Pathology of diabetes mellitus complications

Question 1

What is the aetiology of type 1 diabetes mellitus?

Answer 1

• Not entirely known
• Genes found so far =
  * Molecules that help T cells recognise self from non-self= Human Leukocyte Antigen (HLA) molecules
• Autoimmune attack on islet cells –> lymphocyte infiltration of islets (insulitis) –> destruction of B cells
• Environment - ? Environmental triggers:
  * ? Chemicals
  * ? Viral infection - ? Molecules on viral surface mimic molecules on outside of B cells

Question 2

What is the aetiology of type 2 diabetes mellitus?

Answer 2

• Not entirely known
• Combination of:
  1) reduced tissue sensitivity to insulin (insulin resistance)
  2) inability to secrete very high levels of insulin
• Environment: Expanded upper body fat mass is due to increased intake of food + lack of exercise (genes relatively unimportant)
• Genes: Multiple genes involved in causing inadequate ‘high level’ insulin secretion by B cells

Question 3

Why is it that an expanded upper body mass results in type 2 diabetes mellitus?

Answer 3

• Results in increased free fatty acids in blood
• because ‘overweight’ adipocytes are probably ‘stressed’ and release fatty acids
• leads to decreased insulin receptor sensitivity
• not clear why the fatty acids interfere with the insulin receptor pathway
• Now have insulin receptors that do not work very efficiently (some glucose gets into the cell but some does not)
• need more insulin to get same amount of glucose into cells
• pancreas needs to secrete more insulin to move glucose into cells

Question 4

What are the long term complications of DM?

Answer 4

• Annual mortality is 5.4% (double the rate of non-diabetics)
• Life expectancy is decreased by 5-10 years
• Myocardial infarction is the commonest cause of death
• Occur regardless of the cause of the DM
• Result from prolonged poor glycaemic control

Question 5

What is the main complication of DM?

Answer 5

• Damage to vessels
• Small vessel disease (arterioles and capillaries)
  ~ accelerates athersclerosis
• Large vessel disease (arteries)

Question 6

What are happens due to accelerated atherosclerosis?

Answer 6

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

Question 7

How is atherosclerosis accelerated? (give one example of a mechanism)

Answer 7

• 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
• This results in atherosclerosis

Question 8

What happens that causes small vessel disease in DM?

Answer 8

• Molecules flux into subendothelial space but find it hard to flux back to blood
• Build up of ‘trapped’ molecules under endothelial cell
• Basal lamina also becomes thickened

Question 9

What is the relative risk of morbidity in small vessel disease?

Answer 9

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

Question 10

How does small vessel disease occur in DM? (give one example of a mechanism)

Answer 10

• Glucoses added to proteins = glycosylation
• Non-enzymatic
• Reversible at 1st
• Irreversible if covalent bonds= Advanced Glycosylation End-products (AGE’s)
• Glycosylation
  1) Accumulation trapped plasma proteins
  2) Accumulation of cross linked basal lamina proteins