inches, women over 35 inches; 2.
Low high-density lipoprotein (HDL): men less than 40 mg/dL or women less than 50 mg/dL or taking medication; 3.
High triglycerides: over 150 mg/dL or taking medication; 4.
High blood pressure: over 130 mmHg systolic (top number) or over 85 mmHg diastolic (bottom number) or taking medication; 5.
Fasting blood glucose > 100 mg/dL or taking medication.
Metabolic syndrome affects almost one-third of the adult population of North America2 and this linked group of problems increases the risk of heart disease by almost 300 percent.
Metabolic syndrome also increases the risk of stroke, cancer, NASH, PCOS, and obstructive sleep apnea.
Even more worrisome, MetS is increasingly being diagnosed in our children.3 So what does metabolic syndrome have to do with diabetes?
A lot, as it turns out.
UNDERSTANDING METABOLIC SYNDROME
IN 1988, Dr.
Gerald Reaven of Stanford University introduced the concept of a single syndrome in his Banting Medal address, one of the highest- profile academic lectures in all of diabetic medicine.4 He called it Syndrome X to denote a single variable, then unknown, that caused this constellation of problems.
But what was this X factor?
Our understanding of metabolic syndrome began in the 1950s, when researchers showed a close association between high levels of triglycerides and cardiovascular disease.
To their surprise, hypertriglyceridemia was not caused by eating too much fat; instead, it resulted primarily from excess dietary carbohydrates and the subsequent hyperinsulinemia.5 Around the same time, early insulin assays confirmed that many people with relatively minor blood glucose elevations had severe hyperinsulinemia.
This was understood as a compensatory mechanism in response to elevated insulin resistance.
In 1963, Dr.
Reaven observed that patients with heart attacks often had both high triglycerides and hyperinsulinemia,6 firmly linking these two diseases.
Researchers noted a link between high blood pressure (hypertension) and hyperinsulinemia as early as 1966.7 By 1985, research showed that much of essential hypertension, so called because the underlying cause remained unidentified, was also closely associated with high insulin levels.8 Remember that metabolic syndrome identifies patients with a shared group of risk factors that all have a common origin.
High blood glucose, resulting from increased insulin resistance, central obesity, high blood pressure, and abnormal lipids all reflect a single underlying problem.9 And each additional component of metabolic syndrome increases the risk of future cardiovascular disease.
In fact, the major diseases of the twenty-first century, heart disease, cancer, diabetes, have all been related to metabolic syndrome and its common cause, the X factor.
That X factor, as it turns out, is hyperinsulinemia.10 It is worth noting that while obesity, as defined by BMI, is commonly associated with metabolic syndrome, MetS can also be found in approximately 25 percent of non-obese individuals with normal glucose
tolerance levels.
This emphasizes again that the problem is not obesity per se, but abdominal obesity.
Similarly, high levels of low-density lipoprotein (LDL, or “bad” cholesterol) are pointedly not one of the criteria for developing metabolic syndrome.
Despite the current obsession with lowering LDL cholesterol with statin medications, high LDL is not a component of the metabolic syndrome and may not have the same origins.
Recent research has supported and extended this concept of a single syndrome with a common cause.
Let’s see how this all develops.
FROM FATTY LIVER TO METABOLIC SYNDROME
AS WE’VE SEEN previously, the liver lies at the nexus of metabolism and nutrient flow, particularly for carbohydrates and proteins.
Situated immediately downstream from the intestines, nutrients enter the blood in the portal circulation and pass directly to the liver.
The major exception is dietary fat, which is absorbed directly into the lymphatic system as chylomicrons.
These chylomicrons empty into the bloodstream without first passing through the liver.
As the major organ responsible for storing and distributing energy, the liver is naturally the main site of action of the hormone insulin.
When carbohydrates and proteins are absorbed, the pancreas releases insulin.
It travels in the portal vein, an expressway to the liver.
Concentrations of glucose and insulin are often ten times higher in the blood of the portal system and liver than in the rest of the body.
Insulin promotes the storage of food energy for later use, a mechanism that has allowed us to survive the periods of famine inherent in human history.
The liver prefers to store extra glucose in long glycogen chains since it is an easily accessible form of energy.
However, there is limited space inside the liver for that glycogen.
Think of a refrigerator.
We can easily place food (glucose) into the refrigerator (glycogen) and take it out again.
Once the glycogen stores are full, the liver must find a different storage form for the excess glucose.
It transforms this glucose through de novo lipogenesis (DNL) into newly created molecules of triglycerides, also known as body fat.
Hypertriglyceridemia
THESE NEWLY CREATED triglycerides are made from the substrate glucose, not from dietary fat.
This distinction is important because fats made by DNL are highly saturated.
Eating dietary carbohydrates, not dietary saturated fat, increases saturated fat levels in the blood.
Saturated fats in the blood, not the diet, are highly associated with heart disease.
When needed, the triglyceride molecule from body fat can be broken into three fatty acids, which most organs use directly for energy.
The process of converting this fat to energy and back again is far more cumbersome than using glycogen.
However, fat storage provides the unique advantage of unlimited storage space.
Think of a chest freezer in your basement.
Although it is more difficult to move food (triglycerides) into and out of your freezer (adipocytes, or fat cells), primarily because you have to move it farther, the size of the freezer allows you to store larger amounts.
The basement also has enough space for a second or third freezer, if needed.
These two forms of storage fulfill different and complementary roles.
The stored glucose, or glycogen (fridge), is easily accessible but limited in capacity.
The stored body fat, or triglycerides (freezer), are hard to access but unlimited in capacity.
The two main activators of DNL are insulin and excessive dietary fructose.
High dietary intake of carbohydrates, and to a lesser extent, protein, stimulates insulin secretion and provides the substrate for DNL.
With DNL running at full production, large amounts of new fat are created.
Excessive DNL can overwhelm the export mechanism, resulting in abnormal retention of this new fat in the liver.11 As you stuff more and more fat into the liver, it becomes noticeably engorged and can be diagnosed on ultrasound as fatty liver.
But if the liver is not the appropriate place to store this new fat, where should it go?
First, you could try to burn it off for energy.
However, with all the available glucose around after a meal, the body has no reason to burn the new fat.
Imagine you have gone to Costco and bought waaayyy too much food to store in your refrigerator.
One option is to eat it, but there’s simply too much.
If you cannot get rid of it, much of the food will be left on the counter where it will rot.
So this option is not viable.
Your glycogen “fridge” is full, so the only remaining option is to export the newly created fat (excess food) somewhere else.
This mechanism is known as the endogenous pathway of lipid transport.
Essentially,
triglycerides are packaged with special proteins to create very low, density lipoproteins (VLDL), which are released into the bloodstream to help decompress the congested liver.12 More dietary glucose and fructose means more DNL which means more VLDL must be released.13, 14 This mass export of triglyceride-rich VLDL particles is the major reason for high plasma triglyceride levels,15 which are detectable in all standard blood tests for cholesterol.
Ultimately, eating too much glucose and too much fructose causes this hypertriglyceridemia.
Figure 9.1.
Hormonal obesity VI: The effect of high triglycerides
High-carbohydrate diets increase VLDL secretion and raise blood triglyceride levels by 30 to 40 percent.16 Called carbohydrate-induced hypertriglyceridemia, this phenomenon can occur with as little as five days of high intake. Dr. Reaven showed that hyperinsulinemia and fructose shared responsibility for most of the rise in blood triglyceride levels.17 Simply put, higher insulin levels and fructose ingestion produce higher blood triglyceride levels. There’s just too much sugar.