Metabolic effects of dietary fructose

JUDITH HALLFRISCH’
Gerontology Research Center, National Institute on Aging Baltimore, Maryland 21224, USA

for the last 20 years, the introduction of high fructose

ABSTRACT corn syrups in 1967 has led to an exponential increase
in free fructose in the food supply of the United States
Fructose, a naturally occurring hexose, is a component (1). Fructose may have some metabolic advantages for
of many fruits, vegetables, and sweeteners. Because of certain segments of the population. In 1874, fructose
the introduction of high fructose corn sweeteners in was reported to be better tolerated than sucrose or glu-
1967, the amount of free fructose in the diet of Ameri- cose by diabetic persons (2). However, other metabolic
cans has increased substantially in the last 20 years. effects may be detrimental to the health of other seg-
Fructose is sweeter, more soluble, and less glucogenic ments of the population (e.g., hypertriglyceridemics).
than glucose or sucrose, so it has been recommended In view of the recent increase in consumption of free
as a replacement for these sugars in the diets of dia- fructose in the United States, this review will discuss
betic and obese people. Although an acute dose of fruc- sources of fructose in the diet, present and projected
tose causes smaller increases in glucose and insulin consumption levels, digestion and absorption, metabo-
than a comparable dose of glucose, there are a number lism, recent reports of metabolic effects in humans,
of changes after dietary adaptation that may reduce its where possible, or animals, and make recommenda-
desirability as a sugar replacement in certain segments tions for specific segments of the population.
of the population. Fructose is absorbed primarily in the
jejunum and metabolized in the liver. When consumed
in excess of dietary glucose, it may be malabsorbed. CONTENT OF FRUCTOSE IN FOODS
Fructose is more lipogenic than glucose or starches,
Fructose (a-D-fructofuranose) is the predominant mono-
and usually causes greater elevations in triglycerides saccharide (3) in a number of fruits including apples,
and sometimes in cholesterol than other carbohydrates. grapes, oranges, and watermelon (Table 1). Vegetables
Dietary fructose has resulted in increases in blood pres- may contain by weight 1 to 2% free fructose and up to
sure, uric acid, and lactic acid. People who are hyper-
3% fructose as sucrose. These low percentages by weight
tensive, hyperinsulinemic, hypertriglyceridemic, non-
may constitute a significant percentage of the total
insulin-dependent diabetic, or postmenopausal are calories. For example, watermelon is 90% water by
more susceptible to these adverse effects of dietary weight, 0.6% protein, and 0.4% fat. Fructose accounts
fructose than healthy young subjects. Although con- for about 60% of the calories (40% from fructose alone
sumption of fructose as a component of fruits and
and 20% as fructose from sucrose). Inulin, a polymer
vegetables is an unavoidable consequence of eating a
of fructose (f3-D-fructofuranose linked by 2, 1 bonds)
healthy diet, added fructose seems to provide little ad- not absorbed by the human intestine, is present in
vantage over other caloric sweeteners and compares chicory, sweet potatoes, and Jerusalem artichokes. Fruc-
unfavorably to complex carbohydrates in susceptible
tose also occurs in some legumes as the trisaccharide
segments of the population. HALLFRISCH, J. Meta- raflinose (a-D-galactopyranosyl-(l,6)-a-D-glucopyranosyl-
bolic effects of dietary fructose. FASEB j 4: 2652- (l,2-l1-fructofuranoside) and the tetrasaccharide stachyose
2660; 1990.
(a-D-galactopyranosyl-(l,6)-c-D-ga1actopyranosyl-(1,6)-a-
D-glucopyranosyl-(l,2)-f3-D-fructofuranoside). These com-
Key Words: fructose glucose tolerance hyperinsulinemia
pounds are not absorbed by the human small intestine.
diabetes triglycerides uric acid
.
They are, however, fermented by bacteria in the large
intestine, and may be sources of the flatulence that
occurs after digestion of legumes. Fructose is found in
a variety of sweets either free or as a component of su-
crose, a disaccharide containing 1 molecule of fructose
FRUC1DSE, ALSO CALLED LEVULOSE AND fruit sugar, is a
and 1 molecule of glucose. Honey provides the highest
naturally occurring keto sugar. It is found in fruits and
concentration of fructose (42.4% of weight) as a natural
vegetables, and makes up approximately 50% of honey
and sucrose. Fructopyranose is the only known crystal-
line form of fructose and it is probably the sweetest
‘Address reprint requests to: Judith Hallfrisch, Metabolism Sec-
naturally occurring sugar. Although intakes of the tion, Gerontology Research Center, 4940 Eastern Ave., Baltimore,
natural sources of fructose have been reasonably stable MD 21224, USA.

2652 0892-6638/90/0004-2652/$01 .50. © FASEB

TABLE 1. Selected sugar content of foods” of carbonated beverages. Most candies contain small
amounts of fructose. If they are made with honey they
Food Glucose Fructose Sucrose Total sugars may contain 7-8% fructose. The fructose content of
breakfast cereals ranges from nil to about 10% of dry
Fruits weight.
Apple, raw 2.3 7.6 3.3 13.3
Banana, raw 4.2 2.7 6.5 15.6
Cherry, raw 8.1 6.2 0.2 14.6
Grape, raw 6.5 7.6 0.4 18.1 PRESENT CONSUMPTION LEVELS OF
Pineapple, raw 2.9 2.1 3.1 11.9 FRUCTOSE IN THE UNITED STATES
Watermelon 1.6 3.3 3.6 9.0
Vegetables Fructose consumption as a component of corn sweeteners
Carrot, raw 1.0 1.0 3.6 6.6 (1) has increased 10-fold since 1975 (Table 2). Per capita
Corn, sweet 0.5 0.3 1.5 2.6 consumption of this source alone accounts for 49.1
Onion, raw 2.4 0.9 1.3 6.2
pounds/year. These data are reported by the U.S.
Peas, cooked 0.2 0.1 4.8 5.8
Tomato, raw 1.1 1.4 0 2.8
Department of Agriculture as per capita consumption,
Legumes but are based on the disappearance of foods in the food
Beans, w/pork 1.6 1.4 4.3 8.3 supply and do not adjust for waste. Although refined
Chick-peas 0.1 0.1 1.2 4.8 sucrose intake (cane and beet) has declined from 89.2
Lentils, cooked 0 0.1 0.5 1.8 to only 62.1 pounds/year in the last 15 years, overall
Peanuts, dried 0.2 0 3.8 4.3 caloric sweetener consumption including refined sugars,
Soybeans 0.1 0.2 0.5 3.0
honey, syrups, and corn sweeteners has increased from
Sweets
Corn syrup 14.9 1.2 2.2 37.0 118 pounds for 1975 to 134.2 pounds estimated for
Honey 33.8 42.4 1.5 81.9 1989-an increase of 14%. Caloric sweeteners account
Molasses 7.4 7.9 26.9 42.8 for a mean of more than 165 g/day for every man,
Maple syrup 2.3 0.9 59.1 62.3 woman, and child in the United States. Fructose from
Brown sugar 5.2 0.4 84.3 89.9 corn sweeteners and honey accounts for approximately
Processed foods
32 g/day. Fructose as a component of refined sugar adds
Fruit cocktail 6.0 6.0 3.3 15.3
Orange juice 5.3 4.6 0.7 10.6
approximately 39 more g/day. These figures do not in-
Bread, white 1.8 1.5 0.1 3.9 clude any fructose that is consumed as a component of
Fruitcake 11.3 11.3 20.5 43.1 fruits and vegetables or other sources. Fruits and
Cola 4.0 4.4 2.1 10.6 vegetables account for 10-15% of total simple sugars,
Milk chocolate 0.2 0.1 46.8 52.1 but data on the proportion of fructose are not available.
Toffee 6.7 5.2 40.9 55.4 The rate of replacement of cane sugar with fructose
Raisin bran 7.3 8.2 10.1 26.6
corn sweeteners seems to be reaching a plateau as is
Shredded wheat 0.1 0 0.3 0.4
Cherry brandy 16.5 16.1 0 32.6
overall sugar intake; however, metabolic effects on the
population from this rapid change from the 1970s to the
‘Grams per 100 g edible portion. Adapted from ref 3.
1980s may not be apparent for some time. Fructose (4
kcal/g) from caloric sweeteners now accounts for ap-
sweetener; corn sugar is mostly glucose; cane and proximately 284 kcal/day, or about 8% of total calorie
maple sugar are predominantly sucrose; molasses con- intake based on per capita kilocalorie availability of
tains mostly sucrose, but is 8% fructose. 3400/day (4).
Fructose is more soluble in water than sucrose or glu-
cose. It is the difference in this property, solubility, that
makes fructose corn sweeteners the more popular
sweetener for beverages and canned fruits, whereas TABLE 2. U.S. per capita consumption of caloric sweeteners’
sucrose is more popular for baked goods. Since fructose
tends to form crystals less readily than sucrose, it is Refined
Year sucrose HFCSb Honey Total sweeteners
preferred in some candies in which crystallization is not
desired. Canned fruits and juices contain 4-8% fruc- lbs dry wt/year
tose. Baked products may contain 1-2% fructose unless
1975 89.2 4.9 1.0 118.0
they are predominantly fruit, such as fruit pies or
1980 83.6 18.0 0.8 123.9
cakes, which may contain as much as 11% fructose. As 1985 63.4 44.1 1.0 132.8
a result of the lower cost of corn compared to cane 1989 62.1 49.1 1.0 134.8
sugar, carbonated beverages produced in the United
g/day
States now almost exclusively use high fructose corn
sweeteners rather than sucrose. High fructose corn 1975 111 6 1 147
sweeteners, introduced in 1967, are produced from 1980 104 22 1 154
1985 79 55 1 165
isomerization of glucose syrups extracted from corn as
1989 77 61 1 168
starches and dextrins and then hydrolyzed. Fructose ac-
counts for 4-6% of the weight and 50% of the calories ‘Ad apted from ref 1. bHFCS High fructos e corn sweeteners.

METABOLIC EFFECTS OF DIETARY FRUCTOSE 2653

DIGESTION AND INTESTINAL ABSORPTION concentrations of glucose, fructose, and glucose-polymer
solutions were determined by aspiration from nasogas-
OF FRUCTOSE
tric tubes. At rest, gastric emptying rates were faster for
Studies examining digestion and absorption of fructose isocaloric fructose and glucose-polymer solutions than
have been reviewed by Reiser (5). In humans, sucrose for isocaloric glucose solutions (9). Fructose and glucose-
is the only usable dietary source of fructose that re- polymer solutions presented more calories to the small
quires hydrolysis before it is absorbed by the small in- intestine for absorption more rapidly than did com-
testine. Although fructose absorption was thought to parable concentrations of glucose. Depletion of muscle
occur largely by facilitated diffusion, more recent evi- glycogen and the subsequent fall in blood glucose that
dence indicates that, in the rat intestine, fructose trans- occur during prolonged exercise result in fatigue. Blood
port may be partially active and carrier-mediated. The glucose levels of athletes were recorded both at rest and
rate of fructose absorption is intermediate between the during prolonged moderate exercise when the athletes
rates of actively transported sugars such as glucose and drank glucose, fructose, or glucose-polymer solutions
galactose and the rates of passively transported sugars. (10). During exercise, blood glucose remained stable
Fructose transport models based on studies of isolated with both fructose and glucose ingestion. However, glu-
intestinal rat cells or intestinal segments indicate that it cose utilization from the fructose solution was lower
is probably Na-independent and mediated by a carrier than from glucose. Therefore, even with the faster gas-
in the brush border that is distinct from that for glucose tric emptying rate, although blood glucose was main-
transport. Since fructose transport can occur against a tained, fructose may not be an advantage in terms of
concentration gradient, it is an active mechanism that energy availability.
requires energy. This is confirmed by reported inhibi-
tion of transport by dinitrophenol and fluoride. Trans- METABOLISM OF FRUCTOSE
port of both glucose and fructose is greater in the jeju-
num than in the ileum. Fructose absorption appears to In humans and the rat, fructose is metabolized primarily
be enhanced by the presence of glucose. When carbo- in the liver, although both the small intestinal mucosa
hydrates such as lactose or fructose are not absorbed by and kidney also contain the enzymes necessary for the
the human small intestine, high osmolarity of the gut catabolism of fructose (11). There is minimal utilization
contents causes secretion of fluids into the gut, which of fructose in peripheral tissues. The initial step in the
causes abdominal distention, cramps, and increased catabolism of fructose and other sugars is phosphoryla-
gastrointestinal motility. The undigested carbohydrate tion. Fructose can be phosphorylated either by hexo-
is then fermented in the colon, producing CO2 and kinase, which occurs throughout the body and phos-
hydrogen. Increased breath hydrogen can be measured phorylates a number of 6 carbon sugars at carbon 6,
and is a marker for the degree of malabsorption of or and fructokinase, which occurs predominantly in the
intolerance to various carbohydrates. In humans, fruc- liver and phosphorylates at carbon I (Fig. 1). Glucose
tose given alone or in excess of glucose resulted in inhibits the phosphorylation of fructose by hexokinase.
greater breath hydrogen than an equal amount of glu- In the brain, hexokinase has 20-fold the affinity for glu-
cose alone, fructose with an equal amount of glucose, cose it has for fructose. Fructokinase can also catalyze
or sucrose, indicating that fructose was not absorbed as the phosphorylation of other ketoses, including galacto-
completely as glucose or sucrose (6). Sorbitol may ag-
gravate this malabsorption (7). Consumption of exces-
sive amounts of fruits and/or juices containing fructose H /O\
- OH HO-C
has been proposed as a cause of chronic diarrhea in H 0-C-

some children (8). In humans, a small amount of fruc- FRUCTOJCINA5I

tose is converted into glucose or lactate within the epi-

thelial cell. Alp ADP

After transport into the epithelial cell, fructose Q-D- P! U C lOS #{163} a-D-F RUC lOSE-I - PH OS PH AT!

diffuses to the serosal side. The majority of the fructose 2 UCTOS!-

enters the portal blood and is transported to the liver I-PHOSPHATE

for metabolism. Increasing the amount of fructose in

the diets of baboons and rats causes an increase in the
rate of intestinal fructose transport (5). To understand
the mechanism of improvement in athletic performance C-H H-C-O-P O

reported with carbohydrate-loading, a number of studies I

H-C-OH
I
C0
involving exercise have examined differential gastric
N-C-OH N-C-OH
emptying and absorption rates of various carbohydrates. u H
There is controversy as to whether gastric emptying 5.OITC!RALOIHTDI DIHYDNOXYACETON!

rate is dependent on the osmolality of stomach contents PH OSP H A T #{163}

or whether gastric emptying is controlled by a feedback Figure 1. Initial steps in the metabolism of fructose. 1. Phospho-
mechanism dependent on the number of calories deliv- rylation of cs-D-fructose to a-D-fructose-l-phosphate. 2. Cleavage of
ered to the duodenum. In a study of endurance-trained cs-D-fructose-l-phosphate to D-glyceraldehyde and dihydroxyace-
athletes, gastric emptying rates of 400 ml of various tone phosphate.

2654 Vol. 4 June 1990 The FASEB Journal H AL LFRISC H

heptulose, sorbose, tagatose, and xylulose. Increasing
the amount of fructose in the diets of rats and humans
F,uC,0sH1PhOSOldt
results in increases in the activity of fructokinase.
F,ococc-1-Pho,pl,eu
Fructose-i-phosphate, which accumulates rapidly in the GIyc,,iddhyd .-, AkjoI,,H

liver, is then cleaved to dihydroxyacetone phosphate

and glyceraldehyde by fructose-I-phosphate aldolase GIoconeogen,i ,nd/o, Gycog., Synch.,,, Lipid Syn,h,HH

(Fig. 1). The deficiency of this enzyme (fructose-i- 6 D.PhOH4*IHIHiIP4OSP\1 Ohyd,o:mc,,oc,

phosphate aldolase) results in the most serious of the in- F,ccc,H-6-PhoSpheu \ Phowhido

born errors of metabolism involving fructose, which is GIoco,,-6-PhoSphi, Gyce,Idhyd,-3- PhoWhHH 3-Phowho9Iyc’Ht
hereditary fructose intolerance. This defect is charac- 2 Pho,phogIyco,e
terized in children by nausea after consuming fructose-
__
Ghico GIuco,e-1-PhOSple T,55e
f Pt,o,phoenOIpy,uvatt
containing foods, usually noted after weaning. It can GIvcogn F.m..d
5ynhOSiS
Acidyl oA .±rat.tc
Co,dd,ons
Anob.c
Py,uva#{248}
Condt,ons
-
Laclic Acid
result in growth retardation, liver damage, and even
death. Accumulation of fructose-i-phosphate causes
depletion of ATP and inorganic phosphorus and in- Figure 3. Possible metabolic paths of dihydroxyacetone phosphate.
creases degradation of nucleotides to uric acid (11).
Phosphorus is not available to rephosphorylate ADP.
AMP deaminase activity is stimulated by low levels of phate aldolase. The two trioses formed by the cleavage
phosphorus, resulting in greater degradation of AMP of fructose-i-phosphate can each follow three paths
to uric acid (Fig. 2). (Fig. 3 and Fig. 4). 1) Dihydroxyacetone phosphate
Increasing the amount of fructose in the diets of hu- can be isomerized to glyceraldehyde phosphate and
mans and rats increases the activity of fructose-i-phos- continue through the glycolytic pathway to ultimately
yield pyruvate, which is converted to either lactic acid
under anaerobic conditions or enters the citric acid cycle
as acetyl coenzyme A under aerobic conditions (Fig. 3).
OH OH H O
I I I The acetyl coenzyme A can then either produce energy
HCU H-C--O--P-O
0 I via the respiratory chain or be used as the substrate for
0
H ‘40 fatty acid synthesis. 2) Dihydroxyacetone phosphate
OH
HO H
may be reduced to glycerol-3-phosphate and provide
FRUCTOSE. I - P$40$PHATE the glycerol backbone of synthesized triacyiglycerols,
Aop
ADENVt.ATE KINA$E
phospholipids, and other lipids. 3) Dihydroxyacetone
phosphate may also be condensed with glyceraldehyde-
3-phosphate by aldolase to form fructose-I,6-diphos-
phate, and ultimately glucose or glycogen (the storage
NUCLEOTIDASE form of carbohydrate in the body). Forster (12) has
measured glycogen storage in rats infused with glucose,
fructose, xylitol, and sorbitol. Glycogen deposition was
greater in animals infused with fructose and the two
sugar alcohols, xylitol and sorbitol, than in those in-
0-I fused with glucose. Glycogen synthesis is impaired in
diabetics either because glycogen synthase activity is
inhibited or hepatic glucose uptake and/or glucose
phosphorylation are impaired. Because fructose phos-
phorylation does not require hexokinase, it may over-
come the impairment of glycogen synthesis in diabetics.
Glycogen synthesis was measured in isolated rat hepat-
ocytes from diabetic and normal rats incubated in solu-
tions containing fructose and/or glucose (13). The pres-
ence of fructose stimulated glycogen synthesis enzymes
in both normal and diabetic rats, whereas glucose alone
failed to increase either the enzymes or glycogen ac-
cumulation in hepatocytes from diabetic rats. The com-
bination of the two sugars produced a synergistic in-
crease in glycogen accumulation in hepatocytes from
both normal and diabetic rats. However, studies in-
X*MTHINS
volving isolated hepatocytes may be hard to assess, be-
OXIDASE
cause metabolism of fructose is not homogeneous
Ii
throughout the liver (14). Gluconeogenesis from fruc-
URIC Ado tose was reported to be much greater in hepatocytes iso-
Figure 2. Nucleotide degradation resulting from fructose lated from around the portal vein than in those from
catabolism. the pericentral regions of the liver lobule (14).

METABOLIC EFFECTS OF DIETARY FRUCTOSE 2655

 level of fructose-2,6-bisphosphate. This lowered level of
F,uctos.- T-Phospha,
fructose-2,6-bisphosphate stimulates fructose-i,6-diphos-
Dhydrocyace,one Phospha,e phatase, which favors the conversion of fructose-I,6-
Gluconeogeness and/or Glycogen Synthesis
diphosphate to fructose-6-phosphate, an intermediate
2 Phonphogtyc,,ar, .-
Trok,naSe Aldehyde
GIvce,a’e .-.--
- #{176}
I
- #{176}“ Tnokinase
-. GIyceaIdehydo-3Phosghat, of gluconeogenesis. In contrast, an increase in fructose-
Delryd,ogenan, - #{176}“
2,6-bisphosphate stimulates 6-phosphofructo-i-kinase,
Glycolysis D-glyc,raldehod, Glycolysis
which converts fructose-6-phosphate to fructose-i,6-
I
j
Alcohol 0,hvd,ogenase
Aldoso
diphosphate, which favors glycolysis. Fructose-2 ,6-
Gly1ero: bisphosphate has been studied in the liver, muscle, in-
testine, and pancreas of mice and rats, as well as in
Triglyceodes .,__Glyoerol 3p0$py,,0__#{149}OIhrldrOsCOtOflO
Phosphate yeasts. The effect that dietary fructose has on levels of
fructose-2,6 bisphosphate has not been studied, and
many details concerning its role need to be investigated
Figure 4. Possible metabolic paths of D-glyceraldehyde.
further.

The glyceraldehyde formed from the cleavage of METABOLIC EFFECTS OF DIETARY FRUCTOSE
fructose-i-phosphate also has three possible metabolic ON RISK FACTORS FOR DISEASE
routes (Fig. 4). 1) It can be phosphorylated by triose-
kinase found in the livers of rats, cattle, and guinea In evaluating human nutrition studies, it is important
pigs. This enzyme increases in animals fed fructose and to examine the actual comparisons being made. Re-
may be specific for its metabolism. Phosphorylated sponses to a single dose of fructose may be much differ-
glyceraldehyde can continue through glycolysis or be ent from responses to a meal containing fructose or to
a chronic diet containing added fructose. Since in-
used for gluconeogenesis or glycogen storage. 2) Glyc-
eraldehyde may be converted to glycerate and then dividual differences are usually the greatest source of
enter glycolysis after phosphorylation to 2-phospho- variation, the crossover design in which each subject
glycerate. Glycerate accumulates in the liver after fruc- consumes a controlled weight-maintaining diet in
tose infusion. 3) Glyceraldehyde formed from fructose
which one single nutrient is altered during different
may also be reduced to glycerol by alcohol dehydroge- periods is the most powerful design in which to evaluate
nase or aldose reductase. Glycerol may be phosphoryl- effects of that single nutrient. Unfortunately, these ex-
ated and form a component of triacylglycerols and periments are both expensive and confining for the sub-
other lipid compounds or be converted to dihydroxy- jects. Usually subjects are given diet counseling, a few
acetone phosphate. More fructose is converted to lipids days of diet records are collected, blood is drawn,
than is glucose. Rats fed 66% of their diet as fructose weights taken, a supplement may be distributed, and
were more hypertriglyceridemic than rats fed 66% glu- then measurements are taken again at the end of the
cose or laboratory chow for i wk (15). Conversion of study. Often there is no control group. Changes or lack
fructose and glucose to lipids was also measured in iso- of changes are then attributed to the supplement, when
lated human fibroblasts (16). Incubation with 27.5 mM in fact they could be due to changes in weight, changes
fructose resulted in incorporation of twice the amount in overall composition of the diet due to the addition of
of lipids as incubation with 27.5 mM glucose. the supplement, differences in compliance, or a multi-
tude of other changes that cannot be assessed. Recent
studies discussed here used a variety of designs, varying
CONTROL OF FRUCTOSE METABOLISM amounts of fructose, a wide range in the length of treat-
ment periods, and compared fructose to no added fruc-
A recently discovered form of fructose (fructose-2,6- tose, other sugars, or complex carbohydrates.
bisphosphate) may serve as an important regulator of
carbohydrate metabolism in the liver (i7). The synthesis GLUCOSE TOLERANCE AND INSULIN
and degradation of fructose-2,6-bisphosphate are cata- RESPONSES
lyzed by a single enzyme complex (6-phosphofructo-2-
kinase/fructose-2,6-bisphosphatase). As in many other Owing to the lower acute glucose and insulin responses
systems, control is achieved by phosphorylation or de- to fructose compared with other sugars, it has been sug-
phosphorylation of the enzyme complex, so that when gested as a replacement for sucrose or glucose for dia-
energy is needed, carbohydrates are metabolized via betics (18, 19) and obese people (20). For juvenile or
glycolysis, but under anabolic conditions, gluconeogen- insulin-dependent diabetes (type i) whose pancreases
esis predominates. The level of fructose-2,6-bisphosphate produce no insulin, glucose cannot be transported into
appears to affect the activities of two important regula- muscle and other tissues to be used for energy, and glu-
tory enzymes controlling carbohydrate catabolism and cose accumulates in blood unless exogenous insulin is
anabolism in the liver (6-phosphofructo-i-kinase and injected. Very high circulating levels of glucose are
fructose-I,6-diphosphatase). The amount of this fruc- responsible for the vascular deterioration that can
tose compound is regulated by the enzyme complex. result in blindness, neurological damage, and infections
Cyclic AMP stimulates fructose-2 ,6-bisphosphatase, leading to amputations that often occur in diabetics.
which then forms fructose-6-phosphate, lowering the For onset of maturity or non-insulin-dependent diabetes

2656 Vol. 4 June 1990 The FASEB journal HALLFRISCH

(type 2), which usually occurs after age 40, although in- not reported, so it is difficult to explain the changes, es-
sulin is produced, the amount is either insufficient or is pecially the worsening of glucose control in the control
not effective in removing glucose from the circulating group whose treatment was supposedly unchanged.
blood for use in muscle and other tissues because there Anderson et al. (27) examined effects of long-term
is an insufficient number of receptors or receptors are fructose supplementation in i4 type 2 diabetics. The
defective. Plasma glucose does not increase as much men were consuming a self-selected diet upon entry to
after an acute oral dose of fructose alone as after an the hospital for 5 days, followed by a 7-day controlled
equal amount of glucose. Therefore, since strict control diet period when 50-60 g fructose was added to a high-
of hyperglycemia (that is, using insulin, glucose-lowering fiber, low-fat diet. At home they continued to supple-
oral drugs, and diet to maintain blood glucose below ment their usual diets with fructose for 23 wk, then re-
those high levels that damage tissues) may be a primary sumed their usual diets for 16 wk without added fruc-
factor in delay or prevention of the consequences of tose. After the hospital stay, measurements were taken
end-stage diabetes, fructose is considered by some to be every 4 wk. Diet was controlled only during the hospital
a preferable replacement for other sugars. stay of 12 days. During the self-selected fructose period,
Fructose alone is much less insulinogenic than are fat intake was significantly lower and simple carbohy-
comparable amounts of glucose or sucrose. However, in drates significantly greater than baseline control periods
12 insulin-dependent diabetics given fructose alone, based on averages of 14.7 vs. 4.2 diet records. Adher-
glucose alone, and fructose with glucose, the glycemic ence to diet varied widely based on evaluation of diet
response (that is, the elevation in blood glucose after an records. Body weight was lowest at 175 lb during the
oral dose of sugar) to fructose given with glucose (as it hospital control period and increased through the fruc-
occurs in high fructose corn sweeteners) was no different tose period to 183 lb (final weight at wk 48 182 lb), =

than the response to glucose alone (21). In 24 normal even though patients reported consuming an average of
men and women, fructose consumed when plasma glu- 1669 kcal during the fructose period and only 1421 kcal
cose was elevated (such as would occur during a meal) during the postcontrol period. Fasting plasma glucose
stimulated insulin secretion 60-288% above basal was significantly lower after the 7-day hospital con-
levels (22). Effects of an acute dose of fructose may vary trolled fructose period than after the 5-day hospital con-
from those that occur after dietary adaptation; that is, trol period (138 vs. i68 mg/dl). No other glucose values
a period of chronic consumption (at least 2-3 wk) of were different although the highest values (216 and 214
higher levels of fructose in the diet. During dietary mg/dl) occurred during self-selected fructose period.
adaptation, enzyme and hormone responses adjust to Glycosylated hemoglobin was not affected.
the chronic diet. Reiser (23) reviewed previous studies Bantle (i8), in an evaluation of some recent fructose
in which fructose was consumed. studies, reported fasting glucose and glucose responses
Although results are not uniform, some recent studies after meals of type 1 diabetics to be significantly lower
have reported increases in insulin and glucose responses when they consumed 21% of calories as fructose for 8
to a glycemic stress after dietary adaptation to fructose. days than when they consumed 23% of calories as su-
In rats fed 35% of calories as glucose or fructose for crose or almost all carbohydrates as starch. Fasting glu-
4 wk, fructose feeding resulted in impaired insulin ac- cose levels in 12 type 2 diabetics on the same regimens
tion in the liver and peripheral tissues (24). In 10 hyper- were not different, but glucose responses after meals
insulinemic and 11 normoinsulinemic men fed a weight- were higher after the sucrose and starch diets. Dietary
maintaining controlled diet with 20% of calories as fructose may be less effective for maintenance of blood
fructose or a high-amylose cornstarch in a crossover de- glucose and control of insulin secretion than more
sign, insulin binding to erythrocytes was decreased complex carbohydrates in normal subjects, but it is
after fructose only in hyperinsulinemic men. However, controversial whether it is detrimental to glucose con-
although fasting glucose levels were higher when men trol of diabetics when used in limited amounts as a
consumed fructose, responses of glucose and insulin to specific replacement for sucrose or glucose. For type 1
meals containing fructose or starch, were, if anything, or insulin-dependent diabetics, where strict glucose
lower after a fructose meal than a starch meal (25). Osei control is crucial, fructose replacement of glucose-
et al. (26) compared two groups of type 2 diabetics in containing sugars may be a useful tool; however, in
an outpatient study. The fructose group (7F, 2M) was type 2 diabetics, 70-90% of whom are obese, weight
given 60 g fructose to be added to their usual self- reduction should be the first priority, with restriction of
selected diets for 12 wk. The control group (8F, iM) any unnecessary empty calories. In a mixed diet, added
was matched for age, duration of diabetes, percentage fructose apparently offers little or no advantage in glu-
of ideal body weight, fasting serum glucose, and gly- cose control over other sugars, but is generally worse
cosylated hemoglobin. Seven patients in each group than starch.
received insulin twice daily. The fructose group was
counseled to remove all sources of sucrose from their BLOOD LIPIDS
diets. The control group was allowed noncaloric sweet-
eners. Measurements were reported at baseline, 4 wk, Although fructose may offer an advantage for glucose
and 12 wk. Glucose and glycosylated hemoglobin de- control in type i diabetic subjects, there is substantial
clined in the fructose group and increased in the con- evidence that it has adverse effects on the levels of
trol group. Daily food records kept by the subjects were plasma lipids. Elevated plasma cholesterol is a well-

METABOLIC EFFECTS OF DIETARY FRUCTOSE 2657

 accepted risk factor for coronary disease in middle- Although effects of fructose-containing diets on
aged men (28). Although an elevation in plasma tri- plasma triglycerides are often substantial, the reported
glyceride level is not as well accepted, some consider it effects on plasma cholesterol in response to fructose in
to increase coronary disease risk, especially in women the diet are not clear-cut. The increase in the synthesis
(29). Many studies, both of animals and humans, have of VLDL, which contains 10-20% cholesterol, to trans-
reported increases in triglycerides after consumption of port triglycerides produced in the liver may be a cause
diets with fructose compared with complex carbohy- of the increase in plasma cholesterol after dietary fruc-
drates and other sugars (30). Consumption of fructose tose consumption reported in a few studies. Another
favors synthesis of fat over gluconeogenesis. This is the mechanism by which fructose could increase plasma
result of increased hepatic synthesis of glycerol and cholesterol is by interaction between fructose and cop-
fatty acids compared with glucose (1.4- to 18.9-fold per. Animal (33) and human (34) studies report that
greater), as shown in numerous rat studies. Adaptation diets containing fructose aggravate copper deficiency,
to a diet containing fructose results in increased activi- which results in hypercholesterolemia and may be re-
ties of lipogenic liver enzymes. The increased synthesis lated to coronary disease (35). The hypercholesterole-
of lipids results in higher levels of circulating total and mia of copper deficiency is not well understood, but
very low density lipoprotein (VLDL) triglycerides. Of may result from reduced lecithin:cholesterol acyl trans-
the 33 animal studies reviewed by Reiser (30), 26 re- ferase and lipoprotein lipase activities found in copper-
ported higher triglyceride levels after fructose consump- deficient animals. Reiser (30) found only 2 of 14 animal
tion. In humans, some groups are more susceptible than studies to report increases in plasma cholesterol after
others to hypertriglyceridemia that follows fructose con- fructose diets. In humans, there are mixed effects on
sumption. Postmenopausal women, hyperinsulinemic plasma cholesterol levels. Of nine human studies re-
men, and type 2 diabetics are more likely to become viewed (30), cholesterol increased in only two. Choles-
hypertriglyceridemic after fructose consumption than terol increased in normal and hyperinsulinemic men
normoinsulinemic and nondiabetic men and young after consuming as little as 7.5% of total kilocalories as
women (30). Other dietary components such as fructose and in hypertriglyceridemic men consuming
amount and type of fat and fiber may also influence the 300 g/day for 2-4 wk (a huge amount); but there were
lipid response. There is a synergistic effect between fat no differences in four studies involving young men and
and fructose that results in slower clearance and greater women, older women, hypertriglyceridemic subjects,
postprandial hypertriglyceridemia when both are fed and type 2 diabetics. In three studies, dietary fructose
(31). A recent crossover study in which fructose re- resulted in decreases in cholesterol. In one of these
placed starch in a controlled typical American diet for studies in which ‘cholesterol declined, subjects con-
5 wk reported increased triglycerides in hyperinsulin- sumed fructose for only 4 days, and the other two com-
emic and normal men (32). Addition of 60 g fructose pared sucrose and fructose, finding lower cholesterol
to the usual self-selected diets of type 2 diabetics for levels after fructose consumption than after sucrose
12 wk did not adversely affect triglycerides; however, consumption. A study comparing two groups of type 2
the control group initially had triglyceride levels 50% diabetics found no increase in cholesterol after addition
higher than the fructose group, and control triglyceride of fructose to self-selected diets (26), but replacement of
levels increased an average of 96 mg/dl during the 12 high-amylose cornstarch with fructose in a controlled
wk of a supposedly consistent diet (26). Bantle (i8) crossover study (32) raised total and VLDL cholesterol
compared replacement of 21 or 23% of total kcal of in hyperinsulinemic men as well as total and low-
complex carbohyodrate with fructose or sucrose for density lipoprotein cholesterol in normal men. Ander-
8 days in type 1 and type 2 diabetics. There were no son et al. (27) found no significant changes in choles-
significant differences in triglycerides, although in terol levels of type 2 diabetics during fructose supple-
type 2 diabetics the highest level of fasting and post- mentation of self-selected high-fiber, low-fat diets.
prandial triglycerides (234 and 308 mg/dl) occurred Lowest values occurred after a 7-day controlled hospital
after consumption of fructose and the lowest (212 and diet supplemented with fructose, but this might be at-
277 mg/dl) occurred after starch consumption. Sucrose tributed to lower fat intake or weight loss during this
values were intermediate. There were no significant period. The predominant effect of dietary fructose on
differences in type 1 diabetics, but levels after the con- blood lipids is on triglycerides, but when replacing
sumption of starch were again lowest; triglyceride levels complex carbohydrates, it may cause elevations in cho-
after sucrose consumption were highest, and levels after lesterol as well.
fructose consumption were intermediate (18). In another
study of type 2 diabetics in which high-fiber, low-fat URIC ACID
diets were supplemented with fructose (27), there was
no significant increase in triglycerides; however, tri- Elevated plasma uric acid may also be a risk factor in
glycerides varied from 193 mg/dl after 1 wk of hospital- coronary disease and hypertension (36). A number of
controlled fructose supplementation when patients ap- studies reviewed by Reiser (37) reported elevations in
peared to be losing weight, to 361 mg/dl after 16 wk of plasma uric acid after dietary consumption of fructose.
self-selected diet plus fructose supplementation when Hypertensive patients are more susceptible to eleva-
patients gained weight. tions in uric acid after fructose than normotensive con-

2658 Vol. 4 June 1990 The FASEB Journal HALL FRISCH

trol subjects. Approximately 25% of hypertensive sub- acute conditions replacement of other sugars such as
jects are reported to have elevated uric acid levels. Uric sucrose or glucose with fructose may result in better
acid responses after an infusion of fructose were greater glucose and insulin control in type 1 diabetics, there are
in hypertensive men than in control subjects. The a number of deleterious effects that occur after dietary
hyperuricemia produced after fructose consumption adaptation to diets containing substantial amounts of
could result from increased catabolism of nucleotides, fructose, and certain segments of the population that
as shown in Fig. 2, or increased de novo synthesis of are more susceptible to these effects. Diets that contain
purines. There is evidence for both theories. A number fructose in excess of glucose may be malabsorbed by
of fructose infusion studies have resulted in rapid in- substantial numbers of people and may cause diarrhea.
creases in uric acid levels in the blood and urine of chil- Not enough research has been done to determine the
dren, normal men, diabetics, and hypertensive and effects of fructose on glycogen deposition in athletes or
normotensive subjects (38). Nucleotide content of liver to determine whether it may provide a better source of
biopsies decreases after fructose infusion, but not after carbohydrate under endurance exercise conditions than
glucose infusion. Increased radioactive glycine incorpo- other sugars or polysaccharides. Although fructose
ration into urinary urate after fructose infusion indi- alone is less insulinogenic and glucogenic than equal
cates increased purine synthesis (39). There are few amounts of glucose or sucrose, when consumed with
studies reporting uric acid levels after feeding dietary glucose and after dietary adaptation to a mixed diet
fructose, but a number of studies have reported in- containing fructose, these responses usually are not
creases after sucrose diets compared with glucose or different from responses after dietary adaptation to
starch in men and obese subjects, suggesting that it other sugars, or are greater than after dietary adapta-
may be the fructose moiety of sucrose that is responsi- tion to complex carbohydrate diets. Insulin sensitivity
ble for the increase (37). A recent crossover study (32) may be impaired before changes in fasting glucose or
reported elevated uric acid responses to a meal after insulin are altered. Therefore, fructose may be con-
adaptation to a fructose-containing diet compared with sidered no worse than other sugars, but also no better.
the same diet replaced with starch. Uric acid levels With regard to blood lipids, there is overwhelming evi-
were not significantly affected by supplementing self- dence that fructose increases plasma triglycerides.
selected diets in two separate studies involving type 2 Under some conditions, dietary fructose may cause in-
diabetics (26, 27). creases in plasma cholesterol. Other risk factors that
may be increased in some people include uric acid and
lactic acid. Although it is virtually impossible and cer-
LACTIC ACID
tainly undesirable to consume a fructose-free diet, as
Lactic acid is produced as a result of anaerobic glycoly- fructose is a component of many fruits and vegetables,
sis in most mammalian tissues. Extreme elevations cause there is little evidence, except possibly for type I dia-
metabolic acidosis and can result in death (11). Many betes, that in a mixed diet added fructose provides any
studies have shown that more lactate is formed from advantage over other sugars. In patients with hyperten-
fructose than from glucose (37). This increased lactate sion, obesity, hyperlipidemia, and gout, it may be dis-
production occurs because fructokinase activity is in- advantageous to replace other sugars with fructose.5j
creased, the rate-limiting step for glycolysis (phospho-
fructokinase) is bypassed, and pyruvate kinase activity I would like to thank Dr. Sheldon Reiser for his patience and ad-
is stimulated by the accumulation of fructose-I-phosphate. vice on the preparation of this manuscript, and Drs. Reubin
Andres, Richard Pratley, and John Sorkin for reviewing it.
Fructose infusions in humans have resulted in danger-
ous increases in blood lactic acid, especially in patients
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2660 Vol. 4 June 1990 The FASEB Journal HA LL FRISC H