Examining the Health Effects of Fructose

JAMA ^ | June 3, 2013 | David S. Ludwig, MD, PhD

[neverdem]

In the 1990s, excessive fat consumption was commonly believed to be the main cause of obesity. High sugar consumption was often considered to be innocuous and possibly protective against obesity by displacing dietary fat.¹ A decade later, the American Heart Association linked intake of added sugars to weight gain and recommended substantial decreases in consumption to a daily maximum of 100 kcal for women and 150 kcal for men.² Some experts now argue that sugar comprises the single most important cause of the worldwide epidemics of obesity and diabetes, primarily through the effects of fructose at prevailing levels of consumption.³ This Viewpoint examines the physiological effects of common sugars and argues against a narrow public health focus on fructose.

FRUCTOSE VS GLUCOSE

Fructose, a 6-carbon sugar, is more than twice as sweet as its isomer glucose. Most caloric sweeteners contain approximately equal amounts of these 2 sugars, either linked covalently in sucrose (table sugar) or as monosaccharide mixtures in high-fructose corn syrup and honey. Pure glucose, as found in unmodified corn syrup, has relatively little sweetness, and pure fructose may cause malabsorption in some people, limiting its practical use.

Despite chemical similarities, the metabolism of these 2 sugars differs markedly, and this difference underlies recent health concerns.³ Following consumption, glucose potently stimulates insulin secretion, promoting glycogen synthesis in the liver and glucose uptake by tissues throughout the body. In contrast, fructose does not directly elicit insulin secretion and is taken up almost exclusively by the liver. Moreover, unlike glucose, the metabolism of fructose is not tightly regulated by liver cell energy state. Consequently, fructose rapidly undergoes glycolysis, fueling de novo lipogensis under some conditions. This newly synthesized lipid may accumulate locally, causing fatty liver and hepatic insulin resistance, or be exported, increasing serum triglycerides, systemic insulin resistance, and fat deposition in adipose tissue. Fructose metabolism may also up-regulate hepatic signal transduction pathways involved in inflammation and drive uric acid production, possibly contributing to hypertension and endothelial dysfunction. Consistent with these mechanisms, feeding studies have demonstrated marked metabolic aberrations—including insulin resistance, dyslipidemia, higher blood pressure, and increased visceral adiposity—among obese individuals consuming fructose compared with glucose.³

However, these feeding studies have been criticized for providing unrealistically high amounts of fructose, typically exceeding the 95th percentile of consumption by 50% or more.⁴ A recent meta-analysis found no adverse effects of isocaloric substitution of fructose and glucose at average consumption levels for body weight, lipids, blood pressure, uric acid, or insulin levels and found possible benefit for glucose tolerance and glycemic control in diabetes.⁵ The monosaccharide feeding studies have also been criticized because humans virtually always consume fructose together with glucose, as in sucrose, high-fructose corn syrup, or honey, not in isolation.⁴

Another argument against fructose having uniquely harmful effects involves the glycemic index, a measure of how food affects blood glucose in the postprandial period. Glucose and most commonly consumed starchy foods (all starches are polymers of glucose) have a high glycemic index, whereas fructose has an exceptionally low value. If the effects of fructose on health predominated, and the various forms of glucose were innocuous, then the glycemic index should have a null or inverse association with disease risk. However, systematic reviews and meta-analyses have linked a high glycemic index diet to the same adverse effects as fructose, including obesity and diabetes.^{6- 7}

In light of these considerations, a critical scientific question is whether replacement of fructose-containing sweeteners at prevailing consumption levels with glucose (as a monosaccharide or as starch) would provide health benefits. If so, a specific public health focus on fructose may be warranted. If not, then broader measures targeting all highly processed carbohydrate foods would be indicated. However, no modern controlled feeding studies adequately address this question, but research dating back to the 1970s is informative. In 1 study, 9 men and women, aged 37 to 62 years, living in a metabolic ward consumed a high-sugar diet (containing 70% of carbohydrate as sucrose, an average of about 675 kcal/d) or a sucrose-free diet (containing wheat and potato starch), each for 4 weeks. Upon repeated measurements, fasting blood glucose was slightly higher (3 mg/dL) for the sucrose condition but no differences between diets were found in body weight, glucose tolerance, fasting and stimulated insulin, cholesterol, triglycerides, or nonesterified fatty acids.⁸

DIGESTION RATE, NOT DOSE

Fruit is the primary natural source of fructose. Most fruits have about 10 g of fructose, as monosaccharide or sucrose, per 80-kcal serving, comprising at least half the total sugar content. If fructose were toxic at high dosage, then individuals consuming large amounts of fruit might experience adverse effects. However, observational studies report inverse associations between fruit consumption and body weight or risk of obesity-associated diseases, with no evident upper threshold for protection,⁹ although some studies do not adequately distinguish between fruits and vegetables.

In possibly the only interventional study of its kind, 17 Bantu and white adults in South Africa, aged 20 to 64 years, consuming a Western diet were instructed to eat primarily fruit (20 servings per day for the typical participant) supplemented with nuts to satisfy basic macronutrient requirements.¹⁰ Despite the extraordinarily high fructose content of this diet, presumably about 200 g/d, the investigators reported no adverse effects (and possible benefit) for body weight, blood pressure, and insulin and lipid levels after 12 to 24 weeks. Nevertheless, findings from this study must be interpreted cautiously because of important design limitations, including lack of an active control group.

The absence of harm from high fruit consumption likely relates to the slow digestion rate of whole fruit compared for example with a sugar-sweetened beverage, producing portal fructose concentrations that do not exceed hepatic metabolic capacity. Although soluble fiber helps to reduce sugar absorption rates from the digestive tract (primarily by increasing luminal viscosity), the physical form and cellular structure of whole fruit probably have a greater effect, by sequestering sugar away from the absorptive surface of the small intestine. In addition, the high micronutrient and antioxidant content of fruit may protect against hepatic inflammation and systemic insulin resistance.

CONCLUSIONS

Few modern studies have compared the long-term effects of glucose, fructose, and starch under physiologically relevant condition, and such research should assume high priority. The available evidence suggests 3 key points. First, fructose in its primary natural form (whole fruit) is not associated with adverse effects up to the limits of human consumption. Second, excessive intake of refined sugar plays a significant role in the epidemics of obesity and related diseases, in part because large amounts of rapidly absorbed fructose can overwhelm hepatic biochemical pathways. Third, rapidly absorbed forms of glucose—present in both sugar and high glycemic index starch—also contribute importantly to these diseases, especially considering their much greater caloric contribution to typical diets than fructose. Therefore, the recommendation to replace fructose with glucose lacks an evidence basis. Rather, public health efforts should focus on reducing intakes of all highly processed carbohydrates, not just refined sugar.

AUTHOR INFORMATION

Corresponding Author: David S. Ludwig, MD, PhD, Boston Children's Hospital, 300 Longwood Ave, Boston, MA 02115 (david.ludwig@childrens.harvard.edu).

Published Online: June 3, 2013. doi:10.1001/jama.2013.6562

Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported receiving grants from the National Institutes of Health and foundations for obesity-related research, mentoring, and patient care and receiving royalties from a book about childhood obesity.

Funding/Support: Dr Ludwig is supported in part by an endowment from Boston Children's Hospital and career award K24DK082730 from the National Institute of Diabetes and Digestive and Kidney Diseases.

Role of Sponsors: The funders had no role in the preparation, review, or approval of the manuscript or in the decsion to submit the manuscript for publication.

Disclaimer: The content of this article is solely the responsibility of the author and does not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases or the National Institutes of Health.

Additional Contributions: I thank Marion Nestle, PhD, of New York University, Dariush Mozaffarian, MD, DrPH, and Frank Sacks, MD, of Harvard School of Public Health, Bruce Bistrian, MD, PhD, of Harvard Medical School, and Cara Ebbeling, PhD, of Boston Children's Hospital for providing detailed comments on an earlier version of the manuscript. None of these individuals received compensation for their efforts.

REFERENCES

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Johnson RK, Appel LJ, Brands M, et al; American Heart Association Nutrition Committee of the Council on Nutrition, Physical Activity, and Metabolism and the Council on Epidemiology and Prevention. Dietary sugars intake and cardiovascular health: a scientific statement from the American Heart Association. Circulation. 2009;120(11):1011-1020
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Lustig RH. Fructose: it's “alcohol without the buzz.” Adv Nutr. 2013;4(2):226-235
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White JS. Challenging the fructose hypothesis: new perspectives on fructose consumption and metabolism. Adv Nutr. 2013;4(2):246-256
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Ludwig DS. The glycemic index: physiological mechanisms relating to obesity, diabetes, and cardiovascular disease. JAMA. 2002;287(18):2414-2423
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Barclay AW, Petocz P, McMillan-Price J, et al. Glycemic index, glycemic load, and chronic disease risk—a meta-analysis of observational studies. Am J Clin Nutr. 2008;87(3):627-637
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[aruanan]

Yes, this is true. Is a diet of only protein and fat as healthy as one that includes carobohydrates?

Your body has an indispensable need for glucose/fructose for DNA synthesis and repair and for brain metabolism. If you have no carbohydrates whatsoever in your diet, you can use certain amino acids and other products of the catabolism of fats and proteins to produce glucose through gluconeogenesis.

[Huskrrrr]

Yes, I know most of the metabolic pathways and how they work, I teach biochemistry in college. My question is what are the long term health effects of a no carb diet (eg heart disease). There seems to be a disagreement among researchers as to the health consequences of a no carb diet. I was wondering what your opinion was on this subject.

[BobL]

“Besides that, real cane sugar in that amount actually seems to be a plus for digestion and feeling full and satisfied from foods.”

Yep, I think there’s something to that...I’ll try it too.

[Fractal Trader]

Eating it as a solid, bound up in fiber, as in fruit, results in an extended period of moderate levels of fructose entering the system.

I don't think anyone has suggested that fruit juice, for example, is as dangerous as HFCS soda, and I have never heard that carbonation, per se, is deleterious to your health.

[jdege]

I don't think anyone has suggested that fruit juice, for example, is as dangerous as HFCS soda

Actually, quite a few people have suggested that:

http://articles.mercola.com/sites/articles/archive/2010/06/19/richard-johnson-interview-may-18-2010.aspx

http://drjulindalee.wordpress.com/2013/05/13/what-fruit-juices-fructose-and-low-glycemic-index-really-mean/

[csmusaret]

I have no idea what the long term effects are, but for me my cholesterol improved quite a bit as a result of a 45 day no carb regimen.

[jdege]

There seems to be a disagreement among researchers as to the health consequences of a no carb diet.

Prolonged Meat Diets with a Study of Kidney Function and Ketosis

[Fractal Trader]

Interesting. I have been following a blog for the past two years which I have found authoritative on a wide variety of nutrition/obesity subjects, and he has never mentioned fruit juice to date, even though he has covered a wide variety of topics.

An interesting related subject is “de novo lipogenesis,” or the idea that sugar is turned into fat. Lots of research papers suggest that this is impossible, or quite uncommon.

Any way, here’s the link to his blog:

http://wholehealthsource.blogspot.com/

[napscoordinator]

without my fruit and protein I would keel over.

Stop eating it then....PLEASE!

[RipSawyer]

I had a doctor tell me that I could safely eat cantaloupe but not watermelon because supposedly the watermelon had a much higher fructose content. Having grown up hauling both of them to the market by the pickup load I had an idea he was wrong. A little research confirmed my suspicions, the sugar content varies more between varieties than it does between the average of the two categories, some varieties of cantaloupe have MORE sugar than some watermelons.

[Huskrrrr]

Thanks!

[Huskrrrr]

Thanks!

[jdege]

Lots of research papers suggest that this is impossible, or quite uncommon.

I'm unaware of any research papers that suggest that de novo lipogenesis is impossible, or that it is uncommon. Quite the contrary. The metabolic pathways exist in every animal species, from bacteria on up. The only question is the rate at which it happens, and whether it is a significant source of fat deposition.

On this, studies are mixed, at least with respect to glucose. There have been a number of studies that suggested that de novo lipogenesis is not a major pathway for most people. Which may be true.

The more important question, in my mind, is whether it becomes a major pathway for those with metabolic syndrome. And they suggest that for that population, DNL is a significant source of fat:

http://ajcn.nutrition.org/content/77/1/43.full

Until recently, DNL was believed to be an insignificant pathway in humans who eat a Western, high-fat diet. In addition, very little was known about the effect of the often recommended alternative diet, which is a low-fat, high-carbohydrate diet, on hepatic metabolism. However, with the development of new methodologies for measuring hepatic DNL, it was shown that hepatic DNL varies greatly depending on the health of the subjects (12, 13, 15) and the types of diets they consume (4, 5, 7, 9–11, 18, 19). The present study sought to answer 3 questions. First, do hyperinsulinemic obese subjects fed a Western, high-fat diet have higher fractional hepatic DNL than do normoinsulinemic lean or obese subjects fed the same diet? Second, is hepatic DNL increased when simple carbohydrate represents 54% of a low-fat, high-carbohydrate diet? And third, what is the relation of increased hepatic DNL to VLDL-triacylglycerol concentrations?

[...]

With the high-fat, low-carbohydrate diet, DNL was minimal and did not differ significantly between the lean and obese subjects with normal fasting insulin concentrations. In contrast, hyperinsulinemic obese subjects had a significantly higher DNL compared with both lean and obese normoinsulinemic subjects (Figure 1⇓; P < 0.05). Interestingly, although DNL did not differ significantly between the lean normoinsulinemic and the obese hyperinsulinemic subjects who consumed the low-fat, high-carbohydrate diet (Figure 1⇓), DNL was significantly higher (P < 0.05) with the low-fat, high-carbohydrate diet for both groups when compared with the normoinsulinemic subjects who consumed a high-fat, low-carbohydrate diet for 5 d (Figure 1⇓; P < 0.05).

(And one thing to note - this study's "low carb diet" was 45% of calories from carbs - which is anything but low carb the way the low carb community would define it. Atkins induction is less than 5% of calories from carbs, and I'd be willing to guess that at that level, DNL would be minimal even for those who were hyper-insulinemic.)

[poobear]

??? You being a prick or something?
How fat and unhealthy are you?
Can you ride 80 miles per week?
IOW screw yourself!