Are All Sugars Created Equal? Let’s Talk Fructose Metabolism

By Chris Radlicz

According to NHANES (National Health and Nutrition Examination Survey) 2005-2010 the average American consumes about 20 teaspoons of sugar per day, with sugar consumption being the highest in teens and men (1). Interestingly, 33% of calories from added sugars come from beverages, and the majority of those beverages are sweetened with high fructose corn syrup (HFCS) (1).

But what is the novelty of HFCS? Aren’t the grams of sugar on the package all that matters? Although calorically equivalent, not all sugars are metabolized the same way.

Previous papers have established epidemiological links between fructose consumption, obesity, and metabolic disease. To take this further, recent literature has indicated that fructose, particularly in high concentrations, as present in high fructose corn syrup and sucrose, are proving to be toxic. HFCS is composed of about 60% fructose and 40% glucose (2). Prior to the processing of sugars, it was nearly impossible to find such high concentrations of sugar in the diet, but it now seems to be commonplace.

Dr. Kimber Stanhope out of University of California Davis published a recent review paper that touched on the metabolic dysregulation that occurs with high consumption of fructose.

Dr. Stanhope’s group has previously shown that subjects consuming fructose-sweetened beverages for 10 weeks, in addition to their normal diet, had increased de novo lipogenesis, dyslipidemia, circulating uric acid levels, visceral adiposity, reduced fatty acid oxidation, and insulin resistance. In contrast, subjects who consumed glucose-sweetened beverages, had comparable weight gain to the fructose group, but did not exhibit the aforementioned metabolic changes (3). These adverse effects seen in the fructose group all increase the likelihood of chronic diseases such as obesity, fatty liver, type-2 diabetes, and cardiovascular disease.

When consuming glucose, the liver is initially bypassed and the glucose reaches systemic circulation to be used by tissues such as the brain and muscles. If excess glucose is consumed in the diet, it will first be stored as glycogen, and secondarily as fat. Fructose on the other hand, takes a different path. When fructose is consumed, it is exclusively metabolized in the liver, where a particular enzyme, fructokinase, will allow for the uptake of fructose (3). Fructose metabolism as a whole lacks many of the cellular controls that are present in the glucose metabolism, which allows for unrestrained lipid synthesis (2).

Significant metabolic issues arise when a high concentration of fructose is consumed, such as in HFCS. An overload of fructose in the liver will lead to de novo lipogenesis and subsequent lipid droplet accumulation in the liver. With these high levels of fructose, the increase in lipid accumulation consequently decreases the breakdown of fat in the liver (3).

This intra-hepatic lipid will promote the production and secretion of very low-density lipoprotein 1 (VLDL1) leading to an increase in post-prandial triglycerides. A vicious cycle occurs effecting insulin resistance as well. The lipid in the liver will increase insulin resistance resulting in increases in circulating diacylglycerol. Additionally, the insulin resistance will lead to further lipid deposit in the liver with sugar having a greater propensity to turn to fat (3). A downstream effect of increased apoCIII and apoB will lead to muscle lipid accumulation, and end in whole body insulin resistance. All of this metabolic dysregulation results from the direct route fructose initially takes to the liver.

Although there is this well-defined and unique pathway for fructose metabolism, many industry-funded studies, haven’t shown the negative metabolic outcomes of consuming HFCS or sucrose (3). More research is certainly needed, but it is best to remember that added sugar in such high concentrations, no matter the culprit monosaccharide, is not favorable for overall health.

It is interesting to note a possible evolutionary perspective, which proposes the advantage of enhanced fructose to fat conversion. At the end of a growing season, ripened fruit will tend to have high levels of fructose. Therefore the fruit consumed at the end of the season may allow for increased fat storage, which would have been beneficial because of the low food availability in the ensuing months (2).

1.U.S. adults, 2005– 2010. NCHS data brief, no 122. Hyattsville, MD: National Center for Health Statistics. 2013.

2.Lyssiotis CA, Cantley LC. F stands for fructose and fat. Nature. 2013; 508:181-182.

3.Stanhope KL. Sugar consumption, metabolic disease and obesity: The state of the controversy. Crit Rev Clin Lab Sci. 2015;1-16.

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Highlights from the Presidential Symposium: Developmental Origins of Health and Disease

By Teresa Johnson, MSPH, RD

Robert Waterland, PhD, an associate professor at Baylor College of Medicine, described nutritional influences on human developmental epigenetics. Waterland defined epigenetics as “mitotically heritable stable alterations in gene expression potential that are not caused by changes in DNA sequence.” Multiple factors likely contribute to epigenetic changes, including cytosine methylation, histone modification, auto-regulatory transcription factors, and non-coding RNAs, Waterland pointed out, and they tend to work in a synergistic fashion to influence gene transcription. Waterland said he is particularly interested in DNA methylation because methylation requires dietary donors and cofactors, which is influenced by nutritional factors. He presented data demonstrating that periconceptual maternal nutrition status predicts hypomethylation in a mother’s infant. These changes are stable and maintained over a lifetime, Waterland said, and may point to evidence of metabolic imprinting as an adaptive response to early nutrition.

“We live in a microbial world,” said Dingding An, PhD, a researcher at Boston Children’s Hospital. An elaborated on the role of early life gut microflora in immune system development, and explained that microbial exposure begins at birth and influences our risk for chronic diseases such as inflammatory bowel disease, asthma, arthritis, and autism later in life. Many early-life factors impact the makeup of the gut microbial population in particular, such as nutrition, hygiene, and antibiotic use. An presented data indicating that some gut microbes enhance immune cell maturation and immune response. But the timing of microbial exposure is critical, An added, because later exposure diminishes the response, indicating that key windows of regulation have been missed.

Deborah Sloboda, PhD, an associate professor at McMaster University, provided insights into the impacts of fructose consumption during pregnancy. Fructose is a monosaccharide present in honey, maple syrup, and fruit sugar, and is widely available in processed foods. Fructose consumption differs by sex and age, Sloboda said, with highest consumption reported among lower socioeconomic status females during their reproductive years. This is important, Sloboda said, because “the early-life environment plays a very big role in determining health and disease risk later in life.” Her data from animal models indicate that high fructose intake during pregnancy induces changes in the offspring’s metabolic response. Taurine supplementation reversed fructose-induced adverse metabolic programming, Sloboda said, but not in the presence of a high fat diet, emphasizing the importance of correctly identifying the population in need of intervention.

Growing up in the now well-studied Swedish village Överkalix strongly influenced the research of Lars Bygren, MD, PhD, a professor at University of Umea. Bygren, who addressed the topic of transgenerational outcomes associated with paternal nutrition, explained that human responses to early-life exposures, especially in males, have the potential to impact development for multiple generations. In particular, exposure to high food availability during slow-growth periods negatively affects the health of subsequent generations, and could explain the present day prevalence of many chronic diseases. Byrgen said data from other studies, including the Taiwan betel nut study and the ALSCAP study, lend support to these conclusions.