21. The Metabolic Syndrome Flashcards
Summarise the postulated links between insulin resistance and other CVD risk factors known as the metabolic syndrome
look up answer - probs in diagram
Discuss the mechanisms that could explain how insulin resistance and/or Hyperinsulinaemia increase other CVD risk factors
- Decreased HDL-C
- Decreased LDL size
- Increased TAG
- Increased Blood Pressure
- Increased PAI-1
which all lead to an increase in the risk of CVD
What are the health risk associated with diabetes?
- substantial increase in mortality
Insulin resistance can be counter balanced by what?
Hyperinsulinaemia. This compensation may restore normal glycaemic control. However, insulin resistance and Hyperinsulinaemia are implicated in the clustering of many risk factors for CVD
The metabolic syndrome =
resistance to insulin-stimulated glucose uptake Hyperinsulinaemia Obesity Increased VLDL TG Decreased HDL-C Smaller, more dense LDL particles Hypertension High plasminogen activator inhibitor 1
You are diagnosed with Metabolic syndrome If you have 3 or more of what symptoms?
Abdominal obesity High TG Low HDL High BP High Fasting Glucose
The risk for getting metabolic syndrome increases as you get older….
Odds ratio for metabolic syndrome increase as a function of BMI
if you have an extremely high BMI your risk can be 40/50/60 times more likely to have metabolic syndrome than normal
What effect does obesity have on insulin resistance
Bad effect - positive effect as it increases resistance. through factors such as
FFA, Ceramide, TNK-a, Leptin, Resistin, Adiponectin, IL-6
When you eat, LPL in the tissues goes up. If you carry on snacking you’ll find that LPL will decrease in the muscle, but will increase in the adipose tissues.
Prolonged elevation of insulin stimulated LPL activity in the adipose tissue but inhibited LPL activity in the muscle. Thus, snacking may direct TGs away from the muscle and into adipose tissue for storage.
How does insulin affect Lipoprotein Lipase and Hormone Sensitive Lipase? and how does this then change in an insulin resistant person
it will switch LPL and inhibit HSL. this will mean that there is more fat packaged away in the tissue and less in circulation. In an insulin resistant person, these 2 things work less well so there is more in the circulation.
What is the role LPL activity and how this affects lipid transportation
LPL releases free fatty acids from VLDL TGs and so these are taken up from the lumen and into the muscle or adipose tissue. It also causes VLDL to release cholesterol and for it to be taken up by HDL, which is favourable in the body to prevent getting fat. However, in an insulin resistant person this doesn’t happen as there is less activity of the LPL.
why is a lot of TAG-rich VLDLs bad for the body?
TAG-rich VLDLs unload TAG onto HDLs and LDLs. TAG-rich HDLs catabolised by kidney leading to fewer HDLs. TAG get hydrolysed in TAG-rich LDLs leading to smaller and more dense LDLs
If you have more TG, your LDLs tend to be smaller in size so that are riskier to the body and you are more likely to develop atherosclerosis
The bigger the LDLs, you’re more likely to be more sensitive to insulin
What drugs are there to treat people with insulin resistance?
Thiazolidinesdione’s
- Troglitazone
- Rosiglitazone
- Pioglitazone
- All ligands for nuclear transcription factor peroxisome-proliferator-activated receptor y (PPAR y)
When you are insulin resistant what does this do to your lipoprotein profiles?
- VLDL increases – so too does the cholesterol content. Therefore. Increases delivery of cholesterol to vessel walls
- Fewer HDL particles to engage in reverse cholesterol transport
- Also, HDL has an antioxidant role on LDL: modified LDL are pro-inflammatory and initiate plaque formation
- Transfer of HDL cholesterol to VLDL results in less reverse cholesterol transport
- Small dense LDL particles are particularly atherogenic
Is there any evidence in insulin resistance that is likely to make is hypertensive (high BP)
- Insulin mediated glucose uptake during insulin infusion study comparing normal and high blood pressure people the group with high blood pressure don’t respond as well to the insulin and don’t store away as much glucose.
- Normal glycaemic control vs insulin resistance the Hyperinsulinaemic people tend to have a higher resting systolic blood pressure.
Insulin sensitivity and the risk of hypertension - The higher your insulin sensitivity the lower your risk of developing hypertension
What is the relationship between insulin and muscle blood flow?
Insulin is a vasodilator. In an obese person with impaired glucose tolerance you need over 3 times as much insulin to cause this compared to normal people in order to produce 50% of maximal leg muscle blood flow
How is PAI-1 a mechanism to lead to an increased CVD risk through insulin resistance
In a healthy person there is a balance between the amount of PAI in the body, and there is a balance in how much fibrinolysis (removes successful clots, and prevents inappropriate clot formation) occurs. If the PAI level went up then you would knock out the activator and you’d reduce the amount of fibrin dissolved. Therefore your blood would become more hypercoaguable and become more viscous, therefore more likely to clot.
The more sensitive to insulin you are, the less PAI - this is good
Explain the development of diet induced insulin resistance
- Insulin stimulated glucose uptake is impaired after just 2 weeks of a high-fat refined-sugar diet compared to a low-fat complex-carbohydrate diet. Large consumption of fructose increases the circulating levels of TG in males, but not in females
