Pathology of Diabetes Mellitus

Question 1

What is the pancreas composed of?

Answer 1

Lobules of glandular tissue surrounded by fat

Question 2

What part of the pancreas is the endocrine pancreas?

Answer 2

Islets of Langerhans

Question 3

How many of the Islet of Langerhan cells are B cells?

Answer 3

2/3

Question 4

What does insulin do?

Answer 4

Acts on many tissues, such as fat, where is binds to its receptor and drives glucose into the cell

Question 5

Explain the pathway of increases glucose in plasma leading to glucose decreasing?

Answer 5

Question 6

What genetic relationship to the aetiology of type 1 diabetes has been found?

Answer 6

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

So, in type 1 diabetes cannot distinguish own cells from other cells so autoimmune attack on B cells

Question 7

What does the autoimmune attack on B cells in type 1 diabetes cause?

Answer 7

Lymphocyte infiltration of islet (insulitis) leading to destruction of B cells causing decreases insulin production

Question 8

What environmental triggers are possible linked to type 1 diabetes?

Answer 8

? Chemicals

? Bacteria in gut altered in infancy

? Viral infection (molecules on viral surface mimic molecules on outside of B cells)

Question 9

What is the aetiology of type 2 diabetes?

Answer 9

Combination of:

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

Question 10

What is a major risk factor for type 2 diabetes?

Answer 10

Explanded upper body visceral fat (pot belly)

also called central adiposity, which is how men and woman after menopause put on weight

Question 11

What does central adiposity occur due to?

Answer 11

Increased intake of food and lack of exercise (genes relatively unimportant)

Question 12

How does pot belly lead to type 2 diabetes?

Answer 12

Causes increased free fatty acids in blood (patients not yet diabetic) which causes decreases insulin receptor sensitivity

So more insulin is needed to get same amount of glucose into cells

Pancreas reaches point where cannot secrete enough insulin

Question 13

What does central adiposity lead to?

Answer 13

Hyperinsulinaemia

Question 14

What are the genetic risks to get type 2 diabetes?

Answer 14

Multiple genes involved in causing inadequate “high level” insulin secretion by B cells

Not HLA genes

Not adiposity genes

Question 15

What is the link between a gene variant of B cells and type 2 diabetes?

Answer 15

If gene is a variant may promote insulin production at low levels but not high levels, which is needed when there is a decreases receptor sensitivity to insulin

So genes involved in type 2 diabetes are ones for poor B cell ‘high end’ insulin secretion

(if have few abnormal genes can still produce lots of insulin, if may genes are abnormal cannot)

Question 16

In type 1 and type 2 diabetes is anything wrong with insulin receptors?

Answer 16

Type 1 - nothing wrong with receptors, problem is destruction of B cells and decreased insulin production

Type 2 - problem with receptors, decreased insulin sensitivity (occurs because central adiposity causes receptor complex to not work so insulin cannot bind tightly)

Question 17

What is the annual mortality of people with diabetes?

Answer 17

5.4%, double what people with no diabetes is

Question 18

How does life expectancy change due to diabetes?

Answer 18

Decreased by 5-10 years

However, this is not accurate as there are two groups - well managed whos life expectancy barely changes and not well managed whos life expectancy massively drops

Question 19

What is the commonest cause of death for people with diabetes?

Answer 19

Myocardial infarction

Question 20

What do long term complications in diabetes occur due to?

Answer 20

Prolonged poor glycaemic control

Question 21

What is the main complication in diabetes?

Answer 21

Damage to vessels:

• macrovascular complications
• microvascular complications

Question 22

What is a macrovascular complication of diabetes?

Answer 22

Accelerates atherosclerosis (does not cause it but accelerates it)

Question 23

What mechanism explains diabetes accelerating atherosclerosis?

Answer 23

Lots of glucose attaches to LDL (low density lipoprotein) due to more than normal levels

Stopping it binding to its receptor on liver cells tightly

So LDL is not removed and stays in blood, causing hyperlipidaemia then atherosclerosis

Question 24

What is a microvascular complication of diabetes in arterioles?

Answer 24

Molecules flux into subendothelial space but find it hard to flux back to blood

Causing build up of trapped molecules under endothelial cells, basal lamina becomes thickened

Question 25

Where do microvascular complications due to diabetes (in arterioles) often occur?

Answer 25

Kidneys, peripheral tissues (foot), eyes and arterioles supplying nerves

Question 26

What are microvascular complications of diabetes in capillaries?

Answer 26

Collagen glycosylation

Cross linked proteins

Question 27

What is the mechanism of collagen glycosylation?

Answer 27

Glucose added to proteins (which is non-enzymatic reversible at first, but irreversible if covalent bonds form - advanded glycosylation end products (AGEs)

Collagen is glycosylated, collagen is in normal basal lamina and albumin can sometimes get into subendothelial space, albumin does not normally combine with collagen and fluxes out of space with no accumulation

But glycosylated collagen does bind to albumin causing accumulation

Question 28

What is teh mechanism of cross linked proteins?

Answer 28

Many normal basal lamina proteins do not cross link and can be removed easily

But glycosylated proteins bind their neighbouring proteins

Rigid, crosslinked proteins cannot easily be removed, causing persistence of protein in arteriole wall

Question 29

What is arteriolar disease also called?

Answer 29

Hyaline change

Question 30

What does hyaline change cause?

Answer 30

Narrows arteriole causing poor blood flow and then ischaemia

Question 31

Is microvascular and macrovascular damage reversible?

Answer 31

Is typically irreversible ones it is established, but can stop the decline if achieve good glycaemic control