LETTERS TO THE EDITOR
3. Parks EJ, Krauss RM, Christiansen MP,
Neese RA, Hellerstein MK. Effects of a low-
fat, high-carbohydrate diet on VLDL-triglyc-
eride assembly, production, and clearance.
J Clin Invest. 1999;104:1087-1096.
4. Stanhope KL, Schwarz JM, Keim NL, Griffen
SC, Bremer AA, Graham JL, Hatcher B, Cox
CL, Dyachenko A, Zhang W, McGahan JP,
Seibert A, Krauss RM, Chiu S, Schaefer EJ, Ai
M, Otokozawa S, Nakajima K, Nakano T, Bey-
sen C, Hellerstein MK, Berglund L, Havel PJ.
Consuming fructose-sweetened, not glucose-
sweetened, beverages increases visceral adi-
posity and lipids and decreases insulin sensi-
tivity in overweight/obese humans. J Clin
Invest. 2009;119:1322-1334.
5. Tappy L, Lê KA. Metabolic effects of fructose
and the worldwide increase in obesity.
Physiol Rev. 2010;90:23-46.
6. Marriott BP, Cole N, Lee E. National esti-
mates of dietary fructose intake increased
from 1977 to 2004 in the United States. J
Nutr. 2009;139:1228S-1235S.
7. Sievenpiper JL, Carleton AJ, Chatha S,
Jiang HY, de Souza RJ, Beyene J, Kendall
CW, Jenkins DJ. Heterogeneous effects of
fructose on blood lipids in individuals with
type 2 diabetes: Systematic review and
meta-analysis of experimental trials in hu-
mans. Diabetes Care. 2009;32:1930-1937.
8. Livesey G, Tagami H. Interventions to lower
the glycemic response to carbohydrate foods
with a low-viscosity fiber (resistant malto-
dextrin): Meta-analysis of randomized con-
trolled trials. Am J Clin Nutr. 2009;89:114-
125.
9. Vaisman N, Niv E, Izkhakov Y. Catalytic
amounts of fructose may improve glucose
tolerance in subjects with uncontrolled non-
insulin-dependent diabetes. Clin Nutr. 2006;
25:617-621.
10. Moore MC, Davis SN, Mann SL, Cher-
rington AD. Acute fructose administration
improves oral glucose tolerance in adults
with type 2 diabetes. Diabetes Care. 2001;24:
1882-1887.
11. Petersen KF, Laurent D, Yu C, Cline GW,
Shulman GI. Stimulating effects of low-dose
fructose on insulin-stimulated hepatic glyco-
gen synthesis in humans. Diabetes. 2001;50:
1263-1268.
12. Jenkins DJA, Srichaikul K, Kendall CWC,
Sievenpiper JL, Abdulnour S, Mirrahimi A,
Meneses C, Nishi S, He X, Lee S, So YT,
Esfahani A, Mitchell S, Parker TL, Vidgen
E, Josse RG, Leiter LA. The relation of low
glycaemic index fruit consumption to glycae-
mic control and risk factors for coronary
heart disease in type 2 diabetes [published
online ahead of print October 27, 2010]. Dia-
betologia. doi:10.1007/s00125-010-1927-1.
doi: 10.1016/j.jada.2010.12.001
Authors’ Response:
We thank Sievenpiper and col-
leagues for their letter, which allows
us to address several commonly held
misconceptions about the role of fruc-
tose in human obesity and metabolic
syndrome. We agree that the results
of animal studies assessing the effect
of chronic fructose feeding can’t be
generalized without valid human
220 February 2011 Volume 111 Number 2
studies. However, those data are in,
and do not paint a pretty picture.
First, the respondents question the
role and metabolic importance of he-
patic de novo lipogenesis (DNL) by
fructose in humans. When assessing
DNL, the following experimental con-
ditions need to be clearly defined: 1)
Are the measurements made in fast-
ing or fed conditions? The delay
(hours) between hepatic fat synthesis
and very-low-density lipoprotein tri-
glyceride (VLDL-TG) production
needs to be taken into account. For
example, the effect of feeding on DNL
is delayed by at least 2 to 3 hours and
a fasting DNL measurement can be
assessed after 8 hours with an addi-
tional 2 to 3 hours necessary to pro-
duce the VLDL-TG used to determine
hepatic DNL. 2) What is the percent-
age of energy intake from carbohy-
drates and what is the proportion of
simple to complex carbohydrate in
the diet? 3) Are the subjects overfed,
underfed, or in energy balance? This
is not a trivial aspect and can only be
guaranteed if subjects are admitted
as inpatient in a clinical research unit
allowing a strict control of energy ex-
penditure (activity) and energy in-
take (controlled diet) for at least a 4 to
5-day period. 4) Are the subjects
healthy or insulin resistant?
Sievenpiper and colleagues quote
Parks and colleagues (1), which states
that DNL is insignificant (⬍5%) even
with a low-fat/high-carbohydrate (LF/
HC) diet. However, this paper re-
ported DNL after a 16-hour fast, re-
sulting in glycogen depletion and
providing a shunt for fructose away
from DNL. Other studies, such as
Schwarz and colleagues (2), used a
similar LF/HC diet composition (68%
energy from carbohydrate) with
stricter control of energy balance (in-
patient for 5 days) and showed that in
healthy subjects after a 12-hour fast,
DNL was three times higher (⬎12%).
We agree that most fructose-DNL stud-
ies are confounded by moderate over-
feeding conditions. However, Stanhope
and colleagues (3) showed that when
a normal diet was supplemented with
fructose, it lead to significantly higher
rates of DNL compared to the same
diet isocalorically supplemented with
glucose. Furthermore, data from
Schwarz and colleagues (unpublished,
2008) argue that during the fed state
with strict control of energy balance,
higher fructose intake led to signifi-
cantly higher DNL when compared to
low fructose intake, even when the
overall carbohydrate intake was ex-
actly matched. Finally, the effect of
fructose on hepatic DNL is often ex-
pressed as quantity of lipid made de
novo, rather than the overall meta-
bolic effect of fructose and hepatic
DNL on lipid profile, liver and vis-
ceral fat accumulation, and cardio-
vascular risk. The respondents’ own
meta-analysis of isocaloric fructose-
for-glucose exchange in diabetics (4)
shows that fructose increases triglyc-
eride levels in type 2 diabetics who
are insulin resistant. Thus, fructose
consumption in the face of insulin re-
sistance is a potent stimulator of DNL
with resultant dyslipidemia and he-
patic steatosis. But this not the only
effect of fructose on the liver, as stud-
ies now implicate fructose as the fac-
tor that exacerbates hepatic steatosis
to progress on to nonalcoholic steato-
hepatitis (5).
Which leads to the second question
of how much fructose is being con-
sumed nowadays. Although the re-
spondents concede that high doses of
fructose can induce dyslipdemia in a
hypercaloric state, they base their
contention that fructose is not conse-
quential in humans on a total fructose
consumption of less than 50 g/day and
less than 10% of energy intake, based
on the paper by Marriott and col-
leagues (6). This study performed com-
plicated extrapolations of estimated in-
take, and pooled data from 1999 to
2004 to determine that percent fructose
consumption had not changed. How-
ever, mean consumption in this paper
was 49 g/day. A more recent paper from
the same group examining the years
2003-2006 using similar methods esti-
mates that 25% of adults consume
⬎10% of their calories as fructose (7).
However, the American Heart Associ-
ation has stated that consumption of
added sugars in the United States
currently averages 22 tsp/day (55
g/day fructose) (8). In the recent adult
study of National Health and Nutri-
tion Examination Survey (NHANES)
by Welsh and colleagues, which ex-
cluded patients who had type 2 diabe-
tes or hypertriglyceridemia (both
likely groups for high fructose con-
sumption), a full 38% and 12% had
fructose intakes ⬎ 9% and ⬎12% of
total energy consumed, respectively (9).
Also using the adult NHANES data-
base, Jalal and colleagues found a me-

dian fructose intake of 74 g/day (10). In
children, mean fructose consumption
has reached 75 g/day, with 25% of ado-
lescents consuming greater than 15%
of their calories as fructose (11). In-
deed, using the same NHANES data-
base, we showed that 46% of adoles-
cents consume more than 24 oz/day in
sugar-sweetened beverages alone (12).
Based on a high-fructose corn syrup
(HFCS) fructose content of 55%, this
would amount to 51 g fructose; how-
ever, a recent report argues that
many commercially available soft
drinks are actually 65% fructose (13).
In our own pediatric obesity clinic and
assuming an HFCS fructose content
of 55%, Latinos and African Ameri-
cans consume a mean of 50 g/day of
fructose from sugar-sweetened bever-
ages alone (unpublished data, 2003-
2009). The effects are clearly dose-
dependent; fructose toxicity likely has
a threshold effect at 50 g/day, similar
to ethanol (14); thus, studies looking
at lower levels of consumption may
not be able to discern its detrimental
effects. Indeed, the obesity epidemic
started in the late 1970s, when mean
fructose consumption exceeded 50
g/day (11).
Third, Sievenpiper and colleagues
base their queries on controlled feeding
studies of fructose; either isocaloric ex-
change of fructose for carbohydrate
(4), or hypercaloric fructose supplemen-
tation (5). While such studies are
essential for quantitating peripheral
kinetics and dynamics of fructose ad-
ministration, they are not akin to
real-world feeding, as they ignore ef-
fects of fructose on free-range energy
consumption, in terms of effects on
the hypothalamus (starvation) and
the nucleus accumbens (reward) (15).
We have previously hypothesized
that through induction of central ner-
vous system insulin resistance, fruc-
tose increases leptin resistance and
promotes excessive food intake (16).
Studies demonstrate that fructose
consumption results in greater caloric
intake (17), while fructose restriction
reduces total caloric consumption and
body weight (18). These effects are
reminiscent of positive feed-forward ef-
fects of ethanol, and likely due to the
same genes and neuroanatomic path-
ways (19). Indeed, this third point re-
flects back on the first one; as no one is
eucaloric or glycogen-depleted any-
more; NHANES documents over the
last 25 years increases in calories of
187 kcal/day in men, 335 kcal/day in
women, and 275 kcal/day in adoles-
cents. In addition, controlled feeding
exchange studies substitute fructose
for glucose; however, in the real
world, fructose (either in sucrose or
HFCS) is always consumed with an
equal amount of glucose, which by
saturating hepatic levels of fructose-
1,6-bisphosphate forces the fructose
toward DNL. Thus, controlled feeding
studies do not capture what is hap-
pening in the free-range feed-forward
situation.
Fourth, Sievenpiper and colleagues
recall the work of Moore and col-
leagues (20), who demonstrated “cat-
alytic” effects of fructose on glucoki-
nase, thereby increasing the insulin
response; and of Petersen and col-
leagues (21), who demonstrated im-
proved hepatic glycogenesis via glyco-
gen synthase, thereby potentially
improving glycemia in type 2 diabetic
individuals. We agree with this the-
sis; indeed the same improvement in
insulin sensitivity is seen with low-
dose ethanol consumption (22). The
problem is that there is no catalytic
effect with either substrate with in-
creased dosage and chronic adminis-
tration.
The fifth and last point concerns
the role of glycemic index (GI) in ei-
ther developing or preventing obesity
and metabolic syndrome. The respon-
dents are among the biggest propo-
nents of a low-GI diet to prevent obe-
sity, and have performed seminal
research in the field. Fructose has a
low GI (a soft drink has a GI of 53);
but surely the respondents are not
suggesting that sodas are good for
you. Furthermore, the low-GI diet
doesn’t work for everybody. There are
two separate but overlapping disor-
ders of insulin dynamics in obesity: a)
insulin hypersecretion (a vagally-me-
diated beta-cell phenomenon); and b)
insulin resistance (a hepatic/muscle
phenomenon) (23). Ebbeling and col-
leagues demonstrated the low-GI diet
was effective in those subjects who
exhibited insulin hypersecretion (24).
Our work with insulin suppression
using the somatostatin analog oct-
reotide confirmed that insulin hyperse-
cretion is a primary entity in a subset
of obese adults, and that pharmacologic
insulin suppression is a viable treat-
ment for such patients (25,26); but in-
sulin suppression is ineffective in pa-
tients with insulin resistance. Fructose
February 2011 ● Journal of the AMERICAN DIETETIC ASSOCIATION
LETTERS TO THE EDITOR
doesn’t cause insulin hypersecretion;
indeed fructose doesn’t even cause an
acute insulin response, as the beta-cell
lacks the Glut5 transporter (27), thus
accounting for the low GI of soft
drinks. Rather fructose causes he-
patic insulin resistance and resultant
fasting hyperinsulinemia, for which
the low-GI diet is ineffective (24). In
other words, fructose isn’t the only
cause of obesity, but it’s the agent, by
inducing hepatic insulin resistance,
that escalates obesity to metabolic
syndrome.
In summary, Sievenpiper and col-
leagues find fault with our Journal
article (14) implicating fructose in the
pathogenesis of metabolic syndrome
for being “a story of mice but not
men,” relying on: a) animal rather
than human data; and b) the results
of overfeeding studies. We contend
that the human data are even more
convincing, egregious, and damning
than the animal data. Humans get to
choose their food, while mice just eat
what they’re given. Controlled feed-
ing studies assess only half the story;
the peripheral half, not the central
half. The fructose glut promotes det-
rimental effects at both the liver (pro-
moting disease) and the brain (pro-
moting excessive consumption); thus,
the reason for tying them together in
this review. The studies Sievenpiper
and colleagues reference fail to take
into account the populations who
abuse fructose most; adults who are
insulin resistant or already diabetic,
and children. We have an epidemic of
childhood obesity and metabolic syn-
drome on our hands. We suggest the
respondents take a walk down to Dr
Jill Hamilton’s pediatric obesity clinic
at Sick Kids in Toronto, take a look at
the kids in the waiting room and what
they’re eating and drinking, and then
tell us that fructose isn’t a dose-de-
pendent hepatotoxin and substance of
abuse.
Robert H. Lustig, MD
Professor of Pediatrics
Department of Pediatrics
University of California,
San Francisco
Jean-Marc Schwarz, PhD
Professor of Biochemistry
Touro University, Vallejo, CA
221
LETTERS TO THE EDITOR
References
1. Parks EJ, Krauss RM, Christiansen MP,
Neese RA, Hellerstein MK. Effects of a low-
fat, high-carbohydrate diet on VLDL-triglyc-
eride assembly, production, and clearance.
J Clin Invest. 1999;104:1087-1096.
2. Schwarz JM, Linfoot P, Dare D, Aghajanian
K. Hepatic de novo lipogenesis in normoin-
sulinemic and hyperinsulinemic subjects
consuming high-fat, low-carbohydrate and
low-fat, high-carbohydrate isoenergetic di-
ets. Am J Clin Nutr. 2003;77:43-50.
3. Stanhope KL, Schwarz JM, Keim NL,
Griffen SC, Bremer AA, Graham JL,
Hatcher B, Cox CL, Dyachenko A, Zhang W,
McGahan JP, Seibert A, Krauss RM, Chiu S,
Schaefer EJ, Ai M, Otokozawa S, Nakajima
K, Nakano T, Beysen C, Hellerstein MK,
Berglund L, Havel PJ. Consuming fructose-,
not glucose-sweetened beverages increases
visceral adiposity and lipids and decreases
insulin sensitivity in overweight/obese hu-
mans. J Clin Invest. 2009;119:1322-1334.
4. Sievenpiper JL, Carleton AJ, Chatha S,
Jiang HY, de Souza RJ, Beyene J, Kendall
CW, Jenkins DJ. Heterogeneous effects of
fructose on blood lipids in individuals with
type 2 diabetes: Systematic review and
meta-analysis of experimental trials in hu-
mans. Diab Care. 2009;32:1930-1937.
5. Abdelmalek MF, Suzuki A, Guy C, Unalp-
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6. Marriott BP, Cole N, Lee E. National esti-
mates of dietary fructose intake increased
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7. Marriott BP, Olsho L, Hadden L, Connor P.
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Shulman GI. Stimulating effects of low-dose
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doi: 10.1016/j.jada.2010.12.003
Labeling Solid Fats and
Added Sugars As Empty
Calories
To the Editor:
My purpose is to question the logic
of grouping solids fats with added
sugars and labeling the combination
as empty calories. These terms are
used extensively in the Journal’s Oc-
tober 2010 research paper by Reedy
and Krebs-Smith (1). The authors de-
termined that about 54% of the empty
calories consumed by children and ad-
olescents were from solid fats and
46% were from added sugars.
The 2005 Dietary Guidelines for
Americans (2) used the same termi-
nology as does the Report of the Di-
etary Guidelines Advisory Committee
on Dietary Guidelines for Americans,
2010 (3).
First: Added Sugars. These are
primarily sucrose and high-fructose
corn syrup. Both are highly refined
food ingredients and are devoid of
food nutrients other than being
sources of energy. Certainly they are
empty calories.
Second: Solid Fats. Foods contain-
ing solid fats as a separate added ingre-
dient (usually as shortening) contrib-
ute only about 25% of total solid fats
consumption (4). Grain-based desserts
and fried potatoes have the most.
Dairy products, meat, and mixed
dishes that contain meat and/or dairy
are the primary sources (4) for the
solid fats. They account for two thirds
to three quarters of our intake (4).
These fats are a part of a food (like the
solid fat in cheese which is in pizza)
and in the beverage milk. They are
not extracted or refined.
Reference 4 (Bachman and col-
leagues) is the key reference. Their
data were calculated from the 2001-
2002 National Health and Nutrition
Examination Survey and were uti-
lized in the Journal research paper
cited by Reedy and Krebs-Smith.
Bachman and colleagues listed the 14
top sources of solid fats and their per-
cent contribution to total solid fats
(Table).
In contrast to added sugars, the
solid fats, other than those in grain-
based desserts and fried white pota-
toes, contain numerous nutrients.
Dairy and meat solid fats are par-