The Frenzy Over Fructose

Ask a clinician about the dietary effects of fructose, and you’ll likely get an impassioned response. Not since the low-fat vs. low-carb wars of the 1990s has a nutritional topic received so much media attention and garnered so much debate in the medical and scientific communities. At the heart of the debate lies the role of fructose in America’s battle with obesity and its related metabolic disorders. Some researchers say fructose is particularly lethal, while others question the value of singling fructose out, and maintain that obesity is driven simply by consuming more energy than one needs.

“The people who say a sugar is a sugar are caloriecentric, and it’s probably true from a caloric standpoint that fructose and other sugars are equal,” says Michael I. Goran, PhD, professor of preventive medicine, physiology and biophysics, and pediatrics at the University of Southern California’s Keck School of Medicine. “But that misses the consequences of the metabolic fate of different sugars. This issue goes well beyond calories.”

Earlier this year Goran and colleagues published a paper in Global Public Health in which they noted that countries that use high fructose corn syrup (HFCS) in their food supplies have a 20% higher prevalence of diabetes than countries that do not — even though there were no significant differences between them in terms of body mass index (BMI) or other dietary variables such as caloric intake and total sugar intake.

Another study, appearing earlier this year in PLOS One by Sanjay Basu, MD, PhD, assistant professor of medicine at the Stanford Prevention Research Center and his colleagues, found that every 150-calorie increase per person per day in sugar availability was associated with increased diabetes prevalence by 1.1%.

Metabolic Mayhem

Fructose has been the subject of research going back to the 1950s, when a team at Harvard University demonstrated that fructose could induce insulin resistance in rats, results replicated in enough laboratories since then that it’s accepted as fact.

“There is unequivocal evidence in careful biologic studies in animals and cell culture that clearly document that fructose has effects independent of its calories,” says Richard J. Johnson, MD, professor in the Department of Medicine at the University of Colorado– Denver. “If you feed animals either fructose or glucose and they all eat the same number of calories, the ones that eat fructose will have worse metabolic features than those that eat glucose.”

Johnson adds that fructose is well-known to cause other problems in animals as well, such as fatty liver, high triglycerides, and resistance to leptin, a hormone that helps to control appetite. Last year, he and his colleagues published a paper in the Journal of Biological Chemistry in which they suggest that high levels of uric acid induced by fructose play a role in metabolic syndrome and the development of diabetes by causing oxidative stress in cells.

Research has borne similar results in humans. Several small studies, such as a trial in women led by the University of Pennsylvania’s Karen Teff, PhD, in 2004, suggests that fructose contributes to obesity because it does not stimulate insulin and leptin.

Leptin is of great concern for Robert Lustig, MD, MSL, professor of pediatrics in the Division of Endocrinology at the University of California, San Francisco, member of the Endocrine Society’s Obesity Task Force, and one of Basu’s co-authors.

“Leptin tells the brain to burn energy at normal levels. It’s the signal to the brain of peripheral energy adequacy. When insulin goes up, it interferes with brain leptin signaling, which the brain reads as starvation,” Lustig says.

As a result, consuming fructose does not lead to a feeling of fullness and instead promotes a distinct lack of energy that makes it difficult for people to find the motivation to exercise, he adds. “The biochemistry actually changes the behavior.”

In the January 2 issue of the Journal of the American Medical Association, research at Yale University led by Kathleen Page, MD (now with USC’s Keck School of Medicine) suggests that fructose and glucose affect the brain differently. In a small, blinded study of healthy adults who were given drinks with either fructose or glucose, the team found that after glucose-sweetened drinks, the participants’ bodies produced insulin and activity slowed in the hypothalamus, the area of the brain that stimulates appetite. The participants also said they didn’t feel as hungry. However, after the fructose-sweetened drink, they experienced almost no increase in insulin, the hypothalamus remained active, and they said they felt hungrier.

Evidence has begun to point to a darker side of fructose. Kimber Stanhope, PhD, RD, associate research nutritional biologist in the Department of Molecular Biosciences at the University of California at Davis, has led two studies that fuel the debate. In one, the team compared the effects of consuming 25% of calories from either fructose or glucose in overweight and obese participants — the maximal intake level of calories from added sugar suggested in the 2010 Dietary Guidelines for Americans. As described in the May 2009 issue of The Journal of Clinical Investigation, the team found that although both groups of patients gained similar amounts of weight, the fructose group experienced increased fat production in the liver and increased intra-abdominal fat, which raises cardiovascular risk more than subcutaneous fat. Fasting glucose and insulin levels increased and insulin sensitivity decreased in the fructose group as well.

In the other study, appearing in the October 2011 issue of the Journal of Clinical Endocrinology and Metabolism, the team compared the effects of fructose, HFCS, and glucose as 25% of total calories in adults between 18 and 40 years old with a lower average BMI than the participants in the previous study, including participants with BMIs as low as 18. This time, the fructose and HFCS groups experienced increased risk factors for cardiovascular disease such as higher post-meal triglycerides and higher fasting and post-meal concentrations of LDL cholesterol compared to the glucose group.

Stanhope points to fructose metabolism in the liver as a likely culprit. “Fructokinase, the enzyme that regulates the uptake and metabolism of fructose in the liver, is turned on all the time. Therefore whether the liver needs energy or not, nearly all the fructose from the beverages ends up in the liver. The metabolic pathways become overloaded and the result is increased fat and uric acid production.”

Studies such as these are enough to make Goran leery of fructose. “You can’t dispute the metabolic machinery of the cell,” he says.

“The question is now about tipping the balance. How much more fructose do you need to produce a metabolically damaging effect and send you down the path toward diabetes? We should all be consuming less sugar, but if you had to choose, [know that] added sugar that contains fructose is going to be more damaging [in general],” Goran adds, noting that current food labeling does not spell out how much fructose or HFCS is in a product. “In a previous study, we measured fructose in sodas and showed that it may be higher than we think.”

Fructose in a Vacuum?

Some critics of current fructose research question the usefulness of singling out fructose.

“The effects [of fructose and glucose] may be somewhat different based on chemical structures, but rather than substitute one for the other, let’s instead focus on reducing all highly processed carbohydrates because they all have adverse effects,” says David S. Ludwig, MD, PhD, director of the New Balance Foundation Obesity Prevention Center and the Optimal Weight for Life Clinic at Boston Children’s Hospital.

Ludwig stresses that fructose occurs naturally in fruit, and that people who eat several servings of fruit daily tend to have better health.

“Fructose per se is not likely to be the problem, but rather the manner in which we consume it. Unprocessed sources of fructose, as in fruit, digest more slowly and do not overwhelm the liver,” Ludwig says, adding that it would be a disservice to tell patients not to eat fruit.

“We don’t consume fructose by itself. We always consume it with glucose,” says James Rippe, MD, professor of biomedical sciences at the University of Central Florida, who also serves as a consultant to the Corn Refiners Association. “Sucrose, the leading sweetener worldwide, is half fructose and half glucose. High-fructose corn syrup, the second-leading sweetener, is also glucose and fructose, with the most common form being 55% fructose and 45% glucose.”

Rippe says what happens in the lab is different than what happens on the plate. “A lot of confusion comes into this because people compare large amounts of pure fructose to large amounts of pure glucose to show that they behave differently, but we don’t consume them separately.”

He adds that studies that supply 25% of calories as either fructose or glucose, as Stanhope and other researchers have done, exceed average consumption. “It’s an artificial condition, and it’s not relevant to human nutrition.”

Nonetheless, Rippe and his colleagues conducted a study in which participants with an average age of 42 were assigned one of three different levels of sucrose or HFCS at 8%, 18%, or 30% of the calories required for weight maintenance. Their results, published in the June 2013 issue of Applied Physiology, Nutrition, and Metabolism, indicated no change over the course of 10 weeks in the fat content of the liver or several major muscle groups.

“I’m not in any way recommending that people consume excessive amounts of sugar, but I’m saying that there is no demonstrated harm from up to 25% of calories from added sugar,” Rippe says, adding that researchers should instead consider the overall increase in daily calories consumed by Americans in the last 30 years.

According to survey data from the nine National Health and Nutrition Examination Surveys conducted between 1971 and 2010, average daily total intake rose 314 calories from 1971 to 2003. Although it then fell 74 calories between 2003 and 2010 — with no corresponding dip in obesity rates — there remains a net gain of 240 more calories per day in 2010 compared to 1971.

“When you look at the increase in calories, focusing on fructose is like chasing a zebra in a herd of horses,” Rippe says. “The fact is that we [as a nation] are eating too much of everything, and until we get people to pay attention to their overall diet, that isn’t going to change. If I could wave a magic wand and take away all fructose, I don’t think anything would change.”

— D’Arrigo is a health and science writer based in Holbrook, N.Y., and a regular contributor to Endocrine News

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