Pathology of Diabetes Mellitus and its Complications

Question 1

What are the cells that make up the endocrine portion of the pancreas?
How much of this is accounted for by B cells?

Answer 1

• Islets of Langerhans

- 2/3 B cells

Question 2

Which genes are compromised in type 1 diabetes?

Answer 2

• Genes for T cells that help the body distinguish self antigens from foreign ones
• HLA: human leukocyte antigen molecules

Question 3

Pathophysiology of type 1 diabetes?

Answer 3

• Autoimmune attack on islets

- Lymphocyte infiltration of islets (Insulitis), causes destruction of B cells

Question 4

What is the hypothesis supporting the theory that viral infection leads to type 1 diabetes?

Answer 4

• Molecular mimicry
• Virus infects host and presents same antigen as found on human B cell, immune system gets rid of virus but then goes on to attack B cells

Question 5

Is type 1 diabetes all genetic or does it have environmental components too?

Answer 5

• Not really known

- Slide says that it is a combination of genes + environment

Question 6

Why is glucose uptake insufficient in type 2 diabetes?

Answer 6

Combination of:
- Reduced tissue sensitivity to insulin (insulin resistance)

• Inability to secrete very high levels of insulin

Question 7

What type of fat deposits correspond to increased type 2 diabetes risk?

Answer 7

• Central adiposity (pot belly): accumulation of fat around the waistline
• Being thicc with a slim waist doesn’t correspond to diabetes

Question 8

What causes the central adiposity often seen alongside type 2 diabetes?

Answer 8

• Increased food intake + lack of exercise

- Not much genetic contribution, estimated a max of 10%

Question 9

Why does accumulation of central adiposity lead to insulin resistance?

Answer 9

• Central adiposity = more FFA’s in plasma (probably because overweight adipocytes are “stressed” and release fatty acids)
• Increased FFA’s in blood interfere with insulin receptors causing reduced insulin sensitivity (not sure how)
• Reduced insulin sensitivity means more insulin needs to be produced…

Question 10

How does the pancreas attempt to respond to insulin resistance? How does this affect chances of getting diabetes?

Answer 10

• Make more insulin
• If you have the genes to make enough insulin you won’t become diabetic, if you don’t then insulin resistance is the first step to becoming diabetic

Question 11

Which genes are implicated in type 2 diabetes?

Answer 11

• Genes for how much insulin you can produce, having many low insulin production variants increases chance of diabetes
• NOT genes for how easily you put on weight

Question 12

How are insulin production and insulin resistance related to diabetes?

Answer 12

• Insulin resistance alone: makes you fat
• Inability to produce large amounts of insulin: makes you more vulnerable to diabetes
• Both: very likely to become diabetic

Question 13

How can a slim person who puts on a bit of weight become diabetic?

Answer 13

• If they’ve got shit genes

- Lots of low insulin production variants of insulin genes, can’t cope with even small amounts of weight put on

Question 14

How does diabetes influence life expectancy?

Commonest cause of death in diabetics?

Answer 14

• Unmanaged diabetes reduces lifespan 5-10 years, significant. If managed nearly no reduction on lifespan though
• Myocardial Infarction

Question 15

What is the main complication associated with diabetes?

Answer 15

Damage to vessels, 2 types:
- Large vessel disease

• Small vessel disease

Question 16

What is the main large vessel (macrovascular) complication associated with diabetes?

Answer 16

• Accelerated Atherosclerosis

Question 17

How does does diabetes cause atherosclerosis? (proposed mechanism)

Answer 17

• Hyperglycaemia results in high blood glucose concentration, the glucose binds to LDL
• Glucose binding means LDL can’t bind it’s receptor on liver cells, therefore LDL not removed from plasma by liver
• Causes hyperlipidaemia, and hyperlipidaemia causes atherosclerosis

Question 18

Which vessels are affected in small vessel (microvascular) disease caused by diabetes?

Answer 18

Arterioles

the “resistance vessels”

Question 19

Describe normal structure of an arteriole

Answer 19

• Endothelial cells line inside, sit on a basal lamina (potential space between the two, molecules often flux into and out of subendothelial space)
• Smooth muscle cells line outside of basal lamina

Question 20

What happens to arterioles in diabetic patients?

Answer 20

• Molecules (ablumin etc.) flux into subendothelial space but can’t get back into blood
• Causes buildup of substrate underneath endothelial cells, thickening of basal lamina then also occurs
• Narrowed arteriole: poor blood flow (ischaemia) and less ability to contract / widen (“resistance vessels”)

Question 21

What are the changes to arterioles due to diabetes called?

Which tissues do these changes affect most?

Answer 21

• “Hyaline Change”

Most damaging to:

• Kidneys
• Peripheral tissues (feet)
• Eyes
• Nerves

Question 22

How are the risks of amputation, end stage renal disease and blindness increased by diabetes?

Answer 22

Amputation 40x
End stage renal disease 25x
Blindness 20x

Question 23

What are the two mechanisms by which proteins become trapped in the subendothelial space of small vessels?

Answer 23

• Collagen glycosylation

- Cross linking

Question 24

Explain how collagen glycosylation in diabetics causes small vessel disease?

Answer 24

• When blood glucose is elevated for a long time the collagen in the subendothelial space can covalently bond with it: AGE’s (advanced glycosylation end-products)
• Normal collagen doesn’t bind albumin, glycosylated collagen does
• Albumin fluxing into subendothelial space becomes trapped, narrows lumen

Question 25

Explain how protein cross linking in diabetics causes small vessel disease?

Answer 25

• Elevated glucose causes glycosylation of proteins in basal lamina
• Normal basal lamina proteins have linear shape, so slide over one another and are easily removed
• Glyosylated proteins are not linear and so cross link with one another, trapping proteins in the basal lamina and narrowing lumen

Question 26

When do large and small vessel disease occur in diabetics? How reversible are they?

Answer 26

• Occur after prolonged, poorly managed diabetes (hyperglycaemia)
• Typically irreversible