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Sugar Wars, Episode 4: A New Hope for Fructose

There are good reasons to suspect that fructose could negatively impact glycemic control compared to other sugars. But the best way to know whether it does or not is to look and see.


Concern over the impact of sugar on health has grown over the past several decades. The World Health Organization’s 2015 report on sugar consumption recommends limiting free sugar intake (which does not occur naturally in food) to below 10% of daily calories, based in part on data showing that increasing free sugar consumption commonly results in an energy surplus[1] and consequential weight gain that may contribute to obesity. Some researchers have even proposed warning labels[2] for sugar-sweetened beverages.

Added sugars go by many names, but, with few exceptions, all are either glucose, fructose, or some combination of the two. Glucose is obtained from the diet and produced in the body. It can be considered a universal energy source for all cells. Blood glucose levels are tightly regulated because levels that are too high or too low have pathologic consequences. By contrast, fructose is obtained almost exclusively from the diet and is quickly removed from circulation to be metabolized[3] primarily by the liver and, to a lesser extent, fat cells and muscle tissue.

Much of the discussion over the health impact of added sugars has focused on fructose. The central issue[4] with fructose, as illustrated in Figure 1, is that it bypasses the main rate-limiting steps of glycolysis in the liver and therefore acts as an unregulated substrate[5] for fat synthesis and uric acid production. There is no shortage of research publications blaming fructose for causing insulin resistance[6] and related cardiometabolic diseases[7][8] such as type 2 diabetes[9] because of the way it is handled in the body. Further evidence implicating a role of fructose in obesity and diabetes comes from genetic evidence[10] that suggests humans developed a mutation that enhances the effect of fructose to increase fat stores, which may at one time have provided a survival advantage, but is now working against us in the modern world (although this “thrifty gene” hypothesis is not without[11] controversy).

Figure 1: Fructose as an unregulated substrate

Reference: Khitan et al. J Nutr Metab. 2013 May.

The fructose hypothesis is not a settled matter, though. Meta-analyses of observational data have shown that although sugar-sweetened beverages[12] are associated with an increased risk of type 2 diabetes, other sources of fructose, such as 100% fruit juices[13], are not. Another recent meta-analysis[14] reported that total sugar intake and fructose intake were not associated with increased incidence of type 2 diabetes. If fructose was uniquely detrimental to health, then one could reasonably expect it to be associated with disease regardless of its dietary source. However, this does not appear[15] to be the case. Furthermore, the fructose hypothesis has been criticized[16][17][18][19] for its heavy reliance on unrealistic and circumstantial evidence derived from animal models that use extremely high doses of pure fructose.

Clinical trials in humans also do not support a link between fructose and diabetes. One meta-analysis[20] evaluated how chronically consuming small doses of fructose (22-36 grams per day, which is below the average American intake[21] of 49 grams) in place of an equal amount of other carbohydrates positively impacted glycemic control, with fructose significantly lowering HbA1c and fasting blood glucose but not fasting insulin. Another meta-analysis[22] restricted to people with type 2 diabetes reported similar findings even though the median intake of fructose was substantially higher at 60 grams per day, with a range of 22-137 grams per day. For reference, a standard 12-ounce can of soda has about 22 grams of fructose.

The most common comparator carbohydrate in these meta-analyses was starch. Realistically, however, people at risk for developing diabetes or concerned with managing their blood sugar levels are likely to swap out other added sugars for fructose, rather than other carbohydrates in general. Additionally, neither meta-analysis evaluated the acute effects of fructose on post-meal glycemia, which has been linked to[23] an increased risk of all-cause mortality, diabetes, and cardiovascular disease, in both people with[24] and without[25] impaired glucose tolerance.

To address these knowledge gaps, a group of researchers published two companion meta-analyses focusing on the effect of substituting fructose for an equal amount of glucose or sucrose. The first meta-analysis evaluated the acute effects on post-meal glycemia while the second evaluated the chronic effects on glycemic control.

Concern over the health effects of added sugars has grown over the past several decades, and much of this attention has been given to fructose as being particularly detrimental because of the unique way the body handles it metabolically. However, the role of fructose in cardiometabolic diseases such as type 2 diabetes remains controversial. Current evidence suggests that it may benefit long-term glycemic control compared to other carbohydrates. Two companion meta-analyses add to the evidence by comparing the effects of fructose to other sugars, rather than carbohydrates in general, on post-meal glycemia and long-term glycemic control.

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Other Articles in Issue #33 (July 2017)