Metabolic Syndrome: The New Scourge
Diana is an eight-year-old Latino girl who weighs 200 pounds. Despite not yet starting puberty, she has already been diagnosed with type 2 diabetes. For the past two years, she and her mother have lived in a homeless shelter. The child constantly cries for food despite being given ample portions. To feel that she can provide for her daughter, her mother also gives Diana her own portion of every meal served by the shelter. Worse yet, Diana gets a third breakfast at the school as part of the USDA School Nutrition Program. While Diana’s mother does what she feels is in the best interest of her daughter, she is inadvertently making her sicker and likely contributing to an early death.
The numbers don’t lie: the fatter you are, the quicker you die. At least at a population level. An actuarial analysis in 2003 demonstrated that those with a BMI of 45 lost a total of twenty years of life.1 As a rule, the fat die young. Ford now makes cars specifically suited for the obese in America, and we’ve even super-sized our caskets. But we’re talking statistics for large populations of people here. At an individual level, all bets are off. Twenty percent of the obese population have a normal metabolic profile, whereas up to 40 percent of normal-weight people have an abnormal metabolic profile. Knowing where you stand is crucial to taking steps to prolong your life.
Metabolic Syndrome
You don’t die of obesity; you die of the diseases that “travel” with it. It’s these metabolic decompensations that make obesity the scourge that it is. Diabetes, hypertension, heart disease, cancer, and dementia—the things that kill you are collectively packaged under the concept of “metabolic syndrome.”
Metabolic syndrome is classically defined by the National Cholesterol Education Program’s Adult Treatment Panel (NCEP-ATP) as a cluster of five chronic conditions (obesity, diabetes, lipid problems such as high triglyceride and low HDL, hypertension, cardiovascular disease), any or all of which increase your chance of early death. The NCEP states that if you’ve got three of the five, you’ve got metabolic syndrome. However, the syndrome is not nearly so easy to define. Other professional organizations have chosen to define it using slightly different criteria.2 The reason for these alternate diagnostic benchmarks is that we really don’t know the true cause. All the benchmarks try to establish cutoffs, which are fraught with error. Establishing criteria for metabolic syndrome in children is even more difficult.3 But it’s crucial, because the problem is increasing at alarming rates and translates into fifteen to twenty years of life lost. Metabolic syndrome may soon overtake smoking as the leading cause of heart disease worldwide.
The concept that cardiometabolic risk factors “cluster” in certain individuals has been known for several decades. However, it was not until the early 1980s that the relationship between obesity, dyslipidemia (an abnormal amount of cholesterol and/or fat in the blood), and hypertension was recognized. Only then did the roles of insulin resistance and abdominal obesity become apparent. But metabolic syndrome should be considered a spectrum of diseases. And not all the diseases hit each person; it tends to be “mix and match.”
Racial/Ethnic/Sex Differences in Metabolic Syndrome
Males with metabolic syndrome are seven times more likely than females with metabolic syndrome to have nonalcoholic fatty liver disease (NAFLD). Race is one of the biggest determinants of what diseases you are susceptible to. For example, blacks do not get the hypertriglyceridemia (high levels of triglycerides in the blood; see chapter 10) that Caucasians do, but they tend to have higher blood pressure levels independent of body weight. Hence, despite having higher rates of diabetes and cardiovascular disease, blacks are diagnosed with metabolic syndrome less frequently. Conversely, Latinos have an increased prevalence of hypertriglyceridemia, but they have less hypertension. Hispanic males are approximately seven times more likely to have the diagnosis than non-Hispanic males. Blacks and Latinos also appear to be more insulin resistant than Caucasians. All these data reinforce the fact that racial/ethnic/sex differences in metabolic syndrome and its components make it very hard to use hard-and-fast cutoffs for its diagnosis.
How Insulin Resistance Becomes Metabolic Syndrome
You don’t have to be obese to have metabolic syndrome. After all, up to 40 percent of normal-weight adults have it! Obesity is a “marker” for metabolic syndrome, but not the only marker; it is not the cause. Whether it resides in fat people or not, the one thing everyone seems to agree on is that insulin resistance is the hallmark of metabolic syndrome. And thin people can be insulin resistant, too. But how? And where? And why does the body become insulin resistant? Here is one postulated scheme by which metabolic syndrome occurs4:
1. Metabolic syndrome starts as your body accumulates energy, storing it in the liver and in visceral fat tissue. This makes the liver insulin resistant, which starts metabolic dysfunction—a detrimental cascade of effects that damages every organ in the body.
2. Liver insulin resistance causes the liver to transport energy improperly. The pancreas responds by increasing insulin release to make the liver do its job. This drives insulin levels even higher (hyperinsulinemia), which causes further energy deposition into subcutaneous fat tissue and causes the persistent weight gain that drives obesity.
3. The liver tries to export the excess fat as triglycerides, to be stored in the subcutaneous fat tissue. The blood lipids rise to drive dyslipidemia (see chapter 10), one of the risk factors for heart disease.
4. The high insulin acts on blood vessels, causing the smooth muscle cells that surround each blood vessel to grow more rapidly than normal. This process tightens the artery walls and promotes high blood pressure.
5. The combination of insulin resistance, lipid problems, and high blood pressure wreaks havoc throughout the body. This promotes cardiovascular disease, which can result in heart attack or stroke.
6. The fat in the liver causes inflammation, which drives further insulin resistance. Eventually the liver can scar, which results in nonalcoholic fatty liver disease (see chapters 11 and 14). This can later progress to cirrhosis.
7. Insulin resistance and hyperinsulinemia in women can drive the ovary to make extra testosterone and reduce estrogen, resulting in polycystic ovarian syndrome, hirsutism (excess body hair), and infertility.
8. As the liver insulin resistance gets worse and the body fat grows, the pancreas has to make more insulin. Eventually the pancreatic beta-cells can’t keep up with the body’s requirements, which leads to a relative insulin deficiency. Eventually the beta-cells fail, precipitating type 2 diabetes.
9. Insulin is one of the hormones that cause cells to divide. Hyperinsulinemia is associated with the development and growth of various forms of cancer.
10. There is early evidence, although by no means proven, that insulin resistance in the brain leads to dementia.
Basically, the various diseases of metabolic syndrome are where virtually all our health care dollars are going. So understanding these disease processes is essential for making any headway in our current health care debacle.
The First Hit: The Liver Dilemma
Under normal circumstances, approximately 20 percent of your caloric intake goes to the liver. The liver uses that energy for three tasks. First, it burns some of it for its own metabolism and livelihood. Second, when the energy source is glucose (the major energy source of all living things, and the building block of complex carbohydrates), the liver turns the excess glucose into glycogen (liver starch), stimulated by the hormone insulin. Glycogen is the storage form of glucose in the liver. Glycogen isn’t dangerous; it provides us with a ready supply of glucose should we need it. Third, the liver has to deal with excess energy, which may arrive in several forms: as fatty acids from digestion of dietary fat or as amino acids from the digestion of protein, the consumption of alcohol, or from the molecule fructose (which is half sucrose, or table sugar, and roughly half high-fructose corn syrup). This extra energy is processed by the liver into fat. The liver needs to transport this fat out, or it will muck up the works. If it can’t, the liver can get very sick, very fast. Bottom line: in the liver, glycogen is good, fat is bad. And anything that drives liver fat accumulation, even in children such as Diana, is a potential driver of metabolic disease (see chapters 10 and 11).
The Second Hit: Reactive Oxygen Species (ROS) and Disease
Okay, that’s one problem. What else drives metabolic dysfunction? And in so many tissues? Glucose is the preferred energy source of all organisms on the planet. If you don’t consume glucose, your liver will make it out of what’s available. Glucose metabolism occurs through two distinct pathways. The first is called glycolysis, which converts glucose into the energy intermediate pyruvate, liberating a small amount of energy. The second step is called the Krebs cycle. It occurs within the mitochondria (the cell’s equivalent of a coal furnace), and burns the pyruvate down to carbon dioxide and water, liberating a lot of energy in the process. About 80 percent of energy intake will be metabolized in this way. When your body burns energy, some toxic metabolites (breakdown products of a reaction) get manufactured within the mitochondria; these are called reactive oxygen species (ROS). They are the body’s equivalent of hydrogen peroxide. In some parts of the body, ROS are put to good use. For instance, when found within your white blood cells, ROS are part of your body’s immune defense system to kill foreign invaders so you don’t get infected.
But ROS are also by-products of normal energy metabolism. When they are made in other types of cells, such as those of the liver or pancreas, they can do damage to the cells’ DNA, proteins, or membranes. ROS require the help of antioxidants to quench them before they have a chance to do damage. That is the function of another part of the cell, called the peroxisome, which is full of antioxidants. Most of these come from the foods you eat in the form of micronutrients (see chapter 14). Peroxisomes live right next to mitochondria, and act as the “mop-up crew” for excess ROS. When the peroxisomes can keep up with the ROS generated inside the cell, you and your cells stay healthy. When they can’t, the cell either is damaged or dies. These two hits together cause the cell to crap out, and when enough cells give up, you’ve got the basis for metabolic syndrome.5
The Four Foodstuffs of the Apocalypse
Many investigators have spent considerable resources searching for the gene or genes that cause metabolic syndrome. As with obesity, the genetic analyses have thus far been unrevealing. In fact, it has been suggested that only about 10 percent of metabolic syndrome can be explained by genetics.6 This leaves approximately 90 percent to changes in the environment, specifically the quality and quantity of our food intake, and how these promote liver insulin resistance.7
When the energy bolus comes as glucose (starch), the liver has several safety mechanisms, including letting the other organs deal with it (spread the pain), and conversion to glycogen, keeping the liver safe. But when the liver has to deal with foodstuffs that can’t be metabolized by other organs, the result is the excess production of ROS and liver fat, which gets transported out as triglycerides (blood fats) (see chapter 11). When energy supplies overwhelm the mitochondria’s ability to handle them, the result is a buildup of ROS and fat deposition in the liver (“mitochondrial constipation,” if you will), leading to chronic metabolic disease. These foodstuffs tend to affect different age groups based on their frequency in the American diet. What foodstuffs have this unique signature to cause this metabolic disturbance? There are four, by my count.
1. Trans fats. These can’t be broken down by the mitochondria because of their synthetic nature.8 Trans fats have long been assumed to contribute to chronic metabolic disease, especially atherosclerosis (hardening of the arteries). Trans fats used to be in every processed food, although slowly they are leaving our diet. But they are still in baked goods and candy bars. In fact, any food in a wrapper at room temperature that’s meant to sit on a store shelf is suspect. The FDA and the food industry have since recognized the problem that trans fats pose, and while there is no nationwide ban on them, there is currently a concerted effort to remove them from our diet. For instance, Mayor Michael Bloomberg has banned the use of trans fats within restaurants in New York City. Yet, despite the cutback on trans fats, the rates of obesity and diabetes continue to rise.
2. Branched-chain amino acids. These are essential amino acids, meaning our bodies cannot make them so they must be eaten in our diet. Blood levels of branched-chain amino acids are directly related to consumption. These amino acids are in high concentration in corn, so every animal fed on corn (e.g., U.S. beef and pork) is a potential contributor to your total body load. While these amino acids are necessary for building proteins all around the body, any in excess are burned for energy in the liver. Body builders consume these with abandon in their protein powders, and as long as these people are building their bodies, no problem. For everyone else, however, big problem. When branched-chain amino acids are metabolized for energy, they bypass glycogen in the liver and go straight to the mitochondria for burning, or to be turned into fat (see chapter 10). Christopher Newgard at Duke University has demonstrated that patients with metabolic syndrome exhibit higher levels of these amino acids in the bloodstream.9 But at this point, we only have correlation, not causation.
3. Alcohol. Alcohol is interesting because a small daily ration, especially when consumed as wine, has been shown to prevent metabolic syndrome. (If you have high cholesterol, your doctor may recommend a glass or two of red wine with dinner.)10 But increased consumption of booze clearly contributes to metabolic syndrome’s development. Furthermore, alcoholic beverages that also contain glucose, such as beer and shochu (a Japanese fermented drink) have been clearly implicated in the promotion of metabolic syndrome in America and Japan, respectively.11 Alcohol also goes to the mitochondria without stopping at glycogen. However, alcohol certainly does not explain how children get metabolic syndrome or why metabolic syndrome is rampant in alcohol-abstaining Muslim countries such as Saudi Arabia and Malaysia.
4. Fructose. Finally, we come to the Voldemort of the dietary hit list: the sweet molecule in sugar. If it’s sweet, and it’s caloric, it’s fructose. Period. This is the one foodstuff whose consumption has increased worldwide, and with reckless abandon. And it is the one that children eat with no holds barred. We have animal and human data. We also have the golden ticket: correlation and causation. Every age group, including infants, has increased its consumption of fructose in the last thirty years. As far as I am concerned, this is where the action is, and will be fully elaborated in chapter 11.
Can’t We Just Pop a Pill?
In a word, no. There’s no drug target to stop this process, because ROS formation is a fact of life. We’ve got medicines that can treat the various downstream outcomes. We have statins and fibrates for lipid problems; antihypertensives to reduce blood pressure; insulin and other hypoglycemic agents to treat diabetes; loads of drugs to make the heart beat better and stronger; vitamin E and metformin for fatty liver; dialysis and transplantation for chronic kidney disease; various chemotherapies once you get cancer; and even new Alzheimer’s drugs. But your mitochondria are still screwed. And the lipogenesis and ROS damage will continue unabated. Your cells will die, and so will you. But you and Diana aren’t doomed. You can slow the process down considerably.
The easiest and most rational approaches to reducing ROS formation and toxicity are preventive. You can: limit specific substrate availability (modify your diet; see chapters 11, 17, 18); reduce the rate at which the liver metabolizes energy (eat more fiber; see chapter 12); increase your antioxidant capacity (consume micronutrients; see chapter 14); and/or increase mitochondrial formation and number to improve mitochondrial capacity and efficiency (exercise; see chapter 13). We’re talking altered intake and expenditure. If you’ve overindulged your entire life, and you want to get on the bandwagon now, all is not lost. Studies of patients with diabetes who improve their lifestyle (e.g., eat properly and exercise) demonstrate reduction in total body burden of ROS, improved health, and increased longevity.12
Oh no! Diet and exercise again! Is this whole book just a crock? Why did I spend good money for the same message? Didn’t I already know this? No, because it’s not just “eat less, exercise more.” We’re talking about something specific. Because a calorie is not a calorie.