Pathology of Type 2 Diabetes

Question 1

What is GLUT4 sensitive to?

Answer 1

Insulin

Question 2

In T2D, why does diabetes occur even if someone still has insulin?

Answer 2

• There is a complicated multi-stage intracellular pathway that occurs when insulin binds to its receptor and exerts its effects
• Therefore, even if you have insulin, if something is wrong in any of these intracellular steps in insulin signalling (incl. termination of signal), this will lead to insulin resistance
• Don’t know which stage is wrong

Question 3

What are the effects on insulin?

Answer 3

1) Increased uptake of glucose from the blood

2) Effects on gene expression and cell differentiation and proliferation

Question 4

What is insulin resistance?

Answer 4

A condition in which normal amounts of insulin are inadequate to maintain normal concentrations of blood glucose often associated with obesity

Question 5

In insulin resistance what happens to insulin and glucose?

Answer 5

Both are high (initially glucose is normal)

Question 6

What are the effects of insulin resistance?

Answer 6

1) In muscle cells, there is reduced glucose uptake, therefore reduced glycogen synthesis and storage
2) In liver cells there is reduces storage of glycogen
3) In fat cells it causes lipolysis and increased fatty acid concentrations in the blood (fat breakdown but still see obesity)

Question 7

What do high plasma levels of insulin and glucose due to insulin resistance often lead to?

Answer 7

Metabolic syndrome and T2D

Question 8

What are causes of insulin resistance?

Answer 8

1) Insulin receptors are down-regulated bc of high concentration of circulating insulin (fewer receptors)
2) Interference with insulin signalling pathway
3) Inflammation
4) Interaction between products of adipose and defective insulin signalling
5) Some adipose tissue produced hormones and metabolites may inhibit insulin receptor substrate activation
6) Switching off mechanisms may be activated

Question 9

Why is insulin receptors being down-regulated not enough to explain the insulin resistance?

Answer 9

Bc for maximum insulin action you don’t need to occupy all the receptors anyway (normally there are spares)

Question 10

Which type of adipose tissue is mainly implicated in insulin resistance?

Answer 10

Visceral

Question 11

What are characteristics of the obese state which are key in the development of insulin resistance?

Answer 11

1) Chronic inflammation
2) Oxidative stress
3) Hyperinsulinaemia
4) Lipotoxicity

Question 12

Characteristics of the obese state lead to the development of insulin resistance bc they interfere with what processes?

Answer 12

1) Insulin secretion
2) Insulin signalling pathways
3) Glucose transport
4) Insulin receptor numbers and binding affinity

Question 13

How do the adipose derived products lead to insulin resistance?

Answer 13

1) Leptin resistance and decreased adiponectin (both would increase insulin sensitivity)
2) FFS and DAG (released by lipolysis) can impair insulin sensitivity by interfering with IRS activation
3) TNFalpha interferes with IRS activation

Question 14

What are the features of metabolic syndrome?

Answer 14

Need 1) and 2 of others:

1) Abdominal (central) obesity - waist circumference over BMI
2) High BP
3) High blood glucose
4) High serum triacylglycerols (VLDL)
5) Low HDL concentration

Question 15

What marker of systemic inflammation is often increased in metabolic syndrome?

Answer 15

CRP

Question 16

What is the relationship between T2D and metabolic syndrome?

Answer 16

• T2D is considered a complication of metabolic syndrome
• In a pt with impaired glucose tolerance or impaired fasting glucose (high) who also has the characteristics of metabolic syndrome the risk of developing T2D is twice as high

Question 17

What is the type of insulin deficiency present in T2D?

Answer 17

Relative insulin deficiency

Question 18

What do some people with T2D have?

Answer 18

Lower C peptide

Question 19

What is the main factor linked to insulin resistance?

Answer 19

Waist circumference

Question 20

How is obesity linked to insulin resistance?

Answer 20

• There is a level of obesity where insulin resistance goes up to a level where the pancreas cannot keep up with insulin secretion
• This level where insulin resistance develops is different for everyone and depends on genetic factors - i.e. two people at the same weight may not both have T2D (only one will)
• If people had two parents with T2D this level will be lower

Question 21

What happens to the pancreas in T2D?

Answer 21

• The pancreas works to its maximum trying to keep insulin secretion up with insulin resistance
• Then beta cell destruction occurs and there is progressive decline in beta cell function over the years

Question 22

Describe the problem with bridging the gap between insulin secretion and insulin resistance in T2D?

Answer 22

• Can do this early on with diet and exercise but this becomes harder the greater the gap, when you need insulin
• Progressive disease
• Even if the person’s weight/insulin requirements are stable, the amount of medication to bridge that gap will be increasing year on year unless decrease weight and bring insulin resistance back below insulin secretion, reducing the requirement for insulin

Question 23

What is NGT?

Answer 23

Normal glucose tolerance - when insulin resistance is rising but can keep up with it

Question 24

What is IGF/IGT?

Answer 24

Impaired glucose fasting/tolerance - where the gap is starting to increase and then get T2D when gap is too big

Question 25

When do microvascular and macrovascular complications begin?

Answer 25

• Microvascular as soon as the glucose starts to rise

- Macrovascular linked to insulin resistance

Question 26

What do genes involved in T2D affect?

Answer 26

1) Beta cell function
2) Insulin granule formation
3) Insulin signalling
4) Energy metabolism
- Mainly affect pancreas

Question 27

When is sub-clinical inflammation detected in T2D?

Answer 27

When you measure acute phase protease e.g. CRP