When chemists Richard Marshall and Earl Kooi started fiddling with cornstarch, the powder made from the dense insides of corn kernels, their intention was to turn glucose, which is easily produced from the starch, into fructose, which is sweeter. The idea wasn’t that far-fetched. The two sugar molecules are cousins, both made from the same atomic parts slightly rearranged.
The duo’s experiment, which took place at the Corn Products Refining Company in Argo, Ill., was a success. Marshall and Kooi discovered that the bacterium Aeromonas hydrophila produced an enzyme that could reconfigure the components of glucose from corn like so many Lego blocks. It was the first leap forward for a food industry dream: a mass-produced glucose-fructose-blend sweetener that would free commercial food manufacturers from the historical volatility of cane sugar crops.
The scientists announced their triumph in a short report in Science in 1957. There the discovery sat in quiet obscurity for almost two decades, until a worldwide spike in sugar prices sent manufacturers scrambling. By the end of the 1980s, high fructose corn syrup had replaced cane sugar in soft drinks, and it soon became popular among makers of baked goods, dairy products, sauces and other foods.
Few consumers seemed to care until 2004, when Barry Popkin, a nutrition scientist at the University of North Carolina at Chapel Hill, along with George Bray, at the Pennington Biomedical Research Center in Baton Rouge, La., published a commentary in the American Journal of Clinical Nutrition pointing out that the country’s obesity crisis appeared to rise in tandem with the embrace of high fructose corn syrup by food producers. That shift began in the early 1970s — just about the time Japanese researchers, who had noted Marshall and Kooi’s experiment with keen interest, overcame the technical hurdles of industrial production.
Popkin’s paper was far from an indictment of high fructose corn syrup. It offered only the weakest kind of evidence — a provocative correlation and a graph (see next page) showing an eerily similar upward trajectory for both obesity and the preference for high fructose corn syrup over sucrose, or table sugar. “The original article actually was a scientific speculation saying we need research,” Popkin says.
What he didn’t anticipate was the birth of blogging, which catapulted his theory across the digital universe.
Much of what has emerged since then has kept bloggers well supplied and turned high fructose corn syrup into a dietary boogeyman. Excessive fructose is cited as an accomplice in the twin epidemics of obesity and diabetes, and among the constellation of risk factors (including abdominal fat, high blood pressure and elevated triglycerides) that produce the dangerous condition known as metabolic syndrome. Further damaging are studies suggesting that once in the body, fructose is more likely to take up residence as fat around the belly and less likely to engage the appetite-control mechanisms that help put the brakes on eating. The story gets worse: In addition to the consequences for American waistlines, data also point to unique threats to the kidneys, liver and other organs.
Yet some caution that public opinion has gotten ahead of science and that fructose tunnel vision may distract us from the complex causes of the country’s obesity crisis. Having a corn-based bad guy in the crosshairs has been an advertising boon for the sugar industry, Popkin says. The phrase on food labels that says “made with natural sugar” is popularly interpreted as “healthier,” as is “no high fructose corn syrup.” In truth, the consumption of high fructose corn syrup has been falling since 2004. Yet obesity rates remain high.
Fructose turns sour
Perhaps chief among the concerns over fructose are its effects on the liver, which is the first stop after sugar leaves the intestine. The liver either absorbs sugar or allows it to pass into the bloodstream to be turned into energy for the brain, muscles and other organs. But it matters what kind of sugar it is. Table sugar, or sucrose, is a bound dimer of glucose and fructose, which means the two sugar molecules are locked arm in arm until broken apart by the intestine. In high fructose corn syrup, fructose and glucose are not chemically bound. (The ratio of fructose to glucose depends on the type of corn syrup: the kind typically used in soda is 55 percent fructose and 42 percent glucose. Other types have more glucose and less fructose.) An enzyme called phosphofructokinase acts as a kind of thermostat to detect whether the liver needs fuel. If it doesn’t, glucose moves into the blood straightaway.
But fructose seeps into the liver whether or not the energy is needed. This is a major concern to scientists like Kimber Stanhope, a nutritional biologist at the University of California, Davis. “The enzyme that controls fructose metabolism is fructokinase,” she says. “It appears to be almost always turned on.” Unless you are energy depleted, really starved of calories that the rest of the body needs, “when you consume fructose, it all goes to the liver,” says Robert Lustig, a pediatric endocrinologist at UC San Francisco who has become one of the most outspoken critics of added sugar, and especially of fructose. This flood of energy makes its way to the mitochondria, which are the power plants of a cell. “When your mitochondria get overloaded, the excess energy is turned into liver fat,” Lustig says. In a paper this year in Advances in Nutrition, he characterized fructose as “alcohol without the buzz,” because of its potential to cause liver damage.
Once in the liver, some fructose may wind up packaged for short-term storage as glycogen or for long-term storage as fat. Fructose encourages the liver to increase production of uric acid, a metabolic end product that is best known for causing gout, but which is also a risk factor for high blood pressure and kidney disease. Studies in animals — and more recent research in humans — raise the possibility that when compared with similar intakes of other beverages, drinks with high fructose corn syrup may promote fatty liver disease (often a consequence of alcoholism) and raise levels of triglycerides, fat molecules that circulate in the bloodstream. High triglycerides are a risk factor in heart disease.
In 2009, Stanhope and her colleagues reported in the Journal of Clinical Investigation that among volunteers who consumed beverages sweetened with either glucose or fructose, those who drank fructose experienced significantly higher accumulations of fat within the abdomen, even though both groups gained about the same amount of weight. And while this experiment found that glucose was more likely than fructose to raise fasting triglyceride levels, fructose caused triglyceride levels to rise after a meal. In 2011, in the Journal of Clinical Endocrinology and Metabolism, Stanhope reported that volunteers who drank beverages with high fructose corn syrup experienced a rise in triglycerides during the day that was almost twice as high as that produced by glucose.
In October 2012, writing in PLOS ONE, researchers from the University of Colorado Denver, with others, added another dimension to the story of fructose metabolism, describing evidence that in liver cells uric acid can accelerate the metabolism of fructose to fat. If the finding holds up in further work, it might help explain why some people appear more sensitive to the effects of fructose — uric acid levels vary from person to person.
Concerns about fructose also extend to influences on overall body weight, based on evidence that normal appetite controls do not engage as they should after an influx of calories from fructose. One of the latest studies appeared in January in the Journal of the American Medical Association. A team of researchers from Yale University and elsewhere performed fMRI scans on healthy young adults after the subjects drank liquids containing either glucose or fructose. They found that blood flow to regions of the brain that control appetite decreased after drinking glucose but not fructose, suggesting that fructose has a weaker impact on appetite.
Fructose may also affect diabetes risk. Though insulin levels remain relatively unperturbed by fructose, there are indications that fructose, even more than glucose, can lead to insulin resistance. (Such resistance is caused when the body loses sensitivity to insulin, prompting the pancreas to work harder to pump out higher and higher amounts of the hormone.) A trial comparing insulin sensitivity in young men after consuming either glucose, fructose or sucrose appeared in January in Diabetes Care. Sucrose and fructose, even in moderate amounts, rendered insulin less potent.
Science gets sticky
While individual studies can make a damning case against fructose, it’s not so easy to reach a verdict when the evidence is considered as a whole, says John Sievenpiper, a nutrition researcher at St. Michael’s Hospital in Toronto. People are not only consuming more calories from fructose, they are consuming more calories period. Weight gain alone poses serious health risks, Sievenpiper and others point out, regardless of where the extra calories come from.
Over the last few years, Sievenpiper has published several studies that compile the body of work on fructose into a sweeping analysis. This is the only way to get a true sense of the health effects, he contends, and the danger he’s found so far is underwhelming. Although his recent fructose studies were funded by the Canadian government, Sievenpiper readily reveals that he has received unrestricted research grants from the beverage industry. Still, he says, “My frame of mind going in, to be honest with you, was that we were going to find a signal for harm because of the biochemistry.”
That has not been the case. In February 2012, in the Annals of Internal Medicine, he and his coauthors tallied 41 human feeding studies that examine whether fructose is more likely to lead to weight gain than other forms of carbohydrates. The result: When people eat the same number of calories of any carbohydrate, “it doesn’t look like the fructose is behaving differently,” he says. But when volunteers consume more energy from fructose than they burn, the sugar does appear to cause weight gain. It’s hard to tell, however, whether that’s because of the fructose or just the overabundance of calories, Sievenpiper says.
Other researchers point out that many experiments finding reason for concern about fructose have been conducted in animals. Or studies compare intake of pure glucose and pure fructose, neither of which is what’s in a soda bottle. “If fructose is really causing a problem, demonstrate it in physiological or real-world diets,” says John White, a former corn industry researcher who is now a consultant. He says he would like to see a study that examines high fructose corn syrup the way most people consume it. “Do that experiment, and publish it, and prove to us that it’s a problem,” White says. He also points out that the graph published by Popkin and Bray, when plotted today, does not show the correlation it did in 2004. “High fructose corn syrup has been in decline now for 14 years,” White says. “What’s happened to obesity rates? They’ve continued to climb.”
Fructose could pose a particular harm — but not for everyone at the same dose, says Miriam Vos, a pediatric liver specialist at Emory University School of Medicine. Just as certain people are more susceptible, probably because of genetics, to the effects of salt on blood pressure or tobacco on cancer risk, some may be more sensitive to the biochemical complications of fructose. Last year in the Journal of Clinical Endocrinology and Metabolism, Vos reported that fructose raised triglyceride levels in teenagers with fatty liver disease more than in healthy teens, even when they consumed the same number of calories. “My impression is that fructose alone would not cause fatty liver disease in someone who is not susceptible,” she says.
The focus on fructose has been scientifically beneficial, but Vos worries that one unintended consequence has been to make other sweeteners look good by comparison. Sucrose and high fructose corn syrup are both made of glucose and fructose. “From a public health standpoint, it may be less important which half of the sugar is causing the problem, because first of all, maybe it’s both together, and then second of all, maybe the real question is, what’s a safe dose? Not which half is safer,” she says. “Because no one is going to advocate for a pure glucose drink.”
The bigger problem may be that Americans have developed too much of a sweet tooth for their own health. A 2012 study from Popkin in the Journal of the Academy of Nutrition and Dietetics found that 75 percent of packaged foods and beverages contain added sweetener, and plain old corn syrup (not the high fructose version) was the most common. High fructose corn syrup was invented to make sweet foods cheaper, Lustig says. It is not only cheap, but stable in foods, and easy to transport and store because it is a liquid. Once it became widely available, companies that previously did not sweeten their foods so much were able to because they could afford to, he says.
Today many manufacturers are returning to natural sugar or fruit-juice concentrate, knowing that fructose-wary consumers are scrutinizing labels. But Vos wonders if this is truly public health progress. “If you replaced all of the high fructose corn syrup with cane sugar, would we be better off?” she asks. “No. We would be exactly in the same place.”
Editor's note: On 5/20/13, the online version of this story was changed to clarify Kimber Stanhope's title and her work on the effects of glucose and fructose on triglyceride levels.
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