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 is the name of the cells that make up 2/3rd of pancreatic islets?

Answer 3

B cells

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 T1 DM?

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 mean the beta cells are 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.

In someone with central adiposity the stressed adipocytes release free FA’s into the blood which interrupts the insulin receptor pathway. This person will need to secrete a lot more insulin to get [BG] back to normal and counteract the insulin resistance. This is why if they have a high dosage of genes disabling them from producing a large quantity of insulin then the pathway will not work and you will get hyperglycaemia

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).

Between basal lamina/collagen and endothelial cell is potential space. Molecules flux into and out from this subendothelial ‘space’

In 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.

This process (arteriolar disease) is also called hyaline change. The basal lamina becomes thickened.

This happens throughout the body and narrows the arterioles 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

Advanced glycosylation end-products form when Glucose is added to proteins (collagen) and a covalent bond forms between them.

Normally albumin can flux out of the endothelial space and back into the blood meaning there is no accumulation of albumin in the subendothelial space of arterioles.

Glycosylated collagen does bind to albumin which results in the accumulation of albumin trapped in the 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 accumulation 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