Pathology of Diabetes Mellitus and Its Complications

Question 1

Which part of the pancreas is responsible for insulin secretion?

Answer 1

Islets of langerhans

Question 2

What is the tissue of the normal pancreas?

Answer 2

Lobules of glandular tissue surrounded by fat

Question 3

What portion of the islet cells are beta cells?

Answer 3

2/3rds

Question 4

What is the aetiology of type 1 diabetes?

Answer 4

•Autoimmune attack on islet cells – lymphocyte infiltration of islets (insulitis) – destruction of B cells

Genes found so far: •Molecules that help T cells recognise self from non-self = Human Leukocyte Antigen (HLA) molecules

Question 5

What is a potential environmental cause of diabetes?

Answer 5

Chemicals?

Viral infection?

Molecules on viral surface can mimic molecules on the outside of Beta cells

Question 6

What is the aetiology of type 2 diabetes mellitus?

Answer 6

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

Question 7

How do insulin receptors become ineffective in type 2 diabetes?

Answer 7

1. Expanded upper body visceral fat mass (Too much food and not enough exercise)
2. Resulting increase in free fatty acids because the adipocytes are probably stressed and release fatty acids
3. Fatty acids interfere with the insulin receptor pathway (peripheral insulin resistance)
4. Pancreas needs to secrete more insulin to move glucose in person (hyperinsulinaemia)
5. Genes involved are the beta cells uncapable of mass unsulin secretion (variant genes)
6. A patient with lots of these genes cannot produce large amounts of insulin
7. Insulin secretion does not increase enough to counteract the insulin resistance caused by the central adiposity

Question 8

NOTE:

Answer 8

•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 9

What is the most common cause of death in diabetes mellitus?

Answer 9

MI

Question 10

What causes the long term complications of diabetes?

Answer 10

Poor glycaemic control

Question 11

What is the main complication of DM?

Answer 11

Damage to vessels including:

Arteries

Arterioles

Capillaries

(accelerates atherosclerosis)

Question 12

How is atherosclerosis accelerated in DM?

Answer 12

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 therefore lipoprotein and lipid stay in blood which leads to Hyperlipidaemia

ATHEROSCLEROSIS

Question 13

What is disease called in the arteries, arterioles and capillaries?

Answer 13

Arteries: Large vessel disease (atherosclerosis)

Arterioles and Capillaries: Small vessel Disease

Question 14

How does small vessel disease arise?

Answer 14

Arteriole lining is composed of several endothelial cells which sit on a basal lamina (collagen).

Around the basal lamina are smooth muscle cells

Between basal lamina and endothelial cell is potential space

Molecules flux into and out from this subendothelial ‘space’

Diabetes Mellitus – molecules flux into subendothelial space but find it hard to flux back to blood, there is a build up of trapped molecules (plasma proteins e.g albumin and connective tissues e.g collagens) under the endothelial cell

The process (arteriolar disease) is also called hyaline change

The basal lamina also becomes thickened

Happens throughout the body and narrows the arteriole causing poor blood flow and ischaemia

Question 15

Where is arteriolar disease very damaging?

Answer 15

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

Question 16

What is the role of advanced glyocosylation end-products in small vessel disease?

Answer 16

Glucose is added to proteins (collagen) - called glycosylation

Non-enzymatic and is initially reversible however it is irreversible once covalent bonds have formed (Advanced glycosylation end-products)

Normally albumin can flux out of the endothelial space meaning there is no accumulation of albumin in subendothelial space of arterioles

Glycosylated collagen does bind to albumin, accumulation of albumin in subendothelial space of arterioles

Question 17

What is the role of cross linking in small vessel disease?

Answer 17

Basal lamina proteins become cross linked as a result of glycosylation, meaning the protein can no longer be easily removed

These proteins persist in the walls of the arteriole even in normoglycaemia

Small artery disease comes from the combination of acumulation of trapped plasma proteins and accumulation of cross-linked basal lamina proteins

Question 18

When does large and small vessel disease typically occur and is it reversible?

Answer 18

• Occurs in setting of prolonged, poor diabetic control
• Typically irreversible when established