Run for Your Life

by Mark Cucuzzella

  My running colleagues and I got away with consuming high-carb diets because we exercised athletically, and believed that if the fire is hot enough it can burn (metabolize) anything. My race times were reasonably good, partly because I understood pacing and training. And my weight remained stable, so I assumed my diet was on the right track. I urged others to follow my example. As a doctor and a competitive runner, I even promoted pre-race “carbo loading” dinners.

  Except for a distracting problem. I couldn’t seem to shake a perpetual state of hunger, and an unexplainable sense of fatigue. I didn’t realize it at the time, but I was on the path to type 2 diabetes. My blood labs showed that I already had the condition known as prediabetes.

  CALORIE BALANCE DOES NOT COMPUTE

  I had carefully measured and recorded my activity levels, but I began to wonder: was it possible that my fatigue and hunger had more to do with diet than with how active I was? Nutrition was one ingredient in my performance cocktail that I figured I could adjust. But I knew of no alternative to the diet regimen I was on.

  That’s when I became intrigued, then obsessed, with what happens to us when we consume food. I tumbled down the scientific rabbit hole of physiology and metabolism, and devoured age-old and emerging studies on nutrition, energy balance, obesity, the hormones that affect appetite, fat storage, and the urge to exercise. I sought out experts, queried and observed members of the military, chatted with patients who came through our hospital, and engaged the citizens in our community.

  WHERE DOES YOUR SUGAR GO?

  So, what was going on? How does the food we eat affect how we feel and what happens in our bodies?

  Our bodies demand that glucose levels in the blood remain within a narrow range. That level is regulated by a complex interplay of hormones, chemicals, signaling proteins, and glucose disposal pathways, which in turn are signaled by environmental factors such as our level of exertion, the types of food we eat, stress, sleep, and even the microbes in our gut. For most of us, moments after we consume refined carbohydrates or a sugared drink, the sugar level in our blood rises. The muscles, brain, and other organs use this glucose as their fuel, and if there’s an immediate demand for energy from these organs, they can directly utilize some of the recently ingested glucose.

  But the blood can’t store more than a teaspoon of glucose, so there’s not a lot of buffer for maintaining blood sugar levels within a narrow healthy range. When the blood glucose level rises after eating a breakfast bar, for instance, the pancreas releases the hormone insulin, which drives that sugar from the bloodstream and into our muscles and liver, in the form of glycogen.

  These “glycogen tanks” within the liver and muscles aren’t very large, either. If you ate your breakfast bar before doing much activity, those tanks are likely already full.

  When the glycogen tanks are full, the liver converts additional incoming sugars to a type of fat called triglycerides, through a process called de novo lipogenesis. Much of those triglycerides are then stored in the cells of our adipose tissue, or (long-term) visceral fat, also known as belly fat.

  If you are insulin sensitive, your body responds quickly and appropriately to the rise in blood sugar and insulin, and vigorously manages the sugar/energy balance. But if the incoming sugar just keeps on coming, the triglyceride fat builds up faster than the liver can ship it out, and the liver can no longer respond normally to insulin’s signals.

  This is the beginning of insulin resistance. Now, in response to persistent sugar elevation, the pancreas has no choice but to further elevate insulin levels in a desperate attempt to overcome the resistance. A vicious carb- and insulin-driven cycle begins. That’s why the body and mind of the insulin-resistant person are persistently hijacked by fatigue and hunger. A simplified version of a complex progression summarizes this endless loop:

  More sugar ➞ more insulin ➞ more insulin resistance ➞ more calorie/fat storage ➞ less energy available to muscles ➞ more hunger ➞ more sugar…

  Fructose (found in high concentration in processed foods and drinks) compounds the problem, because it can be metabolized only in the liver; the quantities and concentrations of fructose that we typically consume quickly inundate the liver. Essentially, fructose metabolism is not as well regulated as glucose metabolism—it appears to have less “metabolic flexibility”—and tends to force the body into building fat.

  If you are insulin resistant (carbohydrate intolerant, or prediabetic), the active muscles are deprived of the energy they seek. That’s when the appetite—sensing insufficient energy available for use by the muscles—becomes supercharged with an urgent drive to eat, as it attempts to compensate for the perceived lack of fuel.

  After a decade or more of this “normal” abuse, the pancreas may lose its ability to compensate, and the body can no longer control blood sugar levels. Those with escalating insulin resistance risk developing a fatty liver, which we’ll discuss below.

  DIABETES: A REVERSIBLE PANDEMIC

  The incidence in America of type 2 diabetes is near-epidemic. But few are aware of the condition known as prediabetes—the state of insulin resistance and higher-than-normal blood glucose levels that aren’t yet high enough to be labeled as type 2 diabetes. With unchecked prediabetes, insulin levels continue to rise, while increasing amounts of sugar are converted to visceral fat. Our typically late diagnosis of prediabetes is akin to waiting until a large, visible tumor appears before thinking about cancer.

  Most folks with prediabetes don’t realize they have it, and are unaware of its long-term risks: fully developed diabetes, heart attack, stroke, and even Alzheimer’s. A recent article in the Journal of the American Medical Association reports that more than half of adult Americans—and increasing numbers elsewhere—have diabetes or prediabetes. And the Centers for Disease Control and Prevention (CDC) project that if current trends continue unaddressed, nearly half of people with prediabetes will develop type 2 diabetes within five years. We are now seeing this condition in children and no longer label it “adult diabetes.”

  TOO MUCH TREATMENT, NOT ENOUGH CARE

  Every day I witness at least one case of prediabetes that has been dismissed as “normal” or has been missed altogether, despite the ease with which it can be detected. Any change in body configuration in the direction of accumulating abdominal fat is a preliminary sign. To put it bluntly: if you’re a male, you should be able to see your private parts while standing in the shower. For women, the circumference of your waist shouldn’t be greater than that of your chest. Or simply multiply your waist circumference by two. It should be less than your height.

  Sadly, I see too many insulin-resistant, prediabetic patients who advance to full-blown diabetes without a health care provider having ever urged them to modify their diet or lifestyle beyond suggesting that they “eat less and exercise more.” Even when care providers do intervene, they often send patients in the wrong direction, typically by recommending a low-fat, high-carb diet—the opposite of what most need. Indeed, the American Diabetes Association’s “Create Your Plate” dietary guidelines don’t restrict carbs and reduce the saturated fats. And the current CDC/AMA/ADA-supported site So…Do I Have Prediabetes? doesn’t even suggest reducing carb intake, despite these groups’ recognition in their own papers that carbohydrates are the main drivers of high blood glucose levels. Again and again, dietary fat remains the perceived culprit. So what are we to replace the fat with? Carbohydrates? No wonder remission from diabetes is rarely seen.

  We all fit somewhere along this spectrum.

  Most of us move to the left as we age.

  SUGAR AND CARBS

  Medical literature has established that the prevalence of diabetes and the development of prediabetes correlate with the duration and degree of exposure to sugar and refined carbohydrates. But the food, pharmaceutical, and medical industries are slow to catch up. They have little interest in reversing
diabetes, because ongoing treatment for it as a chronic disease forms a lucrative revenue stream. Better to offer a lifetime of treatment than a cure.

  Diabetes isn’t the only condition to fear from sugar. Long before diabetes develops, high insulin and blood sugar levels can trigger inflammation, which contributes to vessel stiffening and development of plaque and “intimal thickening” in the inner lining of the arteries. (The oxidation of manufactured oils, including vegetable oils, amplifies this process.)

  This thickening and stiffening can inhibit optimal blood flow to the heart and brain, and (even more dangerously) the plaque can rupture and cause heart arrhythmia or stroke. The body’s attempt to “heal” the rupturing plaque can cause a thrombus, or clot, which can also block an artery. Contrary to decades of conventional wisdom (and increasingly confirmed population studies, and meta-analyses of pooled trials and prospective trials), atherosclerosis doesn’t result from consumption of dietary fat. The most likely suspect is inflammation driven by insulin resistance. The recent PURE (Prospective Urban Rural Epidemiology) study in eighteen countries with 130,000 patients again confirmed this.

  THERE’S EVEN MORE TO (NOT) LOOK FORWARD TO…

  High blood sugar levels and manufactured fats (i.e., vegetable oils) also produce nasty metabolic by-products that drive inflammation and further contribute to cardiovascular disease. These include reactive oxidative species (ROS), and also advanced glycated end-products (AGES), or glycations, in which glucose binds with proteins on the outer surface membranes of cells. Once the glucose is stuck onto the cell membrane, it can’t get off. This makes the cells less pliable and more vulnerable to damage and premature aging.

  This process (and the inflammatory cascade from persistently high insulin levels) eventually leads to what is called metabolic syndrome, the precursor to diabetes and its grim manifestations: blindness, atherosclerosis, high blood pressure, heart attacks, strokes, kidney damage, impotence, loss of feeling in the feet, and dementia. Metabolic syndrome might better be termed something more descriptive but suitably alarming, such as “insulin resistance/carbohydrate intolerance” or, more accurately, “hyperinsulinemia.”

  In 1980, Gerald Reaven identified “Syndrome x,” which is nowadays called metabolic syndrome. The path on the right summarizes the clinical syndromes related to the inflammatory and hormonal dysfunction of persistent high insulin levels. The path on the left follows the development of hyperglycemia. Driving it all is insulin resistance.

  DESTINATION: LIVER

  A hundred years ago, Americans ate 4 pounds of added sugar a year. Now each of us consumes over 125 pounds of sugar, much of it as fructose in sugar-sweetened beverages. Add to that our annual per capita consumption of 140 pounds of processed flour, which is quickly converted to glucose during digestion. This is the direct cause of a condition known as fatty liver, or nonalcoholic fatty liver disease (NAFLD)—which in turn drives diabetes.

  The physiology of the insulin resistance and fatty liver disease relationship is not fully understood, but the results are clinically significant. Now unfortunate victims of this sugar-driven disease are lining up for liver transplants, without being offered measures to reverse it, nor knowledge of how they acquired it. (It may be instructive that food producers create foie gras, the delicacy made from the fatty liver of geese, by force-feeding the birds starch, an easily digestible form of carbohydrate.)

  WHICH SUGAR IS WHICH?

  Table sugar and sodas are a mix of glucose and fructose. Fruit is primarily fructose, but tends to be absorbed more slowly because it travels with fiber. Flour is mostly glucose—thus the high “glycemic index” of flour products. High fructose corn syrup (HFCS, a staple ingredient in soft drinks) is a mixture of both, and present in many foods, not just soft drinks.

  Almost every cell in our body can utilize glucose. Fructose, however, because of its structure, needs to pass through the liver. This means that fructose has a lower glycemic index, because the absorption happens more slowly. But this isn’t a good thing: a high fructose load on the liver overwhelms the metabolic processes, causing fat to accumulate in the liver. This may be the first stage of insulin resistance.

  BACK TO THE LIVER

  Most people, including many physicians, dismiss “fatty liver” as a largely innocuous condition stemming from being fat, or from consuming too much dietary fat. (More accurately, one might describe NAFLD as “carby liver” because it originates from insulin resistance and the conversion of excess sugar and carbohydrates that are converted to triglycerides.) But the condition is much more insidious, and its effects can be quite rapid. Dr. Robert Lustig recently published a study comparing the effect of fructose intake in children. Compared to children who consumed the same number of calories of better-quality carbohydrates, the high fructose consumption group showed markers of liver dysfunction and metabolic syndrome in just ten days.

  The only effective treatment for fatty liver is to short-circuit its causes—meaning at the source, by reducing the ingestion of carbs, especially fructose, and lowering body weight by 10 percent. Fortunately, fatty liver can be readily diagnosed: it appears in a panel of liver enzymes as a rise in the transaminases GGT, AST, and ALT. It is often picked up “incidentally” during an ultrasound or CT scan of the liver.

  So what are the early indicators of insulin resistance that a doctor might look for in a clinical setting? We have known for some time that one’s waist is more important than one’s weight. It’s healthy, in fact, to carry a certain amount of fat under your skin. This is metabolically active “brown fat.” Belly fat, or “white fat,” is a different beast, as it indicates that you are storing fat in and around the internal organs, such as the liver and heart. In the presence of obesity, a high TG/HDL ratio, a high fasting or post-meal insulin or glucose level, or any hemoglobin A1c reading (a key diabetes screen) higher than 5.5 (the ideal is below 5.0) is also cause for concern. Fatigue, constant hunger, an irritable GI tract, feelings of low blood sugar or “crashes”—or any chronic pain or inflammatory disorder—are additional flags for insulin resistance/carbohydrate intolerance (metabolic syndrome). But insulin resistance can be detected even before waist circumference expands, in the form of fat accumulation under the mandible, particularly in normal-weight people.

  A CHERISHED ADDICTION

  One of the biggest challenges in treating diabetes and obesity-related diseases is that sugars hit the happy center of the brain. Dr. Lustig has illuminated how fructose in particular stimulates the nucleus accumbens, or “hedonic pathway,” by creating a tasty reward, habituation, and possible dependence that parallels that of alcohol or other drug addiction. We eat carbs for comfort, as a handy after-school snack, a nightly treat, or simply to relieve stress. Like the hourly hit of a cigarette, we get rewarded and become habituated. Nutritionists even encourage “small, frequent meals,” which are almost always low-fat and high-carb. Fruit juice is a culprit, too. But implicating the citrus industry in this public health disaster would be political suicide. Remember your grandmother’s juice glasses? They were the size of a shot glass.

  The public health implications of this are immense. If you consider the role that the sugar and flour industries play in our society and economy, curtailing the consumption of these products presents a sizable political challenge. As with any substance of abuse, combating the obesity epidemic will require proactive social and legislative measures to reduce sugar consumption. As with dieting in general, as we will discuss, willpower alone cannot be relied upon as a sustainable regulator of behavior.

  OBESITY: EGG FIRST, OR CHICKEN?

  Obesity is a disorder of abnormal fat accumulation, in most cases driven by eating more carbohydrates than an insulin-resistant body can handle. The excess insulin generated from overeating of carbs begins to act as an accelerator, in essence, for the growth of body fat. We may continue to argue over whether obesity (defined as a body mass index gr
eater than 30) is a disease as such, but it is an important marker for all the other metabolic diseases we see today.

  Is BMI the sole indicator of insulin resistance? Dr. Lustig estimates that 40 percent of U.S. adults with a normal BMI have some spectrum of this condition, and are referred to as TOFI (“Thin on the Outside, Fat on the Inside”). And some who are overweight do not have insulin resistance. It is possible to be obese and healthy, with normal metabolic functioning, but this is less common. Most college football players would be considered obese, judging by BMI alone, but they are often metabolically healthy. At the same time, 40 percent of non-obese Americans have early or full-blown metabolic syndrome.

  Obesity is commonly dismissed as a product of being gluttonous and lazy. But it’s not the behavior of overeating and sitting on one’s butt that drives obesity. It’s the obesity that drives the behavior. How does this work? The condition of insulin resistance begets the drive to eat. As incoming carb calories are converted to fat, the desire to move or exercise is reduced, which begets more insulin resistance, which increases hunger—all in a negative feedback loop.

  One powerful actor here is the dysfunction of the hunger gauge—the brain’s appestat, which tells us when we are hungry and full. Leptin, a recently discovered satiety hormone, is released by our fat cells and signals the feeling of fullness. We now know that leptin brain signaling is inhibited by insulin. So for our appestat to reset at a healthy level, we need the high insulin levels to go away. A hormone called ghrelin (think of your stomach growling) is another satiety hormone secreted mostly by the stomach, and it also regulates the appestat.