Lecture 4 - Metabolic Syndrome Flashcards Preview

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Flashcards in Lecture 4 - Metabolic Syndrome Deck (30):
1

Discuss the definition of metabolic syndrome

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

2

What is the definition of central obesity?

Ethnicity dependent

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

3

What are the triglyceride criteria for MS?

> 1.7 mmol/L, or, on specific treatment

4

What is the HDL criteria for MS?

<1.29 in women

5

What is the criteria of BP for MS?

>/= 130/85, or on specific treatment

6

What is the definition of elevated FBG?

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

7

Describe the cases of Mr McDonalds and Mr Smith

  • 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

8

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

  • 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

9

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

  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

10

Describe the effect of obesity signalling pathways downstream from insulin

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

(NB Obesity results indirectly in increased MAPK signalling)

11

Describe insulin therapy

  • 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

12

Describe the effect of insulin therapy on hypertension

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

13

Which intracellular transduction pathways are activated by insulin?

  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

14

Describe impairment of MAPK in obesity, and the implications

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

15

What is 11β-HSD-1?

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

16

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

  • 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

17

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

Increased corticosterone production

18

What is VLDL?

Very low density lipoprotein

19

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

 

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

20

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

What about in 11β-HSD-1 KO mice?

  • 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

21

Describe the uptake of Glucose from the blood

Plasma glucose moves through GLUT transporters into cells

22

Describe the metabolism of glucose

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

23

What is PEPCK?

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

24

How does insulin result in increased BP?

  • Stimulates Na+ retention
  • Stimulates the sympathetic NS

25

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

Increased cytokines

26

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

  • 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

27

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

A biological basis that unites all of the features

28

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

Insulin hyper-stimulates MAPK

29

What are the effects of elevated cytokines?

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

30

Describe the animal model that Proietto et al used

  • 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