ME63CH22-Stanhope ARI 12 December 2011 13:50

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Kimber L. Stanhope
by University of Guelph on 07/10/12. For personal use only.

Department of Molecular Biosciences, School of Veterinary Medicine, Department of

Nutrition, University of California, Davis, California; email: klstanhope@ucdavis.edu

Annu. Rev. Med. 2012. 63:329–43 Keywords

First published online as a Review in Advance on
October 27, 2011
The Annual Review of Medicine is online at
med.annualreviews.org
This article’s doi:
10.1146/annurev-med-042010-113026
Copyright  c 2012 by Annual Reviews.
All rights reserved
0066-4219/12/0218-0329$20.00
sucrose, high-fructose corn syrup, fructose, glucose, lipid
dysregulation, insulin resistance
Abstract
There is controversy concerning the role of sugar in the epidemics of
obesity and metabolic syndrome. There is less controversy concerning
the effects of fructose on components of metabolic syndrome; consump-
tion of fructose has been shown to increase visceral adipose deposition
and de novo lipogenesis (DNL), produce dyslipidemia, and decrease
insulin sensitivity in older, overweight/obese subjects. This review ex-
amines the potential mechanisms of these effects of fructose and consid-
ers whether these mechanisms are relevant to the effects of consuming
sucrose or high-fructose corn syrup. Evidence demonstrating that the
commonly consumed sugars increase visceral adipose deposition, DNL,
and insulin insensitivity is limited or inconclusive. Evidence that sugar
consumption promotes development of an unfavorable lipid profile is
strong and suggests that the upper added sugar consumption limit of
25% of energy or less, suggested in the Report of the Dietary Guide-
lines Advisory Committee on the Dietary Guidelines for Americans
2010, may merit re-evaluation.

329
 ME63CH22-Stanhope ARI 12 December 2011 13:50
INTRODUCTION
The Report of the Dietary Guidelines Advi-
sory Committee on the Dietary Guidelines
HFCS: high-fructose
corn syrup for Americans 2010, released in June of 2010,
suggested a maximal intake level of 25% or less
DNL: de novo
lipogenesis of total energy from added sugars (1). In August
of 2009, the American Heart Association Nu-
trition Committee recommended that women
consume no more than 100 kcal/day and men
consume no more than 150 kcal/day of added
sugars (2). Added sugars are those added to
foods during processing, preparation, or at the
table, and do not include the sugars intrinsic
to fruit, vegetables, and milk or milk products
Annu. Rev. Med. 2012.63:329-343. Downloaded from www.annualreviews.org
(1). There is considerable evidence suggesting
that intake of added sugars or sugar-sweetened
beverages is associated with increased body
by University of Guelph on 07/10/12. For personal use only.
weight (3, 4), presence of unfavorable lipid
levels (5–7), insulin resistance (8, 9), fatty liver
(10, 11), type 2 diabetes (12, 13), cardiovascular
disease (14), and metabolic syndrome (15).
However, the authors of a recent meta-analysis
conclude that long-term sugar intakes as high
as 25%–50% of energy have no adverse effects
with respect to components of metabolic
syndrome (16). Clearly, there is much con-
troversy concerning the role of dietary sugar
in the epidemics of obesity and metabolic
syndrome.
There is less controversy concerning the
specific effects of the monosaccharide fructose
on components of the metabolic syndrome. Au-
thors of recent reviews conclude that high fruc-
tose intakes have substantial, even profound
(17), deleterious metabolic consequences that
possibly predispose individuals to chronic con-
ditions such as type 2 diabetes and cardio-
vascular disease (18). These conclusions are
supported by studies in which the experimen-
tal diets were supplemented with pure fruc-
tose, and usually compared to the effects of
isocaloric diets supplemented with pure glu-
cose. Studies comparing fructose and glucose
are important because both monosaccharides
have been proposed to be involved in metabolic
disease. For many years, high doses of fructose
have been used to induce metabolic disease in
330 Stanhope
animals (19). High-glucose diets increase cir-
culating glucose and insulin levels, which are
suggested to mediate adverse effects associated
with increased risk for type 2 diabetes and car-
diovascular disease (20). Therefore, to deter-
mine the mechanistic basis for the associations
between sugar consumption and metabolic dis-
ease, it is necessary to separate the specific ef-
fects of glucose, which increases glucose and
insulin excursions, from the effects of fructose,
which may produce adverse metabolic effects
via other mechanisms. This cannot be accom-
plished when the experimental diets consist of
the commonly consumed sugars, sucrose or
high-fructose corn syrup (HFCS), since they
contain approximately equal amounts of both
fructose and glucose.
To distinguish the metabolic effects of fruc-
tose from those of glucose, my colleagues
and I investigated the effects of consuming
fructose- or glucose-sweetened beverages at
25% of energy requirements (E), and demon-
strated that consumption of fructose increased
visceral adipose deposition and de novo li-
pogenesis (DNL), produced dyslipidemia, and
decreased glucose tolerance/insulin sensitivity
in older, overweight/obese men and women,
whereas consumption of glucose did not (21).
These results have limited direct relevance to
the typical American diet because foods are sel-
dom sweetened with pure fructose or pure glu-
cose. Therefore, although 13% of the U.S. pop-
ulation consumes 25%E as added sugar (22)
[the U.S. per capita intake is 477 kcal/day (23)],
the number that consume 25%E as added fruc-
tose is quite low. Also, this study did not ad-
dress the possibility that there are synergistic
effects when fructose and glucose are consumed
in combination. However, the results were im-
portant in that they established that there are
marked differences between the metabolic ef-
fects of dietary glucose and fructose in humans,
and they provided potential mechanistic expla-
nations for the associations between the com-
monly consumed sugars and metabolic disease.
This review presents the mechanisms that
are suggested by studies investigating the
 ME63CH22-Stanhope ARI 12 December 2011 13:50
effects of pure fructose, and considers whether
these mechanisms are relevant to the effects of
consuming sucrose or HFCS.
OBESITY
Fructose and Obesity:
Potential Mechanism
Our in vitro studies in isolated adipocytes
led to the observation that production of the
adipocyte hormone leptin is regulated by
insulin-mediated glucose metabolism (24).
Since ingestion of fructose does not result in
Annu. Rev. Med. 2012.63:329-343. Downloaded from www.annualreviews.org
meal-related increases of circulating glucose or
insulin concentrations, we tested the hypothe-
by University of Guelph on 07/10/12. For personal use only.
sis that consumption of fructose compared with
glucose would lower plasma leptin concentra-
tions. Our short-term studies showed that the
24-h leptin area under the curve (AUC) was
reduced by 20%–30% when normal-weight
women (25) and overweight men and women
(26) consumed meals accompanied with
fructose compared with glucose-sweetened
beverages. Leptin is a key regulator of energy
homeostasis (19, 27). Along with insulin, it acts
in the hypothalamus to regulate food intake and
energy metabolism via neuropeptide systems
including neuropeptide-Y and melanocortins.
Accordingly, leptin-deficient patients exhibit
increased hunger and impaired satiety (28).
Additionally, functional MRI studies have
shown that the areas of the brain associated
with pleasure and reward are markedly acti-
vated when leptin-deficient patients are shown
pictures of food, but this activation decreases to
the level of normal subjects following 7 days of
leptin administration (27). Leptin-responsive
neurons also project to pathways that modulate
signals to the periphery involved in the regu-
lation of energy expenditure and fat oxidation.
Therefore, we hypothesized that a reduction
of circulating leptin concentrations during
prolonged consumption of diets high in energy
from fructose could lead to increased energy
intake and/or decreased energy expenditure
and weight gain.
www.annualreviews.org • Sugar, Obesity, and Metabolic Syndrome
Fructose and Obesity:
Testing the Hypothesis
In order to test this hypothesis, we included
in the study protocol of our recent investi-
gation (21) an eight-week outpatient period
during which subjects consumed their usual
ad libitum diets along with three servings/day
of fructose- or glucose-sweetened beverages
which provided 25%E. During this period,
the two groups reported consuming compa-
rable amounts of energy and gained compa-
rable amounts of weight. However, subjects
consuming fructose exhibited decreases of en-
ergy expenditure and fat oxidation that were
not observed in subjects consuming glucose
(29). We also obtained equivocal results when
we tested the hypothesis that the consump-
tion of fructose-sweetened beverages for one
year would promote weight gain compared with
glucose-sweetened beverages in rhesus mon-
keys (30). The monkeys consuming fructose
exhibited significantly increased body weight
and reduced energy expenditure at three and
six months of intervention, while monkeys con-
suming glucose did not. However, by the 12-
month time-point, body weight was increased
and energy expenditure was decreased similarly
in both groups (30).
Fructose Malabsorption:
a Possible Confounder
More recently, we have investigated the ef-
fects of consuming 25%E fructose-, HFCS-,
or glucose-sweetened beverages for two weeks
in young, normal- and overweight adults (31).
This study included a 12-day outpatient period
during which the subjects consumed their usual
ad libitum diets along with the assigned sugar-
sweetened beverage. Results from this study
also did not support the hypothesis that con-
sumption of fructose leads to greater weight
gain, as the subjects consuming glucose (0.5 ±
0.3 kg) and HFCS (0.5 ± 0.3 kg) tended
to gain weight and the subjects consuming
fructose did not (−0.1 ± 0.3 kg). However,
it has been reported that at high levels of
331
 ME63CH22-Stanhope ARI 12 December 2011 13:50
INTERACTION OF DIETARY SUGAR AND FAT
As shown in Supplemental Figure 1 (see the Supplemental
Material link in the online version of this article or at
http://www.annualreviews.org/), there are plausible mecha-
nisms by which diets high in both sugar and fat may produce
more adverse effects than diets high in sugar and complex carbo-
hydrate. Dietary fat increases postprandial chylomicron appear-
ance, which competes with VLDL1 for lipoprotein lipase (LPL)
binding and hydrolysis, thus prolonging VLDL1 residence in
the circulation. The exchange of dietary fat for carbohydrate
lowers postmeal glucose and insulin responses, leading to re-
duced LPL activity, which may also prolong VLDL1 residence
Annu. Rev. Med. 2012.63:329-343. Downloaded from www.annualreviews.org
in the circulation and promote visceral adipose tissue accumula-
tion. Lowered postmeal glucose and insulin responses may reduce
circulating leptin levels, thereby promoting increased energy in-
by University of Guelph on 07/10/12. For personal use only.
take and/or reduced energy expenditure. In the liver, fructose-
containing sugar upregulates de novo lipogenesis (DNL), thereby
concurrently inhibiting fatty acid oxidation. Less dietary triglyc-
eride (TG), taken up as chylomicron remnants, is oxidized and
more is shunted into the intrahepatic lipid pool, along with
newly synthesized TG. The resulting increase of hepatic lipid
(a) increases production/secretion of VLDL1 and (b) decreases
hepatic insulin sensitivity, which exacerbates VLDL1 produc-
tion/secretion. This further contributes to prolonged residence
of VLDL1 in the circulation. Accordingly, production of small
dense LDL cholesterol is exacerbated due to both overproduc-
tion and decreased clearance of VLDL1.
intake, consumption of fructose as a monosac-
charide can overwhelm the absorptive capacity
of the small intestine, leading to fructose mal-
absorption and gastrointestinal distress (32).
Therefore, we also measured breath hydrogen
concentrations in these subjects, which is an
index of the hydrogen derived from bacte-
rial fermentation of unabsorbed carbohydrate
reaching the colon (33). These measures were
taken every 30 min following consumption of
the assigned sugar-sweetened beverage con-
taining 8% of the daily energy requirement.
Supplemental Material Hydrogen breath levels after consumption of
fructose-sweetened beverages were 5–20 times
higher at all time-points than those after con-
sumption of beverages sweetened with glucose
332 Stanhope
or HFCS (55% fructose). This suggests that
fructose malabsorption could indeed confound
testing of the hypothesis that consumption of
fructose compared to glucose promotes body
weight gain. Fructose malabsorption would
lead to less energy availability, and the asso-
ciated gastrointestinal distress may reduce ad
libitum consumption of other foods in subjects
consuming fructose.
Thus, testing the hypothesis that reduced
circulating leptin concentrations during pro-
longed consumption of fructose, compared
with glucose, could lead to greater weight
gain due to higher energy intake and/or lower
energy expenditure requires a study protocol
that includes accurate adjustment for fructose
malabsorption (i.e., repeated measures of sugar
content in 24-h stool collections from each
subject). The results from such a study would
be interesting from a scientific perspective,
but whether the effort and costs that would
be involved can be rationalized by their rele-
vance to the obesity epidemic is questionable.
Fructose malabsorption is likely to be low in
normal subjects consuming sucrose or HFCS,
because fructose when ingested along with
glucose is much more completely absorbed
than when ingested as pure fructose (34). Fur-
thermore, our recent study results demonstrate
that, although subjects consuming 25%E as
fructose exhibited the expected decrease in
24-h leptin AUC compared to when they con-
sumed the baseline complex-carbohydrate diet,
the 24-h leptin AUC of the subjects consuming
HFCS was unchanged. Therefore, the mecha-
nism by which consumption of sugar compared
with complex carbohydrate may promote
body weight gain does not appear to involve a
fructose-induced lowering of circulating leptin.
However, it is interesting to speculate whether
a lowered leptin profile may be contributing
to weight gain when diets high in both sugar
and fat are consumed [see sidebar “Interaction
of Dietary Sugar and Fat” and Supplemental
Figure 1 (follow the Supplemental Material
link in the online version of this article or see
http://www.annualreviews.org/)].
 ME63CH22-Stanhope ARI 12 December 2011 13:50
Fructose-Containing
Sugars and Obesity
The studies of particular relevance to obesity
are those comparing ad libitum diets with high
and low levels of the commonly consumed
sugars. Three studies have demonstrated that
consumption of sucrose (35, 36) and HFCS
(37) promote weight gain compared with the
consumption of non-nutritive sweeteners.
These studies provide useful evidence that
human subjects may consume less energy when
caloric beverages or foods are replaced with
similar beverages or foods that are less caloric,
but they do not provide evidence that sucrose or
Annu. Rev. Med. 2012.63:329-343. Downloaded from www.annualreviews.org
HFCS have inherent metabolic properties that
promote weight gain. To date, only one study
by University of Guelph on 07/10/12. For personal use only.
has compared the ad libitum consumption of
a high-sugar diet (23%E sucrose) with that of
a high–complex carbohydrate diet (2%E su-
crose), while maintaining similar proportions of
protein and fat during both interventions (38).
In this 14-day crossover study, subjects con-
sumed more energy and gained more weight
during consumption of the sucrose diet than
the complex carbohydrate diet. However, as the
principal investigator of this study points out
(39), these results could possibly be explained
by the fact that the complex carbohydrate diet
contained more fiber than the sucrose diet, and
additional trials strictly controlling macronu-
trient ratios and fiber content are necessary.
Fructose and Regional
Adipose Distribution
Although our 10-week intervention study did
not provide support for the hypothesis that
fructose consumption promotes weight gain
compared with glucose consumption, it did
allow us to observe some important metabolic
differences between effects of fructose and glu-
cose consumption that were not confounded
by differences in body weight gain. These
differences include our reported observations
that consumption of fructose increased vis-
ceral adipose tissue (VAT) deposition, and
consumption of glucose resulted primarily
in an increase of subcutaneous adipose tissue
www.annualreviews.org • Sugar, Obesity, and Metabolic Syndrome
(SAT) deposition (21). A potential mechanistic
explanation for these results involves activation
of lipoprotein lipase (LPL), the rate-limiting
VAT: visceral adipose
enzyme involved in the uptake of triglyceride tissue
(TG) from the circulation for storage in the
LPL: lipoprotein
adipose depots. LPL associated with SAT lipase
is significantly more sensitive to activation
TG: triglyceride
by insulin than LPL associated with VAT
(40). This observation is pertinent because
consumption of glucose-sweetened beverages
resulted in increased postmeal glucose and
insulin peaks, whereas postmeal glucose
and insulin peaks were decreased during
consumption of fructose-sweetened bever-
ages (41). Thus, as shown in Supplemental
Figure 2 (see the Supplemental Material
link in the online version of this article or at
http://www.annualreviews.org/), we hypoth-
esize that activation of LPL in SAT is greater
in subjects consuming glucose, and therefore
uptake of TG in SAT is increased. In contrast,
activation of LPL in SAT is reduced in subjects
consuming fructose, resulting in increased
availability of TG for uptake into VAT.
Fructose-Containing Sugars
and VAT Accumulation
To our knowledge, there are no previous re-
ports suggesting that the macronutrient com-
position of the diet can influence adipose distri-
bution in humans; therefore, these results await
corroboration, as well as evidence that the pro-
posed mechanism may be relevant to the con-
sumption of sucrose or HFCS. Our own recent
results suggest that it may not be relevant, in
that the 24-h insulin AUC and the postmeal in-
sulin peaks were unchanged during consump-
tion of the 25%E HFCS diet compared with the
55%E complex carbohydrate diet (31). How-
ever, it was recently reported that consump-
tion of fructose-sweetened beverages or 50%
glucose + 50% fructose-sweetened beverages
at 13%E for three weeks increased the waist
to hip ratio in healthy young men, whereas
consumption of glucose-sweetened beverages
did not (42). Studies investigating the effects
of sucrose and HFCS on VAT accumulation
are clearly needed. Also, if activation of LPL
333
 ME63CH22-Stanhope ARI 12 December 2011 13:50

by insulin (or lack thereof ) is indeed mech-
anistically involved in VAT accumulation, it
is again interesting to speculate about the
effects of consuming diets that are high in
both sugar and fat [sidebar and Supplemental
Supplemental Material Figure 1 (follow the Supplemental Material
link in the online version of this article or see
http://www.annualreviews.org/)].
FRUCTOSE IN THE LIVER
Fructose and DNL:
Potential Mechanism
Annu. Rev. Med. 2012.63:329-343. Downloaded from www.annualreviews.org
when hepatic citrate and ATP levels are high,
hepatic glucose metabolism and uptake are
inhibited. Much of the consumed glucose will
then bypass the liver and reach the systemic
circulation. In contrast, the metabolism of fruc-
tose to fructose-1-phosphate is metabolized
by fructokinase. Fructokinase is not inhibited
by ATP or citrate—instead it is a virtually
unregulated enzyme (43). Therefore, even
when hepatic energy status is high, fructokinase
continues to metabolize fructose to fructose-1-
phosphate, thus allowing unregulated uptake
of fructose by the liver. Most of the consumed
fructose will be taken up by the liver and

Ten weeks of fructose consumption at 25%E comparatively little will reach the systemic
increased the rate of hepatic DNL in older, circulation. In the liver, fructose can be me-
overweight/obese subjects, whereas glucose tabolized to unregulated amounts of substrates
by University of Guelph on 07/10/12. For personal use only.

consumption did not (21). The major under- for DNL, acetyl-coA, and glyceraldehyde
lying mechanism for this differential effect 3-phosphate, thus upregulating DNL. Fur-
involves regulation by hepatic energy status thermore, fructose may activate sterol receptor
(Figure 1). Both sugars are delivered directly element binding protein–1c (SREBP-1c)
from the intestine to the liver by the portal independently of insulin, which activates genes
vein. Metabolism of glucose is regulated by involved in DNL (44). A detailed review of
phosphofructokinase (PFK), which in turn is mechanisms by which fructose may upregulate
regulated by hepatic energy status (19). Thus, DNL has recently been published (45).
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−→
Figure 1
Proposed pathways and mechanisms underlying the differential effects of fructose compared with glucose consumption on postprandial
lipid metabolism and glucose tolerance/insulin sensitivity. Hepatic glucose metabolism is regulated by phosphofructokinase, which is
inhibited by ATP and citrate. Thus, when energy status is high, hepatic uptake of dietary glucose is limited and most of the consumed
glucose will bypass the liver and reach the systemic circulation (see arrow a). Fructose is metabolized to fructose-1-phosphate by
fructokinase, which is not regulated by hepatic energy status. Therefore, even when ATP and citrate levels are high, there is
unregulated uptake and metabolism of fructose by the liver, and comparatively little of the consumed fructose will reach the systemic
circulation (see arrow b). In the liver, the large fructose load can result in increased production of DNL substrates, increased
lipogenesis, and inhibited fatty acid oxidation. The resulting increased hepatic lipid decreases apoB degradation and increases
production/secretion of VLDL-TG, mainly as TG-rich VLDL1. This, along with chlylomicron competition for LPL-mediated TG
hydrolysis and reduced LPL activation by insulin, results in longer VLDL residence time. As a result, the proatherogenic pathway is
upregulated, with VLDL1 becoming the major acceptor of CETP-mediated CE transfer from LDL and HDL, as well as a donor of
TG to LDL and HDL. Thus, postprandial levels of RLP, LDL-TG, and HDL-TG are all increased. Hydrolysis of LDL-TG by
hepatic lipase increases plasma sdLDL concentrations. Hydrolysis of HDL-TG by hepatic lipase may lead to the generation of smaller,
denser HDL particles from which apoA1 is more easily dissociated. The dissociated apoA1 may be conserved and recycled when HDL
concentrations are low, and cleared by the kidney when HDL concentrations are normal. After an overnight fast, DNL is no longer
elevated and VLDL and chylomicron remnants have been cleared, so plasma TG levels are normal. Postprandially, the increment of
plasma apoB levels is associated with VLDL particles; in the fasting state, it is presumably associated with sdLDL, which turns over
more slowly. Increased hepatic lipid supply may also induce hepatic insulin resistance, possibly through increased levels of
diacylglycerol, which activates novel-PKC. Novel-PKC decreases tyrosine phosphorylation of the insulin receptor/IRS-1, resulting in
increased hepatic glucose production, impaired glucose tolerance, and increased fasting glucose and insulin concentrations. Red arrows
represent the proatherogenic pathway, whereas dashed black arrows represent the antiatherogenic pathway. Abbreviations: CE,
cholesteryl ester; CETP, cholesteryl ester transfer protein; DNL, de novo lipogenesis; HDL, high-density lipoprotein; LDL, low-
density lipoprotein; LPL, lipoprotein lipase; PKC, protein kinase C; RLP, remnant-like particle lipoprotein; sdLDL, small dense LDL;
VLDL-TG, very low-density lipoprotein–triglyceride.

334 Stanhope
 ME63CH22-Stanhope ARI 12 December 2011 13:50

Fructose-Containing Sugars and DNL with a 0.8-g/kg glucose bolus. However,

lipogenic activity was tripled when a 0.5-g/kg
Studies investigating the effects of long-term glucose + 0.5-g/kg fructose bolus was con-
(at least one week) consumption of sucrose sumed compared with the 0.5-g/kg fructose
or HFCS on DNL have not been conducted. bolus (46). These results suggest the possibility,
Acute studies show that lipogenesis is stim- and support previous reports (48, 49), that
ulated when boluses containing fructose + fructose may stimulate hepatic glucose uptake.
glucose are consumed compared with boluses Thus, long-term consumption of sucrose or
containing pure glucose (46, 47). Interestingly, HFCS may result in greater increases of DNL
lipogenic activity was doubled when subjects than would be expected based on the fructose
consumed a 0.5-g/kg fructose bolus compared content of the sugars.

Fructose Glucose
beverage ↓ Post-meal insulin ↑ Post-meal insulin beverage
Annu. Rev. Med. 2012.63:329-343. Downloaded from www.annualreviews.org

secretion secretion
Portal vein

Portal vein
Systemic circulation

Post-meal increase of Post-meal increase of

by University of Guelph on 07/10/12. For personal use only.

plasma fructose <0.5 mM plasma glucose = 4–5 mM

b a
Fructose Glucose
Regulation
Fructokinase None by energy ATP Phosphofructokinase
status citrate
Fructose-1-P Fructose 1,6 bis-P
Fatty acid
oxidation
Glyceraldehyde
3-P + acetyl CoA
Liver Glyceraldehyde
3-P + acetyl CoA
↓ ApoB
degradation
↑ De novo ↔ De novo
lipogenesis lipogenesis
↑ ApoB ↔ ApoB degradation
↔ VLDL production
↑ Hepatic lipid TG ↔ VLDL secretion ↔ Hepatic lipid

↑ Diacylglycerol VLDL2

LPL Chylomicron
↑ Novel PKC ↑ PP chylomicron remnants cleared
by morning
↑ VLDL1
↓ Hepatic insulin Competition
sensitivity for LPL

LPL
↑ Hepatic glucose
production
VLDL remnants ↑↑ PP VLDL1 ↑ PP VLDL2
cleared by
morning
CETP CETP
TG CE CE TG LPL
Hepatic
↑ Impaired ↑ PP TG-enriched lipase
glucose tolerance LDL PP HDL CE PP LDL PP IDL
↑ Fasting LDL
Hepatic CETP
↑ Fasting glucose lipase Recycled CE-enriched LDL ↑ PP TG-enriched
for RCT LDL
↑ sdHDL
↑ Insulin secretion ↑ Fasting insulin Cleared by LDL Hepatic
receptor lipase

Dissociated
ApoA1 ↑↑ Fasting sdLDL

Recycled for Cleared by

RCT (subjects kidney (subjects
with ↓ HDL?) with ↑ HDL?)

www.annualreviews.org • Sugar, Obesity, and Metabolic Syndrome 335

 ME63CH22-Stanhope ARI 12 December 2011 13:50

Fructose and Hepatic Lipid: DNL leads to increased hepatic lipid. When
Potential Mechanisms hepatic lipid is increased, the degradation of
apolipoprotein (apo)B, the essential lipoprotein
The increased rate of DNL generates fatty acids
for the intracellular assembly of TG into very
for production of hepatic TG. Additionally, the
low-density lipoprotein (VLDL), is reduced
concurrent increase in the levels of malonyl-
(52), resulting in increased production and
coA reduces the entry of fatty acids into the mi-
secretion of VLDL. It was recently shown
tochondria, thus limiting fatty acid oxidation in
that postprandial levels of VLDL-TG increase
the liver (50). We have reported that net fatty
in parallel with total TG during steady-state
acid oxidation, calculated from hourly (7:30
fructose feeding (46). However, it is likely that
to 22:30 h) measures of indirect calorimetry,
delayed TG clearance also contributes to the
was decreased by 38% in the overweight/obese
marked increases of postprandial TG in sub-
subjects consuming fructose, but unchanged in
jects consuming fructose. Factors that may have
subjects consuming glucose (29). Thus, con-
delayed TG clearance include competition
sumption of fructose may increase hepatic lipid
Annu. Rev. Med. 2012.63:329-343. Downloaded from www.annualreviews.org

between VLDL1 and chylomicron for LPL-

levels by activating DNL via increased supply
mediated lipolysis, lowered LPL activity in
of substrate and via SREBP-1c, and by inhibit-
subjects consuming fructose compared to those
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ing the hepatic oxidation of endogenous and

exogenous fatty acids.
Fructose and Hepatic Lipid: Evidence
While we suggest that consumption of fructose
increases hepatic lipid levels, direct experimen-
tal evidence in humans is lacking. Imaging tech-
niques for measuring liver lipid levels were not
available to us when the 10-week intervention
study was initiated. Hepatic lipid was increased
in subjects who consumed an energy-balanced
diet for one week prior to baseline measurement
and then consumed a high-fructose diet that
exceeded energy requirements by 35% (51).
However, because there was only one experi-
mental group, it cannot be determined whether
the increase in liver TG was the result of the
fructose or the excess energy or both.
FRUCTOSE AND LIPID
DYSREGULATION
Fructose and Postprandial TG
Postprandial circulating TG concentrations
were increased in overweight/obese subjects
consuming fructose, but not in those con-
suming glucose (21). As shown in Figure 1,
despite the current lack of direct experimental
evidence, we hypothesize that fructose-induced
consuming glucose (21), and apoCIII. Both
fasting and postprandial levels of apoCIII were
significantly increased in the overweight/obese
subjects consuming fructose and unchanged in
subjects consuming glucose. ApoCIII can affect
TG clearance by inhibiting LPL activity and
by interfering with the binding of chylomicron
and VLDL remnants to hepatic receptors (53).
Fructose-Containing Sugars
and Postprandial TG
Our recent study demonstrated that young,
normal and overweight subjects consuming
25%E as HFCS-sweetened beverages for two
weeks had significantly increased levels of post-
prandial TG, as indexed by 24-h TG AUC and
late-evening TG concentrations, compared to
when they consumed the baseline complex car-
bohydrate diet (31). These parameters, how-
ever, were not as markedly increased as in
the subjects who consumed 25%E as fructose-
sweetened beverages. This difference may be
due to subjects consuming HFCS having less
VLDL production/secretion or greater TG
clearance (or both). It is likely that the subjects
consuming fructose had delayed TG clearance,
via less activated LPL (post-heparin LPL activ-
ity measurements are pending) due to reduced
postmeal insulin peaks (31). The only other
long-term study to assess postprandial TG

336 Stanhope
 ME63CH22-Stanhope ARI 12 December 2011 13:50
responses to high-sucrose or high-HFCS di-
ets reported that the 8-h TG AUC was in-
creased during consumption of a two-week
high-sucrose diet (23%E) compared with a
high–complex carbohydrate diet (59%E total
carbohydrate, 2% sugar) (54).
VLDL1 as an Initiator
of Lipid Dysregulation
In addition to postprandial TG, over-
weight/obese subjects consuming fructose also
exhibited increased fasting concentrations of
apoB, LDL, small dense LDL cholesterol
(sdLDL), and oxidized LDL, and significantly
Annu. Rev. Med. 2012.63:329-343. Downloaded from www.annualreviews.org
increased postprandial levels of apoB, LDL,
remnant-like particle lipoprotein (RLP)-TG,
and RLP-cholesterol compared to subjects
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consuming glucose (21). There is evidence to
suggest that the increased concentrations of
proatherogenic lipoproteins are mediated by
the increased concentrations of postprandial
TG (55). Increased hepatic lipid has been
shown to be specifically associated with the
increased synthesis and secretion of VLDL1,
the large VLDL particles that transport the
greatest quantity of TG (56). It has been
suggested that high circulating levels of large
VLDL particles specifically initiate the se-
quence of lipoprotein changes that result in
the development of an atherogenic lipoprotein
phenotype (57). The level of involvement
of VLDL1 in cholesterol ester transfer pro-
tein (CETP)-mediated lipid transfers may
explain the role of VLDL1 as an initiator
of lipid dysregulation (58). In the absence
of postprandial hypertriglyceridemia, the
major acceptor of CETP-mediated trans-
fer of cholesteryl ester (CE) from HDL is
LDL. The resulting CE-enriched LDL has
high affinity for the LDL receptor and is
rapidly cleared, and the CE-depleted HDL
is available for continued reverse cholesterol
transport; thus, this pathway is described as
antiatherogenic (58). In hypertriglyceridemic
states, due to the increased number and
prolonged residence of VLDL1 particles in
the circulation, VLDL1 becomes the major
acceptor of CETP-mediated CE transfer from
www.annualreviews.org • Sugar, Obesity, and Metabolic Syndrome
LDL and HDL, as well as a donor of TG to
LDL and HDL. This pathway is described
as proatherogenic (58), because the resulting
sdLDL: small dense
TG-enriched LDL has a prolonged residence low-density
time in the circulation, which allows for the lipoprotein cholesterol
lipolysis of TG by hepatic lipase and generation
of smaller, denser LDL particles (59). The
resulting TG-enriched HDL is also a substrate
for hepatic lipase, which lipolyzes the TG,
resulting in the dissociation and clearance of
the apoA1 from the circulation (60).
Fructose-Induced Lipid Dysregulation
To assess whether these mechanisms may
underlie the development of dyslipidemia in
the overweight/obese subjects consuming fruc-
tose (21), we measured the TG and choles-
terol content of 20 lipoprotein subfractions
[7 TG-rich lipoprotein (TGRL), 6 LDL, and
7 HDL subfractions] separated by particle
size in fasting and postprandial plasma col-
lected before and after the 10-week interven-
tion. Although this method does not differ-
entiate between apoB100-containing particles
and apoB48-containing particles, the pattern
of change of TG content within the TGRL
subfractions was supportive of the hypothesis
that consumption of fructose promotes produc-
tion/retention of large, TG-rich particles in the
postprandial state. Fructose induced increases
of TG in all postprandial TGRL subfractions
compared to glucose. However, the percent of
the total TGRL-TG associated with the four
subfractions containing the largest TGRL par-
ticles was increased during fructose consump-
tion, and the percent of total TGRL-TG as-
sociated with the three subfractions containing
the smaller TGRL particles was decreased.
Fructose and LDL
In contrast to the subjects consuming glucose,
subjects consuming fructose exhibited TG en-
richment in all LDL subfractions, specifically
in the postprandial period. These results sup-
port the suggestion that in hypertriglyceri-
demic states there are CETP-mediated trans-
fers of TG from TRLP to LDL particles. In
337
 ME63CH22-Stanhope
Annu. Rev. Med. 2012.63:329-343. Downloaded from www.annualreviews.org
by University of Guelph on 07/10/12. For personal use only.
ARI 12 December 2011 13:50
the fasting state, the changes in TG content
in the LDL particles were not different be-
tween groups, but the cholesterol content was
significantly increased by consumption of fruc-
tose compared to glucose, with the highest in-
creases occurring in the smaller LDL particles.
These results confirm our original observation
that sdLDL was increased in the subjects con-
suming fructose (21) and support the sugges-
tion that the TG-enrichment of LDL leads to
retention in the circulation, lipolysis, and the
generation of smaller, denser LDL particles.
Fructose and HDL
Fructose consumption increased TG enrich-
ment in all postprandial HDL subfractions
compared with glucose consumption, which
supports the suggestion that in hypertriglyceri-
demic states there are CETP-mediated trans-
fers of TG from TRLP to HDL as well as
LDL particles. We have reported that fasting
plasma levels of HDL cholesterol were un-
changed after 10 weeks of fructose consump-
tion (21). This is surprising, given that TG-
enriched HDL particles are prone to lipoly-
sis and to dissociation and clearance of apoA1.
However, when the subjects who consumed
fructose were divided on the basis of having low
(men <40 mg/dl, women <50 mg/dl) versus
normal levels of HDL at baseline, subjects with
normal HDL levels exhibited the expected de-
crease of fasting cholesterol in large HDL par-
ticles, while subjects with low baseline HDL
levels showed an unexpected increase of fasting
cholesterol in large HDL particles. It is possi-
ble that in the subjects with normal HDL lev-
els, the dissociated apoA1 was eliminated by the
kidneys; in the subjects with low HDL levels,
dissociated apoA1 was conserved. This scenario
is plausible in that it has been shown that dis-
sociated apoA1 can also be recycled for further
reverse cholesterol transport (61).
Fructose-Containing Sugars
and Lipid Dysregulation
Results from four older studies and two re-
cent studies suggest that consumption of the
338 Stanhope
commonly consumed sugars promote lipid dys-
regulation. In four separate cross-over studies,
subjects exhibited increased concentrations of
total and LDL cholesterol when consuming su-
crose compared to complex carbohydrate (62–
65). In a recent crossover comparison of mod-
erate (13%E) doses of fructose, 50% glucose +
50% fructose, and glucose, the fructose and
50% glucose + 50% fructose interventions led
to significant reductions of LDL particle size
in three weeks in healthy, normal-weight men,
whereas the glucose intervention did not (42).
In our recent study, consumption of HFCS-
sweetened beverages for two weeks at 25%E
increased LDL, non-HDL-cholesterol, apoB,
apoB/apoAI, postprandial remnant lipoprotein
TG and cholesterol, and sdLDL comparably
to fructose-sweetened beverages and more than
glucose-sweetened beverages in normal-weight
and overweight young adults (31).
FRUCTOSE AND INSULIN
RESISTANCE
Fructose and Insulin Resistance:
Potential Mechanism
Consumption of fructose-sweetened beverages
decreased glucose tolerance/insulin sensitivity
in older, overweight/obese adults, while con-
sumption of glucose-sweetened beverages did
not (21). We suggest that fructose may pro-
mote hepatic insulin resistance by providing a
direct source of intrahepatic lipid via DNL (66).
This mechanistic explanation contrasts with the
more established paradigm for the develop-
ment of insulin resistance, which proposes that
increased visceral adiposity and increased vis-
ceral adipocyte insulin resistance leads to in-
creased circulating and portal levels of free fatty
acids (FFA). The resulting increase in hepatic
FFA uptake increases hepatic lipid availability,
VLDL production and secretion, and hepatic
insulin resistance.
There were two reasons why this mecha-
nism, often termed the portal hypothesis, did
not appear to explain the effects of fructose
consumption in the older, overweight/obese
 ME63CH22-Stanhope ARI 12 December 2011 13:50
subjects. First, the increases of visceral adipose
tissue (VAT) after 10 weeks of fructose or
glucose consumption were not correlated with
the decreases of insulin sensitivity. Overall,
men exhibited more accumulation of VAT than
women, whereas women exhibited larger de-
creases of insulin sensitivity than men. Second,
24-h FFA exposure (the mean FFA concen-
tration of 36 samples collected over 24 h) was
significantly increased in subjects consuming
glucose and unchanged in subjects consuming
fructose. Thus, as shown in Figure 1, the
unregulated hepatic uptake and metabolism
of fructose that we hypothesize leads to DNL
Annu. Rev. Med. 2012.63:329-343. Downloaded from www.annualreviews.org
and increased liver lipid levels, and then
dyslipidemia, could also lead to hepatic insulin
resistance. As recently reviewed (67), lipid
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accumulation is associated with increased
levels of diacylglycerol, which activates novel
protein kinase C (novel-PKC). Novel-PKC de-
creases tyrosine phosphorylation of the insulin
receptor and/or insulin receptor substrate 1,
resulting in increased hepatic glucose produc-
tion, impaired glucose tolerance, and increased
fasting glucose and insulin concentrations.
Fructose-Containing Sugars
and Insulin Resistance
Evidence that the commonly consumed sugars
promote insulin resistance (IR) is inconclusive.
In our recent study, HOMA-IR (homeostasis
model of assessment for insulin resistance) was
unchanged after two weeks’ consumption of
25%E HFCS, and after consumption of fruc-
tose or glucose as well (31). This lack of a differ-
ential effect of fructose compared with glucose
consumption may be related to the subjects be-
ing younger and leaner (28 ± 7 years; 25.5 ±
4.0 kg/m2 ) than the previous subjects (52.3 ±
8.7 years; 29.3 ± 2.6 kg/m2 ), who exhibited in-
creased glucose and insulin concentrations after
two weeks of fructose consumption and a 17%
decrease in insulin sensitivity after 10 weeks
(21). It could also be related to the duration
of study. In a six-week crossover study com-
paring a 30%E sucrose diet with an isocaloric
wheat starch diet, the weekly measurements of
www.annualreviews.org • Sugar, Obesity, and Metabolic Syndrome
fasting glucose and insulin concentrations were
increased due to both an effect of sucrose diet
and an effect of time (68). The subjects (aver-
age 42 years, 9% over ideal body weight) also
displayed higher insulin responses to an oral su-
crose load during the sucrose intervention.
Reiser et al. measured the same parameters
in subjects of a crossover study in which stan-
dardized diets containing 5%, 18%, or 33% of
energy as sucrose were consumed (69). Fast-
ing glucose, fasting insulin, and the glucose and
insulin responses to the oral sucrose test were
all increased during the 18% and 33% com-
pared with the 5% sucrose diet. It is important
to note that the 24 subjects (average 36 years,
25 kg/m2 ) enrolled in this study were chosen
out of 150 potential participants for their exag-
gerated responses to an oral sucrose test. Also,
it is worth noting that the fat content of the
diets consumed in both of the studies con-
ducted by Reiser et al. was 41.5%–43% (see
sidebar). Thus, differences in subject charac-
teristics, study duration, and dietary fat content
may all be contributing to the variable study
results.
SUMMARY
We have proposed mechanisms to explain our
reported results that consumption of fructose-
sweetened beverages for 10 weeks increased
VAT deposition and DNL, produced dyslipi-
demia, and decreased glucose tolerance/insulin
sensitivity in older, overweight/obese adults,
whereas consumption of glucose-sweetened
beverages did not. Despite the limited number
of studies, there is evidence to suggest that these
mechanisms may be relevant to the consump-
tion of sucrose and HFCS. The evidence is most
limited with regard to the effects of the com-
monly consumed sugars on VAT accumulation
and DNL. The evidence concerning the effects
of sucrose or HFCS on indices of glucose toler-
ance and insulin sensitivity is variable and sug-
gests that subject characteristics (age and insulin
sensitivity), duration of study, and the fat con-
tent of the experimental diets may contribute
to the variability. The evidence is strongest
339
 ME63CH22-Stanhope ARI 12 December 2011 13:50

concerning the effects of sucrose or HFCS on
lipid dysregulation. Two studies have demon-
strated that sucrose and HFCS increase post-
prandial TG concentrations, and six studies
show they increase concentrations of athero-
genic lipoproteins. Based on this evidence, it
would appear that the maximal upper limit of
25% of total energy requirements from added
sugar, suggested in the Report of the Dietary
Guidelines Advisory Committee on the Dietary
Guidelines for Americans 2010 (1), may need to
be reevaluated.

DISCLOSURE STATEMENT
The author is not aware of any affiliations, memberships, funding, or financial holdings that might
be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS
Annu. Rev. Med. 2012.63:329-343. Downloaded from www.annualreviews.org

The author thanks Peter J. Havel for his expert advice and editing, and James Graham for his
work on the figures.
by University of Guelph on 07/10/12. For personal use only.

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www.annualreviews.org • Sugar, Obesity, and Metabolic Syndrome 343

 ME63-frontmatter ARI 20 December 2011 12:3

Annual Review of
Medicine

Contents Volume 63, 2012

Huntington’s Disease: Advocacy Driving Science

Nancy S. Wexler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
Direct-to-Consumer Genetic Testing: Perceptions, Problems,
Annu. Rev. Med. 2012.63:329-343. Downloaded from www.annualreviews.org

and Policy Responses

Timothy Caulfield and Amy L. McGuire p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p23
by University of Guelph on 07/10/12. For personal use only.

Human Genome Sequencing in Health and Disease

Claudia Gonzaga-Jauregui, James R. Lupski, and Richard A. Gibbs p p p p p p p p p p p p p p p p p p p p p35
The Genetic Architecture of Schizophrenia: New Mutations
and Emerging Paradigms
Laura Rodriguez-Murillo, Joseph A. Gogos, and Maria Karayiorgou p p p p p p p p p p p p p p p p p p p p63
CCR5 Antagonism in HIV Infection: Current Concepts
and Future Opportunities
Timothy J. Wilkin and Roy M. Gulick p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p81
New Paradigms for HIV/AIDS Vaccine Development
Louis J. Picker, Scott G. Hansen, and Jeffrey D. Lifson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p95
Emerging Concepts on the Role of Innate Immunity in the Prevention
and Control of HIV Infection
Margaret E. Ackerman, Anne-Sophie Dugast, and Galit Alter p p p p p p p p p p p p p p p p p p p p p p p p p 113
Immunogenetics of Spontaneous Control of HIV
Mary Carrington and Bruce D. Walker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 131
Recent Progress in HIV-Associated Nephropathy
Christina M. Wyatt, Kristin Meliambro, and Paul E. Klotman p p p p p p p p p p p p p p p p p p p p p p p p 147
Screening for Prostate Cancer: Early Detection or Overdetection?
Andrew J. Vickers, Monique J. Roobol, and Hans Lilja p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 161
Targeting Metastatic Melanoma
Keith T. Flaherty p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 171
Nanoparticle Delivery of Cancer Drugs
Andrew Z. Wang, Robert Langer, and Omid C. Farokhzad p p p p p p p p p p p p p p p p p p p p p p p p p p p p 185

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Circulating Tumor Cells and Circulating Tumor DNA

Catherine Alix-Panabières, Heidi Schwarzenbach, and Klaus Pantel p p p p p p p p p p p p p p p p p p p 199
Translation of Near-Infrared Fluorescence Imaging Technologies:
Emerging Clinical Applications
E.M. Sevick-Muraca p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 217
Familial and Acquired Hemophagocytic Lymphohistiocytosis
G.E. Janka p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 233
The Management of Gastrointestinal Stromal Tumors: A Model
for Targeted and Multidisciplinary Therapy of Malignancy
Heikki Joensuu and Ronald P. DeMatteo p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 247
Carotid Stenting Versus Endarterectomy
Annu. Rev. Med. 2012.63:329-343. Downloaded from www.annualreviews.org

David Doig and Martin M. Brown p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 259

Mitral Valve Prolapse
by University of Guelph on 07/10/12. For personal use only.

T. Sloane Guy and Arthur C. Hill p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 277

Telomeres, Atherosclerosis, and the Hemothelium: The Longer View
Abraham Aviv and Daniel Levy p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 293
Aquaporins in Clinical Medicine
A.S. Verkman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 303
Role of Endoplasmic Reticulum Stress in Metabolic Disease
and Other Disorders
Lale Ozcan and Ira Tabas p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 317
Role of Fructose-Containing Sugars in the Epidemics of Obesity
and Metabolic Syndrome
Kimber L. Stanhope p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 329
Vaccines for Malaria: How Close Are We?
Mahamadou A. Thera and Christopher V. Plowe p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 345
Crisis in Hospital-Acquired, Healthcare-Associated Infections
David P. Calfee p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 359
Novel Therapies for Hepatitis C: Insights from the Structure
of the Virus
Dahlene N. Fusco and Raymond T. Chung p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 373
Multiple Sclerosis: New Insights in Pathogenesis and Novel
Therapeutics
Daniel Ontaneda, Megan Hyland, and Jeffrey A. Cohen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 389
Traumatic Brain Injury and Its Neuropsychiatric Sequelae
in War Veterans
Nina A. Sayer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 405

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Eosinophilic Esophagitis: Rapidly Advancing Insights

J. Pablo Abonia and Marc E. Rothenberg p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 421
Physician Workforce Projections in an Era of Health Care Reform
Darrell G. Kirch, Mackenzie K. Henderson, and Michael J. Dill p p p p p p p p p p p p p p p p p p p p p p p 435
Reducing Medical Errors and Adverse Events
Julius Cuong Pham, Monica S. Aswani, Michael Rosen, HeeWon Lee,
Matthew Huddle, Kristina Weeks, and Peter J. Pronovost p p p p p p p p p p p p p p p p p p p p p p p p p p p p 447
Relationships Between Medicine and Industry: Approaches to the
Problem of Conflicts of Interest
Raymond Raad and Paul S. Appelbaum p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 465
Wireless Technology in Disease Management and Medicine
Annu. Rev. Med. 2012.63:329-343. Downloaded from www.annualreviews.org

Gari D. Clifford and David Clifton p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 479

Geographic Variation in Health Care
by University of Guelph on 07/10/12. For personal use only.

Tom Rosenthal p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 493

Deep Brain Stimulation for Intractable Psychiatric Disorders
Wayne K. Goodman and Ron L. Alterman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 511
Contemporary Management of Male Infertility
Peter J. Stahl, Doron S. Stember, and Marc Goldstein p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 525

Indexes

Cumulative Index of Contributing Authors, Volumes 59–63 p p p p p p p p p p p p p p p p p p p p p p p p p p p 541

Cumulative Index of Chapter Titles, Volumes 59–63 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 545

Errata

An online log of corrections to Annual Review of Medicine articles may be found at

http://med.annualreviews.org/errata.shtml

Contents vii