Pathology of Diabetes Mellitus

Question 1

What is the normal macroscopic appearance of the pancreas?

Answer 1

Lobules of glandular tissue surrounded by fat

Question 2

How does a normal pancreas appear histologically?

Answer 2

• Endocrine part: Islets of Langerhans

- Exocrine part

Question 3

What cells make up 2/3rd of the islets of Langerhans?

Answer 3

B cells

Question 4

What do B cells secrete?

Answer 4

Insulin

Question 5

What stimulates insulin release?

Answer 5

Intake of food which is converted to glucose

Question 6

What is insulin secreted into?

Answer 6

Blood capillaries

Question 7

How does insulin act on various tissues?

Answer 7

Binds to its receptor and drives glucose into the cells

Question 8

What does the glucose metabolism pathway require?

Answer 8

• Increase in glucose
• Increase in insulin
• Increase glucose uptake by cells
• Decrease of glucose in serum

Question 9

What is the aetiology of T1DM?

Answer 9

• Not entirely known
• Genes found so far are molecules that help T cells recognise self from non-self = Human Leukocyte Antigen (HLA) molecules
• Environmental triggers?
  1. Chemicals
  2. Viral infection? Molecules on viral surface mimic molecules on outside of B cells

Question 10

How are the B cells destroyed in T1DM?

Answer 10

• In type 1 DM, 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> decreased insulin
• Genes+ environment leads to destruction of B cells

Question 11

What is the aetiology of T2DM?

Answer 11

• Not entirely known
• Combination of:
  1. Reduced tissue sensitivity to insulin (insulin resistance)
  2. Inability to secrete very high levels of insulin
• Environment

Question 12

What environmental factors contribute to T2DM?

Answer 12

Expanded upper body visceral fat mass

Question 13

What doe expanded upper body visceral fat mass result in?

Answer 13

Results in increased free fatty acids in blood (NOTE, the patient is not yet diabetic) because overweight adipocytes are probably stressed and release fatty acids which leads to decreased insulin receptor sensitivity

Question 14

Why do increased free fatty acids decrease insulin sensitivity?

Answer 14

It is not clear why the increase in fatty acids leads to a decrease in insulin receptor sensitivity

Question 15

What does the decreased insulin sensitivity caused by central obesity result in?

Answer 15

• Now have insulin receptors that do not work very efficiently. Some glucose gets into cells but some does not
• Now need more insulin to get same amount of glucose into cells, so pancreas needs to secrete more insulin to move glucose into cells in person with central adiposity

Question 16

When will diabetes not occur with central obesity?

Answer 16

If the individual can increase their insulin substantially

Question 17

If peripheral insulin resistance is present, how are glucose levels kept normal?

Answer 17

Needs a pancreas that will produce larger quantities of insulin

Question 18

Which genes control insulin secretion in pancreas?

Answer 18

• Many different genes
• Some of these genes control whether you can secrete very large amounts of insulin or not
• If a gene is a variant it may promote insulin production at low levels but not high levels

Question 19

What are the genes involved in T2DM?

Answer 19

• Multiple genes involved in causing inadequate ‘high level’ insulin secretion by B cells
• NOT HLA genes
• NOT adiposity genes
• So if you have only a few genes abnormal you will be able to secrete lots of insulin
• Some patients have many gene variants for lower insulin secretion and cannot produce large amounts of insulin

Question 20

When will T2DM occur?

Answer 20

When there are numerous defective genes for high end insulin secretion and central adiposity which means there is insufficient insulin for the volume of glucose in the plasma

Question 21

What is the essential mechanism of T2DM?

Answer 21

-Insulin secretion does not increase enough to counteract insulin resistance caused by central adiposity

Question 22

When may a slim person develop T2DM?

Answer 22

Slim person who puts on a small amount of weight may get type 1 diabetes if they have very high dosage of genes resulting in inability to even modestly raise insulin

Question 23

What is T2DM?

Answer 23

A multiple gene defect of pancreatic B cell insulin production which is unmasked by central adiposity

Question 24

What are the long term complications of DM?

Answer 24

• 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
• Vessel disease

Question 25

What is the main complication of DM?

Answer 25

Damage to vessels

Question 26

What large vessel disease can DM play a part in?

Answer 26

Atherosclerosis

Question 27

How does DM accelerate atherosclerosis?

Answer 27

- There are many mechanisms proposed - Glucose 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 leads to atherosclerosis

Question 28

How does DM cause small vessel disease?

Answer 28

- Several endothelial cells line lumen of arterioles making basal lamina - Between basal lamina and endothelial cells is a potential space which molecules flux in and out of. - In DM molecules flux into subendothelial space but find it hard to flux back to blood - Build-up of trapped molecules under endothelial cells - Basal lamina also becomes thickened - Subendothelial accumulation of plasma proteins (e.g. albumin) and connective tissue (e.g. collagens)

Question 29

What is arteriolar disease also known as?

Answer 29

Hyaline change

Question 30

What does arteriolar disease lead to?

Answer 30

- Process occurs throughout the body | - Narrow arteriole leads to poor blow flow and ischaemia

Question 31

Where is arteriolar disease especially damaging?

Answer 31

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

Question 32

How does small vessel disease occur?

Answer 32

Via glycosylation in a non-enzymatic mechanism

Question 33

When does small and large vessel disease occur in DM?

Answer 33

It occurs in settings of prolonged, poor diabetic control

Question 34

How is small and large vessel disease cured?

Answer 34

It is irreversible and so cannot be cured

Question 35

How does expanded upper body visceral fat lead to hyperinsulinaemia?

Answer 35

- 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 increase to make glucose go back to normal levels - So in summary, central adiposity leads to hyperinsulinemia

Question 36

Describe the mechanism of glycosylation leading to small vessel disease.

Answer 36

- Collagen=normal basal lamina is glycosylated - Glycosylated collagen binds to albumin which enters the sub endothelial space of arterioles leading to an accumulation of trapped albumin - Glycosylated proteins will also bind to neighbouring proteins via cross-links which cannot be easily removed. - This leads to further persistence of proteins in vessels walls.

Question 37

What does glycosylation of collagen in arterioles lead to?

Answer 37

- Accumulation of trapped plasma proteins | - Accumulation of cross-linked basal lamina