Pathology of Type 2 Diabetes Flashcards
What is GLUT4 sensitive to?
Insulin
In T2D, why does diabetes occur even if someone still has insulin?
- 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
What are the effects on insulin?
1) Increased uptake of glucose from the blood
2) Effects on gene expression and cell differentiation and proliferation
What is insulin resistance?
A condition in which normal amounts of insulin are inadequate to maintain normal concentrations of blood glucose often associated with obesity
In insulin resistance what happens to insulin and glucose?
Both are high (initially glucose is normal)
What are the effects of insulin resistance?
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)
What do high plasma levels of insulin and glucose due to insulin resistance often lead to?
Metabolic syndrome and T2D
What are causes of insulin resistance?
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
Why is insulin receptors being down-regulated not enough to explain the insulin resistance?
Bc for maximum insulin action you don’t need to occupy all the receptors anyway (normally there are spares)
Which type of adipose tissue is mainly implicated in insulin resistance?
Visceral
What are characteristics of the obese state which are key in the development of insulin resistance?
1) Chronic inflammation
2) Oxidative stress
3) Hyperinsulinaemia
4) Lipotoxicity
Characteristics of the obese state lead to the development of insulin resistance bc they interfere with what processes?
1) Insulin secretion
2) Insulin signalling pathways
3) Glucose transport
4) Insulin receptor numbers and binding affinity
How do the adipose derived products lead to insulin resistance?
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
What are the features of metabolic syndrome?
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
What marker of systemic inflammation is often increased in metabolic syndrome?
CRP
What is the relationship between T2D and metabolic syndrome?
- 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
What is the type of insulin deficiency present in T2D?
Relative insulin deficiency
What do some people with T2D have?
Lower C peptide
What is the main factor linked to insulin resistance?
Waist circumference
How is obesity linked to insulin resistance?
- 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
What happens to the pancreas in T2D?
- 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
Describe the problem with bridging the gap between insulin secretion and insulin resistance in T2D?
- 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
What is NGT?
Normal glucose tolerance - when insulin resistance is rising but can keep up with it
What is IGF/IGT?
Impaired glucose fasting/tolerance - where the gap is starting to increase and then get T2D when gap is too big
When do microvascular and macrovascular complications begin?
- Microvascular as soon as the glucose starts to rise
- Macrovascular linked to insulin resistance
What do genes involved in T2D affect?
1) Beta cell function
2) Insulin granule formation
3) Insulin signalling
4) Energy metabolism
- Mainly affect pancreas
When is sub-clinical inflammation detected in T2D?
When you measure acute phase protease e.g. CRP
