summarize this "Fat also begins to infiltrate your abdomen, accumulating in between your
organs. Where subcutaneous fat is thought to be relatively harmless, this
“visceral fat” is anything but. These fat cells secrete inflammatory cytokines
such as TNF-alpha and IL-6, key markers and drivers of inflammation, in
close proximity to your most important bodily organs. This may be why
visceral fat is linked to increased risk of both cancer and cardiovascular
disease.
Fat storage capacity varies widely among individuals. Going back to our
tub analogy, some people have subcutaneous fat-storage capacity equivalent
to a regular bathtub, while others may be closer to a full-sized Jacuzzi or hot
tub. Still others may have only the equivalent of a five-gallon bucket. It also
matters, obviously, how much “water”is flowing into the tub via the faucet (as
calories in food) and how much is flowing out via the drain (or being
consumed via exercise or other means).
Individual fat-storage capacity seems to be influenced by genetic factors.
This is a generalization, but people of Asian descent (for example), tend to
have much lower capacity to store fat, on average, than Caucasians. There are
other factors at play here as well, but this explains in part why some people
can be obese but metabolically healthy, while others can appear “skinny”
while still walking around with three or more markers of metabolic
syndrome. It’s these people who are most at risk, according to research by
Mitch Lazar at the University of Pennsylvania, because a “thin” person may
simply have a much lower capacity to safely store fat. All other things being
equal, someone who carries a bit of body fat may also have greater fat-storage
capacity, and thus more metabolic leeway than someone who appears to be
more lean.
It doesn’t take much visceral fat to cause problems. Let’s say you are a
forty-year-old man who weighs two hundred pounds. If you have 20 percent
body fat, making you more or less average (50th percentile) for your age and
sex, that means you are carrying 40 pounds of fat throughout your body. Even
if just 4.5 pounds of that is visceral fat, you would be considered at
exceptionally high risk for cardiovascular disease and type 2 diabetes, in the
top 5 percent of risk for your age and sex. This is why I insist my patients
undergo a DEXA scan annually—and I am far more interested in their
visceral fat than their total body fat.
—
It may have taken you a long time to get there, but now you are in trouble—
even if you, and your doctor, may not yet realize it. You have fat
accumulating in many places where it should not be, such as in your liver,
between your abdominal organs, even around your heart—regardless of your
actual weight. But one of the first places where this overflowing fat will cause
problems is in your muscle, as it worms its way in between your muscle
fibers, like marbling on a steak. As this continues, microscopic fat droplets
even appear inside your muscle cells.
This is where insulin resistance likely begins, Gerald Shulman concludes
from three decades’ worth of investigation. These fat droplets may be among
the first destinations of excess energy/fat spillover, and as they accumulate
they begin to disrupt the complex network of insulin-dependent transport
mechanisms that normally bring glucose in to fuel the muscle cell. When
these mechanisms lose their function, the cell becomes “deaf” to insulin’s
signals. Eventually, this insulin resistance will progress to other tissues, such
as the liver, but Shulman believes that it originates in muscle. It’s worth
noting that one key ingredient in this process seems to be inactivity. If a
person is not physically active, and they are not consuming energy via their
muscles, then this fat-spillover-driven insulin resistance develops much more
quickly. (This is why Shulman requires his study subjects, mostly young
college students, to refrain from physical activity, in order to push them
towards insulin resistance.)
Insulin resistance is a term that we hear a lot, but what does it really
mean? Technically, it means that cells, initially muscle cells, have stopped
listening to insulin’s signals, but another way to visualize it is to imagine the
cell as a balloon being blown up with air. Eventually, the balloon expands to
the point where it gets more difficult to force more air inside. You have to
blow harder and harder. This is where insulin comes in, to help facilitate the
process of blowing air into the balloon. The pancreas begins to secrete even
more insulin, to try to remove excess glucose from the bloodstream and cram
it into cells. For the time being it works, and blood glucose levels remain
normal, but eventually you reach a limit where the “balloon” (cells) cannot
accept any more “air” (glucose).
This is when the trouble shows up on a standard blood test, as fasting
blood glucose begins to rise. This means you have high insulin levels and high
blood glucose, and your cells are shutting the gates to glucose entry. If things
continue in this way, then the pancreas becomes fatigued and less able to
mount an insulin response. This is made worse by, you guessed it, the fat now
residing in the pancreas itself. You can see the vicious spiral forming here: fat
spillover helps initiate insulin resistance, which results in the accumulation of
still more fat, eventually impairing our ability to store calories as anything
other than fat. There are many other hormones involved in the production and
distribution of fat, including testosterone, estrogen, hormone-sensitive
lipase[*3] and cortisol. Cortisol is especially potent, with a double-edged effect
of depleting subcutaneous fat (which is generally beneficial) and replacing it
with more harmful visceral fat. This is one reason why stress levels and sleep,
both of which affect cortisol release, are pertinent to metabolism. But insulin
seems to be the most potent as far as promoting fat accumulation because it
acts as kind of a one-way gate, allowing fat to enter the cell while impairing
the release of energy from fat cells (via a process called lipolysis). Insulin is
all about fat storage, not fat utilization.
When insulin is chronically elevated, more problems arise. Fat gain and
ultimately obesity are merely one symptom of this condition, known as
hyperinsulinemia. I would argue that they are hardly even the most serious
symptoms: as we’ll see in the coming chapters, insulin is also a potent growthsignaling hormone that helps foster both atherosclerosis and cancer. And
when insulin resistance begins to develop, the train is already well down the
track toward type 2 diabetes, which brings a multitude of unpleasant
consequences.
—
Our slowly dawning awareness of NAFLD and NASH mirrors the emergence
of the global epidemic of type 2 diabetes a century ago. Like cancer,
Alzheimer’s, and heart disease, type 2 diabetes is known as a “disease of
civilization,” meaning it has only come to prominence in the modern era.
Among primitive tribes and in prior times, it was largely unknown. Its
symptoms had been recognized for thousands of years, going back to ancient
Egypt (as well as ancient India), but it was the Greek physician Aretaeus of
Cappadocia who named it diabetes, describing it as “a melting down of the
flesh and limbs into urine.”
Back then, it was vanishingly rare, observed only occasionally. As type 2
diabetes emerged, beginning in the early 1700s, it was at first largely a disease
of the superelite, popes and artists and wealthy merchants and nobles who
could afford this newly fashionable luxury food known as sugar. The
composer Johann Sebastian Bach is thought to have been afflicted, among
other notable personages. It also overlapped with gout, a more commonly
recognized complaint of the decadent upper classes. This, as we’ll soon see,
was not a coincidence.
By the early twentieth century, diabetes was becoming a disease of the
masses. In 1940 the famed diabetologist Elliott Joslin estimated that about
one person in every three to four hundred was diabetic, representing an
enormous increase from just a few decades earlier, but it was still relatively
uncommon. By 1970, around the time I was born, its prevalence was up to
one in every fifty people. Today over 11 percent of the US adult population,
one in nine, has clinical type 2 diabetes, according to a 2022 CDC report,
including more than 29 percent of adults over age sixty-five. Another 38
percent of US adults—more than one in three—meet at least one of the
criteria for prediabetes. That means that nearly half of the population is either
on the road to type 2 diabetes or already there.
One quick note: diabetes ranks as only the seventh or eighth leading cause
of death in the United States, behind things like kidney disease, accidents,
and Alzheimer’s disease. In 2020, a little more than one hundred thousand
deaths were attributed to type 2 diabetes, a fraction of the number due to
either cardiovascular disease or cancer. By the numbers, it barely qualifies as
a Horseman. But I believe that the actual death toll due to type 2 diabetes is
much greater and that we undercount its true impact. Patients with diabetes
have a much greater risk of cardiovascular disease, as well as cancer and
Alzheimer’s disease and other dementias; one could argue that diabetes with
related metabolic dysfunction is one thing that all these conditions have in
common. This is why I place such emphasis on metabolic health, and why I
have long been concerned about the epidemic of metabolic disease not only
in the United States but around the world.
Why is this epidemic happening now?
The simplest explanation is likely that our metabolism, as it has evolved
over millennia, is not equipped to cope with our ultramodern diet, which has
appeared only within the last century or so. Evolution is no longer our friend,
because our environment has changed much faster than our genome ever
could. Evolution wants us to get fat when nutrients are abundant: the more
energy we could store, in our ancestral past, the greater our chances of
survival and successful reproduction. We needed to be able to endure periods
of time without much food, and natural selection obliged, endowing us with
genes that helped us conserve and store energy in the form of fat. That
enabled our distant ancestors to survive periods of famine, cold climates, and
physiologic stressors such as illness and pregnancy. But these genes have
proved less advantageous in our present environment, where many people in
the developed world have access to almost unlimited calories.
Another problem is that not all of these calories are created equal, and not
all of them are metabolized in the same way. One abundant source of calories
in our present diet, fructose, also turns out to be a very powerful driver of
metabolic dysfunction if consumed to excess. Fructose is not a novel nutrient,
obviously. It’s the form of sugar found in nearly all fruits, and as such it is
essential in the diets of many species, from bats and hummingbirds up to
bears and monkeys and humans. But as it turns out, we humans have a unique
capacity for turning calories from fructose into fat.
Lots of people like to demonize fructose, especially in the form of highfructose corn syrup, without really understanding why it’s supposed to be so
harmful. The story is complicated but fascinating. The key factor here is that
fructose is metabolized in a manner different from other sugars. When we
metabolize fructose, along with certain other types of foods, it produces large
amounts of uric acid, which is best known as a cause of gout but which has
also been associated with elevated blood pressure."