2. Fatty liver causes insulin resistance. 3. Insulin resistance leads to compensatory hyperinsulinemia.
4. Repeat cycle. Figure 7.2. Hormonal obesity IV: High insulin → fatty liver → insulin resistance
Fat inside the liver, rather than overall obesity, is the crucial stepping stone toward insulin resistance and diabetes.
Fatty liver is associated at all stages of insulin resistance from obesity to prediabetes to full-blown diabetes.
And that relationship holds in all racial groups and ethnicities.
Fatty liver is the clearest sign that hyperinsulinemia and insulin resistance are developing, and one of the earliest.
Fatty liver precedes the clinical diagnosis of type 2 diabetes by ten years or more.6 As the liver slowly accumulates fat it becomes increasingly insulin resistant.
Fatty liver can be diagnosed by ultrasound, but an increased waist circumference or waist-to-height ratio is an important clue to its presence.
Blood markers of liver damage also often mirror that slow rise, and this phase has been termed “the long, silent scream from the liver.” Two main types of fatty liver disease exist: alcohol-related liver disease and non-alcoholic fatty liver disease.
The first is associated, as the name suggests, with drinking too much alcohol.
Since most alcohol is metabolized solely in the liver, too much, too often forces the body to deal with the overflow.
The result is fatty liver.
But a lot of people who develop fatty liver disease and diabetes are not alcoholics, and it’s only recently that scientists have begun to understand that connection.
Non-alcoholic fatty liver disease (NAFLD) DR. ALFRED FRÖHLICH from the University of Vienna first began to unravel the neuro-hormonal basis of obesity in 1890. He described a young boy with the sudden onset of obesity who was eventually diagnosed with damage to the hypothalamus area of the brain, which resulted in
intractable weight gain.
This established this region as a key regulator of energy balance.
In rats, injury to the hypothalamic area of the brain could experimentally produce insatiable appetites and induce obesity.
Researchers quickly noticed something else, too.
All these obese animals shared characteristic liver damage, which was occasionally severe enough to progress to complete destruction.
Genetically obese mice shared the same liver lesions.
Strange, they thought.
What does the liver have to do with obesity?
Dr.
Samuel Zelman, a physician at the Veterans Administration Hospital in Topeka, Kansas, first made the connection in 1952.7 Alcoholism was known to cause fatty liver, but he observed the disease in a hospital aide who drank, not alcohol, but more than twenty bottles of Coca-Cola a day!
That obesity could cause similar liver damage by itself was completely unknown at that time.
Zelman, aware of the data from experiments involving rats, spent the next few years tracking down twenty other obese, non-alcoholic patients with evidence of liver disease and found they unanimously preferred carbohydrate-rich diets.
Almost thirty years later, Dr.
Jürgen Ludwig of the Mayo Clinic also described twenty patients with non-alcoholic fatty liver disease (NAFLD).8 All these patients also suffered from obesity and obesity-associated diseases, such as diabetes.
There was also varying evidence of liver damage.
Those with NAFLD whose blood tests showed evidence of organ damage were said to have non-alcoholic steatohepatitis (NASH), a term derived from steato, which means “fat,” and hepatitis, which means “inflammation of the liver.” NASH is simply the more serious manifestation of NAFLD.
At the time of its discovery in 1980, Dr.
Ludwig wrote that NAFLD spared doctors “the embarrassment (or worse) that may result from the ensuing verbal exchanges.” In other words, the realization that fatty liver could occur without alcohol saved patients from their doctors’ repeated accusations that they were lying about their alcohol intake.
More importantly, the new recognition of NAFLD confirmed the extraordinarily close association between obesity, hyperinsulinemia/insulin resistance, and fatty liver.
Where you found one, you almost invariably found the others.
Obese individuals have five to fifteen times the rate of fatty liver.
Up to
85 percent of type 2 diabetics have fatty liver.9 Even without diabetes, those with insulin resistance alone have higher levels of liver fat.10 NAFLD is estimated to affect at least two-thirds of those with obesity.11 Moreover, the incidence of NAFLD in both children and adults has been rising at an alarming rate,12 increasing in parallel with obesity and type 2 diabetes.
Hepatic steatosis, the deposition of fat in the liver, is consistently one of the most important markers of insulin resistance.13 In obese children, rising levels of alanine transaminase (ALT), an important blood marker of liver damage,14 is directly linked to insulin resistance and the development of type 2 diabetes.
The severity of fatty liver correlates to prediabetes, insulin resistance, and impairment of beta cell function.
Furthermore, NASH has become one of the leading causes of end stage liver disease, known as cirrhosis, and one of the top indications for liver transplant in the Western world.
In North America, the prevalence of NASH is estimated at 23 percent of the entire population.15 This is a truly frightening epidemic.
In the space of a single generation, non-alcoholic fatty liver disease has gone from being unnamed and completely unknown to being the commonest cause of abnormal liver enzymes and chronic liver disease in the Western world.16 This is the Rocky Balboa of liver diseases.
Figure 7.3. Insulin resistance rises with liver fat17
Why some people have severe fatty infiltration of the liver without evidence of damage while others have minimal fat and severe damage remains unknown.
As the liver slowly accumulates fat, insulin resistance escalates in lockstep.
In type 2 diabetic patients, a close correlation exists between the amount of liver fat and the insulin dose required,18 reflecting greater insulin resistance.
In short, the fattier the liver, the higher the insulin resistance.
Therefore, to understand insulin resistance, we must first understand how fatty liver develops.
How fatty liver develops HERE’S A STARTLING fact: I can give you fatty liver. Actually, I can give anybody fatty liver. What’s the scariest part? This crucial first step toward type 2 diabetes only takes three weeks! Excessive glucose and insulin drives new fat production (DNL). If this occurs faster than the liver can export it out to the adipocytes (fat cells), fat accumulates in the liver. This condition can be achieved simply by
overeating sugary snacks.
Hey presto, fatty liver disease.
Researchers fed overweight volunteers an extra thousand calories of sugary snacks daily in addition to their regular food consumption.19 This sounds like a lot, but it only means ingesting an extra two small bags of candy, a glass of juice, and two cans of Coca-Cola per day.
After three weeks, body weight increased by a relatively insignificant 2 percent.
However, liver fat increased by a whopping 27 percent, caused by an identical increase in the rate of DNL.
This fatty liver was far from benign, as blood markers of liver damage increased by a similar 30 percent.
But all was not lost.
When volunteers returned to their usual diets, their weight, liver fat, and markers of liver damage all completely reversed.
A mere 4 percent decrease in body weight reduced their liver fat by 25 percent.
Fatty liver is a completely reversible process.
Emptying the liver of its surplus glucose and dropping insulin levels returns the liver to normal.
Hyperinsulinemia drives DNL, which is the primary determinant of fatty liver disease.
Normalizing insulin levels reverses the fatty liver.
Refined carbohydrates, which cause large increases in insulin, are far more sinister than dietary fat.
High carbohydrate intake can increase DNL tenfold, whereas high fat consumption, with correspondingly low carbohydrate intake, does not change hepatic fat production noticeably.20 Specifically, the sugar fructose, rather than glucose, is the main culprit,21 even though fructose does not produce much insulin response.
The next chapter explains why in more detail.
By contrast, in type 1 diabetes, insulin levels are extremely low, causing decreased liver fat.22 Producing fatty liver in animals is simple, too.
The delicacy known as foie gras is the fatty liver of a duck or a goose.
Geese naturally develop large fatty livers to store energy in preparation for the long migration ahead, but more than four thousand years ago the Egyptians developed a technique known as gavage.
Originally done by hand, this deliberate overfeeding is now administered using more modern and efficient methods.
A large amount of high-starch corn mash is fed directly into the goose or duck’s digestive system several times per day through a tube called an embuc.
In just ten to fourteen days, the liver becomes fatty and enlarged.
Producing foie gras in animals and fatty liver in humans is basically the same process.
Deliberate carbohydrate overfeeding provokes the
high insulin levels necessary to develop fatty liver.
In 1977, the Dietary Guidelines for Americans strongly advised people to eat less fat and more carbohydrates, such as bread and pasta.
The result?
Dramatically increased insulin levels.
Little did we know that we were, in essence, making human foie gras.
Fatty liver is the harbinger of insulin resistance, but it is only the beginning.
The fat within other organs, including the skeletal muscles and the pancreas,23 also play a leading role in this disease.