answer 30

several endothelial cells that make a basal lamina to “sit on” - around basal lamina smooth muscle cells

Question 31

what lies between the basal lamina and endothelial cells

Answer 31

potential space where molecules flux in and out (at same rate)

Question 32

what happens to the flux of molecules in/out the basal lamina in DM

Answer 32

flux in is bigger than flux out

Question 33

how does this decreased flux out of the potential space lead to arteriolar disease

Answer 33

build up of trapped molecules under endothelial cells (e.g. albumin and collagen) - basal lamina becomes thickened - lumen becomes narrow - leads to poor blood flow = ISCHAEMIA throughout body

Question 34

what areas are particularly damaged by arteriolar disease

Answer 34

kidneys, peripheral tissues (feet), eyes, arterioles supplying nerves

Question 35

what happens to capillaries on small vessel disease

Answer 35

increased connective tissue around capillaries - e.g. glomerulus in kidney

Question 36

what is the mechanism that leads to build up of trapped molecules in the basal lamina

Answer 36

glycosylation - glucose added to proteins

• non-enzymatic
• reversible at first

Question 37

when does glycosylation become irreversible

Answer 37

if covalent bonds form - advanced glycosylation end-products (AGE’s)

Question 38

describe how glycosylation leads to build up of molecules in the basal lamina

Answer 38

collagen in the basal lamina is glycosylated - albumin (+ other proteins) bind to glycosylated collagen - glycosylated proteins also form crosslinks with each other - cannot be easily removed

Question 39

what happens to the cross linked glycosylated proteins in arteriole walls if the body returns to normal blood glucose levels

Answer 39

proteins persist in walls even when blood glucose back to normal due to advanced stage of glycosylation - AGE