Metabolic Syndrome: diet related inflammatory disease Flashcards
What is Metabolic Syndrome?
A clustering of cardiometabolic risk factors, including:
- Abdominal obesity
- Insulin resistance (type 2 diabetes)
- Glucose intolerance (type 2 diabetes)
- Dyslipidemia (high TAGs, low HDL)
- Non-alcoholic fatty liver disease (NAFL)
- Hypertension
These factors more commonly occur together than can be explained by chance, leading to the hypothesis of an underlying pathology that links them.
Name some other conditions that are linked to obesity and metabolic syndrome include:
- Cancer
- Osteoarthritis
- Sleep apnoea
- Reproductive disorders
What are the alternative terms for metabolic syndrome?
- Syndrome X
- Polymetabolic syndrome
- Insulin resistance syndrome
- Deadly quartet
- Civilization syndrome
What is a syndrome?
A syndrome is defined as a group of symptoms that consistently occur together, and collectively indicate or characterize a disease, psychological disorder, or other abnormal condition.
There are several diagnostic criteria for MetS from different societies or organizations, but they mostly include the measurements of the following factors:
Abdominal obesity (waist circumference in cm):
>102 (men) >88 (women)
Blood pressure (mm/Hg):
>140/90
Fasting plasma glucose (mg/dL):
>110
Triglycerides (mg/dL):
>150
HDL Cholesterol (mg/dL):
<40 (men) <50 (women)
Compare the different types of cholesterol
- HDL is regarded as “good cholesterol” as it collecting peripheral cholesterol and returns it to the liver for processing.
- LDL and VLDL are regarded as “bad cholesterol” as they transport cholesterol from the liver to the tissues, and their levels go up with high lipid consumption and general over-nutrition.
State Cholesterol levels in plasma (fasted)
- Less than 100 mg/dL (2.59 mmol/L) — Optimal
- 100-129 mg/dL (2.59-3.34 mmol/L) — Near optimal, above optimal
- 130-159 mg/dL (3.37-4.12 mmol/L) — Borderline high
- 160-189 mg/dL (4.15-4.90 mmol/L) — High
- Greater than 189 mg/dL (4.90 mmol/L) — Very high
Define the different cholesterol measurements
- Total Cholesterol (TC) - this is the total amount of cholesterol in your blood. Ideally it should be 5 mmol/L* or less
- Non HDL-Cholesterol this is your total cholesterol minus your HDL-cholesterol (good cholesterol) and is the sum all the “bad” cholesterols added together (including LDL cholesterol) - ideally it should be 4 mmol/L* or less
- LDL-Cholesterol (LDL-C) - this is the amount of LDL-cholesterol), ideally it should be 3 mmol/L* or less
- HDL-Cholesterol (HDL-C) - the amount of good cholesterol, ideally it should be over 1 mmol/L* (men) and over 1.2 mmol/L* (women).
- TC:HDL ratio-This is the TC figure divided by the HDL-C figure. A ratio above 6 is considered high risk - the lower this figure is the better.
- Triglyceride (TG) -this represent your body’s ability to clear fat from the blood after a meal. Ideally it should be less than 1.7 mmol/L* on a fasting sample or less than 2.3 mmol/L on a non fasting sample)
How does waist circumference relate to CVD risk?
Waist Circumference indicates body fat distribution and relates to CVD risk
Describe Apple-shaped versus Pear-shaped fat patterning
How does it apply to overweight men and women?
- Apple-shaped corresponds to a waist-to-hip ratio of more than:
- 0.8 for women and 1.0 for men
- Apple-shaped relates to a large amount of abdominal or visceral fat. The fat surrounds the organs and this has an increased risk of disease, in contrast with fat on the hips, buttocks, thighs, which is subcutaneous.
- Overweight women tend to be pear-shaped, and men apple-shaped
Obesity (BMI) increases the Risk of Type 2 Diabetes
How is BMI calculated?
BMI = Body mass index
- It is calculated Weight (Kg) / Height² (m²)
- Obesity is defined as a BMI > 30
Why is waist circumference a preferred measure of obesity?
Waist circumference is a preferred measure of obesity because BMI can overestimate obesity in very muscular people, and underestimate it in elderly people.
When was the adverse effects of obesity first recognized?
The adverse effects of obesity were recognized two and a half thousand years ago, firstly by the Indian physician Sushrauta (6th Century BC) and then by Hippocrates.
Both wrote that obesity led to other diseases, and should be combatted by eating in moderation and exercise.
Draw a diagram to show that Insulin resistance and obesity are considered the major factors in MetS
But there are probably other factors that also contribute
Explain how Obesity involves energy intake exceeding energy expenditure
- Excess calories are stored mainly as triglycerides (lipids) in white adipose tissue.
- Carbohydrates and proteins can all be converted to fatty acids, which are stored as triglycerides.
- Fatty acids can be converted to acetyl-CoA and used as an energy source when required.
- They cannot be converted back to glucose because the conversion of pyruvate to acetyl-CoA (catalysed by pyruvate dehydrogenase) is irreversible.
Metabolic Homeostasis: Explain how appetite, energy expenditure and body weight are normally closely regulated
- The body has satiety and hunger signals to control the amount eaten and the processes of energy utilization.
- Insulin (from pancreas) and leptin (from adipose tissue) are both satiety signals that reduce appetite, increase energy storage and energy utilization.
- They act directly or indirectly on the hypothalamus.
In obesity and MetS this regulation is dysfunctional
The hypothalamus controls many basic functions of the body and behaviours, by secreting peptide hormones that act on other organs; e.g. neuro-anorectic peptides reduce appetite.
Which hormones can act directly on neurones in the hypothalamus to control appetite?
- Both insulin and leptin can act directly on neurones in the hypothalamus to control appetite
- The hypothalamus interacts with the pituitary and thyroid glands (both involved in energy metabolism).
- Leptin improves optional body functions that are reserved for time of plenty
- Insulin triggers leptin production→Leptin increases insulin sensitivity
Describe post-prandial Metabolism
- After a meal, nutrients are absorbed from the intestines and increase the blood glucose level and the blood lipid levels (in VLDL, LDL etc)
- The body responds to this by secretion of insulin from pancreatic b cells. Insulin secretion indicates the fed-state.
- Insulin signals to many cells in the body to take up glucose and lipids, which can be stored as glycogen and TAGs respectively.
- Insulin binds to insulin receptors (IRs) on cell, leading to a signalling network responsible for cell nutrient uptake and anabolic metabolism.
Explain Physiological Insulin Signalling Pathways
Gab and IRS (Insulin receptor substrate) are signalling factors associated with the insulin receptor.
- When insulin binds the receptor, they get activated. IRS is normally activated by being phosphorylated on a tyrosine residue.
- Gab switches on one of the MAPK pathways, leading to mitogenesis and cell proliferation, whereas IRS switches on phosphoinositol-3-phosphate kinase and then the serine/threonine kinase Akt.
- This alters energy metabolism, upregulating glycogen synthesis and decreasing gluconeogenesis.
- It increases glucose uptake by signalling to glucose transporters (GLUTs) to go to the membrane.
There is also a crossover between the pathways as Akt can activate mTOR leading to cell survival but also many effects on energy metabolism.
Draw a diagram of Pathophysiological Insulin Resistance
How was Leptin discovered?
- Leptin was discovered in animal models of obesity
- Friedmann et al (1994): identification of leptin as the gene product of the ob gene which is mutated in the obese mouse model ob/ob.
- Both the fa/fa phenotype in rats and the db/db (diabetic) phenotype in mice have now been established as resulting from mutations in the leptin receptor gene (ObR).
- Thus mutations of either the gene for leptin or its receptor cause extreme overeating and obesity in rodents, clearly demonstrating the role of leptin signalling in weight control.
The animals are fed “ad libitum” which means as much as they want; they are not diet restricted.
It is interesting that although both leptin deficiency and leptin receptor deficiency cause obesity, the LepR deficiency also gives a clear diabetic phenotype.
Draw a diagram to show the balance of adipokines secreted by “healthy-lean” and “toxic-fat” adipocytes
Draw a diagram to show mechanisms by which insulin and leptin resistance cause hypertension
ET-1 is endothelin-1, which causes vasoconstriction. RAAS also leads to hypertension.
