Nutrition & Metabolism BioMed Central

Review Open Access

Fructose, insulin resistance, and metabolic dyslipidemia
Heather Basciano, Lisa Federico and Khosrow Adeli*

Address: Clinical Biochemistry Division, Department of Laboratory Medicine and Pathobiology, Hospital for Sick Children, University of Toronto,
Toronto, Ontario, Canada
Email: Heather Basciano - [email protected]; Lisa Federico - [email protected]; Khosrow Adeli* - [email protected]
* Corresponding author

Published: 21 February 2005 Received: 15 February 2005

Accepted: 21 February 2005
Nutrition & Metabolism 2005, 2:5 doi:10.1186/1743-7075-2-5
This article is available from: http://www.nutritionandmetabolism.com/content/2/1/5
© 2005 Basciano et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract
Obesity and type 2 diabetes are occurring at epidemic rates in the United States and many parts of
the world. The "obesity epidemic" appears to have emerged largely from changes in our diet and
reduced physical activity. An important but not well-appreciated dietary change has been the
substantial increase in the amount of dietary fructose consumption from high intake of sucrose and
high fructose corn syrup, a common sweetener used in the food industry. A high flux of fructose
to the liver, the main organ capable of metabolizing this simple carbohydrate, perturbs glucose
metabolism and glucose uptake pathways, and leads to a significantly enhanced rate of de novo
lipogenesis and triglyceride (TG) synthesis, driven by the high flux of glycerol and acyl portions of
TG molecules from fructose catabolism. These metabolic disturbances appear to underlie the
induction of insulin resistance commonly observed with high fructose feeding in both humans and
animal models. Fructose-induced insulin resistant states are commonly characterized by a profound
metabolic dyslipidemia, which appears to result from hepatic and intestinal overproduction of
atherogenic lipoprotein particles. Thus, emerging evidence from recent epidemiological and
biochemical studies clearly suggests that the high dietary intake of fructose has rapidly become an
important causative factor in the development of the metabolic syndrome. There is an urgent need
for increased public awareness of the risks associated with high fructose consumption and greater
efforts should be made to curb the supplementation of packaged foods with high fructose additives.
The present review will discuss the trends in fructose consumption, the metabolic consequences
of increased fructose intake, and the molecular mechanisms leading to fructose-induced
lipogenesis, insulin resistance and metabolic dyslipidemia.

Emerging epidemic of the Metabolic Syndrome ring at epidemic rates in the United States [2-4] and devel-
The new millennium has witnessed the emergence of a oping countries including China [5] and India [6]. From
modern epidemic, the metabolic syndrome, with frightful 1935 to 1996, the prevalence of diagnosed type 2 diabetes
consequences to the health of humans worldwide. The climbed nearly 765% [7]. The global figures are predicted
metabolic syndrome, also referred to as "Diabesity" [1] to rise 46% from 150 million cases in 2000 to 221 million
describes the increasing incidence of diabetes in combina- in 2010 [8]. This epidemic of type 2 diabetes is compli-
tion with obesity as a result of changes in human behav- cated by the fact that it is a multi-factorial disease, fre-
iour, available nutrition, and the adoption of more quently associated with a cluster of pathologies including
sedentary lifestyles. Obesity and type 2 diabetes are occur- obesity, hypertriglyceridemia, impaired glucose tolerance,

Page 1 of 14
(page number not for citation purposes)
Nutrition & Metabolism 2005, 2:5 http://www.nutritionandmetabolism.com/content/2/1/5

and insulin resistance, collectively referred to as the meta- the epidemic of metabolic syndrome. In the past, physi-
bolic syndrome (formerly known as syndrome X and cians and scientists have made an association between
insulin resistance syndrome). Although there is no univer- dietary energy from fat and body fat. A large market has
sally accepted definition of the metabolic syndrome, most developed for the popularity and promotion of low fat
would agree that the syndrome includes a cluster of com- diets. Interestingly, however, the decline in dietary fat
mon pathologies: obesity, insulin resistance, dyslipi- consumption has not corresponded to a decrease in obes-
demia, and hypertension. It is present in 25–50% of the ity – in fact, the opposite trend has emerged [30]. Cer-
United States population [9]. There has been a heightened tainly, diets high in saturated fats have been shown to
awareness of the metabolic syndrome and a subsequent induce weight gain, insulin resistance, and hyperlipi-
increase in clinical attention directed towards prevention, demia in humans and animals [19-22,31], but the
due to its strong association with premature morbidity emphasis on fat reductions has had no significant benefits
and mortality [8,10]. In particular, these risk factors pre- relative to the obesity epidemic. More importantly, the
dispose the individual to greater risk for developing cardi- focus on dietary fat is more likely a distraction to more sig-
ovascular disease and Type 2 diabetes. Recently, the nificant causes of metabolic syndrome [30]. If fat is not
National Cholesterol Education Panel (NCEP) has offi- the culprit in metabolic disorders, then what is? Increas-
cially described and identified a number of these risk fac- ing evidence now suggests that the rise in consumption of
tors for cardiovascular diseases [11]. These include: 1) carbohydrates, particularly refined sugars high in fructose,
abdominal obesity, 2) elevated TG levels, 3) low high appears to be at least one very important contributing
density lipoprotein (HDL)-cholesterol levels, 4) increased factor.
blood pressure, and 5) impaired fasting glucose [12].
There is also now consensus that insulin resistance and Carbohydrates and the link to the Metabolic
obesity are actually part of one common pathologic Syndrome
mechanism of the metabolic syndrome [13,14]. Evidence The general increases in consumption of calories, and spe-
shows that the metabolic syndrome process begins early cifically of refined carbohydrates and fructose, is clear and
in life and persistence from childhood to adolescent/adult correlates positively with an alarming increases in meta-
life produces type 2 diabetes and cardiovascular disease bolic syndrome. Can these seemingly harmless nutrients
[15,16]. The symptoms of metabolic syndrome are not actually be directly associated with metabolic syndrome?
necessarily manifestations of age, but develop over a pre- Recent studies appear to support this link. In a 2004
disposed background established at a young age [17,18]. study, Gross et al examined nutrient consumption in the
This is a dangerous predisposition, with trends in modern United States between 1909 and 1997, and discovered
diet and habit likely influencing health and behaviour in there was a significant correlation in the prevalence of dia-
increasingly younger populations. betes with fat, carbohydrate, corn syrup, and total energy
intakes. Most striking was the fact that when total energy
The main driving forces for the increased prevalence of intake was accounted for, corn syrup was positively asso-
insulin resistance are modern Westernized diets and pat- ciated with type 2 diabetes, while protein and fat were not
terns of eating associated with the dramatic rises in obes- [32]. High fructose corn syrups (HFCS) are quite com-
ity. Insulin resistance is often linked to the macronutrient monly found in soft drinks and juice beverages, and are
content in the diet. In the past, diets high in saturated fats incorporated into many convenient pre-packaged foods,
have been shown to induce weight gain, insulin resist- such as breakfast cereals and baked goods. Fructose con-
ance, and hyperlipidemia in humans and animals [19- sumption has thus largely increased over the past few dec-
22]. Recent research suggests that a high intake of refined ades most likely as a result of this increased use of HFCS,
carbohydrates may also increase the risk of insulin resist- which contains between 55–90% fructose. The use of
ance [23-26]. In addition, diets specifically high in fruc- HFCS has increased an alarming 1000% between 1970
tose have been shown to contribute to a metabolic and 1990 [33]. In 1970, individual consumption of fruc-
disturbance in animal models resulting in weight gain, tose was only 0.5 lb/year. However, in 1997, this figure
hyperlipidemia [27], and hypertension [28]. rose to an alarming 62.4 lb/year [34]. The type of com-
mon, general use sweeteners represent as large an impact
Nutritional factors influencing the development as the dramatic increase in the use of these caloric sweeten-
of the Metabolic Syndrome ers. Between 1909 and 1997, sweetener use increased by
Nutrition represents a lifestyle element that can be con- 86%; and specifically, corn syrup sweeteners now repre-
trolled, and that can directly influence health; therefore sent over 20% of total daily carbohydrate intake, at an
preventative nutrition and weight control should become increase of 2100% [32].
a main focus of consumers and prepared-food providers
[29]. The Westernization of diets, with an increase in These documented trends have inspired a number of con-
availability of high calorie foods certainly contributes to sumption studies and recommendations towards HFCS

Page 2 of 14
(page number not for citation purposes)
Nutrition & Metabolism 2005, 2:5 http://www.nutritionandmetabolism.com/content/2/1/5

intake. In 1992, the USDA recommended that only 40 g cant increases in added fructose, leading to typical daily
of extra sugars should be added to a standard 2000 calorie consumptions amounting to 85–100 grams of fructose
a day diet [35]. The amount of HFCS found in only one per day. The exposure of the liver to such large quantities
12-oz soft drink equals this total proportion of daily of fructose leads to rapid stimulation of lipogenesis and
intake. HFCS consumption trends are further exacerbated TG accumulation, which in turn contributes to reduced
by the fact that soft drink and fruit juice consumption insulin sensitivity and hepatic insulin resistance/glucose
itself has increased dramatically, adding even more extra- intolerance. These negative effects of fructose are the rea-
neous calories and fructose to the diet. From 1965 to son that fructose metabolism has gained recent research
1996, a food consumption study involving 11 to 18 year attention. Interestingly, small catalytic quantities of fruc-
olds revealed that total energy and fat intakes were tose can have positive effects, and actually decrease the
decreasing. There were significant decreases in milk con- glycemic response to glucose loads, and improve glucose
sumption but large increases in the consumption of soft tolerance. These effects are also observed without any
drinks and non-citrus juices [36]. Increasingly, children changes in insulin responses and non-esterified fatty acid
seem to be choosing mass-produced, 'tasty' artificial juices (NEFA) and TG levels [40,41]. In 1976, sugar substitutes
and sodas over healthier alternatives. In a recent letter to such as fructose had been found to offer the 'advantage' of
the editor, Jacobson [37] illustrates some important fac- a 'better' utilization in conditions of limited insulin pro-
tors that contribute to increased consumption of soft duction. Fructose had a smaller influence on serum insu-
drinks, and the link to obesity; a) Society is constantly lin concentrations than glucose, and no influence on
bombarded by huge million-dollar advertising campaigns plasma glucose levels. At that time, this evidence was con-
for soft drinks, offered extra-extra-large serving sizes with sidered to support fructose as a positive treatment for dia-
free refills, and surrounded by ubiquitous access to soft betic control [40]. In 1986 HFCS were even proposed as a
drink vending machines even in schools, and b) children's low-cost substitute for fructose in diabetic management.
standard drinks to accompany meals, and especially fast Based on these early observations, nutritive sweeteners
food, have become soft drinks. The increased use of HFCS were considered safe by the Food and Drug Administra-
in soft drinks and food products are thus exacerbated by tion, although, it has now been found that intakes above
increased exposure, and consumption of these products. 25% of total energy consumed will cause hypertriglyceri-
HFCS are the main caloric sweeteners utilized in soft demia and gastrointestinal symptoms [42]. Even with the
drinks in the United States, with fructose representing early positive results, researchers noticed accompanying
over 40% of sweeteners added to prepared foods and bev- "unfavorable" influences of these so-called diabetic sugars
erages [33]. In a study of females aged 12 to 19 years milk on obesity and weight gain. Certain metabolic differences
intake decreased by 36%, whereas sodas and fruit drink exist between glucose and fructose, and the results that
consumption increased to nearly double from the 1970s were once thought favorable, proved exacerbating to insu-
to the mid 1990s. From 1994 to 1996, it was found that lin resistance and obesity. In a study comparing normal
even though intake of soda, juices, tea, and alcoholic bev- and diabetic patients, glycemic effects of HFCS were com-
erages remained constant, the steady decrease of milk pared to glucose. The negative results of HFCS on immu-
intake continued [38]. This becomes a major problem, noreactive insulin, glycemic effect, and immunoreactive
because while these high-calorie beverages are being con- C-peptide did not support its use as a substitute for glu-
sumed, calories from the rest of the diet are not subse- cose in diabetic patients [43].
quently reduced. The reality is that people do not
eliminate or reduce their food portions because they Unfortunately, one out of every four children in the
drank a can of soda that day. Data indicate that energy United States consumes above the recommended 25% of
from beverages generally does not displace or decrease total energy intake from sweeteners [42] and the harmful
energy from other foods consumed, leading to energy effects of fructose have been extensively studied in
imbalances [39]. The main diet issues involve a general healthy, non-diabetic patients. Studies involving com-
lack of education and/or understanding of the implica- monly consumed fruit juices showed that natural fructose
tions with recent consumption patterns. Despite educa- carbohydrates can alter lipid and protein oxidation
tion programs to prevent obesity and diabetes worldwide, biomarkers in the blood, and mediate oxidative stress
there has been little focus on the reduction of fructose and responses in vivo [44]. A comparative study by Raben et al.
HFCS in beverages. examined overweight men and women who consumed
fructose-containing sucrose, as opposed to artificial sweet-
Fructose metabolism eners as supplements to their diet. Weight, fat mass, and
Fructose is readily absorbed and rapidly metabolized by blood pressure were found to be lower in the artificial
human liver. For thousands of years humans consumed sweetener-consuming group compared to the sucrose-
fructose amounting to 16–20 grams per day, largely from consuming group, and the sucrose group did not decrease
fresh fruits. Westernization of diets has resulted in signifi- intake of other nutrients to compensate for their increased

Page 3 of 14
(page number not for citation purposes)
Nutrition & Metabolism 2005, 2:5 http://www.nutritionandmetabolism.com/content/2/1/5

calorie consumption from the sucrose. Subjects consum- appetite in the short term, whereas low GI carbohydrates
ing the sweetener did not exhibit increases in energy possess a more delayed effect on energy intake controls
intake, weight, and blood pressure that seen in the [55]. Fructose appears to have differing effects on appetite
sucrose-consuming subjects [45]. Research in the metabo- compared to glucose, contributing to its negative proper-
lism of fructose has left more questions about the differ- ties. Anderson et al. determined the association between
ence between short-term positive effects, and the negative food intake and blood glucose, comparing glucose and a
effects of chronic, long-term use of fructose sugars [46]. fructose mixture. Glucose was administered as a high GI
The long-term negative effects can include changes in preload, which resulted in lower mealtime energy intakes
digestion, absorption, plasma hormone levels, appetite, compared to the low GI preload of the glucose-fructose
and hepatic metabolism, leading to development of insu- mixture. An inverse relationship was seen between GI
lin resistance, diabetes, obesity, and inevitably cardiovas- (and blood glucose concentrations), and appetite with
cular disease. consequent increased food intakes seen with fructose
[56]. In 2002, Vozzo et al. studied the comparative effects
When the metabolic pathways and characteristics of fruc- of glucose and fructose on blood glucose, insulin, and
tose are examined more closely, many of the questions acute food intake. When subjects drank equienergetic
about its positive and negative effects can be answered. preloads of glucose or fructose before an ad libidum buffet
Fructose is a potent regulator of glycogen synthesis and lunch, glucose concentrations were lower in the fructose
liver glucose uptake. Therefore any catalytic improve- group compared to glucose, and insulin concentrations
ments are due to hepatic glucokinase and glucose uptake were 50% higher in the fructose group in type 2 diabetics
facilitation. However, as mentioned, the beneficial effects than in non-diabetics. The authors concluded that fruc-
do not continue with chronic fructose utilization [47]. tose may be a suitable replacement for glucose in diabetic
Because of its lipogenic properties, excess fructose in the patients – although it was found that satiating efficiencies
diet can cause glucose and fructose malabsorption, and of fructose certainly offered no advantages [57]. This study
greater elevations in TG and cholesterol compared to differs from others with regards to insulin secretion, but
other carbohydrates [48]. There are key differences in the the trend is clear between GI, glucose concentrations, and
metabolic pathways that glucose and fructose follow. appetite. An explanation for the variation in glucose and
Upon gastric absorption both fructose and glucose are fructose glycemic responses appears to be dependent on
delivered via the portal vein to the liver. It is believed that rates of hydrolysis and absorption of glucose, and gastric
the ability of the liver to metabolize high doses of fructose emptying [58]. The variations observed in GI and appetite
is responsible for the disruption in energy stores and fuel control of glucose and fructose can also be explained by
metabolism observed [49-52]. In the liver, fructose is differences in stimulation of insulin and leptin, important
metabolized into glyceraldehyde and dihydroxyacetone players in the long-term regulation of energy homeostasis.
phosphate. These particular fructose end products can Fructose will generally produce smaller insulin excursions
then readily converge with the glycolytic pathway. Of key upon consumption because it does not stimulate the
importance is the ability of fructose to by-pass the main secretion of insulin from pancreatic beta cells, whereas
regulatory step of glycolysis, the conversion of glucose-6- glucose does. Insulin-regulated leptin will also have a
phosphate to fructose 1,6-bisphosphate, controlled by reduced concentration and a decreased net effect on
phosphofructokinase. Thus, while glucose metabolism is reducing appetite. Limited effects on appetite suppres-
negatively regulated by phosphofructokinase, fructose can sion, combined with the fact that fructose is favoured by
continuously enter the glycolytic pathway. Therefore, fruc- the liver to be metabolized into lipid, will subsequently
tose can uncontrollably produce glucose, glycogen, lac- lead to weight gain, hyperinsulinemia, and the associated
tate, and pyruvate, providing both the glycerol and acyl insulin resistance [59]. Glucose and fructose comparison
portions of acyl-glycerol molecules. These particular sub- studies continued examining new hormonal targets. In
strates, and the resultant excess energy flux due to unregu- 2004, Teff et al. showed that subjects served meals with
lated fructose metabolism, will promote the over- either 30% glucose beverages, or 30% fructose beverages,
production of TG (reviewed in [53]). had differing hormonal and metabolic responses. Glyc-
emic excursions and insulin responses were reduced by
The glycemic index (GI) has been commonly used to dif- 66% and 65%, respectively, in the fructose-consuming
ferentiate and compare various nutrients, as well as to subjects. There was a concomitant reduction in circulating
describe how different foods produce different plasma leptin both in the short and long-term as well as a 30%
glucose levels after ingestion. The GI can range from 100 reduction in ghrelin (an orexigenic gastroenteric hor-
for glucose and baked potato compared to approximately mone) in the fructose group compared to the glucose
20 for fructose and whole barley [54]. Foods with varying group. A prolonged elevation of TG was also seen in the
GIs have different time courses associated with satiety. high fructose subjects [60]. Both fat and fructose con-
High GI carbohydrates have been reported to reduce sumption usually results in low leptin concentrations

Page 4 of 14
(page number not for citation purposes)
Nutrition & Metabolism 2005, 2:5 http://www.nutritionandmetabolism.com/content/2/1/5

which, in turn, leads to overeating in populations con- Elevated homocysteine levels are an important risk factor
suming energy from these particular macronutrients. An for vascular disease. Homocysteine was found to be
adipocyte hormone, adiponectin, also plays an important higher in patients with stenotic vessels and coronary
role in lipid homeostasis and insulin action [61]. The artery disease scores, and was in fact highest in diabetic
insulin sensitizer agonist, peroxisome proliferator-acti- patients [68]. This is consistent with the increased TG,
vated receptor-gamma, stimulates adiponectin produc- very low density lipoprotein (VLDL) secretion, and
tion and adiponectin is in fact thought to be part of this atherosclerosis associated with chronic fructose feeding.
agonist's mechanism lowering circulating fatty acids and
increasing fat oxidation. The net effect is to decrease liver Although fructose does not appear to acutely increase
TG and increase insulin sensitivity [62]. Chronic fructose insulin levels, chronic exposure seems to indirectly cause
consumption reduces adiponectin responses, contribut- hyperinsulinemia and obesity through other mecha-
ing to insulin resistance [63]. nisms. One proposed mechanism involves GLUT5, a fruc-
tose transporter that is found to have significantly higher
Animal studies have illustrated various differences expression levels in young Zucker obese rats compared to
between glucose and fructose metabolism. In 2002, Miller lean controls. As the rats age and become diabetic, GLUT5
et al. injected fructose into the cerebroventricles of rats, abundance and activity is compromised, causing an even
and observed enhanced food intake, whereas similar con- more marked insulin resistance over lean rats, implying a
centrations of injected glucose suppressed appetite-ago- possible role of GLUT5 receptors in the pathology of met-
nist stimulated food intake [64]. Feeding rats either 32% abolic syndrome associated with fructose feeding and
glucose, fructose, or sucrose solutions, resulted in insulin resistance [69]. In rats fed 66% fructose for 2
increased weight gain, and energy consumption com- weeks, insulin receptor mRNA, and subsequent insulin
pared to chow fed controls. Rats given the fructose and receptor numbers in skeletal muscle and liver were signif-
sucrose solutions also had a decreased ability to tolerate a icantly lower compared to rats fed a standard chow diet.
glucose load, and fructose animals had greater serum TG Also, blood pressure and plasma TG increased in the fruc-
levels over all other conditions ([65]. This is likely because tose-fed rats, even though there was no change in plasma
the hepatic metabolism of fructose favours de novo lipo- insulin, glucose, or body weight [70]. Evidence shows
genesis. In combination with alterations in insulin signal- these early steps in insulin signaling are important for
ing and leptin regulation, weight gain and unregulated insulin's metabolic effects. In a different study, it was
energy intake can occur [33]. In 1986, Levine et al. found found that after 28 days of fructose feeding there were no
that fructose, administered in the form of the disaccharide changes in insulin receptor concentration, but, insulin
sucrose, promotes obesity more than glucose because stimulated autophosphorylation, a mechanism necessary
fructose does not stimulate thermogenesis [58]. These for insulin action, was reduced to 72% in the liver. Insulin
hormonal and physiological changes illustrate the impor- receptor substrate (IRS) protein levels were similar, but
tant connections between energy intake, appetite control, there were significant decreases in insulin induced IRS (1/
weight gain, and insulin resistance. 2) phosphorylation in both the liver and muscle of the
fructose fed rats [71]. These changes are important,
Fructose and insulin resistance because it has been shown that the products of these insu-
Increasingly, questions have been raised as to whether lin independent metabolic pathways lead to polyol for-
dietary carbohydrate and fructose intake are directly mation and advanced glycation end products, which can
related to the development of type 2 diabetes. As insulin contribute to the numerous complications and premature
resistance is often associated with circulating C-peptide atherosclerosis seen in diabetic patients [58]. It is also
concentrations, a cross-sectional study was performed to known that such inflammations can lead to the pathogen-
assess dietary fructose and carbohydrate, and glycemic esis of diabetes, and there is strong evidence suggesting
loads related to C-peptide concentrations. It was found that increased free fatty acids (FFA) in diabetic subjects
that the highest quintile of fructose intake had 13.9% and fructose fed models play a role in the inflammatory
higher C-peptide concentrations than the lowest quintile. state of insulin resistance. If FFA are not removed from tis-
Of note, subjects with high intakes of cereal fiber had sues, as occurs in fructose fed insulin resistant models,
15.6% lower C-peptide concentrations, indicating that there is an increased energy and FFA flux that leads to the
these types of nutrients may have opposing roles in the increased secretion of TG. Insulin resistance has also been
development of insulin resistance [66]. A definite rela- correlated with intracellular TG stores, which are involved
tionship has also been found between metabolic syn- in lipotoxicity and beta cell failure leading to diabetes
drome and hyperhomocysteinemia, which is associated [72]. Another theory explaining how chronic fructose
with cardiovascular and cerebrovascular diseases. Rats fed overnutrition can lead to type 2 diabetes is the hex-
a fructose-enriched diet had a 72% higher homocysteine osamine hypothesis, where hexosamine flux is thought to
levels after 5 weeks compared to chow-fed controls [67]. regulate glucose and satiety-sensing pathways. With

Page 5 of 14
(page number not for citation purposes)
Nutrition & Metabolism 2005, 2:5 http://www.nutritionandmetabolism.com/content/2/1/5

overexpression of glutamine:fructose-6-phosphate ami- phatase 1B (PTP-1B), which is associated with dysfunc-

dotransferase, the key regulatory enzyme in hexosamine tional insulin signaling, leads to increased mRNA and
synthesis, the liver produces excess fatty acids, skeletal promoter activity of SREBP-1c, and subsequent increases
muscle becomes insulin resistant, and hyperinsulinemia in the expression of FAS. PTP-1B may therefore regulate
results. This pathway of excess hexosamine flux leads to the lipogenesis and hypertriglyceridemia associated with
long-term storage of energy, and eventually obesity and insulin resistance syndrome [87]. In insulin resistant fruc-
type 2 diabetes [73]. tose fed rats, it has been reported that the increase of
hepatic SREBP-1 mRNA [88] occurs in correlation with an
Fructose: a highly lipogenic nutrient increased PTP-1B expression [87]. The authors established
There is considerable evidence supporting the ability of a role for PTP-1B in enhancing SREBP-1 gene expression
high fructose diets to upregulate the lipogenesis pathway, through upregulation of Sp1 transcriptional activity, via
leading to increased TG production [74]. Insulin and glu- an increase in protein phosphatase 2A activity [87]. FAS,
cose are known to directly regulate lipid synthesis and an important downstream component of lipid synthesis,
secretion. Insulin controls hepatic sterol regulatory ele- was extensively studied in rat livers. Dietary carbohydrates
ment binding protein (SREBP) expression, which is a key increased the transcriptional rate of FAS in comparison to
transcription factor responsible for regulating fatty acid proteins. Specifically, fructose feeding increased FAS
and cholesterol biosynthesis. SREBP binds to sterol mRNA concentrations, and somewhat increased tran-
responsive elements (SRE) found on multiple genes, and scriptional rate. This suggests that fructose may increase
can activate a cascade of enzymes involved in cholesterol the stability of FAS mRNA, while carbohydrates stimulate
biosynthetic pathways, such as HMG-CoA reductase [75] FAS through increased transcriptional rate [89]. Other
and fatty acid synthase (FAS) [76]. Miyazaki et al. reported studies using animal models of insulin resistance, for
an induction of the hepatic SREBP-1 isoform and lipo- example, the Wistar fatty rats, showed the effects of dietary
genic gene expression including FAS, acetyl-CoA carboxy- carbohydrates on TG production. Feeding rats fructose
lase (ACC), and stearoyl-CoA desaturase (SCD) in mice stimulated FAS, and created a 56% increase in TG secre-
following 7 days on a 60% fructose diet [77]. It is known tion rate, and an 86% increase in plasma TG. Feeding glu-
that SREBPs are regulated by intracellular sterol concen- cose, however, did not have this effect on TG production,
trations. However, more recently, it has been established nor did it affect induction of FAS. This is likely because
that hormones such as insulin and platelet derived growth glucose stimulates both TG production, and TG removal,
factor play a role in regulating these transcription factors. maintaining homeostasis. Fructose stimulates TG produc-
Expression of SREBP is enhanced by insulin in all three tion, but impairs removal, creating the known dyslipi-
major insulin target tissues, liver, fat, and skeletal muscle demic profile [90]. The human liver possesses a large
[78-81]. Similarly, levels of SREBP are enhanced in the capacity to metabolize fructose to lipids because of its
presence of hyperinsulinemia [82,83]. There is evidence ability to shunt metabolism toward serum TG production.
that the insulin-mediated stimulation of SREBP occurs TG stores supply an energy 'sink', providing an almost
through the MAP kinase pathway [84], with ERK1/2 being unlimited TG production capacity. Conversely, glucose as
shown to activate the SREBP-1a isoform by phosphorylat- opposed to fructose would decrease serum TG [91]. As
ing serine 117) [85]. Despite the fact that SREBP-1 is discussed earlier, the effects of fructose in promoting TG
directly stimulated via insulin signaling, the depletion of synthesis are independent of insulinemia. Hirsch argued
insulin and insulin signaling through streptozotocin that carbohydrate overload results in elevated TG because
(STZ) treatment paradoxically induces SREBP-1c expres- the large amounts of sugar that need to be absorbed so
sion upon glucose, fructose, or sucrose feeding. It would rapidly from the intestine lead to the involvement of other
have been expected that SREBP-1c would be downregu- metabolic pathways, such as the hexose monophosphate
lated concomitantly along with the reduced insulin avail- shunt, that that favour the synthesis of FFA [92]. Again,
ability, but this is not the case. Glucose feeding causes a the liver takes up dietary fructose rapidly where it can be
short-term peak induction, whereas fructose caused a converted to glycerol-3-phosphate. This substrate favours
gradual extended increase in SREBP-1c activity, providing esterification of unbound FFA to form the TG [93]. It has
evidence that lipogenesis can be independent of insulin also been found that increases of 1,2-sn-diacylglycerol
signaling, given carbohydrate, and particularly fructose, and elevated expression of a PKC isoenzyme are associ-
availability [86]. ated with the enhanced synthesis of TG observed with
high fructose diet models [94]. In these scenarios, where
Emerging evidence suggests that a protein phosphatase, there is excess hepatic fatty acid uptake, synthesis and
known as PTP-1B, may link high carbohydrate feeding, secretion, 'input' of fats in the liver exceed 'outputs', and
insulin resistance, and lipogenesis. Recently, PTP-1B has hepatic steatosis occurs [95]. The mechanisms of steatosis
been linked to lipogenesis and SREBP regulation. Shimizu and liver enlargement due to fructose intake are not well
et al. found that overexpression of protein tyrosine phos- understood, but it is believed to be related to microsomal

Page 6 of 14
(page number not for citation purposes)
Nutrition & Metabolism 2005, 2:5 http://www.nutritionandmetabolism.com/content/2/1/5

enzyme induction, increased storage of lipids, peroxisome acids and TG to muscle and other tissues, further inducing
proliferation, and hyperfunction due to excessive hepatic insulin resistance [103]. Induced cellular changes include
'workloads' [96]. All of these factors contribute to fructose alterations in hepatic pyruvate dehydrogenase, changes in
being a highly lipogenic nutrient, and to the resultant insulin signaling phosphorylation, and increases of
hepatic steatosis. inflammatory cytokines [104,105]. It is evident that the
metabolic effects of fructose occur through rapid utiliza-
Mechanisms of fructose induced lipoprotein tion in the liver due to the bypassing of the regulatory
overproduction phosphofructokinase step in glycolysis. This in turn
There is growing evidence that the insulin resistant state causes activation of pyruvate dehydrogenase, and subse-
developed upon fructose feeding is also associated with quent modifications favoring esterification of fatty acids,
stimulated hepatic VLDL secretion. Several animal models again leading to increased VLDL secretion [53]. Increases
have been employed to examine the mechanisms of this in VLDL secretion can then lead to chain reactions in
induction of VLDL, and the subsequent increases in other lipoproteins and lipids, such as low density lipopro-
plasma TG observed. Mechanistic studies based on carbo- tein (LDL). Resultant LDL cholesterol levels induced by
hydrate versus lipid metabolism have recently become high fructose intake are illustrated by comparison of a diet
important because carbohydrate induced hypertriglyceri- including 20% fructose, contrasted to a starch diet of less
demia shares a metabolic basis with high fat diet induced than 3% fructose. The 20% fructose diet initiated a cycle
endogenous hypertriglycerolemia. The similarly induced of increased fasting serum total and LDL cholesterol of 9%
dyslipidemias would therefore have the same or similar and 11%, respectively, over the starch feeding [106].
atherogenic risks [97]. Carbohydrate induced hypertrig- Increased evidence was shown in transgenic apo AI-CIII-
lycerolemia results from a combination of both TG over- AIV mice, fed a fructose solution for 9 months, where dif-
production, and inadequate TG clearance [97,98]. These ferential expressions of the apo AI and apo AIV genes were
disease processes and the hepatic steatosis caused by stim- found. This indicated general perturbations in response to
ulated lipogenesis have been illustrated by fructose fed dietary intakes, causing long-term adverse effects in this
animal models showing how aberrant leptin signaling, hyperlipidemia mouse model [107]. The male Wistar fatty
hyperinsulinemia, and dyslipidemia are related to TG rat model of obese type 2 diabetes has also shown hyper-
induction [95]. Animals maintained on a chronic high glycemia. Remarkably, the female Wistar rats only
fructose diet develop elevated NEFA and hyperinsuline- develop this hyperglycemia when given sucrose, contain-
mia at the expense of glycemic control [99]. This is not ing the responsible element of fructose, which causes
surprising, as fructose-induced metabolic dyslipidemia is increases in gluconeogenic enzymes and decreases in glu-
usually accompanied by whole body insulin resistance cokinase. A hypertriglyceridemic effect is seen, presuma-
[100] and reduced hepatic insulin sensitivity [101]. In the bly due to hepatic overproductions of VLDL and
fructose fed hamster model, animals showed decreased induction of lipogenic enzymes via dietary fructose [108].
glucose disappearance rates, increased plasma NEFA and
increased plasma and liver TG [27]. Figure 1 (adapted Another contributing factor to VLDL overproduction
from ref. 100) shows clear in vivo evidence of fructose- includes fructose effects on lipid peroxidation. High fruc-
induced insulin resistance as assessed by euglycemic tose diets can have a hypertriglyceridemic and pro-oxi-
hyperinsulinemic clamp studies. Taghibiglou et al. further dant effect, and fructose fed rats have shown less
characterized the fructose fed hamster model demonstrat- protection from lipid peroxidation. Replacing the fructose
ing the development of a metabolic dyslipidemic state in these diets with a more natural source of high fructose,
characterized by high plasma levels of VLDL-TG and apol- honey, reduces this susceptibility and lowers plasma
ipoprotein B (apoB) due to hepatic lipoprotein overpro- nitrite and nitrate levels [109]. In 2004, Kelley et al.
duction [100]. Serum TGs are elevated via both an hypothesized that pro-oxidant stress response pathways
increased secretion, and decreased clearance of VLDL may mediate hepatic increases in VLDL secretion and
[102]. Also, high rates of lipolysis in visceral adipose delayed clearance upon fructose feeding. Hypertriglyceri-
depots can increase availability of NEFAs and promote demic fructose fed rats were treated with lipoxygenase
hepatic TG synthesis. The TG is then packaged with apoB, inhibitors, which reversed the inflammatory protein activ-
and secreted as VLDL particles [93]. Evidence has shown ity response, and the lipid dysregulation observed [102].
that there is a complex interplay of cellular enzymes regu- Recent findings have also shown that the hyperlipidemic
lating lipid synthesis and uptake, as well as export and and pro-oxidant effect induced by a high fructose diet can
oxidation. Observations of the actions of insulin affecting be decreased by oligofructose consumption. Oligofruc-
lipid secretion as well as inhibition of TG has brought tose administered to fructose fed rats did not alter insulin
research interests towards the effects of chronic insulin concentrations, and lowered plasma leptin by 50% com-
stimulation on VLDL secretion and transport. Excess pared to control groups. Oligofructose prevented TG
VLDL secretion has been shown to deliver increased fatty changes induced by fructose feeding, and decreased

Page 7 of 14
(page number not for citation purposes)
Nutrition & Metabolism 2005, 2:5 http://www.nutritionandmetabolism.com/content/2/1/5

6 3000
A p < 0.01 B p = ns
5 2500

4
Glucose (mmol/l)

2000

Insulin (pmol/l)
3 1500

2 1000

1 500

0 0

60 6
C p < 0.01 D p = 0.03
50 5
Ginf (Pmol.kg .min )
-1

SI (10 l .kg .min )

-1

40 4
-1

30 3
-1
2

20 2
6

10 1

0 0

Control (n=10)
Fructose fed (n=9)

Fructose-induced
Figure 1 insulin resistance: evidence from euglycemic hyperinsulinemic clamp studies
Fructose-induced insulin resistance: evidence from euglycemic hyperinsulinemic clamp studies. Mean glucose
levels (A) were slightly but significantly higher in fructose-fed vs. control animals during the last 30 mins of the clamp period (p
< 0.01). Mean insulin levels (B) were slightly but not significantly higher in the fructose-fed vs. control hamsters during the
clamp period. The glucose infusion rate (Ginf) (C) during the clamp period was significantly lower in fructose-fed vs. control
animals (p < 0.01). The calculated insulin sensitivity index (SI – see methods) (D) was also significantly lower in the fructose-fed
vs. control hamsters (p = 0.03). Fructose-fed (n = 9), control hamsters (n = 10). (adapted from Taghibiglou et al. [100]).

hepatic TG accumulation. The peroxidation effect of fruc- induced by fructose feeding, and lipid peroxides, diene
tose was also decreased by oligofructose, and had benefi- conjugates, and reactive substances are undeniably ele-
cial protective effects [110]. Oxidative stress has often vated in fructose fed animals, especially accompanying a
been implicated in the pathology of insulin resistance deficient antioxidant system. Administration of alpha-

Page 8 of 14
(page number not for citation purposes)
Nutrition & Metabolism 2005, 2:5 http://www.nutritionandmetabolism.com/content/2/1/5

lipoic acid (LA) has been shown to prevent these changes, well as other models of insulin resistance [117] where
and improve insulin sensitivity [111]. LA treatment also increased levels of MTP and SREBP have been established,
prevents several deleterious effects of fructose feeding: the the regulatory effects of SREBP may play a minor role in
increases in cholesterol, TG, activity of lipogenic enzymes, regulating MTP expression. Rather increased hepatic
and VLDL secretion, the reductions in lipoprotein lipase NEFA and increased TG stores might stimulate MTP
and HDL cholesterol and may even normalize a dyslipi- expression [118]. Recent observations in our laboratory
demic cholesterol distribution of plasma lipoproteins show that oleic acid can stimulate the MTP promoter and
[112]. Taken together, this evidence shows a clear role of the stimulation occurs independently of SRE activity
peroxidative stress pathways involved in VLDL (unpublished observations). Thus, in insulin resistance
oversecretion. states, increased MTP may occur through another mecha-
nism that may block SREBP-mediated inhibition of the
Observations made in our own laboratory have also promoter. These phenomena help explain the increased
shown aberrant lipogenesis activity. In primary hepato- assembly and secretion of apoB in fructose fed models. In
cytes isolated from fructose fed hamsters, there were sig- addition, increased levels of small dense LDL particles
nificant increases in LXRα, SREBP-1, FAS and SCD, which have been observed in insulin resistant states [119]. Early
indicate increased activity of the lipogenic pathways studies by Verschoor et al. showed that fructose diets
(unpublished observations). Fructose has also been altered the structure and function of VLDL particles caus-
implicated in reducing PPARα levels in rat hepatocytes. ing and increase in the TG: protein ratio, and an increased
PPARα is a ligand activated nuclear hormone receptor that total cholesterol and phospholipid content [120]. LDL
is responsible for inducing mitochondrial and peroxiso- particle size has been found to be inversely related to TG
mal β-oxidation. Nagai et al. found that following 8 weeks concentration [121] and therefore the higher TG results in
of a high fructose diet, rats showed decreased PPARα a smaller, denser, more atherogenic LDL particle, which
mRNA and protein levels [88]. In addition, primary rat contributes to the morbidity of the metabolic disorders
hepatocytes treated with fructose also showed decreased associated with insulin resistance. Several theories are pro-
PPARα expression, suggesting that fructose or its metabo- posed for the overproduction of VLDL: more TG per VLDL
lites can directly regulate lipid oxidation. We have also particle, increases in particle number, changes in the pro-
recently detected decreased mRNA levels of PPARα in duction rates of VLDL TG or apoB, decreased TG clear-
both liver and intestine of the fructose fed hamster ance, increased lipoprotein lipase activity, and increased
(unpublished observations). Hence, decreased PPARα de novo lipogenesis. It is likely a combination of some or
expression can result in reduced oxidation, leading to cel- all of these factors that contribute to the elevated TG seen
lular lipid accumulation. For example, PPARα null mice in a fructose rich carbohydrate fed model of metabolic
have extensive hepatic steatosis because of diminished β- disorder. High fructose, which stimulates VLDL secretion,
oxidation capacity, such as seen in the insulin resistant may initiate the cycle that results in metabolic syndrome
state [113]. Other mechanisms have been illustrated by long before type 2 diabetes and obesity develop [103].
Taghibiglou et al., who found evidence for enhanced lipo-
protein assembly, reduced intracellular apoB degradation, More recently, our studies have identified an interesting
and increased microsomal triglyceride transfer protein link between the development of insulin resistance and
(MTP) mass, mRNA and activity in the fructose fed ham- deregulation of intestinal lipoprotein metabolism [122].
ster [100]. These metabolic changes also coincided with a Chronic fructose feeding stimulated intestinal secretion of
decrease in ER-60, a cysteine protease that may play a role apolipoprotein B48-containing lipoprotein particles
in apoB degradation, and an increase in synthesis and accompanied by enhanced intestinal lipid synthesis in the
secretion of apoB [101]. It appears that a complex rela- form of free cholesterol, cholesterol ester, and triglyceride,
tionship exists in the fructose fed animal model that links as well as increases in both MTP mass and activity. These
insulin resistance and dyslipidemia through NEFA flux, results suggest that in insulin resistant or diabetic animals,
SREBP-1 expression, de novo lipogenesis and MTP expres- there may be a mechanism causing enhanced intestinal
sion. Amplified MTP activity and expression would be secretion of lipoproteins in the fasting state. Fructose feed-
expected to stimulate the assembly and secretion of apoB- ing may enhance this basal level of lipoprotein secretion
lipoproteins, as an association has been demonstrated through increased de novo lipogenesis and increased MTP
between MTP levels and VLDL production [114]. As insu- availability. Comparison of plasma lipoproteins from
lin is a negative regulator of MTP gene expression [115], fructose-fed animals showed a significant shift toward
the upregulation of MTP that has been observed in insulin secretion of larger, less dense, chylomicrons in the insulin
resistance states is predictable. MTP is also negatively reg- resistant animals [123].
ulated by SREBP through sterol response element (SRE)
regions located within -124 and -116 of the 5' MTP gene
promoter [116]. However, in fructose fed animals [87] as

Page 9 of 14
(page number not for citation purposes)
Nutrition & Metabolism 2005, 2:5 http://www.nutritionandmetabolism.com/content/2/1/5

Leptin
Fructose
No Control Insulin
Fructokinase
Fructose 1-P

Hepatic Insulin
Resistance Glyceraldehyde

Dihydroxyacetone
Glyceraldehyde 3-P
phosphate

Glycerol 3-P Pyruvate

Lactate
Lipogenesis
Triglyceride Acyl-CoA Acetyl-CoACitrate

CO2 +ATP
ApoB MTP
yt e
VLDL Assembly
to c
a
H ep
VLDL

VLDL

Figure 2fructose metabolism: A highly lipogenic pathway

Hepatic
Hepatic fructose metabolism: A highly lipogenic pathway. Fructose is readily absorbed from the diet and rapidly
metabolized principally in the liver. Fructose can provide carbon atoms for both the glycerol and the acyl portions of triglycer-
ide. Fructose is thus a highly efficient inducer of de novo lipogenesis. High concentrations of fructose can serve as a relatively
unregulated source of acetyl CoA. In contrast to glucose, dietary fructose does NOT stimulate insulin or leptin (which are
both important regulators of energy intake and body adiposity). Stimulated triglyceride synthesis is likely to lead to hepatic
accumulation of triglyceride, which has been shown to reduce hepatic insulin sensitivity, as well as increased formation of VLDL
particles due to higher substrate availability, increased apoB stability, and higher MTP, the critical factor in VLDL assembly.

Page 10 of 14
(page number not for citation purposes)
Nutrition & Metabolism 2005, 2:5 http://www.nutritionandmetabolism.com/content/2/1/5

Concluding remarks HFCS: high fructose corn syrup

The alarming increase in fructose consumption may be an
important contributor to the epidemic of obesity and IR: insulin receptor
insulin resistant diabetes in both pediatric and adult
populations. For thousands of years, the human diet con- IRS: insulin receptor substrate
tained a relatively small amount of naturally occurring
fructose from fruits and other complex foods. Adaptation LA: alpha-lipoic acid
of humans to a high glucose/low fructose diet has meant
that hepatic carbohydrate metabolism is designed to LDL: low density lipoprotein
actively metabolize glucose with a limited capacity for
metabolizing a small daily intake of fructose. The increas- LXR: liver X receptor
ing application of high fructose sweeteners over the past
few decades has resulted in a considerable rise in the die- MAPK: mitogen activated protein kinase
tary intake of fructose. A high flux of fructose to the liver,
the main organ capable of metabolizing this simple car- MTP: microsomal triglyceride transfer protein
bohydrate, disturbs normal hepatic carbohydrate metabo-
lism leading to two major consequences (Figure 2): NEFA: non-esterified fatty acids
perturbations in glucose metabolism and glucose uptake
pathways, and a significantly enhanced rate of de novo PA-1: plasminogen activator inhibitor-1
lipogenesis and TG synthesis, driven by the high flux of
glycerol and acyl portions of TG molecules coming from PI3-kinase: phosphatidylinositol 3 kinase
fructose catabolism. These metabolic disturbances appear
to underlie the induction of insulin resistance commonly PKB: protein kinase B
observed with high fructose feeding in both humans and
animal models. Fructose induced insulin resistant states PKC: protein kinase C
are commonly characterized by a profound metabolic
dyslipidemia, which appears to result from hepatic and PPAR: peroxisome proliferator activated receptor
intestinal overproduction of atherogenic lipoprotein par-
ticles. Taking into consideration that a typical western diet PTP-1B: protein tyrosine phosphatase-1B
not only contains high levels of fructose but is also rich in
both fat and cholesterol, synergistic interactions among SCD: stearoyl-CoA desaturase
these nutrients can readily occur leading to a greater
degree of insulin resistance and dyslipidemia. In conclu- SREBP: sterol regulatory element binding protein
sion, emerging evidence from recent epidemiological and
biochemical studies clearly suggests that the high dietary TG: triglyceride
intake of fructose has rapidly become an important caus-
ative factor in the development of the metabolic syn- VLDL: very low density lipoprotein
drome. There is an urgent need for increased public
awareness of the risks associated with high fructose con- Acknowledgements
sumption and greater efforts should be made to curb the This work was supported by operating grants from Heart and Stroke Foun-
supplementation of packaged foods with high fructose dation of Ontario and the Canadian Institutes of Health Research to KA.
additives.
References
1. Astrup A, Finer N: Redefining type 2 diabetes: 'diabesity' or
List of Abbreviations 'obesity dependent diabetes mellitus'? Obes Rev 2000, 1:57-59.
ACC: acetyl-CoA carboxylase 2. Mokdad AH, Ford ES, Bowman BA, Nelson DE, Engelgau MM, Vinicor
F, Marks JS: Diabetes trends in the US: 1990–1998. Diabetes Care
2000, 23:1278-1283.
apoB: apolipoprotein B 3. Mokdad AH, Bowman BA, Ford ES, Vinicor F, Marks JS, Koplan JP:
The continuing epidemics of obesity and diabetes in the
United States. Jama 2001, 286:1195-1200.
ERK: extracellular signal related kinase 4. Mokdad AH, Serdula MK, Dietz WH, Bowman BA, Marks JS, Koplan
JP: The spread of the obesity epidemic in the United States,
FAS: fatty acid synthase 1991–1998. Jama 1999, 282:1519-1522.
5. Pan XR, Yang WY, Li GW, Liu J: Prevalence of diabetes and its
risk factors in China, 1994. National Diabetes Prevention
GSK-3: glycogen synthase kinase-3 and Control Cooperative Group. Diabetes Care 1997,
20:1664-1669.
HDL: high density lipoprotein

Page 11 of 14
(page number not for citation purposes)
Nutrition & Metabolism 2005, 2:5 http://www.nutritionandmetabolism.com/content/2/1/5

6. Ramachandran A, Snehalatha C, Latha E, Vijay V, Viswanathan M: Ris- 28. Hwang IS, Ho H, Hoffman BB, Reaven GM: Fructose-induced insu-
ing prevalence of NIDDM in an urban population in India. Dia- lin resistance and hypertension in rats. Hypertension 1987,
betologia 1997, 40:232-237. 10:512-516.
7. Centers for Disease Control and Prevention NCfHS, Division of 29. Cummings LE: Commercial foodservice considerations in pro-
Health Interview Statistics: Census of the population and popu- viding consumer-driven nutrition program elements. Part I.
lation estimates. Hyattsville, MD: Centers for Disease Control and Consumer health objectives and associated employee edu-
Prevention; 1997. cation needs. Cater Health 1988, 1:51-71.
8. Zimmet P, Alberti KG, Shaw J: Global and societal implications 30. Willett WC: Dietary fat plays a major role in obesity: no. Obes
of the diabetes epidemic. Nature 2001, 414:782-787. Rev 2002, 3:59-68.
9. Keller KB, Lemberg L: Obesity and the metabolic syndrome. Am 31. Kromhout D: Diet and cardiovascular diseases. J Nutr Health
J Crit Care 2003, 12:167-170. Aging 2001, 5:144-149.
10. Songer TJ: The economic costs of NIDDM. Diabetes Metab Rev 32. Gross LS, Li L, Ford ES, Liu S: Increased consumption of refined
1992, 8:389-404. carbohydrates and the epidemic of type 2 diabetes in the
11. Executive Summary of The Third Report of The National United States: an ecologic assessment. Am J Clin Nutr 2004,
Cholesterol Education Program (NCEP) Expert Panel on 79:774-779.
Detection, Evaluation, And Treatment of High Blood Cho- 33. Bray GA, Nielsen SJ, Popkin BM: Consumption of high-fructose
lesterol In Adults (Adult Treatment Panel III). Jama 2001, corn syrup in beverages may play a role in the epidemic of
285:2486-2497. obesity. Am J Clin Nutr 2004, 79:537-543.
12. Edwards KL, Talmud PJ, Newman B, Krauss RM, Austin MA: Lipo- 34. Putnam J: Food consumption, prices, and expenditures, 1970–
protein candidate genes for multivariate factors of the insu- 91. In Economic Research Service Washington, DC: US Deparment of
lin resistance syndrome: a sib-pair linkage analysis in women Agriculture; 1999.
twins. Twin Res 2001, 4:41-47. 35. United States Dept of Agriculture: The Food guide pyramid [Washing-
13. Avramoglu RK, Qiu W, Adeli K: Mechanisms of metabolic dysli- ton, DC.?]: US Dept of Agriculture; 1992.
pidemia in insulin resistant states: deregulation of hepatic 36. Cavadini C, Siega-Riz AM, Popkin BM: US adolescent food intake
and intestinal lipoprotein secretion. Front Biosci 2003, trends from 1965 to 1996. West J Med 2000, 173:378-383.
8:d464-476. 37. Jacobson MF: High-fructose corn syrup and the obesity
14. Rosmond R: Role of stress in the pathogenesis of the meta- epidemic. Am J Clin Nutr 2004, 80:1081. author reply 1081–1082
bolic syndrome. Psychoneuroendocrinology 2005, 30:1-10. 38. Bowman SA: Beverage choices of young females: changes and
15. Bao W, Srinivasan SR, Berenson GS: Persistent elevation of impact on nutrient intakes. J Am Diet Assoc 2002, 102:1234-1239.
plasma insulin levels is associated with increased cardiovas- 39. Wharton CM, Hampl JS: Beverage consumption and risk of
cular risk in children and young adults. The Bogalusa Heart obesity among Native Americans in Arizona. Nutr Rev 2004,
Study. Circulation 1996, 93:54-59. 62:153-159.
16. Freedman DS, Khan LK, Dietz WH, Srinivasan SR, Berenson GS: 40. Mehnert H: [Sugar substitutes in the diabetic diet]. Int Z Vitam
Relationship of childhood obesity to coronary heart disease Ernahrungsforsch Beih 1976, 15:295-324.
risk factors in adulthood: the Bogalusa Heart Study. Pediatrics 41. Moore MC, Cherrington AD, Mann SL, Davis SN: Acute fructose
2001, 108:712-718. administration decreases the glycemic response to an oral
17. Valek J, Vlasakova Z: [The metabolic syndrome, its heredity, glucose tolerance test in normal adults. J Clin Endocrinol Metab
methods of detection and clinical significance]. Vnitr Lek 1997, 2000, 85:4515-4519.
43:566-573. 42. Position of the American Dietetic Association: use of nutri-
18. Kohen-Avramoglu R, Theriault A, Adeli K: Emergence of the met- tive and nonnutritive sweeteners. J Am Diet Assoc 2004,
abolic syndrome in childhood: an epidemiological overview 104:255-275.
and mechanistic link to dyslipidemia. Clin Biochem 2003, 43. Hung CT: Effects of high-fructose (90%) corn syrup on plasma
36:413-420. glucose, insulin, and C-peptide in non-insulin-dependent dia-
19. Feskens EJ, Virtanen SM, Rasanen L, Tuomilehto J, Stengard J, betes mellitus and normal subjects. Taiwan Yi Xue Hui Za Zhi
Pekkanen J, Nissinen A, Kromhout D: Dietary factors determin- 1989, 88:883-885.
ing diabetes and impaired glucose tolerance. A 20-year fol- 44. Breinholt VM, Nielsen SE, Knuthsen P, Lauridsen ST, Daneshvar B,
low-up of the Finnish and Dutch cohorts of the Seven Sorensen A: Effects of commonly consumed fruit juices and
Countries Study. Diabetes Care 1995, 18:1104-1112. carbohydrates on redox status and anticancer biomarkers in
20. Hill JO, Lin D, Yakubu F, Peters JC: Development of dietary obes- female rats. Nutr Cancer 2003, 45:46-52.
ity in rats: influence of amount and composition of dietary 45. Raben A, Vasilaras TH, Moller AC, Astrup A: Sucrose compared
fat. Int J Obes Relat Metab Disord 1992, 16:321-333. with artificial sweeteners: different effects on ad libitum food
21. Kromhout D, Menotti A, Bloemberg B, Aravanis C, Blackburn H, intake and body weight after 10 wk of supplementation in
Buzina R, Dontas AS, Fidanza F, Giampaoli S, Jansen A, et al.: Dietary overweight subjects. Am J Clin Nutr 2002, 76:721-729.
saturated and trans fatty acids and cholesterol and 25-year 46. Moyer AE, Rodin J: Fructose and behavior: does fructose influ-
mortality from coronary heart disease: the Seven Countries ence food intake and macronutrient selection? Am J Clin Nutr
Study. Prev Med 1995, 24:308-315. 1993, 58:810S-814S.
22. Romieu I, Willett WC, Stampfer MJ, Colditz GA, Sampson L, Rosner 47. McGuinness OP, Cherrington AD: Effects of fructose on hepatic
B, Hennekens CH, Speizer FE: Energy intake and other determi- glucose metabolism. Curr Opin Clin Nutr Metab Care 2003,
nants of relative weight. Am J Clin Nutr 1988, 47:406-412. 6:441-448.
23. Liu S, Manson JE: Dietary carbohydrates, physical inactivity, 48. Hallfrisch J: Metabolic effects of dietary fructose. Faseb J 1990,
obesity, and the 'metabolic syndrome' as predictors of coro- 4:2652-2660.
nary heart disease. Curr Opin Lipidol 2001, 12:395-404. 49. Daly ME, Vale C, Walker M, Alberti KG, Mathers JC: Dietary car-
24. Jenkins DJ, Wolever TM, Taylor RH, Barker H, Fielden H, Baldwin JM, bohydrates and insulin sensitivity: a review of the evidence
Bowling AC, Newman HC, Jenkins AL, Goff DV: Glycemic index of and clinical implications. Am J Clin Nutr 1997, 66:1072-1085.
foods: a physiological basis for carbohydrate exchange. Am J 50. Commerford SR, Ferniza JB, Bizeau ME, Thresher JS, Willis WT,
Clin Nutr 1981, 34:362-366. Pagliassotti MJ: Diets enriched in sucrose or fat increase gluco-
25. Jenkins DJ, Jenkins AL: The glycemic index, fiber, and the die- neogenesis and G-6-Pase but not basal glucose production in
tary treatment of hypertriglyceridemia and diabetes. J Am Coll rats. Am J Physiol Endocrinol Metab 2002, 283:E545-555.
Nutr 1987, 6:11-17. 51. Dirlewanger M, Schneiter P, Jequier E, Tappy L: Effects of fructose
26. Miller JC: Importance of glycemic index in diabetes. Am J Clin on hepatic glucose metabolism in humans. Am J Physiol Endocri-
Nutr 1994, 59:747S-752S. nol Metab 2000, 279:E907-911.
27. Kasim-Karakas SE, Vriend H, Almario R, Chow LC, Goodman MN: 52. Pagliassotti MJ, Wei Y, Bizeau ME: Glucose-6-phosphatase activ-
Effects of dietary carbohydrates on glucose and lipid metab- ity is not suppressed but the mRNA level is increased by a
olism in golden Syrian hamsters. J Lab Clin Med 1996, sucrose-enriched meal in rats. J Nutr 2003, 133:32-37.
128:208-213. 53. Mayes PA: Intermediary metabolism of fructose. Am J Clin Nutr
1993, 58:754S-765S.

Page 12 of 14
(page number not for citation purposes)
Nutrition & Metabolism 2005, 2:5 http://www.nutritionandmetabolism.com/content/2/1/5

54. Truswell AS: Glycaemic index of foods. Eur J Clin Nutr 1992, 77. Miyazaki M, Dobrzyn A, Man WC, Chu K, Sampath H, Kim HJ, Ntambi
46(Suppl 2):S91-101. JM: Stearoyl-CoA desaturase 1 gene expression is necessary
55. Anderson GH, Woodend D: Effect of glycemic carbohydrates for fructose-mediated induction of lipogenic gene expression
on short-term satiety and food intake. Nutr Rev 2003, by sterol regulatory element-binding protein-1c-dependent
61:S17-26. and -independent mechanisms. J Biol Chem 2004,
56. Anderson GH, Catherine NL, Woodend DM, Wolever TM: Inverse 279:25164-25171.
association between the effect of carbohydrates on blood 78. Sewter C, Berger D, Considine RV, Medina G, Rochford J, Ciaraldi T,
glucose and subsequent short-term food intake in young Henry R, Dohm L, Flier JS, O'Rahilly S, Vidal-Puig AJ: Human obes-
men. Am J Clin Nutr 2002, 76:1023-1030. ity and type 2 diabetes are associated with alterations in
57. Vozzo R, Baker B, Wittert GA, Wishart JM, Morris H, Horowitz M, SREBP1 isoform expression that are reproduced ex vivo by
Chapman I: Glycemic, hormone, and appetite responses to tumor necrosis factor-alpha. Diabetes 2002, 51:1035-1041.
monosaccharide ingestion in patients with type 2 diabetes. 79. Kim JB, Sarraf P, Wright M, Yao KM, Mueller E, Solanes G, Lowell BB,
Metabolism 2002, 51:949-957. Spiegelman BM: Nutritional and insulin regulation of fatty acid
58. Levine R: Monosaccharides in health and disease. Annu Rev Nutr synthetase and leptin gene expression through ADD1/
1986, 6:211-224. SREBP1. J Clin Invest 1998, 101:1-9.
59. Elliott SS, Keim NL, Stern JS, Teff K, Havel PJ: Fructose, weight 80. Guillet-Deniau I, Mieulet V, Le Lay S, Achouri Y, Carre D, Girard J,
gain, and the insulin resistance syndrome. Am J Clin Nutr 2002, Foufelle F, Ferre P: Sterol regulatory element binding protein-
76:911-922. 1c expression and action in rat muscles: insulin-like effects
60. Teff KL, Elliott SS, Tschop M, Kieffer TJ, Rader D, Heiman M, on the control of glycolytic and lipogenic enzymes and UCP3
Townsend RR, Keim NL, D'Alessio D, Havel PJ: Dietary fructose gene expression. Diabetes 2002, 51:1722-1728.
reduces circulating insulin and leptin, attenuates postpran- 81. Foretz M, Guichard C, Ferre P, Foufelle F: Sterol regulatory ele-
dial suppression of ghrelin, and increases triglycerides in ment binding protein-1c is a major mediator of insulin action
women. J Clin Endocrinol Metab 2004, 89:2963-2972. on the hepatic expression of glucokinase and lipogenesis-
61. Mora S, Pessin JE: An adipocentric view of signaling and intrac- related genes. Proc Natl Acad Sci U S A 1999, 96:12737-12742.
ellular trafficking. Diabetes Metab Res Rev 2002, 18:345-356. 82. Boizard M, Le Liepvre X, Lemarchand P, Foufelle F, Ferre P, Dugail I:
62. Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamas- Obesity-related overexpression of fatty-acid synthase gene
hita S, Noda M, Kita S, Ueki K, et al.: Adiponectin stimulates glu- in adipose tissue involves sterol regulatory element-binding
cose utilization and fatty-acid oxidation by activating AMP- protein transcription factors. J Biol Chem 1998,
activated protein kinase. Nat Med 2002, 8:1288-1295. 273:29164-29171.
63. Havel PJ: Control of energy homeostasis and insulin action by 83. Shimomura I, Bashmakov Y, Horton JD: Increased levels of
adipocyte hormones: leptin, acylation stimulating protein, nuclear SREBP-1c associated with fatty livers in two mouse
and adiponectin. Curr Opin Lipidol 2002, 13:51-59. models of diabetes mellitus. J Biol Chem 1999, 274:30028-30032.
64. Miller CC, Martin RJ, Whitney ML, Edwards GL: Intracerebroven- 84. Kotzka J, Lehr S, Roth G, Avci H, Knebel B, Muller-Wieland D: Insu-
tricular injection of fructose stimulates feeding in rats. Nutr lin-activated Erk-mitogen-activated protein kinases phos-
Neurosci 2002, 5:359-362. phorylate sterol regulatory element-binding Protein-2 at
65. Kanarek RB, Orthen-Gambill N: Differential effects of sucrose, serine residues 432 and 455 in vivo. J Biol Chem 2004,
fructose and glucose on carbohydrate-induced obesity in 279:22404-22411.
rats. J Nutr 1982, 112:1546-1554. 85. Roth G, Kotzka J, Kremer L, Lehr S, Lohaus C, Meyer HE, Krone W,
66. Wu T, Giovannucci E, Pischon T, Hankinson SE, Ma J, Rifai N, Rimm Muller-Wieland D: MAP kinases Erk1/2 phosphorylate sterol
EB: Fructose, glycemic load, and quantity and quality of car- regulatory element-binding protein (SREBP)-1a at serine
bohydrate in relation to plasma C-peptide concentrations in 117 in vitro. J Biol Chem 2000, 275:33302-33307.
US women. Am J Clin Nutr 2004, 80:1043-1049. 86. Matsuzaka T, Shimano H, Yahagi N, Amemiya-Kudo M, Okazaki H,
67. Oron-Herman M, Rosenthal T, Sela BA: Hyperhomocysteinemia Tamura Y, Iizuka Y, Ohashi K, Tomita S, Sekiya M, et al.: Insulin-inde-
as a component of syndrome X. Metabolism 2003, 52:1491-1495. pendent induction of sterol regulatory element-binding pro-
68. Okada E, Oida K, Tada H, Asazuma K, Eguchi K, Tohda G, Kosaka S, tein-1c expression in the livers of streptozotocin-treated
Takahashi S, Miyamori I: Hyperhomocysteinemia is a risk factor mice. Diabetes 2004, 53:560-569.
for coronary arteriosclerosis in Japanese patients with type 2 87. Shimizu S, Ugi S, Maegawa H, Egawa K, Nishio Y, Yoshizaki T, Shi K,
diabetes. Diabetes Care 1999, 22:484-490. Nagai Y, Morino K, Nemoto K, et al.: Protein-tyrosine phos-
69. Litherland GJ, Hajduch E, Gould GW, Hundal HS: Fructose trans- phatase 1B as new activator for hepatic lipogenesis via sterol
port and metabolism in adipose tissue of Zucker rats: dimin- regulatory element-binding protein-1 gene expression. J Biol
ished GLUT5 activity during obesity and insulin resistance. Chem 2003, 278:43095-43101.
Mol Cell Biochem 2004, 261:23-33. 88. Nagai Y, Nishio Y, Nakamura T, Maegawa H, Kikkawa R, Kashiwagi A:
70. Catena C, Giacchetti G, Novello M, Colussi G, Cavarape A, Sechi LA: Amelioration of high fructose-induced metabolic
Cellular mechanisms of insulin resistance in rats with fruc- derangements by activation of PPARalpha. Am J Physiol Endocri-
tose-induced hypertension. Am J Hypertens 2003, 16:973-978. nol Metab 2002, 282:E1180-1190.
71. Ueno M, Bezerra RM, Silva MS, Tavares DQ, Carvalho CR, Saad MJ: 89. Katsurada A, Iritani N, Fukuda H, Matsumura Y, Nishimoto N,
A high-fructose diet induces changes in pp185 phosphoryla- Noguchi T, Tanaka T: Effects of nutrients and hormones on
tion in muscle and liver of rats. Braz J Med Biol Res 2000, transcriptional and post-transcriptional regulation of fatty
33:1421-1427. acid synthase in rat liver. Eur J Biochem 1990, 190:427-433.
72. Ziegler O, Quilliot D, Guerci B, Drouin P: [Macronutrients, fat 90. Kazumi T, Odaka H, Hozumi T, Ishida Y, Amano N, Yoshino G:
mass, fatty acid flux and insulin sensitivity]. Diabetes Metab Effects of dietary fructose or glucose on triglyceride produc-
2001, 27:261-270. tion and lipogenic enzyme activities in the liver of Wistar
73. McClain DA: Hexosamines as mediators of nutrient sensing fatty rats, an animal model of NIDDM. Endocr J 1997,
and regulation in diabetes. J Diabetes Complications 2002, 44:239-245.
16:72-80. 91. Herman RH, Zakim D, Stifel FB: Effect of diet on lipid metabo-
74. Kok N, Roberfroid M, Delzenne N: Dietary oligofructose modi- lism in experimental animals and man. Fed Proc 1970,
fies the impact of fructose on hepatic triacylglycerol 29:1302-1307.
metabolism. Metabolism 1996, 45:1547-1550. 92. Hirsch J: Role and benefits of carbohydrate in the diet: key
75. Brown MS, Goldstein JL: The SREBP pathway: regulation of issues for future dietary guidelines. Am J Clin Nutr 1995,
cholesterol metabolism by proteolysis of a membrane- 61:996S-1000S.
bound transcription factor. Cell 1997, 89:331-340. 93. Fried SK, Rao SP: Sugars, hypertriglyceridemia, and cardiovas-
76. Bennett MK, Lopez JM, Sanchez HB, Osborne TF: Sterol regulation cular disease. Am J Clin Nutr 2003, 78:873S-880S.
of fatty acid synthase promoter. Coordinate feedback regu- 94. Donnelly R, Reed MJ, Azhar S, Reaven GM: Expression of the
lation of two major lipid pathways. J Biol Chem 1995, major isoenzyme of protein kinase-C in skeletal muscle,
270:25578-25583. nPKC theta, varies with muscle type and in response to fruc-

Page 13 of 14
(page number not for citation purposes)
Nutrition & Metabolism 2005, 2:5 http://www.nutritionandmetabolism.com/content/2/1/5

tose-induced insulin resistance. Endocrinology 1994, tein-B lipoprotein assembly. Biochim Biophys Acta 2000,
135:2369-2374. 1486:72-83.
95. Koteish A, Diehl AM: Animal models of steatosis. Semin Liver Dis 115. Lin MC, Gordon D, Wetterau JR: Microsomal triglyceride trans-
2001, 21:89-104. fer protein (MTP) regulation in HepG2 cells: insulin nega-
96. Bar A: Characteristics and significance of D-tagatose-induced tively regulates MTP gene expression. J Lipid Res 1995,
liver enlargement in rats: An interpretative review. Regul Tox- 36:1073-1081.
icol Pharmacol 1999, 29:S83-93. 116. Sato R, Miyamoto W, Inoue J, Terada T, Imanaka T, Maeda M: Sterol
97. Parks EJ, Hellerstein MK: Carbohydrate-induced hypertriacylg- regulatory element-binding protein negatively regulates
lycerolemia: historical perspective and review of biological microsomal triglyceride transfer protein gene transcription.
mechanisms. Am J Clin Nutr 2000, 71:412-433. J Biol Chem 1999, 274:24714-24720.
98. Kazumi T, Vranic M, Steiner G: Triglyceride kinetics: effects of 117. Bartels ED, Lauritsen M, Nielsen LB: Hepatic expression of micro-
dietary glucose, sucrose, or fructose alone or with somal triglyceride transfer protein and in vivo secretion of
hyperinsulinemia. Am J Physiol 1986, 250:E325-330. triglyceride-rich lipoproteins are increased in obese diabetic
99. Thorburn AW, Storlien LH, Jenkins AB, Khouri S, Kraegen EW: mice. Diabetes 2002, 51:1233-1239.
Fructose-induced in vivo insulin resistance and elevated 118. Au WS, Kung HF, Lin MC: Regulation of microsomal triglycer-
plasma triglyceride levels in rats. Am J Clin Nutr 1989, ide transfer protein gene by insulin in HepG2 cells: roles of
49:1155-1163. MAPKerk and MAPKp38. Diabetes 2003, 52:1073-1080.
100. Taghibiglou C, Carpentier A, Van Iderstine SC, Chen B, Rudy D, Aiton 119. Reaven GM, Chen YD, Jeppesen J, Maheux P, Krauss RM: Insulin
A, Lewis GF, Adeli K: Mechanisms of hepatic very low density resistance and hyperinsulinemia in individuals with small,
lipoprotein overproduction in insulin resistance. Evidence dense low density lipoprotein particles. J Clin Invest 1993,
for enhanced lipoprotein assembly, reduced intracellular 92:141-146.
ApoB degradation, and increased microsomal triglyceride 120. Verschoor L, Chen YD, Reaven EP, Reaven GM: Glucose and fruc-
transfer protein in a fructose-fed hamster model. J Biol Chem tose feeding lead to alterations in structure and function of
2000, 275:8416-8425. very low density lipoproteins. Horm Metab Res 1985, 17:285-288.
101. Taghibiglou C, Rashid-Kolvear F, Van Iderstine SC, Le-Tien H, Fantus 121. Rainwater DL, Mitchell BD, Comuzzie AG, Haffner SM: Relationship
IG, Lewis GF, Adeli K: Hepatic very low density lipoprotein- of low-density lipoprotein particle size and measures of
ApoB overproduction is associated with attenuated hepatic adiposity. Int J Obes Relat Metab Disord 1999, 23:180-189.
insulin signaling and overexpression of protein-tyrosine 122. Haidari M, Leung N, Mahbub F, Uffelman KD, Kohen-Avramoglu R,
phosphatase 1B in a fructose-fed hamster model of insulin Lewis GF, Adeli K: Fasting and Postprandial Overproduction of
resistance. J Biol Chem 2002, 277:793-803. Intestinally Derived Lipoproteins in an Animal Model of Insu-
102. Kelley GL, Allan G, Azhar S: High dietary fructose induces a lin Resistance. EVIDENCE THAT CHRONIC FRUCTOSE
hepatic stress response resulting in cholesterol and lipid FEEDING IN THE HAMSTER IS ACCOMPANIED BY
dysregulation. Endocrinology 2004, 145:548-555. ENHANCED INTESTINAL DE NOVO LIPOGENESIS AND
103. Zammit VA, Waterman IJ, Topping D, McKay G: Insulin stimula- ApoB48-CONTAINING LIPOPROTEIN
tion of hepatic triacylglycerol secretion and the etiology of OVERPRODUCTION. J Biol Chem 2002, 277:31646-31655.
insulin resistance. J Nutr 2001, 131:2074-2077. 123. Guo Q, Kohen-Avramoglu R, Adeli K: Intestinal assembly and
104. Park OJ, Cesar D, Faix D, Wu K, Shackleton CH, Hellerstein MK: secretion of highly dense/lipid-poor apolipoprotein B48-con-
Mechanisms of fructose-induced hypertriglyceridaemia in taining lipoprotein particles in the fasting state: Evidence for
the rat. Activation of hepatic pyruvate dehydrogenase induction by insulin resistance and exogenous fatty acids.
through inhibition of pyruvate dehydrogenase kinase. Biochem Metabolism in press.
J 1992, 282(Pt 3):753-757.
105. Carmona A, Freedland RA: Comparison among the lipogenic
potential of various substrates in rat hepatocytes: the differ-
ential effects of fructose-containing diets on hepatic
lipogenesis. J Nutr 1989, 119:1304-1310.
106. Swanson JE, Laine DC, Thomas W, Bantle JP: Metabolic effects of
dietary fructose in healthy subjects. Am J Clin Nutr 1992,
55:851-856.
107. Ostos MA, Recalde D, Baroukh N, Callejo A, Rouis M, Castro G,
Zakin MM: Fructose intake increases hyperlipidemia and
modifies apolipoprotein expression in apolipoprotein AI-
CIII-AIV transgenic mice. J Nutr 2002, 132:918-923.
108. Noguchi T, Tanaka T: Insulin resistance in obesity and its
molecular control. Obes Res 1995, 3(Suppl 2):195S-198S.
109. Busserolles J, Gueux E, Rock E, Mazur A, Rayssiguier Y: Substituting
honey for refined carbohydrates protects rats from hyper-
triglyceridemic and prooxidative effects of fructose. J Nutr
2002, 132:3379-3382.
110. Busserolles J, Gueux E, Rock E, Demigne C, Mazur A, Rayssiguier Y:
Oligofructose protects against the hypertriglyceridemic and
pro-oxidative effects of a high fructose diet in rats. J Nutr 2003, Publish with Bio Med Central and every
133:1903-1908.
111. Thirunavukkarasu V, Anuradha CV: Influence of alpha-lipoic acid scientist can read your work free of charge
on lipid peroxidation and antioxidant defence system in "BioMed Central will be the most significant development for
blood of insulin-resistant rats. Diabetes Obes Metab 2004, disseminating the results of biomedical researc h in our lifetime."
6:200-207.
112. Thirunavukkarasu V, Anitha Nandhini AT, Anuradha CV: Effect of Sir Paul Nurse, Cancer Research UK
alpha-lipoic acid on lipid profile in rats fed a high-fructose Your research papers will be:
diet. Exp Diabesity Res 2004, 5:195-200.
113. den Boer M, Voshol PJ, Kuipers F, Havekes LM, Romijn JA: Hepatic available free of charge to the entire biomedical community
steatosis: a mediator of the metabolic syndrome. Lessons peer reviewed and published immediately upon acceptance
from animal models. Arterioscler Thromb Vasc Biol 2004,
24:644-649. cited in PubMed and archived on PubMed Central
114. Gordon DA, Jamil H: Progress towards understanding the role yours — you keep the copyright
of microsomal triglyceride transfer protein in apolipopro-
Submit your manuscript here: BioMedcentral
http://www.biomedcentral.com/info/publishing_adv.asp

Page 14 of 14
(page number not for citation purposes)