Lecture 4 - Metabolic Syndrome: Definitions and Causes Flashcards Preview

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Flashcards in Lecture 4 - Metabolic Syndrome: Definitions and Causes Deck (31):
1

Core components of metabolic syndrome

1) Obesity
2) Insulin resistance/glucose intolerance
3) Hypertension
4) Dyslipidaemia

2

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

3

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)

4

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)

5

Lipid-centric guidelines

NCEP ATPIII

6

Insulin resistance-centric guidelines

WHO, IDF

7

Effect of insulin on blood pressure.

Might contribute to hypertension

8

How might insulin contribute to hypertension?

Increases in plasma insulin concentration
within the physiological range stimulate
sodium reabsorption by the distal nephron
segments

9

Most widely accepted metabolic syndrome definition

IDF.
Based mostly on waist measurements.

10

Insulin receptor

Tyrosine kinase

11

Pathways activated by insulin receptor

1) PI-3 kinase
2) MAP kinase

12

MAP kinase role in insulin signalling

Insulin growth effects

13

PI-3 kinase role in insulin signalling

Insulin metabolic effects

14

Causative agent behind proposed metabolic syndrome aetiology

Defective PI-3 kinase pathway from insulin receptor

15

How could defective PI-3 kinase cause metabolic syndrome?
1)
2)
3)
4)
5)
6)
7)
8)

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

16

Does obesity affect insulin receptor MAP kinase?

Not directly.

17

Does obesity affect insulin receptor PI-3?

Yes.

18

How was insulin linked to hypertension?
1)
2)
3)
4)

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

19

Which part of the nervous system does insulin stimulate?

Sympathetic nervous system

20

Cytokines induced by insulin

TNFa, IL-13

21

Action of 11beta HSD I in humans

Converts cortisone to cortisol (active)

22

What can increase liver VLDL levels?

TNFa, corticosterones

23

Transgenic mouse that mirrored mild obesity in humans

Mouse overexpressing human 11beta HSD I selectively in adipose tissue

24

How was this particular model of metabolic syndrome conceived?

Transgenic rats overexpressing PEPCK developed metabolic syndrome

25

Enzyme that is associated with metabolic syndrome?

PEPCK overexpression

26

Enzyme associated with insulin resistance in transgenic rat models

PEPCK overexpression

27

Effect of insulin in PEPCK transgenic rats

IL-6 release.

28

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.

29

Cytokines elevated in PEPCK transgenic rats

TNFa, IL-6, IL-1b

30

11b HSD-1 levels in PEPCK transgene rats

Elevated in adipose tissue (subcutaneous, visceral)

31

Role of PEPCK

Rate-limiting enzyme in gluconeogenesis