George A Bray
This issue of the Journal contains another disturbing article on the biology of fructose (
1).
Why is fructose of concern? First, it is sweeter than either glucose or
sucrose. In fruit, it serves as a marker for foods
that are nutritionally rich. However, in soft drinks
and other “sweets,” fructose serves to reward sweet taste that provides
“calories,” often without much else in the way of
nutrition. Second, the intake of soft drinks containing high-fructose
corn
syrup (HFCS) or sucrose has risen in parallel with the
epidemic of obesity, which suggests a relation (
2). Third, the article in this issue of the Journal (
1) and another article published elsewhere last year (
3) implicate dietary fructose as a potential risk factor for cardiovascular disease.
The intake of dietary fructose has increased significantly from 1970 to 2000. There has been a 25% increase in available “added
sugars” during this period (
4).
The Continuing Survey of Food Intake by Individuals from 1994 to 1996
showed that the average person had a daily added
sugars intake of 79 g (equivalent to 316 kcal/d or 15%
of energy intake), approximately half of which was fructose. More
important,
persons who are ranked in the top one-third of
fructose consumers ingest 137 g added sugars/d, and those in the top 10%
consume
178 g/d, with half of that amount being fructose. If
there are health concerns with fructose, then this increased intake
could
aggravate those problems.
Before the European encounter with the New
World 500 y ago and the development of the worldwide sugar industry,
fructose in
the human diet was limited to a few items. For
example, honey, dates, raisins, molasses, and figs have a content of
>10% of
this sugar, whereas a fructose content of 5–10% by
weight is found in grapes, raw apples, apple juice, persimmons, and
blueberries.
Milk, the main nourishment for infants, has
essentially no fructose, and neither do most vegetables and meats, which
indicates
that human beings had little dietary exposure to
fructose before the mass production of sugar.
Most fructose in the American diet comes not from fresh fruit, but from HFCS or sucrose (sugar) that is found in soft drinks
and sweets, which typically have few other nutrients (
2).
Soft drink consumption, which provides most of this fructose, has
increased dramatically in the past 6 decades, rising
from a per-person consumption of 90 servings/y (≈2
servings/wk) in 1942 to that of 600 servings/y (≈2 servings/d) in 2000
(
5). More than 50% of preschool children consume some calorie-sweetened beverages (
6).
Children of this age would not normally be exposed to fructose, let
alone in these high amounts. Because both HFCS and
sucrose are “delivery vehicles for fructose,” the load
of fructose has increased in parallel with the use of sugar.
Fructose is an intermediary in the metabolism
of glucose, but there is no biological need for dietary fructose. When
ingested
by itself, fructose is poorly absorbed from the
gastrointestinal tract, and it is almost entirely cleared by the
liver—the
circulating concentration is ≈0.01 mmol/L in
peripheral blood, compared with 5.5 mmol/L for glucose.
Fructose differs in several ways from glucose, the other half of the sucrose (sugar) molecule (
4).
Fructose is absorbed from the gastrointestinal tract by a different
mechanism than that for glucose. Glucose stimulates
insulin release from the isolated pancreas, but
fructose does not. Most cells have only low amounts of the glut-5
transporter,
which transports fructose into cells. Fructose cannot
enter most cells, because they lack glut-5, whereas glucose is
transported
into cells by glut-4, an insulin-dependent transport
system. Finally, once inside the liver cell, fructose can enter the
pathways
that provide glycerol, the backbone for
triacylglycerol. The growing dietary amount of fructose that is derived
from sucrose
or HFCS has raised questions about how children and
adults respond to fructose alone or when it is accompanied by glucose.
In one study, the consumption of high-fructose meals
reduced 24-h plasma insulin and leptin concentrations and increased
postprandial
fasting triacylglycerols in women, but it did not
suppress circulating ghrelin, a major appetite-stimulating hormone (
4).
Fructose is metabolized, primarily in the liver, by phosphorylation on the 1-position, a process that bypasses the rate-limiting
phosphofructokinase step (
4). Hepatic metabolism of fructose thus favors lipogenesis, and it is not surprising that several studies have found changes
in circulating lipids when subjects eat high-fructose diets (
4). In the study conducted by Aeberli et al (
1),
dietary factors, especially fructose, were examined in relation to body
mass index, waist-to-hip ratio, plasma lipid profile,
and LDL particle size in 74 Swiss schoolchildren who
were 6–14 y old. In that study, plasma triacylglycerols were higher,
HDL-cholesterol concentrations were lower, and
lipoprotein (LDL) particle size was smaller in the overweight children
than
in the normal-weight children. Fatter children had
smaller LDL particle size, and, even after control for adiposity,
dietary
fructose intake was the only dietary factor related to
LDL particle size. In this study, it was the free fructose, and not
sucrose, that was related to the effect of LDL
particle size. Studies in rodents, dogs, and nonhuman primates eating
diets
high in fructose or sucrose consistently show
hyperlipidemia (
4).
The current report by Aeberli et al suggests that the higher intake of
fructose by school-age children may have detrimental
effects on their future risk of cardiovascular disease
by reducing LDL particle size. It is interesting that this study did
not find a relation of dietary fructose with
triacylglycerols but did find a relation with the more concerning lipid
particle,
LDL cholesterol. Another recent report has proposed a
hypothesis relating fructose intake to the long-known relation between
uric acid and heart disease (
3).
The ADP formed from ATP after phosphorylation of fructose on the
1-position can be further metabolized to uric acid. The
metabolism of fructose in the liver drives the
production of uric acid, which utilizes nitric oxide, a key modulator of
vascular
function (
3). The studies by Aeberli et al and Nakagawa et al suggest that the relation of fructose to health needs reevaluation.
