Fructose—The “Toxin”
Gabriel is a 100-pound eight-year-old boy who has mildly elevated blood pressure. His father is a type 2 diabetic and has already had a gastric bypass. A dietary analysis of the family’s eating habits exhibits no abnormalities, except that the father is a truck driver for the Odwalla juice company and is allowed to bring home as much product as he wants. Gabriel’s mother limits her son to one glass of juice per day, but he admits to drinking three glasses per day. We counsel the parents to remove juice from the house. Within one year, the father loses 20 pounds and his diabetes improves, while Gabriel has not gained any weight and his blood pressure has returned to normal.
The Fructose Epidemic
Can low-fat and low-carb diets both be right? Or both wrong? What do the Atkins diet (protein and fat), the Ornish diet (vegetables and whole grains), and the traditional Japanese diet (carbohydrate and protein) have in common? On the surface they seem to be diametrically opposite. But they all have one thing in common: they restrict sugar. Every successful diet in history restricts sugar. Sugar is, bar none, the most successful food additive known to man. When the food industry adds it for “palatability,” we buy more. And because it’s cheap, some version of sugar appears in virtually every processed foodstuff now manufactured in the world. Sugar, and specifically fructose, is the Lex Luthor of this story.
Nutritionists routinely categorize sugar as “empty calories,” interchangeable with calories from starch. But sugar has a special payload. Sugar (sucrose) is made up of half glucose and half fructose. It’s the fructose that makes it sweet, and that, ultimately, is the molecule we seek. It’s the fructose that causes chronic metabolic disease. So sugar, despite ostensibly being a carbohydrate, is really both a fat (because that’s how fructose is metabolized in the liver) and a carbohydrate (because that’s how glucose is metabolized) all rolled into one. Both pathways have to work overtime, which is why sugar is the real omnivore’s dilemma. Now, if you’re starving and energy-depleted, consuming sugar can replete your liver’s glycogen stores more rapidly, which can be beneficial. So offensive linemen after three hours on the gridiron can consume all the Gatorade they want. But the overwhelming majority of people are neither starving nor energy-depleted (there are now 30 percent more obese individuals than undernourished ones on the planet). Our bodies have not adapted to our current environmental sugar glut, and it is killing us…slowly.
Fructose has increased both as a percentage of our caloric intake and our total consumption. When you add it up, Americans currently consume sugar at a rate of 6.5 ounces a day, or 130 pounds a year. Our current fructose consumption has increased fivefold compared to a hundred years ago, and has more than doubled in the last thirty years.1 A recent survey by the CDC estimates that 50 percent of Americans have one can of sugared soda per day, and 5 percent of Americans have four or more.2 In other words, we’re not just eating more—we’re increasing both the amount of sugar we eat, and sugar as a percentage of our daily caloric allotment. The inescapable reality is that 20–25 percent of all the calories we consume, a total of twenty-two teaspoons per day, comes from some variation of sugar.3 And some adolescents are consuming 40 percent of their calories as sugar. This can’t be good for you.
Okay, America is sugar-dipped and candy-coated. But that’s not true elsewhere—or is it? World sugar consumption has tripled in the last fifty years, while the population has only doubled. That means our global per capita intake of sugar has increased by 50 percent, commensurate with this pandemic. The upper threshold of 200 calories per day of sugar, advocated by the American Heart Association in its scientific statement for optimal cardiovascular health,4 has been exceeded in virtually every country on the planet.5 This is a massive increase from just thirty years ago, when most countries were bereft of sugar.
When reading the title of this chapter, your first reaction may be “Aha! I knew it! High-fructose corn syrup is evil.” You’re half right. Media attention and consumer activist groups have started to vilify HFCS due to its synthetic nature and assumed effect on the obesity epidemic. As a result, its consumption has been declining since 2007. But our rates of obesity remain unchanged. HFCS is ubiquitous in the United States and Canada, but it is used more sparingly in the European Union and Japan. The rest of the world uses sucrose. Australia and the entire Pacific Rim, for example, have only sucrose, but they are right behind us in terms of obesity and metabolic syndrome. Scientific studies of acute satiety versus energy intake and of metabolic alterations support the notion that HFCS is technically no different from sucrose, although HFCS does generate a higher blood fructose level, which could have negative metabolic consequences.6 This has led to a vociferous campaign by the Corn Refiners Association, and its public commercials, arguing that HFCS is a natural, out-of-the ground, and benign sweetener. HFCS is biochemically similar to “natural” sucrose (made of glucose and fructose), taking “corn syrup” (glucose) through an enzymatic process so that approximately half the glucose becomes fructose, in order to make it sweeter. The question is not whether HFCS is worse or better than sugar; the question is whether sugar (in any of its forms) is toxic?
The health-conscious among you may opt for juice over soda. For those of you who can afford it, you skip the Sunny Delite in favor of “natural 100 percent fruit juices” made by Odwalla or other organic companies. They tout multiple health benefits and claim that, because they are devoid of added sweeteners, they are in fact good for you. Wrong. The fruit is good for you, because it also contains fiber (see chapter 12). In fact, calorie for calorie, 100 percent orange juice is worse for you than soda, because the orange juice contains 1.8 grams of fructose per ounce, while the soda contains 1.7 grams of fructose per ounce.
All caloric sweeteners contain fructose: white sugar, cane sugar, beet sugar, fruit sugar, table sugar, brown sugar, and its cheaper cousin HFCS. Add to this maple syrup, honey, and agave nectar. It’s all the same. The vehicle is irrelevant; it’s the payload that matters. Bottom line, sugar consumption is a problem, 33 percent of sugar consumption comes from beverages, and the biggest abusers are the poor and underserved.
A Carbohydrate Is a Carbohydrate—or Is It?
All carbohydrates are not created equal. Just as there are different gradations of fats (see chapter 10), there are different gradations of carbohydrates based on their metabolism.7 To illustrate how this works, consider the following exercise involving the metabolism of three different carbohydrates of equal caloric value (120 calories): glucose, ethanol (grain alcohol), and fructose.
Glucose
Despite its absolute necessity for life (see chapter 10), dietary glucose isn’t perfect. When it exists in nature without fructose, it’s called “starch,” and it truly does supply “empty calories,” energy for either storage or burning. But the Atkins, Paleo, and caloric-restriction adherents will all tell you that the glucose molecule has three metabolic downsides, all of which do damage over time and necessitate the limitation of its consumption. To demonstrate this, let’s consume 120 calories of glucose (e.g., one-half cup cooked white rice). Twenty percent, or 24 calories, will enter the liver, whereas the rest will be metabolized by other organs in the body. Here’s what happens:
1. Glucose metabolism is insulin-dependent. Consuming glucose raises the glucose level in the bloodstream, stimulating insulin release, which promotes energy storage into fat cells and causes weight gain.
2. The overwhelming majority of glucose in the liver will be directed toward forming glycogen, or liver starch, which is not harmful to the liver cell. This also will keep the liver from releasing glucose into the blood, preventing diabetes.
3. A small amount of glucose will be metabolized by the liver mitochondria for energy.
4. Any excess glucose in the liver that is not shunted to glycogen and not metabolized by the mitochondria for energy will instead be converted to triglycerides. High triglyceride levels in the blood can promote development of cardiovascular disease.
5. Glucose can bind to proteins in the cell, which causes two problems:
• When glucose binds to proteins throughout the body, the proteins become less flexible, contributing to the aging process and causing organ dysfunction.
• Every time a glucose molecule binds to a protein, it releases a reactive oxygen species (ROS; see chapter 9), which can cause tissue damage if not immediately mopped up by an antioxidant in the peroxisome (see chapter 14).
Like all things, glucose in excess can be bad for you—especially when it lacks fiber, which limits the insulin response (see chapter 12). However, you would have to consume a lot of it and over a long period of time for glucose to have these detrimental effects. In general, large amounts of glucose (starches such as pasta, white bread, rice, etc.) will cause you to gain pounds but it won’t make you sick. Rather, if over time you gain too much weight from glucose, the visceral fat that is formed will eventually take its toll on your health (see chapter 8). But when you consume the same number of calories as either ethanol or fructose, you get much more of a bang to your liver (more like a hand grenade), and it takes its toll that much faster.
Ethanol (Grain Alcohol)
Ethanol is a naturally occurring by-product of carbohydrate metabolism, called fermentation. Upon ingestion of 120 calories of ethanol (e.g., a 1.5-ounce shot of 80-proof hard spirits), 10 percent (12 calories) is metabolized within the stomach and intestine (called the first-pass effect) and 10 percent is metabolized by the brain and other organs. The metabolism in the brain is what leads to the alcohol’s intoxicating effects. Approximately 96 calories reach the liver—four times more than with glucose. And that’s important, as the detrimental effects are dose-dependent.
1. After ethanol enters the liver in high dosages, it can promote ROS formation and cell damage.
2. In contrast to glucose, which went to glycogen, the ethanol goes straight to the mitochondria.
3. Any excess gets turned into fat by a process called de novo (new) lipogenesis (fat-making). The lipid buildup can lead to liver insulin resistance and inflammation.
4. If this process continues, it can eventually cause alcoholic liver disease. This is a surefire prescription for slow death or, at best, a liver transplant.
5. Alternatively, the lipid can exit the liver and take up residence in skeletal muscle, where it also induces insulin resistance and can cause heart disease.
6. Lastly, ethanol enhances its own consumption, by acting on the brain’s reward pathway. When this goes out of control (chapter 5), addiction sets in.
Thus, for the same number of calories, ethanol is more likely than glucose to cause chronic disease.
Fructose
Fructose is never found alone in nature. Rather, it is always partnered with its more benign sister molecule, glucose. They both have the same chemical composition (C6H12O6), but they are hardly the same. Fructose is much worse. Let’s start with the Maillard, or “browning,” reaction. This is the same reaction that turns hemoglobin in your red blood cells into hemoglobin A1c (HbA1c), the lab test that doctors follow to determine how high a diabetic patient’s blood sugar has risen over time. The reaction product is brown; this is the reason bananas turn brown with time and also why barbecue sauce caramelizes the meat underneath when exposed to heat. So, you can brown your meat at 375 degrees for one hour, or you can brown your meat at 98.6 degrees for seventy-five years. The result is the same. And fructose drives the Maillard reaction seven times faster than glucose.8 This seemingly subtle difference can cause every cell in the body to age more rapidly, driving various degenerative processes such as aging, cancer, and cognitive decline.
There are dozens of studies that now implicate fructose as a major player in causing metabolic syndrome. In fact, it’s metabolized a lot like ethanol. Let’s now consume 120 calories of sucrose (60 of glucose, 60 of fructose)—for example, an 8-ounce glass of orange juice. (As I mentioned before, juice is just as bad as soda, if not worse.) The 60 calories of glucose do the same 20-80 split, so 12 calories of glucose will enter the liver. But, unlike with glucose, which can be metabolized by all organs, the liver is the primary site of fructose metabolism (although the kidney has the capacity to metabolize a few calories in rare cases). Give or take, the whole 60 calories of fructose end up in the liver. So, the liver gets a 72-calorie dose, triple the amount as with glucose alone.
The unique metabolism of fructose can induce each of the phenomena associated with metabolic syndrome:
1. Triple the dose means the liver needs triple the energy to metabolize this combo versus glucose alone, depleting the liver cell of adenosine triphosphate (or ATP, the vital chemical that conveys energy within cells). ATP depletion leads to the generation of the waste product uric acid. Uric acid causes gout and increases blood pressure.
2. The fructose does not go to glycogen. It goes straight to the mitochondria. Excess acetyl-CoA is formed, exceeding the mitochondria’s ability to metabolize it.
3. The excess acetyl-CoA leaves the mitochondria and gets metabolized into fat,9 which can promote heart disease (see chapter 9).
4. Fructose activates a liver enzyme, which is the bridge between liver metabolism and inflammation. This inactivates a key messenger of insulin action, leading to liver insulin resistance.
5. The lack of insulin effect in the liver means that there is no method to keep the glucose down, so the blood glucose rises, which can eventually lead to diabetes.
6. The liver insulin resistance means the pancreas has to release extra insulin, which can force extra energy into fat cells, leading to obesity (see chapter 4). And the fat cells that fill up most are in the visceral fat, the bad kind associated with metabolic disease.
7. The high insulin can also drive the growth of many cancers.10
8. The high insulin blocks leptin signaling (see chapters 4 and 5), giving the hypothalamus the false sense of “starvation,” and causing you to eat more.
9. Fructose may also contribute to breakdown of the intestinal barrier. Normally the intestine prevents bacteria from entering the bloodstream. This intestinal breakdown may lead to a breach in the walls of the intestine. The result is a “leaky gut,”11 which could increase the body’s exposure to inflammation and more ROS. This worsens insulin resistance and drives the insulin levels even higher.12
10. Fructose undergoes the Maillard (browning) reaction 7 times faster than glucose, which can damage cells directly. Although the experiments are in their infancy, preliminary results suggest that in a susceptible environment, fructose can accelerate aging and the development of cancer.
11. The data on fructose and dementia in humans are currently correlative and indirect. However, the data on insulin resistance and dementia show clear causation. African Americans and Latinos are the biggest fructose consumers and those with the highest waist circumference (a marker for insulin resistance). Coincidentally, they also have the highest risk for dementia.
Fructose versus Ethanol: Pick Your Poison
Studies of alcohol use show that a little bit is good for you. Alcohol raises HDL (good cholesterol), and red wine has the compound resveratrol, which is thought to improve insulin sensitivity and longevity (see chapter 14). As with alcohol, a small dose of fructose has been shown in some studies to have a beneficial effect on insulin secretion. The toxic effects of fructose, just like those of alcohol, are dose-dependent. For alcohol, we have empiric evidence that in most people, a maximum dose of 50 grams per day (about three glasses of wine) is the threshold for toxicity.13 This is likely the threshold for fructose as well (slightly less than a quart of orange juice). The problem is that the current average adult fructose consumption is 51 grams per day. That means that more than half the population is over the threshold.
When you look at chronic alcoholics versus those consuming massive amounts of sugar, they often appear very different, at least on the outside. Many alcoholics are thin, if puffy, compared to those consuming massive amounts of sugar. But remember, we’re not concerned with subcutaneous fat. It’s the visceral fat—the fat that surrounds your organs and often remains invisible to the naked eye—that’s going to kill you. Both alcohol and sugar significantly increase your visceral fat and your likelihood of developing associated diseases. The difference between alcoholic fatty liver disease and nonalcoholic fatty liver disease lies only in the terminology—the effect on the body is the same.
Of course, the major difference between alcohol and sugar is alcohol’s intoxicating effects; the brain does not metabolize fructose. People don’t get arrested for driving under the influence of sugar. But the liver’s metabolism of fructose is remarkably similar to that of ethanol. Fructose isn’t the only cause of obesity, but it is the primary cause of chronic metabolic disease, which kills…slowly. Fructose can fry your liver and cause all the same diseases as does alcohol. We know we must limit our ethanol consumption or face the consequences. But sugar flies under the radar. No wonder Saudi Arabia and Malaysia have the highest rates of type 2 diabetes on the planet. No alcohol, but they’re drinking soft drinks like they’re going out of style.
Sugar and the Global Diabetes Pandemic
According to the International Diabetes Federation (IDF), the global diabetes pandemic currently claims 366 million people. That’s a prevalence rate of 5.5 percent of the world’s population. And they’re breaking the bank on health care worldwide (see chapter 1). While it would be easy to lay the blame on the fast food industry, whose outlets continue to propagate worldwide, lots of countries whose populations do not overindulge in McDonald’s are also experiencing increases in obesity and diabetes. What’s changed in the food globally?
My colleague Sanjay Basu and I are attempting to answer that question by looking at food supply data worldwide. The Food and Agriculture Organization (FAO) monitors the world’s food supply. FAO keeps close tabs on food supply data, broken up by type of foodstuff. We linked the FAO food supply database with the IDF prevalence database and with the World Bank Gross National Income database (to control for poverty). We are currently performing an epidemiological analysis for 154 countries around the world, known as an “ecological” analysis, between the years 2000 and 2010. We asked two questions: Does the increase in caloric intake per capita correlate with increase in diabetes prevalence? And if so, is there any aspect of the diet that explains this relationship?
In the time period we studied, diabetes prevalence worldwide rose from 5.5 percent to 7.0 percent. Surprisingly, total calories did not correlate with diabetes prevalence worldwide. Instead, the correlation with the percentage of calories coming from sugar and sugarcrops was enormous. For every 100 calories supplied as sugar, the prevalence of diabetes rose by 0.9 percent, even after controlling for obesity in each country. The amount of sugar availability explains more than one fourth of the increase in diabetes prevalence rates worldwide during the last decade, even after controlling for aging and obesity in the population. And those few countries whose consumption went down experienced a reduction in diabetes prevalence of 0.18 percent. This is not correlation, but rather causation.
If you had any residual doubt about “a calorie is not a calorie,” this analysis should remove it. Every additional 150 total calories per person per day barely raised diabetes prevalence. But if those 150 calories were instead from a can of soda, increase in diabetes prevalence rose sevenfold. Sugar is more dangerous than its calories. Sugar is a toxin. Plain and simple.
There are clear limitations to doing this kind of analysis. First, food supply does not automatically mean consumption. However, in most parts of the world, the two are closely aligned. Only in the United States do we throw away significant amounts of food (up to 30 percent of what we produce). Second, populations are diverse, in socioeconomic status, vulnerability, and food preference. So, what you learn from a population may not be immediately ascribable to one individual. Third, estimating diabetes prevalence is always difficult. Different countries use different criteria for diagnosis, many people go undiagnosed, and the IDF pools people with type 1 and type 2 diabetes. Nonetheless, the robustness of the effect is undeniable. The global industrial diet that revels in sugar consumption clearly negatively affects the metabolic health of entire countries, unrelated to obesity.
The Sweetest Taboo: Fructose, Reward, and Addiction
Now you’re thinking: diabetes, liver dysfunction, cancer, dementia, and aging—it couldn’t get any worse, could it? Oh, but it can. Not only does fructose turn your liver to fat and your proteins brown, but it tells your brain that you need more of it…and more. Remember the starvation pathway (see chapter 4), and the reward pathway (see chapter 5)? Similar to the effects of alcoholism, fructose stimulates excessive and continued consumption by tricking your brain into wanting more. For Gabriel, one glass of juice just wasn’t enough.
Fructose Drives Reward and Food Intake
Recall the lessons of leptin. Anything that blocks leptin signaling will be read as starvation at the hypothalamus (chapter 4) and as lack of reward by the nucleus accumbens (chapter 5); both of which drive long-term food intake. And anything that alters the meal-to-meal hunger and satiety signals will drive short-term food intake. When you don’t feel full, you consume more. Fructose does them all.
1. Consumption of fructose does not stimulate an insulin response, so leptin doesn’t rise and the animal keeps eating (or drinking soda, as the case may be).
2. Long-term fructose consumption generates liver insulin resistance and causes chronic hyperinsulinemia (excessively high blood insulin), which interferes with leptin signaling and promotes further food intake by preventing dopamine clearance from the NA (see chapter 5).
3. Ghrelin, a peptide produced by cells in the stomach, is the “hunger” signal. In humans, ghrelin levels rise with increasing subjective hunger, peak at the time of voluntary food consumption (which is why your stomach grumbles at noon), and decrease after a meal. However, fructose intake does not decrease ghrelin; therefore, caloric intake is not suppressed. Indeed, fructose consumption in the form of a Big Gulp does not reduce the volume of solid food needed to feel satiated, multiplying the total calories consumed during the meal.
Deconstructing Darwin
So why do we have this fascination with sugar in the first place? Why does sugar make us want more? What’s the selective advantage? In chapter 4 we saw that insulin blocks leptin signaling to promote leptin resistance, in order to allow the weight gain associated with puberty and pregnancy to occur. In chapter 5 we saw that sugar stimulates brain dopamine and opiates to let us know what foods are safe. But why should sugar cause insulin resistance and hyperinsulinemia? Naturally occurring sugar in fruit is what makes fruit palatable. But for our ancestors, fruit was readily available for one month per year, called “harvest time.” Then came four months of winter, and no food at all. We needed to stock up—to increase our adiposity in preparation for four months of famine. In other words, in the doses that were available to our forebears, sugar was evolutionarily adaptive. Indeed, fruit binges among orangutans in Indonesia are responsible for their altered energy intake and changes in weight. For their normal diet, they consume 21 percent of their calories as fruit—as opposed to when fruit is plentiful during a binge, at which point that figure rises to 100 percent. This results in high insulin, driving energy storage and cyclic adiposity.14 But with our current global sugar glut, devoid of fiber and in high doses 24/7/365, our weight gain is not cyclic anymore, and this process has become maladaptive.
Face it, we’ve been “frucked.”
Still, while sugar is the biggest perpetrator of our current health crisis, it is by no means the only bad guy. There are “antidotes” to the fructose effect, but they have been removed from our environment as well. The rest of Part 4 will lay bare the rest of our “toxic environment.”