Lecture 4 - Metabolic Syndrome Flashcards
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
What is the definition of central obesity?
Ethnicity dependent
-
Europid:
- > 94cm men
- > 80cm women
-
Asian:
- > 90cm men
- > 80cm women
-
Japanese:
- > 85 men
- > 90cm women
What are the triglyceride criteria for MS?
> 1.7 mmol/L, or, on specific treatment
What is the HDL criteria for MS?
<1.29 in women
What is the criteria of BP for MS?
>/= 130/85, or on specific treatment
What is the definition of elevated FBG?
>= 6.1 mmol/L (IPF: >= 5.6)
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
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
Outline the proposed hypothesis for the aetiology of MS from Proietto et al.
- Obesity
- Impaired PI-3 kinase signalling
- Increased glucose
- Increased insulin
- (→ Hypertension )
- Increased MAPK signalling
- Insulin hyperstimulates MAPK signalling
- Increased cytokines
- Increased 11β-HSD-1
- 11β-HSD-1 increases corticosterone production
- Elevated hepatic VLDL production
- Increased plasma triglycerides
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)
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
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
Which intracellular transduction pathways are activated by insulin?
-
MAPK
- Growth signalling
- Results in change in gene transcription
- Cell proliferation
- Cell survival
- Cytokine transcription
-
PI-3 kinase
- Metabolic signalling
- Glucose uptake
- Glycogen synthesis
- Inhibition of gluconeogenesis
- Inhibition of cytokine synthesis
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
What is 11β-HSD-1?
- 11-beta-hydroxysteroid dehydrogenase type 1
- Involved in the regulation of corticosteroids:
- Cortisone → cortisol
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
What is the effect of increased 11β-HSD-1, as seen in obesity?
Increased corticosterone production
What is VLDL?
Very low density lipoprotein
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
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
- 11β-HSD-1 overexpression:
Describe the uptake of Glucose from the blood
Plasma glucose moves through GLUT transporters into cells
Describe the metabolism of glucose
- Glucose
- G-6-P
- Fructose-6-P
- Triose phosphates
- PEP
- Pyruvate
What is PEPCK?
Enzyme that is involved in an important step of gluconeogenesis (i.e. metabolism of pyruvate into glucose)
How does insulin result in increased BP?
- Stimulates Na+ retention
- Stimulates the sympathetic NS
