Pathology of Diabetes Mellitus

Question 1

What are the endocrine parts of the pancreas?

Answer 1

Islets of Langerhans

Question 2

What does 2/3rd of the islets consist of?

Answer 2

B cells

Question 3

What is the role of beta cells?

Answer 3

Secrete insulin

Question 4

What are HLA molecules?

Answer 4

Molecules that help T cells recognise self from non-self

Question 5

What is the pathophysiology of type 1 diabetes?

Answer 5

Cannot distinguish own cells from other cells (autoimmune attack on pancreatic B cells)

This leads to lymphocyte infiltration of islets + destruction of B cells –> decreased insulin

Question 6

What is involved in the aetiology of T1DM?

Answer 6

Environment - ?chemicals, ?viral infection (molecular mimicry)

Genetic predisposition

Question 7

What is the aetiology of type 2 diabetes?

Answer 7

1. Reduced tissue sensitivity to insulin
2. Inability to secrete very high levels of insulin

i.e. failure of the B cells to meet increased demand for insulin

Question 8

What is it that causes insulin resistance in type 2 diabetics?

Answer 8

Expanded upper body visceral fat mass (due to increased food intake, lack of exercise) –> increased FFA in the blood –> decreased insulin receptor sensitivity to insulin (so need more insulin to get glc into cells)

Question 9

Why does expanded upper body visceral fat mass lead to more FFA in the blood?

Answer 9

Overweight adipocytes are probably stressed + release FFAs

Question 10

Why do increased FFA in the blood lead to decreased insulin receptor sensitivity?

Answer 10

FAs interfere with the insulin receptor pathway

Question 11

Complete the sentence:

The ______ needs to secrete _____ _______ to move glucose into cells in a person with central adiposity

Answer 11

Pancreas
More
Insulin

Question 12

What does decreased insulin receptor sensitivity ultimately lead to?

Answer 12

Decreased removal of glucose from the blood, insulin levels have to markedly rise to make glucose levels return to normal

Question 13

Central adiposity leads to what?

Answer 13

Hyperinsulinaemia

Question 14

If peripheral insulin resistance is present how do we keep glucose levels normal?

Answer 14

If the pancreas is able to compensate and produce more and more insulin (then the patient wont get diabetes)

Question 15

What type of genes are implicated in type 2 diabetes?

Answer 15

Poor B cell ‘high end’ insulin secretion (i.e. not able to compensate for peripheral insulin resistance and produce vast quantities of insulin)

Question 16

If a person has central adiposity and many genes promoting high end insulin secretion will they get diabetes?

Answer 16

No

Question 17

If a person has central adiposity and numerous genes defective for high end insulin secretion, will they get diabetes?

Answer 17

Yes - type 2

Question 18

Is it a single gene involved in causing inadequate high level insulin secretion?

Answer 18

No - it is multiple genes

Question 19

So in summary, explain the aetiology of type 2 diabetes

Answer 19

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

Question 20

What is the commonest cause of death in diabetics?

Answer 20

MI

Question 21

What do the long-term complications of DM result from?

Answer 21

Prolonged poor glycaemic control

Question 22

What is the main complication of diabetes?

Answer 22

Damage to vessels

Question 23

What are the macrovascular (large vessel) complications of DM?

Answer 23

DM accelerates atherosclerosis

Question 24

How is atherosclerosis accelerated in DM?

Answer 24

Glucose attaches to low density lipoprotein
Glucose molecules stop LDL from binding to its receptor on liver cells tightly
LDL not removed by liver cells + stays in blood –> hyperlipidaemia –> atherosclerosis

Question 25

What kinds of cells line arterioles?

Answer 25

Endothelial which sit on a basal lamina

Question 26

What exists between the basal lamina and endothelial cells?

Answer 26

Potential space

Question 27

What can happen in the subendothelial space of arterioles?

Answer 27

Molecules can flux in and out

Question 28

What lines the basal lamina of arterioles?

Answer 28

Smooth muscle cells

Question 29

What happens to the arterioles in DM?

Answer 29

Molecules flux into subendothelial space (e.g. albumin, collages) + find it hard to flux back into blood
These molecules build up in the subendothelial space, and the basal lamina thickens
This is also known as hyaline change

Narrow arteriole –> poor BF –> ischaemia

Question 30

Where is hyaline change most damaging?

Answer 30

Kidneys, peripheral tissues (e.g. feet), eyes, arterioles supplying nerves

Question 31

What happens in the capillaries of diabetics?

Answer 31

Increased connective tissue around capillaries, e.g. glomerulus in kidney

Question 32

What are Kimmelstiel-Wilson lesions?

Answer 32

Nodules of connective tissue in the kidney

Question 33

How does small vessel disease occur in diabetics?

Answer 33

Glucoses added to proteins (glycosylation)

Collagen in the basal lamina is normally in the basal lamina. Albumin normally fluxes in and out the subendothelial space. Normal albumin does not bind to collagen, glycosylated collagen does bind albumin –> accumulation of albumin in the subendothelial space

Many normal basal lamina proteins do not crosslink + can be easily removed but glycosylated proteins bind their neighbouring proteins. Rigid, cross linked proteins cannot be easily removed so there is persistence of proteins in arteriole walls even after return to normoglycemia

Question 34

Is glycosylation reversible?

Answer 34

At first yes, but irreversible once covalent bonds form = advanced glycosylation end products