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High-Fructose Corn Syrup
Tammy Morey
Metropolitan State University of Denver
February 18, 2014
Abstract
High-fructose corn syrup is a liquid sweetener that is a combination of fructose and
glucose; it is used as an alternative to sucrose. The food and beverage industry was first
introduced to high-fructose corn syrup in the early 1970s. Now high-fructose corn syrup is found
in many foods and beverages, because it costs much less to produce than sucrose and it is easier
to transport since it is a liquid. High-fructose corn syrup has also been the source of much
controversy in regards to its role in the growing obesity epidemic as well as being linked to the
cause of several other diseases. For instance, some studies have shown that there may be a link
between the consumption of high-fructose corn syrup and the growing epidemic of metabolic
syndrome and cognitive decline. Other studies suggest that high-fructose corn syrup may play a
role in the development of renal kidney disease due to increased uric acid production. This paper
will provide a brief history of high-fructose corn syrup and how it is similar to sucrose in
structure. In addition it will also briefly review fructose and how it is metabolized in comparison
to glucose. Finally, the paper will discuss the role high-fructose corn syrup plays in renal kidney
disease and what effects it has on cognitive decline as a result of metabolic syndrome.
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High-Fructose Corn Syrup
High-fructose corn syrup (HFCS) is a food additive used to sweeten soft drinks, fruit
juices, bakery goods, cereals and processed foods. It was first introduced to the food and
beverage industry in the 1970s as a liquid alternative to sucrose (table sugar) because they have a
very similar chemical structure.1 Both are a combination of fructose and glucose. HFCS was
widely accepted by the food and beverage industry because it was much cheaper to produce than
sucrose, the sweetness was similar to sucrose, it had an improved stability and functionality, and
it was easier to use. 1, 3, 4
Fructose is one of the main carbohydrates in HFCS so this paper will look at how it is
metabolized in comparison to glucose. In the 1980s there was some speculation that HFCS might
be linked to several metabolic disorders associated with the rise of obesity in the United States. 1,
2, 3
One such disease is metabolic syndrome, which is often related to obesity. Studies are
currently underway to look at how HFCS contributes to metabolic syndrome and cognitive
decline. 2, 3 Additional studies are also being done to determine what affect HFCS has on renal
kidney disease. There is evidence that added sugars that contain fructose, such as high-fructose
corn syrup and sucrose, may increase the production of uric acid which has shown to have
serious affects on renal kidney disease. 2, 3
History and Invention of HFCS
HFCS is derived from a process of enzyme immobilization known as glucose isomerase.
6, 10
The process for glucose isomerase was first discovered when two scientists named Marshall
and Kooi first discovered a D-glucose isomerizing enzyme from pseudomonas hydrophila in
1957.6, 10 However, in order to produce the enzyme it had to be fermented with a substance that
contained both xylose and an isomerization reaction that was enhanced with arsenate. 6 But it
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was the work of two scientists in Japan named Tsumura and Sato who discovered a way to use
xylose isomerase to isomerize D-glucose into D-fructose without the use of arsenate or NAD+25.6
Their process that was later patented in 1967 is the most common method now used to make
HFCS.6, 10
The process to make HFCS was put into production because at the time there was a
shortage of sucrose, partially due to the Cuban revolution in 1958.6 The United States was
introduced to the process of manufacturing HFCS sometime around the late 1960s to early
1970s.1, 2, 3, 6, 10 When the prices of sucrose began to increase sharply the food and beverage
industry began producing HFCS as an alternative sweetener for use in soft drinks, baked goods
and other processed foods. 1,2,3,6, 10 HFCS was a good alternative to sucrose for several reasons.
First it was made from corn which was plentiful and could be grown almost anywhere. Unlike
sucrose which is generally derived from sugar cane which is grown in regions close to the
equator and are often times subject to an unstable climate and political changes, that cause prices
to increase.1,8, 10 Secondly, HFCS was a more stable product in acidic foods unlike sucrose which
had a tendency to undergo chemical alterations in acidic conditions.1,6 Another reason HFCS
was considered to be a good alternative to sucrose is that the 55% level of fructose makes it
slightly sweeter than sucrose on a calorie basis.6 And it has the lowest glycemic index compared
to other simple sugars.6 Lastly, HFCS was a good product for the food and beverage industry
because it is a syrup and it can be pumped directly from delivery trucks into storage and mixing
tanks making it much easier to use.1
There are several different types of HFCS and each have a different amount of fructose
depending on the type of food it is used in. HFCS 55 has 55% fructose and 42% glucose and is
found primarily in soft drinks and ice cream.3, 6, 7 HFCS 42 has 42% fructose and 55% glucose
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and is used primarily in baked goods, dairy products, candy, and breakfast cereals.6 HFCS 90 is
not a very common form of high-fructose corn syrup. But it is found in natural foods and light
foods and it is also used for the production of HFCS 55 and HFCS 42. 6 In the 1970s HFCS 42
became the dominate sweetener used because it had sweetness level that was comparable to
sucrose and because of improved technology it became much more cost effective to produce. 6
As technology advanced even further in the United States beverage companies like Coca Cola
and Pepsi used HFCS 55 almost exclusively instead of sugar in their soft drinks.6, 9
HFCS was a relatively unknown ingredient until around 1984 when it came under
suspicion as having a possible link to the rising rate of obesity in the United States.1, 2, 3, 6,8
Before 1984 many believed that HFCS was a harmless ingredient that did not pose any
significant health risks. 1 Like sucrose, it is composed of almost equal amounts of fructose and
glucose, and many believed it would be metabolized much the same way that sucrose is
metabolized. The main difference between sucrose and HFCS is that about 3% of high-fructose
corn syrup is made up of an additional carbohydrate which is usually maltose or maltotriose. 1, 8
The other difference is that occasionally HFCS has a higher amount of fructose than what is
found in sucrose for example in HFCS 90. Which contains 90% fructose and about 7% glucose
but HFCS 90 only makes up about 5% of the market production of HFCS. 6
Fructose Metabolism
Fructose is a monosaccharide that is found naturally in many fruits and vegetables,
honey, agave syrup, sucrose, and HFCS. Fructose is an isomer of glucose and can be used as fuel
for the body. However; fructose metabolism differs from that of glucose as far as digestion and
absorption are concerned. When it comes to the level of triose-phosphates, metabolism of
fructose and glucose converge and both sugars are used in glycolosis.11,13, 16 One of the major
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differences between glucose and fructose is that glucose begins digestion in the mouth when it is
first broken down by the salivary enzyme amylase.1 Fructose is first digested in the gastro
intestinal tract by enzymes secreted in the small intestine.1 Another major difference between the
two sugars is that glucose requires the use of insulin sensitive transporters to enter the blood
stream while fructose is not insulin sensitive.1, 2, 3, 4, 5, 11, 12, 13
The receptors for glucose are Glut2 and Glut4 and they both require the presence of
insulin in the blood to be activated to go and pick up glucose.11 Glut2 is used to carry glucose to
the brain and into the first step of glycolysis, and Glut4 is used to carry glucose into the
muscles.11 Fructose is taken up by Glut5 transporters that are not insulin sensitive so they do not
require the use of insulin to become activated.11 Because fructose is not insulin sensitive it does
not raise a person’s glycemic index, but the ingestion of glucose will raise ones glycemic index
because it is insulin sensitive.1, 2, 4, 5 Like glucose; fructose is used in glycolysis and it is
transported into the cycle by Glut5.11 But unlike glucose, fructose is phosphorolated without the
use of insulin so it skips the first three steps of glycolysis.11 Once fructose and glucose are in the
glycogenic pathway they can both be metabolized into glycogen and stored in the liver for later
use in the production of glucose.11
In the digestive process, glucose and fructose are also absorbed into the liver differently.
For instance, fructose is quickly absorbed into the liver from the small intestines via the hepatic
portal vein. The liver is also the only organ that contains Glut5 receptors, so when fructose is
ingested almost the entire amount of fructose is taken up by the liver.11 Whereas receptors for
glucose are found in many areas of the body so it is not always absorbed into the liver directly
from the small intestine.11 Glucose travels through the blood stream where it can first be taken up
by organs and tissues that need it to replenish energy supplies.11 When insulin sensors in the
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liver sense an over abundance of glucose in the blood, they activate liver receptor Glut2
transporters to go out and take up the extra glucose and return it to the liver.11
The metabolism of fructose and glucose in the liver consists of both similarities and
differences. Both glucose and fructose can be turned into glycogen and stored for later use when
concentrations of blood glucose are low.11 But the majority of fructose in the liver is converted to
triacylglceride, whereas the majority of glucose in the liver is converted to glycogen with the
help of insulin.11 Fructose does not get converted into glycogen directly unless the supply of
glycogen is depleted due to starvation or exercise.11 Instead fructose is generally phosphorylated
without insulin to fructose-1-phosphate by the enzyme fructokinase.11 Then fructose-1-phosphate
is metabolized into pryuvate during glycolysis and any extra fructose-1-phosphate is used for denovo lipogenesis (DNL) to produce triacylglyceride.11 If both fructose and glucose are received
by the liver at the same time, glucose will go into the glycogenic pathway and force fructose
down the lipogenic pathway.11 When this happens it triples the rate of DNL that occurs in the
presence of fructose alone.11 This can lead to very serious health problems because the
triacylglycerides formed by fructose metabolism have a tendency to accumulate in problematic
areas of the body.
The hepatic triacylglyceride formed by fructose then attaches to apolipoprotein B to be
converted into very low density lipoproteins (VLDL).11 These VLDL are then sent out of the
liver to contribute to fructose induced hypertriglyceridemia, and the production of sd-LDL (small
dense low density lipoproteins).11 Sd-LDL can be oxidized very quickly, and are small enough to
get under the surface of vascular endothelial cell00s and begin the process of foam cells.11
Sometimes the fat produced by fructose DNL escapes the packaging of VLDL transporters and
accumulates as lipid droplets in hepatic cells which may contribute to nonalcoholic fatty liver
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disease.11 Another place where fat formed by fructose tends to accumulate in is visceral adipose
tissue.11, 15, 17 Unlike fructose when there is an excess of glucose in the liver it is converted to free
fatty acid(FFA) and packed into VLDL vesicles which are then shipped out of the liver to be
stored in adipocytes.11
Another way that glucose metabolism differs from fructose metabolism is in the satiety
signals that are sent to the brain and hypothalamus after ingestion of fructose and glucose. When
glucose is ingested satiety signals are sent to the brain and hypothalamus via either leptin or
insulin hormones which tell the brain that the body is now in a fed state and the hunger signals
can be inhibited.2, 3, 11 However; fructose is insulin and leptin resistant, so satiety signals are not
sent to the brain or hypothalamus to inhibit hunger which may allow food intake to continue
above energy needs.2, 3, 5, 11
Role of HFCS in Renal Kidney Disease
When the rate of obesity began to rise at the same time as consumption of HFCS in the
United States, scientists and nutritionist became concerned that HFCS may be a contributing
factor to the obesity epidemic and the diseases related to obesity.1, 2, 3, 4, 5, 9, 10 One area of concern
is the effect of increased intake of fructose on kidney disease and renal function.4, 5, 10 Because
Americans are consuming more added sugars in the form of HFCS; the rate of fructose intake
has increased significantly in the past few decades which may be associated with an increase in
the number of kidney diseases and problems with renal function.4, 5 When fructose is consumed
it is absorbed in the small intestine by Glut5 and transported into the intestine enterocyte.4,5 From
there about 70% of the fructose is then picked up by Glut2 and taken to the liver.4,5 The other
30% gets into the systemic circulation where it can be picked up by other tissues such as the
kidneys.4, 5 The fructose that is circulating in the systemic circulation can either be picked up by
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endothelial cells or it can be excreted into the urine where Glut5 transporters absorb it into the
proximal tubule where it can be metabolized by fructokinase and possibly cause inflammation of
the tubule due to oxidative stress.4, 5
The fructose that is taken to the liver is then phosphorylated to fructose-1-phosphate by
the enzyme fructokinase. This process becomes a potential problem for the kidneys because there
is no negative feedback system to regulate the phosphorylation of fructose.4,5 So the reaction will
continue to run depleting the supply of ATP and phosphate; leading to the production of AMP
which then must be metabolized by AMP deaminase to become inosine monophosphate and
finally uric acid.4, 5 Studies have shown that the overproduction of uric acid can cause a rise in
blood pressure, increase the risk of metabolic syndrome, insulin resistance, and glomerular
hypertension.4, 5
Studies done on animals have shown that fructose promotes all of the symptoms related
to metabolic syndrome especially when it is given in high doses.3, 4, 5 However; there is some
evidence that even doses of fructose as low as 20% when combined with glucose, (as is the case
with HFCS or sucrose) has promoted metabolic syndrome.4,5 Because glucose speeds up the
absorption of fructose.4,5 Studies with rats have shown that fructose and sucrose cause renal
hypertrophy and tubulointerstitial disease.4, 5 And when fructose was given to rats with reduced
renal function it resulted in an accelerated progression of renal disease.4, 5
According to a paper written by Richard Johnson, Gabriela Sanchez-Lozada, and
Takahiko Nakagawa for the Journal of the American Society of Nephrology in 2010, there was
only one human study that examined the relationship between consuming beverages with added
sugar and renal disease.4 However; the “NHANES (National Health and Nutrition Examination
Survey) found that when two or more beverages containing sugars were consumed there was an
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increased risk of having albuminuria.”4 In a study done by Kretowicz et al, subjects with stable
chronic kidney disease were given a low-fructose diet for six weeks.4 The study did not show
any evidence of an effect on renal function but there was evidence of a reduction in
inflammatory markers and a drop in blood pressure in subjects whose blood pressure
spontaneously falls at night while they are sleeping.4 While there appears to be some evidence to
suggest that the increasing intake of fructose, due to the consumption of HFCS, may have a
negative effect on kidney disease and renal function. Further studies need to be done to
determine at what dose HFCS plays a contributing role in the development of renal inflammation
and chronic kidney disease due to metabolic syndrome.
Role of HFCS in Metabolic Syndrome and Cognitive Decline
As previously stated in this paper, there is growing evidence that the increasing
consumption of HFCS leads to an increased intake of fructose that has shown to play a role in the
development of symptoms leading to metabolic syndrome.2, 3, 4, 5, 13, 16, 18, 21 One of the symptoms
of metabolic syndrome is insulin resistance and there is strong evidence to suggest that insulin
resistance plays a role in cognitive1 decline and memory deficits.2, 3 Furthermore, studies show
that there is strong evidence that metabolic syndrome has a broad effect on mental health
disorders, cognitive function, mood changes and depression.2, 3
In recent studies done on animals, the consumption of HFCS has been shown to have
negative effects on lipid levels, insulin resistance, type 2 diabetes, and metabolic syndrome.2, 3
All of which has been shown to have an effect in cognitive decline along with a diet deficient in
omega-3 fatty acids.2, 3
Studies done on rats fed a diet supplemented with HFCS resulted in the rats becoming
more insulin resistant and cognitively impaired on spatial learning and ability tasks than rats that
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were not supplemented with HFCS.2, 3 A study was also done on middle-aged and older Puerto
Rican men without diabetes to determine the effect of HFCS sweetened beverages or foods at
normal intakes had on cognitive function.3 The participants were given seven tests known as
MMSE to measure their general cognitive function, then they were given foods, soft drinks, fruit
juice, and dairy desserts with added sugars at about 21% energy intake.3 The MMSE test were
given again and the results showed that the consumption of HFCS resulted in lower MMSE
scores.3 Which may indicate that the increased consumption of added sugars may have an
association with lower cognitive function in humans.3
Other studies done on humans were used to test how a diet deficient in omega-3 fatty
acids effected the development of insulin resistance.2, 3 They found that a diet deficient in
omega-3 fatty acids proved to be a contributing factor for insulin resistance and metabolic
syndrome which lead to reduced cognitive ability.2,3 However; when diets were supplemented
with omega-3 fatty acids there was an improvement in cognitive function, and insulin
sensitivity.2, 3 This study suggests that omega-3 fatty acids have a positive effect on cognitive
abilities and may have a role in preventing insulin resistance.2,3
Based on the recent studies involving human volunteers, there is now emerging evidence
that a diet deficient in omega-3 fatty acids with a high intake of fructose due to the consumption
of HFCS contributes to the development of metabolic syndrome which results in cognitive
decline.2,3 However; it is encouraging that there is also evidence that the harmful effects of
metabolic syndrome, brain metabolic abnormalities, and insulin resistance may be counteracted
or improved by the addition of omega-3 fatty acids.2, 3
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Conclusions
High-fructose corn syrup has been part of the American diet for over 30 years now and
until recently it was thought to be a fairly harmless ingredient with the exception of an increase
in dental cavities.1 However; the increasing rate of obesity prompted scientists and nutritionists
to take a closer look at the role HFCS may play in this growing epidemic. It is unclear whether or
not the obesity epidemic may be the result of consumption of excess calories or if there is a
correlation with HFCS. Due to the fact that the use of HFCS in the food and beverage industry
has been in decline since 2004, yet the obesity rate continues to rise suggests that it may be the
consumption of excess calories causing obesity. But there is strong evidence to suggest that the
consumption of HFCS leads to a higher intake of fructose which may be associated along with a
diet deficient in omega-3 fatty acids as a contributing factor in the increasing development of
metabolic syndrome and cognitive decline. But it is still unclear what the effects are of HFCS in
regards to kidney disease and renal function. Further studies need to be done to determine if the
consumption of HFCS resulting in higher intake of has a causal effect on kidney disease.
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