Flashcards in Lecture 4 - Metabolic Syndrome: Definitions and Causes Deck (31)
Core components of metabolic syndrome
2) Insulin resistance/glucose intolerance
WHO definition of metabolic syndrome
Mandatory component: High insulin, high fasting blood glucose levels, high post-meal blood glucose levels
At least 2 of the following:
- Abdominal obesity (BMI over 30kg/m2, waist/hip over 0.9)
- Triglyceride level over 1.7mmol/L
- HDL cholesterol under 0.9mmol/L
- Blood pressure of 140/90 or above
NCEP - ATP III definition of metabolic syndrome
Three or more of the following:
1) Central obesity (waist larger than 102cm for men, 88 for women)
2) Triglycerides (over 1.7mmol/L)
3) HDL (under 1.03mmol/L for men, 1.29mmol/L for women)
4) Fasting glucose (over 6.1mmol/L)
5) Blood pressure (over 130)
IDF criteria for metabolic syndrome
Mandatory component: central obesity (differs based on race, gender - Europid, Asian, Japanese)
Two or more of the following:
- Triglycerides (over 1.7mmol/L)
- HDL cholesterol (under 1.03mmol/L in men, under 1.29mmol/L in women)
- Blood pressure (over 130/85)
- Fasting blood glucose (over 5.6mmol/L)
Insulin resistance-centric guidelines
Effect of insulin on blood pressure.
Might contribute to hypertension
How might insulin contribute to hypertension?
Increases in plasma insulin concentration
within the physiological range stimulate
sodium reabsorption by the distal nephron
Most widely accepted metabolic syndrome definition
Based mostly on waist measurements.
Pathways activated by insulin receptor
1) PI-3 kinase
2) MAP kinase
MAP kinase role in insulin signalling
Insulin growth effects
PI-3 kinase role in insulin signalling
Insulin metabolic effects
Causative agent behind proposed metabolic syndrome aetiology
Defective PI-3 kinase pathway from insulin receptor
How could defective PI-3 kinase cause metabolic syndrome?
1) Defective PI-3 impacts glucose metabolism
2) Increase in blood glucose causes pancreas to release insulin
3) Increased insulin leads to hypertension, increase MAP Kinase signalling
4) MAP kinase leads to cytokine release
5) Cytokine release increases 11beta HSD-1 release
6) 11beta HSD-1 leads to increased corticosterone production
7) Cytokines, corticosterones increase hepatic VLDL levels
8) This leads to increased plasma triglycerides
Does obesity affect insulin receptor MAP kinase?
Does obesity affect insulin receptor PI-3?
How was insulin linked to hypertension?
1) 160 patients with NIDDM.
2) Half started on insulin
3) Weight, glucose, blood pressure measured
4) Statistically significant weight increase, blood pressure increase, glucose fall
Which part of the nervous system does insulin stimulate?
Sympathetic nervous system
Cytokines induced by insulin
Action of 11beta HSD I in humans
Converts cortisone to cortisol (active)
What can increase liver VLDL levels?
Transgenic mouse that mirrored mild obesity in humans
Mouse overexpressing human 11beta HSD I selectively in adipose tissue
How was this particular model of metabolic syndrome conceived?
Transgenic rats overexpressing PEPCK developed metabolic syndrome
Enzyme that is associated with metabolic syndrome?
Enzyme associated with insulin resistance in transgenic rat models
Effect of insulin in PEPCK transgenic rats
Why is IL-6 released in PEPCK rats with insulin, but not in wild-type rats?
In wild-type rats, insulin stimulates both MAPK and PI-3 pathways. PI-3 inhibits cytokine release by MAPK pathway.
In PEPCK overexpression transgenic rats, PI-3 doesn't inhibit MAPK, leading to IL-6 release.
Cytokines elevated in PEPCK transgenic rats
TNFa, IL-6, IL-1b