Metabolic Syndrome.

What is Metabolic Syndrome?

Metabolic syndrome is a cluster of medical conditions which if left untreated can lead to disease such as diabetes, stroke and heart disease.

Metabolic syndrome is diagnosed when ≥3 of the 5 criteria are present:

1. Abdominal ObesityWaist circumference >102cm  (>40in) in men; >88cm (>35in) in women.
2. High Fasting Blood Sugar Fasting plasma glucose >5.6mmol/L (>100mg/dl).
3. High Blood PressureBlood pressure >130/85mmHg or drug treatment for hypertension. 
4. High TriglyceridesPlasma triglyceride levels >1.7mmol/L (<150mg/dl).
5. Low High Density Lipoprotein (HDL) Plasma HDL <1mmol/L (<40mg/dl) in men; <1.3mmol/L (<50mg/dl) in women. 

How is Metabolic Syndrome related to Insulin Resistance?

Insulin is involved in the development and/or progression of all of the criteria used for the diagnosis of metabolic syndrome.

1. Abdominal Obesity (visceral obesity):

Visceral adipose tissue refers to the fat cells stored in the abdominal area. This is the fat that surrounds important organs in the abdominal cavity such as the pancreas, liver, gallbladder and intestines. Not only does this fat directly push on these organs, it also releases molecules and hormones which stimulate inflammation, promote fat storage, and further increase insulin resistance.

Insulin also activates Lipoprotein Lipase (LPL) and Glut4. LPL is an enzyme which allows fatty acids to enter the fat cells and Glut4 is a transporter which regulates glucose entry into fat cells. By activating both Glut4 and LPL, the fat cells begin to store this excess energy and increase in size. In order to break down the fatty acids and decrease the size of the adipose cells, Hormone Sensitive Lipase (HSL) must be upregulated. Insulin inhibits HSL, thus, further promoting fat storage and preventing fat breakdown.

2. High Fasting Blood Sugar (hyperglycemia):

The primary role of insulin is to facilitate glucose entry into fat cells. Normally, this can be accomplished with low levels of insulin. However, with consistent glucose consumption, the cells become less sensitive to insulin and stop responding. To compensate, the pancreas begins secreting higher quantities of insulin. This is known as hyperinsulinemia and insulin resistance. Eventually, the pancreas is maxed out and even with this extreme hyperinsulinemia, some sugar is unable to leave the blood. This leads to a condition of high blood sugar or hyperglycemia.

3. High Blood Pressure (hypertension):

To understand this mechanism by which insulin influences blood pressure, it is important to first recognize a couple basic physiological concepts. First, blood pressure is a product of blood volume, heart rate and peripheral resistance. This means that altering any of these components will directly affect blood pressure. 

Second, water always follows sodium.The most studied relationship between insulin and blood pressure is related to blood volume. It is well established that insulin acts on many parts of the kidney to increase sodium reabsorption back into the body. Because water follows sodium, this increases water retention, increasing total blood volume. This means that individuals with insulin resistance experience increased blood pressure which is driven by hyperinsulinemia.
Another mechanism by which insulin may increase blood pressure is through activation of the Sympathetic Nervous System (SNS). The SNS is known as the fight or flight system. It increases blood pressure through increase in heart rate and peripheral resistance.

Lastly, insulin may have a role in constriction of arteries. There are many complex mechanisms which lead to this outcome including damage of arteries by excessive glucose and activation of the MAPK pathway. Regardless of the mechanism involved, vasoconstriction leads to increased peripheral resistance which directly drives increases in blood pressure.

4. High Triglycerides (hypertriglyceridemia):

Triglycerides are the main form of energy storage in the body. One triglyceride molecule is made up of three (tri) free fatty acids attached to a glycerol backbone. Triglycerides are fat soluble and therefore require a transporter in order to be carried through the water soluble areas of the body such as the blood stream any lymph. Triglycerides are therefore packaged and transported in molecules called lipoproteins. The figure below summarizes all the different lipoproteins in which triglycerides are transported.

There are 2 sources of triglycerides. Exogenous and endogenous. Exogenous triglycerides come from diet. They are packaged into a chylomicron within the small intestine and distribute fats and protein to the body. The remnant chylomicrons (Chylomicron remains post distribution) are then taken up by the liver.
In the endogenous pathway, triglycerides are created in the liver from dietary carbohydrates. They are then packaged into very low density lipoproteins (VLDL) which like chylomicrons, distribute triglycerides  to the rest of the body. As the VLDL begin to lose their triglycerides, they turn into intermediate density lipoproteins (IDL) and then low density lipoproteins (LDL). If too much dietary carbohydrates are consumed VLDL and IDL remain high, elevating total blood triglyceride levels, as both these lipoproteins have high percent of triglycerides.
Additionally in order for triglycerides to be taken up by fat and muscle cells for storage , They must first be broken down by an enzyme called Lipoprotein lipase (LPL) LPL is mediated by insulin and can become resistant to insulin, just like the fat cells themselves. Therefore, if LPL stop responding to insulin, higher levels of Triglycerides will remain in the blood. A low carbohydrates diet helps reverse  insulin resistance, allowing triglycerides to leave the blood.

5. Low High Density Lipoprotein (HDL):

High density lipoprotein (HDL) is another lipoprotein which is made in the liver. The role of HDL is to pick up excess cholesterol from the body. However, if there are too many triglyceride rich lipoproteins (VLDL and IDL) due to increased carbohydrate consumption and insulin resistance, HDL molecules begin to exchange the cholesterol they picked up for triglycerides with VLDLs and IDLs. This leads to the reverse conversion of HDL to IDL like particles, decreasing HDL counts. Interestingly if there is an overload of VLDL and IDL, LDL also begins to pick up triglycerides, forming small dense LDL, which is another risk factor for cardiovascular disease. A low carbohydrate diet and intermittent fasting helps decrease VLDL and IDL formation and effectively remove extra triglycerides from the blood by improving insulin sensitivity (as described above). 

Brands, M. W. (2018). Role of Insulin-Mediated Antinatriuresis in Sodium Homeostasis and Hypertension. Hypertension,72(6), 1255-1262. doi:10.1161/hypertensionaha.118.11728 
Tushuizen, M. E. (2005). Postprandial dysmetabolism and cardiovascular disease in type 2 diabetes. Postgraduate Medical Journal,81(951), 1-6. doi:10.1136/pgmj.2004.020511