Lecture 4 - Metabolic Syndrome

Question 1

Discuss the definition of metabolic syndrome

Answer 1

There are various definitions

• All agree on the core components:
  
  • Obesity
  • Insulin resistance / glucose intolerance
  • Hypertension
  • Dyslipidaemia
• Key criteria differ between the definitions
  
  • WHO: High insulin levels
  • IDF: Central obesity+ two or more of the other criteria
  • NCEP: 3 or more of the five criteria

The varying definitions reflect the different interests of the groups who formulated them

Question 2

What is the definition of central obesity?

Answer 2

Ethnicity dependent

• Europid:
  
  • > 94cm men
  • > 80cm women
• Asian:
  
  • > 90cm men
  • > 80cm women
• Japanese:
  
  • > 85 men
  • > 90cm women

Question 3

What are the triglyceride criteria for MS?

Answer 3

> 1.7 mmol/L, or, on specific treatment

Question 4

What is the HDL criteria for MS?

Answer 4

<1.29 in women

Question 5

What is the criteria of BP for MS?

Answer 5

>/= 130/85, or on specific treatment

Question 6

What is the definition of elevated FBG?

Answer 6

>= 6.1 mmol/L (IPF: >= 5.6)

Question 7

Describe the cases of Mr McDonalds and Mr Smith

Answer 7

• Mr McDonalds:
  
  • Has all of the criteria
  • v. high BP, total cholesterol, FBG
  • Family history of Diabetes and IHD
  • Smoker
• Mr Smith
  
  • Meets the criteria for MS
  • No family history of Diabetes or IHD
  • Non-smoker
• Though they both meets the criteria for MS, they have vastly different risks of CHD (coronary heart disease)
• Treatment would be vastly different for these two individuals
• This raises the issue of whether it is useful to diagnose MS

Question 8

What is the message of the Kahn, Buse, Ferrannini & Stern review article?

Answer 8

• Extensive review of the literature on MS Concluded that MS is:
  
  • Imprecisely defined
  • Lack of certainty around pathogenesis
  • Doubt as to its value as a CVD risk marker
• Advice to clinicians:
  
  • Evaluate and treat all CVD risk factors without regard to whether a patient meets the criteria for MS diagnosis

Question 9

Outline the proposed hypothesis for the aetiology of MS from Proietto et al.

Answer 9

1. Obesity
2. Impaired PI-3 kinase signalling
3. Increased glucose
4. Increased insulin
   
   • (→ Hypertension )
5. Increased MAPK signalling
   
   • Insulin hyperstimulates MAPK signalling
6. Increased cytokines
7. Increased 11β-HSD-1
8. 11β-HSD-1 increases corticosterone production
9. Elevated hepatic VLDL production
10. Increased plasma triglycerides

Question 10

Describe the effect of obesity signalling pathways downstream from insulin

Answer 10

Obesity results (directly) in impaired PI-3 kinase signalling

(NB Obesity results indirectly in increased MAPK signalling)

Question 11

Describe insulin therapy

Answer 11

• Treatment of diabetes with exogenous insulin
• Vital for IDDM (type 1)
• May be eventually required by some NIDDM (type 2) patients
  
  • There are many studies that have shown that insulin therapy results in increased BP

Question 12

Describe the effect of insulin therapy on hypertension

Answer 12

• Observed in multiple studies to cause hypertension
• One study (DeFronzo) observed that increased plasma insulin concentration stimulates Na+ reabsorption from distal nephron

Question 13

Which intracellular transduction pathways are activated by insulin?

Answer 13

1. MAPK
   
   • Growth signalling
   • Results in change in gene transcription
     
     • Cell proliferation
     • Cell survival
     • Cytokine transcription
2. PI-3 kinase
   
   • Metabolic signalling
   • Glucose uptake
   • Glycogen synthesis
   • Inhibition of gluconeogenesis
   • Inhibition of cytokine synthesis

Question 14

Describe impairment of MAPK in obesity, and the implications

Answer 14

• Increased MAPK signalling indirectly through increased insulin
• Results in increased cytokine production:
  
  • TNF-α
  • IL-13

Question 15

What is 11β-HSD-1?

Answer 15

• 11-beta-hydroxysteroid dehydrogenase type 1
• Involved in the regulation of corticosteroids:
  
  • Cortisone → cortisol

Question 16

What is the effect of inflammation on 11β-HSD?What brings about this change?

Answer 16

• Studies observed:
  
  • Induction of 11β-HSD type 1 and not type 2 in smooth muscle
• Brought about by:
  
  • Increased cytokines (from impaired MAPK signalling) sets up inflammation
  • Inflammation increases 11β-HSD-1 expressed ion
• Effect:
  
  • Increased cortisol

Question 17

What is the effect of increased 11β-HSD-1, as seen in obesity?

Answer 17

Increased corticosterone production

Question 18

What is VLDL?

Answer 18

Very low density lipoprotein

Question 19

Describe the effect on the liver of inflammatory cytokines such as TNF, IL-1 and IL-6

Answer 19

• Increased production of:
  
  • FAA from adipocytes to liver
  • TG-rich VLDL
  • LDL
• Decreased:
  
  • HDL
  • LDL clearance

Question 20

Describe the observations in transgenic mice over-expressing 11β-HSD-1 in adipose tissue

What about in 11β-HSD-1 KO mice?

Answer 20

• The over-expression of 11β-HSD-1 in the mice is comparable to that in obese humans
• Observations in mice:
  
  • 11β-HSD-1 overexpression:
    
    • Mild obesity
    • Elevated triglycerides
    • Elevated FAAs (free fatty acids)
    • Hypertension
  • 11β-HSD-1 KO:
    
    • Improved lipid and lipoprotein profile

Question 21

Describe the uptake of Glucose from the blood

Answer 21

Plasma glucose moves through GLUT transporters into cells

Question 22

Describe the metabolism of glucose

Answer 22

1. Glucose
2. G-6-P
3. Fructose-6-P
4. Triose phosphates
5. PEP
6. Pyruvate

Question 23

What is PEPCK?

Answer 23

Enzyme that is involved in an important step of gluconeogenesis (i.e. metabolism of pyruvate into glucose)

Question 24

How does insulin result in increased BP?

Answer 24

• Stimulates Na+ retention
• Stimulates the sympathetic NS

Question 25

What is the cause of elevated 11β-HSD-1 in obesity?

Answer 25

Increased cytokines

Question 26

Explain the implication of the discrepancy between the classification of central obesity for people of different ethnicities

Answer 26

• For Asian & Japanese people, a smaller waist circumference is required for the classification of ‘central obesity’
• This means for obese individuals from Asian hereditary, there is a much greater risk of CHD

Question 27

What is required for MS to merit the classification of a ‘syndrome’

Answer 27

A biological basis that unites all of the features

Question 28

What is the effect of insulin on the MAPK signalling cascade?

Answer 28

Insulin hyper-stimulates MAPK

Question 29

What are the effects of elevated cytokines?

Answer 29

1. Increased 11β-HSD-1
2. Increased VLDL (thus, LDL) in liver

Question 30

Describe the animal model that Proietto et al used

Answer 30

• Transgenic mouse that over expresses PEPCK
• PEPCK is enzyme involved the first step of gluconeogenesis (conversion of Pyruvate to PEP)
• These Transgenic mice thus have far too much insulin
• As a result, the mice develop features of Metabolic Syndrome:
  
  • Increased body weight (subtle)
  • Increase in fat pad weight (substantial)
  • Increased plasma glucose (in later life)
  • Increased plasma insulin (throughout life)
  • Elevated triglycerides
  • Elevated cholesterol
  • Insulin resistance
  • Impaired PI-3K signalling
  • (no defect in MAPK signalling)
  • Elevated cytokine mRNA
    
    • IL-6, IL-1β and TNFα
  • Elevated 11β-HSD-1