Insulin resistance determines a differential response to changes in

dietary fat modification on metabolic syndrome risk factors: the

LIPGENE study1
Elena M Yubero-Serrano,2 Javier Delgado-Lista,2 Audrey C Tierney,3 Pablo Perez-Martinez,2 Antonio Garcia-Rios,2
Juan F Alcala-Diaz,2 Justo P Castao,4 Francisco J Tinahones,5 Christian A Drevon,6 Catherine Defoort,7 Ellen E Blaak,8
Aldona Dembinska-Kiec,9 Ulf Risrus,10 Julie A Lovegrove,11 Francisco Perez-Jimenez,2 Helen M Roche,3 and
Jose Lopez-Miranda2*
2
Lipids and Atherosclerosis Unit, Maimonides Institute for Biomedical Research in Cordoba, Reina Sofia University Hospital, University of Crdoba,
Crdoba, Spain; CIBER Physiopathology of Obesity and Nutrition, Institute of Health Carlos III, Spain; 3Nutrigenomics Research Group, University
College Dublin Conway Institute, School of Public Health, University College Dublin, Dublin, Ireland; 4Department of Cell Biology, Physiology and
Immunology, University of Crdoba, Maimonides Institute for Biomedical Research in Cordoba/Reina Soa University, CIBER Maimonides In-
stitute for Biomedical Research in Cordoba, Crdoba, Spain; 5Biomedical Research Institute of Mlaga, Virgen de la Victoria Hospital, University of
Mlaga, Mlaga, Spain; 6Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway; 7NRA-Joint
Research Unit, UMR1260, and French National Institute of Health and Medical Research ERL1025 Lipid Nutrients and the Prevention of Metabolic Diseases,
Faculty of Medicine, Marseille, France; 8Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht School for Nutrition,
Toxicology and Metabolism, Maastricht University Medical Center, Maastricht, Netherlands; 9Department of Clinical Biochemistry, Jagiellonian University,
Collegium Medicum, Krakw, Poland; 10Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism, Uppsala University, Uppsala,
Sweden; and 11Hugh Sinclair Unit of Human Nutrition and Institute for Cardiovascular and Metabolic Research, Department of Food and Nutritional Sciences,
University of Reading, Reading, United Kingdom

ABSTRACT concentrations after consumption of the HMUFA and HSFA diets

Background: Previous data support the benefits of reducing dietary
saturated fatty acids (SFAs) on insulin resistance (IR) and other
metabolic risk factors. However, whether the IR status of those
suffering from metabolic syndrome (MetS) affects this response is
not established.
Objective: Our objective was to determine whether the degree of IR
influences the effect of substituting highsaturated fatty acid (HSFA)
diets by isoenergetic alterations in the quality and quantity of
dietary fat on MetS risk factors.
Design: In this single-blind, parallel, controlled, dietary interven-
tion study, MetS subjects (n = 472) from 8 European countries
classified by different IR levels according to homeostasis model
assessment of insulin resistance (HOMA-IR) were randomly as-
signed to 4 diets: an HSFA diet; a highmonounsaturated fatty acid
(HMUFA) diet; a low-fat, highcomplex carbohydrate (LFHCC)
diet supplemented with long-chain n3 polyunsaturated fatty acids
(1.2 g/d); or an LFHCC diet supplemented with placebo for 12 wk
(control). Anthropometric, lipid, inflammatory, and IR markers
were determined.
Results: Insulin-resistant MetS subjects with the highest HOMA-IR
improved IR, with reduced insulin and HOMA-IR concentrations
after consumption of the HMUFA and LFHCC n3 diets (P ,
0.05). In contrast, subjects with lower HOMA-IR showed reduced
body mass index and waist circumference after consumption of the
LFHCC control and LFHCC n3 diets and increased HDL choles-
terol concentrations after consumption of the HMUFA and HSFA
diets (P , 0.05). MetS subjects with a low to medium HOMA-IR
exhibited reduced blood pressure, triglyceride, and LDL cholesterol
levels after the LFHCC n3 diet and increased apolipoprotein A-I
(all P , 0.05).
Conclusions: Insulin-resistant MetS subjects with more metabolic com-
plications responded differently to dietary fat modification, being more
susceptible to a health effect from the substitution of SFAs in the HMUFA
and LFHCC n3 diets. Conversely, MetS subjects without IR may be
more sensitive to the detrimental effects of HSFA intake. The metabolic
phenotype of subjects clearly determines response to the quantity and
quality of dietary fat on MetS risk factors, which suggests that targeted
and personalized dietary therapies may be of value for its different met-
abolic features. This study was registered at clinicaltrials.gov as
NCT00429195. Am J Clin Nutr 2015;102:150917.
Keywords: dietary fat modification, insulin resistance, metabolic
syndrome, monounsaturated fat, polyunsaturated fat
INTRODUCTION
Metabolic syndrome (MetS)12 is a high-prevalence metabolic
disorder defined by the presence of 3 or more of the following
criteria: central (abdominal) obesity, high blood pressure, hyper-
triglyceridemia, low HDL cholesterol, and/or increased fasting
glucose (1, 2). MetS is also associated with cardiovascular disease
(3, 4), an increased risk of type 2 diabetes mellitus (T2DM) (5),
cancer (6), and other chronic diseases. Both insulin resistance (IR)
and abdominal obesity are considered to be significant contribu-
tors to the development of MetS (5). Thus, prevention or early
intervention for reversal of MetS would likely reduce the in-
cidence of these common diseases.

Am J Clin Nutr 2015;102:150917. Printed in USA. 2015 American Society for Nutrition 1509
1510 YUBERO-SERRANO ET AL.
Lifestyle behaviors, including diet and physical activity,
may be more effective in preventing the development of MetS
than pharmacologic agents (7). Although diet is not identified
as a risk factor for MetS, intervention studies have consistently
shown inverse associations between whole grain, fruit, and
vegetable intake, as well as Mediterranean-type diets (which
are rich in MUFAs), and MetS risk (8, 9), whereas high-fat
diets and particularly those rich in SFAs may increase serum
triglycerides, reduce HDL, and promote obesity, inflamma-
tion, IR, and MetS (1014). Notwithstanding this evidence,
it has also been demonstrated that very-low-carbohydrate,
very-high-fat interventions designed to promote ketogenesis
also improve the risk factors of T2DM (15, 16). Intake of
long-chain n3 PUFAs in intervention studies has failed to
show a consistent effect on IR in subjects with MetS (1719).
However, most of these studies showed an improvement in
some obesity-associated MetS features, such as hyperten-
sion and dyslipidemia, by decreasing plasma triglycerides
(20, 21).
Although previous data support the benefits of dietary fat
modification on MetS, it is difficult to define the optimal diet with
which to treat and prevent MetS from a clinical perspective.
Moreover, it is unclear whether the presence of IR, as one of the
major contributors to the development of MetS, may influence
this response. On the other hand, HOMA-IR has proved to be
a robust tool for the surrogate assessment of IR (22, 23), although
there is great variability in threshold HOMA-IR concentrations to
define and establish IR accurately (24, 25).
Thus, our objective was to determine whether HOMA-IR
influences the effect of substituting highSFA diets by iso-
energetic alterations in the quality and quantity of dietary fat on
MetS risk factors (NCT00429195). This is a post hoc analysis of
the large LIPGENE dietary intervention study, the main out-
comes of which were already reported (17).
1
LIPGENE was funded by the European Union (EU) Sixth Framework
Food Safety and Quality Programme, contract no. 505944, Diet, genomics,
and the metabolic syndrome: an integrated nutrition, agrofood, social and
economic analysis. Funds were also obtained from the Norwegian Founda-
tion for Health and Rehabilitation, South-Eastern Norway Regional Health
Authority, the Johan Throne Holst Foundation for Nutrition Research, and
the Freia Medical Research Foundation. This study was supported by the EU
Sixth Framework Food Safety and Quality Programme, contract no. FOOD-
2003-CT- 505944. Intervention foods were supplied by Unilever Best Foods,
Vlaardingen, Netherlands. Long-chain n3 PUFA supplement (Marinol
C-38; 1.24 g/d long-chain n3 PUFA) and placebo high-oleic acid sunflower
seed oil supplement were supplied by Lipid Nutrition, Loders Croklaan
Wormerveer, Netherlands. The study was also cofinancied by the Ministry
of Economy and Competitiveness (AGL2012-39615/ALI) and the Carlos III
Institute of Health, Spain (PIE14/000015/5), and by the Directorate General
for Assessment and Promotion of Research and the EUs European Regional
Development Fund. The CIBEROBN is an initiative of the Carlos III In-
stitute of Health, Madrid, Spain. HM Roche is supported by the Science
Fundation of Ireland, Principal Investigator Programme (11/PI/1119).
*To whom correspondence should be addressed. E-mail: jlopezmir@uco.es.
12
Abbreviations used: AIRg, acute insulin response to glucose; DBP, di-
astolic blood pressure; DI, disposition index; HMUFA, high MUFA; HSFA,
high SFA; ICAM-1, intracellular adhesion molecule 1; IR; insulin resistance;
ISI, insulin sensitivity index; LFHCC, low-fat, highcomplex carbohydrate;
MetS, metabolic syndrome; SBP, systolic blood pressure; T2DM, type 2
diabetes mellitus; VCAM-1, vascular cellular adhesion molecule 1; WC,
waist circumference.
Received March 15, 2015. Accepted for publication September 15, 2015.
First published online November 11, 2015; doi: 10.3945/ajcn.115.111286
METHODS
Participants and recruitment
The LIPGENE human dietary intervention study was a ran-
domized controlled trial that complied with the 1983 Helsinki
Declarations and was approved by the local ethics committees of
the 8 intervention centers (Dublin, Ireland; Reading, United
Kingdom; Oslo, Norway; Marseille, France; Maastricht, Neth-
erlands; Crdoba, Spain; Krakow, Poland; and Uppsala,
Sweden). Written informed consent was obtained from ev-
ery participant and approved by each institutional ethical
committee. The eligibility of participants, who were aged
3570 y with a BMI (in kg/m2) of 2040, was determined with
the use of a modified version of the National Cholesterol Edu-
cation Program criteria for MetS (26). Participants were
characterized by at least 3 of the following 5 criteria: waist
circumference (WC) .102 cm (men) or .88 cm (women);
fasting plasma glucose concentration 5.57.0 mmol/L; tri-
glycerides $1.5 mmol/L; HDL cholesterol ,1.0 mmol/L (men)
or ,1.3 mmol/L (women); and blood pressure $130/85 mm Hg
or treatment for previously diagnosed hypertension. Detailed
characteristics of this cohort have been published (8, 27).
Anthropometric measurements were recorded according to
a standardized protocol for the LIPGENE study and blood
pressure was measured according to the European Society of
Hypertension guidelines (28). Of a potential 535 eligible vol-
unteers, 486 entered the study and completed most of the pre-
intervention clinical investigation, such as the intravenous
glucose tolerance test and anthropometric and dietary assess-
ments. The present analyses include pre- and postintervention
data for 472 subjects who completed the dietary intervention,
who were divided in the following tertiles according to different
cutoffs for HOMA-IR: tertile 1 (low HOMA-IR): ,1.90; tertile 2
(medium HOMA-IR): 1.902.93; and tertile 3 (high HOMA-
IR): .2.93. HOMA-IR was not available in 14 of these volun-
teers; therefore, analysis was completed in 486 2 14 = 472
subjects.
Random assignment and dietary intervention
Random assignment and intervention have been previously
described (27). Briefly, random assignment was completed
according to age, sex, and fasting plasma glucose concentration.
Each subject was randomly stratified to one of 4 dietary in-
terventions for 12 wk. The diets differed in fat quantity and
quality while remaining isoenergetic, excluding the effects of
weight change.
The composition of the 4 diets was as follows:
1. High-SFA (HSFA) diet (38% energy: 16% SFAs, 12%
MUFAs, and 6% PUFAs; n = 118);
2. High-MUFA (HMUFA) diet (38% energy: 8% SFAs, 20%
MUFAs, and 6% PUFA; n = 124);
3. LFHCC n3 diet [28% energy: 8% SFAs, 11% MUFAs,
and 6% PUFAs, plus 1.24 g/d long-chain n3 PUFAs with
a ratio of 1.4 EPA:DHA (4 3 1-g capsules/d); n = 116]
4. LFHCC control diet [28% energy: 8% SFAs, 11% MUFAs,
and 6% PUFAs, plus a control higholeic acid sunflower
seed oil capsule (4 3 1-g capsules/d); n = 117].
 IR AND DIETARY FAT ON MetS RISK FACTORS
The HSFA diet was the reference diet and reflected the tra-
ditional fat content and composition of typical Northern Euro-
pean diets (27). The intervention diets were specifically designed
to reduce dietary SFAs by replacement with MUFAs or as part of
an LFHCC diet, while keeping dietary energy and n6 PUFAs
unaltered.
Dietary assessment
A common training protocol and standard operating pro-
cedures were developed to standardize collection of biological
samples and dietary data in each center. A 3-d weighted food
dietary record (2 weekdays and 1 weekend day) assessed pre-
intervention habitual dietary intake and was used to design in-
dividualized isoenergetic dietary fat modification (29). Two
weighted 3-d food dietary records were completed mid- and
postintervention at weeks 6 and 12 of the intervention period to
assess compliance (27). Physical activity, alcohol consumption,
and smoking habits were unaltered. Compliance was assessed by
dietary assessment, capsule count, and plasma fatty acid pattern
analysis.
Biochemical measurements
Participants arrived at the clinic center at 0800 after a 12-h fast,
refrained from smoking during the fasting period, and abstained
from alcohol intake during the preceding 7 d. In the laboratory
and after cannulation, fasting blood was taken before and after
intervention (at the end of intervention), as previously described
(30). Total cholesterol and triglycerides were quantified with the
use of an IL Test Triglycerides kit (Instrumentation Laboratory).
An IL Test HDL cholesterol kit (Instrumentation Labora-
tory) was used for direct quantification of HDL cholesterol.
LDL-cholesterol concentrations were estimated with the use of
the Friedewald formula based on total cholesterol, triglyceride,
and HDL-cholesterol concentrations. Plasma concentrations of
adiponectin, leptin, soluble vascular cellular adhesion molecule
1 (VCAM-1), soluble intercellular adhesion molecule 1 (ICAM-
1), IL-6, and TNF-a were measured by ELISA (DuoSet ELISA
Development System DY1065, DY398, DY809, DY720,
DY206 and DY210; R&D Systems).
Plasma glucose concentrations were measured with the use of
an IL Test Glucose Hexokinase Clinical Chemistry kit (In-
strumentation Laboratory). Plasma insulin concentrations were
measured by solid-phase, 2-site fluoroimmunometric assay on
a 1235 automatic immunoassay system (Auto-DELFIA kits,
Wallac Oy).
HOMA-IR was derived from fasting insulin (microunits per
liter) 3 fasting glucose (micromoles per liter)/22.5. An insulin-
modified intravenous glucose tolerance test was performed (31).
Measures of insulin sensitivity [insulin sensitivity index (ISI)]
were determined with the use of the MINMOD Millenium
Program (version 6.02, Richard N Bergman). The acute insulin
response to glucose (AIRg) (first-phase insulin response) was
defined as the incremental AUC from time 08 min. Disposition
index (DI) was calculated as the product of AIRg and ISI.
Statistical analysis
Biochemical variables were assessed for normal distribution,
and skewed variables were normalized by log10 or square-root
1511
transformation as appropriate. Statistical analyses were carried
out with the use of SPSS version 18.0 for Windows. HOMA-IR
was analyzed as tertiles after removal of experimental outliers.
HOMA-IR was categorized into tertiles (smallest to highest) and
analyzed as a categorical variable. This resulted in the following
distribution of HOMA-IR: tertile1HOMA-IR ,1.90; tertile
2HOMA-IR 1.902.93; and tertile 3HOMA-IR .2.93. An
independent-samples t test, repeated-measures ANOVA, and
univariate ANOVA were used where appropriate. Bonferronis
test was used when post hoc analysis was required. Differences
were considered to be significant when P , 0.05. All data are
means 6 SDs.
RESULTS
Baseline characteristics
The clinical characteristics of MetS subjects according
HOMA-IR tertiles are presented in Table 1. Systolic blood
pressure (SBP), diastolic blood pressure (DBP), and plasma
triglyceride concentrations were higher in the MetS subjects
with greater HOMA-IR (tertiles 2 and 3) than in those with the
lowest HOMA-IR (P , 0.05). Weight, BMI, WC, fasting glu-
cose, fasting insulin, AIRg, leptin, VCAM-1, and ICAM-1 con-
centrations were higher, and ISI, DI, HDL cholesterol, and
adiponectin concentrations were lower in the MetS subjects with
the highest HOMA-IR (tertile 3) than in those with medium or
low HOMA-IRs (tertiles 1 and 2) (P , 0.05). Subjects grouped
in tertile 2 for HOMA-IR presented an intermediate effect in
weight, BMI, WC, fasting glucose, insulin, and ISI compared
with low HOMA-IR MetS subjects (tertile 1) (P , 0.05).
Efficacy of dietary fat intervention on markers of IR
determined by degree of IR
The effects of dietary fat interventions (changes between pre-
and postintervention) on markers related to both insulin sensi-
tivity and secretion are presented in Table 2. Fasting insulin and
HOMA-IR concentrations decreased after consumption of the
HMUFA and LFHCC n3 diets in the most insulin-resistant
group (tertile 3) (HOMA-IR .2.93), and these decreases in the
2 markers were significantly lower than with the HSFA diet
(P , 0.05). Interestingly, the dietary fat modificationinduced
changes in IR with the HMUFA diet were not linked to weight
loss, BMI, and WC. In contrast, the least insulin-resistant group
(tertile 1) was most sensitive to the HSFA diet, in which fasting
insulin and HOMA-IR concentrations increased after con-
sumption of the HSFA diet (P = 0.027 and 0.005, respectively).
Moreover, these increases were significant compared with the
HMUFA and LFHCC n3 diets (Table 2). Dietary fat modifi-
cation did not affect other markers of insulin sensitivity, in-
cluding fasting glucose concentrations, ISI, AIRg, and DI. BMI
and WC were reduced after consumption of the LFHCC control
and LFHCC n3 diets in the MetS subjects with low HOMA-IR
(tertiles 1 and 2).
Differential effect of dietary intake determined by the
degree of IR on anthropometric and lipid markers and
blood pressure
The effects of dietary fat interventions (changes produced com-
paring pre- and postintervention) on anthropometric measurements,
1512 YUBERO-SERRANO ET AL.
TABLE 1
Baseline characteristics of the subjects with MetS according to tertiles of low, medium, and high HOMA-IR status1
Tertile 1 Tertile 2 Tertile 3
(n = 157) (n = 157) (n = 158) P2

Anthropometric measurements
Age, y 56 6 6 54 6 12 53 6 7 0.157
Men/women, n/n 76/162 80/152 72/158 0.228
DBP, mm Hg 84 6 7a 88 6 12b 86 6 8b 0.002
SBP, mm Hg 136 6 10a 141 6 18b 140 6 12b 0.009
Weight, kg 86.2 6 9.2a 92.0 6 16.8b 96.8 6 11.8c ,0.001
BMI, kg/m2 30.5 6 2.6a 31.9 6 4.4b 34.5 6 2.4c ,0.001
WC, cm 101.5 6 6.9a 105.6 6 11.7b 111.2 6 11.1c ,0.001
Lipids
LDL cholesterol, mmol/L 3.2 6 0.6 3.2 6 1.4 3.3 6 2.1 0.979
HDL cholesterol, mmol/L 1.13 6 0.38a 1.09 6 0.25a 0.99 6 0.50b ,0.001
Total cholesterol, mmol/L 5.3 6 11.8 5.4 6 11.3 5.30 6 10.0 0.570
Triglycerides, mmol/L 1.52 6 0.63a 1.95 6 1.09b 2.04 6 1.26b ,0.001
ApoB, mmol/L 0.99 6 0.13 1.02 6 0.38 1.06 6 0.38 0.130
ApoA-I, mmol/mL 1.41 6 1.38 1.37 6 0.38 1.38 6 1.13 0.762
Glucose metabolism
Fasting glucose, mmol/L 5.6 6 0.5a 5.8 6 1.1b 6.3 6 1.7c ,0.001
Fasting insulin, mU/L 5.3 6 2.0a 9.3 6 3.3b 15.9 6 5.2c ,0.001
ISI 3.9 6 1.3a 2.8 6 1.5b 2.1 6 1.1c ,0.001
AIRg 282 6 78a 362 6 177a 411 6 103b 0.002
DI 999 6 48a 905 6 91a 718 6 172b 0.003
Cytokines/adipokines
Adiponectin, mg/L 3.9 6 1.6a 3.8 6 2.4a 3.2 6 1.9b 0.025
Leptin, mg/L 16.89 6 8.44a 18.63 6 9.08a 28.19 6 10.93b ,0.001
TNF-a, pg/mL 5.7 6 2.4 5.0 6 3.6 4.8 6 3.9 0.604
IL-6, pg/mL 5.0 6 2.8 5.4 6 4.3 4.8 6 3.9 0.421
VCAM-1, ng/mL 573.7 6 88.0a 588.4 6 99.4a 621.8 6 140.1b 0.016
ICAM-1, ng/mL 268.0 6 47.7a 269.8 6 87.5a 308.9 6 65.4b ,0.001
1
Values are means 6 SDs. Tertile 1: low HOMA-IR (,1.90); tertile 2: medium HOMA-IR (1.902.93); tertile 3: high
HOMA-IR (.2.93). Means in a row without a common superscript letter differ. Apo, apolipoprotein; AIRg, acute insulin
response to glucose; DBP, diastolic blood pressure; DI, disposition index; ICAM-1, intracellular adhesion molecule 1; ISI,
insulin sensitivity index; MetS, metabolic syndrome; SBP, systolic blood pressure; VCAM-1, vascular cellular adhesion
molecule 1; WC, waist circumference.
2
P , 0.05 (repeated-measures ANOVA).

lipid markers, and blood pressure are presented in Table 3.
BMI decreased in the MetS subjects with lower HOMA-IR
(tertiles 1 and 2), and WC was reduced in tertile 1 after
consumption of the LFHCC control and LFHCC n3 diets
compared with the HSFA and HMUFA diets (all P , 0.05).
DBP, SBP, and LDL-cholesterol concentrations decreased
after consumption of the LFHCC n3 diet; these decreases
were significant after consumption of this diet compared with
the other diets only in subjects with the lowest HOMA-IR
(all P , 0.05).
HDL-cholesterol concentrations increased after consumption
of the HMUFA and HSFA diets in MetS subjects grouped in
tertiles 1 and 2 in comparison with the other diets (all P , 0.05).
Apolipoprotein A-I concentrations also increased in subjects
with the lowest HOMA-IR after consumption of the HMUFA
and HSFA diets (P = 0.007 and 0.021, respectively) compared
with the LFHCC control and LFHCC n3 diets (P , 0.05). The
LFHCC n3 diet reduced triglyceride concentrations in the
MetS subjects grouped in tertiles 1 and 2 compared with the
other diets (P = 0.019 and 0.015, respectively) (Table 3). In
contrast, the hypotriglyceridemic potential of long-chain n3
PUFAs was not demonstrated in subjects with the highest
HOMA-IR (tertile 3).
Differential effect of dietary intake determined by the
degree of IR on cytokines and adipokines
In MetS subjects with a lower HOMA-IR (tertiles 1 and 2),
plasma IL-6 concentrations were reduced after consumption of
the HMUFA and LFHCC n3 diets, compared with the HSFA
and LFHCC control diets (all P , 0.05). (Table 4). However,
IL-6 was not modified by these diets in individuals with a high
HOMA-IR. Adiponectin, leptin, TNF-a, VCAM-1, and ICAM-1
concentrations were unaffected by the degree of IR after con-
sumption of the different diets (Table 4).
DISCUSSION
The aim of the current study was to determine whether the
degree of IR affects the response to isoenergetic dietary fat in-
terventions to reduce the risk factors of MetS. The intervention
involved the reduction of dietary SFA intake by substitution with
MUFAs or as part of an LFHCC diet, with or without supple-
mentation with long-chain n3 PUFAs. Indeed, in our initial
analysis without stratifying the LIPGENE population into tertiles
according to HOMA-IR, (17), there was no significant effect on
IR from reducing SFAs. However, it needs to be acknowl-
edged that response to dietary intervention has a significant
 IR AND DIETARY FAT ON MetS RISK FACTORS 1513
TABLE 2
Effect of dietary fat modification on fasting glucose, insulin, and markers of insulin sensitivity and secretion according to tertiles of low, medium, and high
HOMA-IR status1
HSFA diet HMUFA diet LFHCC control diet LFHCC n3 diet
(n = 39) (n = 38) (n = 41) (n = 44)

Pre Post Pre Post Pre Post Pre Post P2

Tertile 1
Fasting glucose, mmol/L 5.6 6 0.7 5.6 6 1.2 5.7 6 0.7 5.8 6 1.2 5.6 6 0.7 5.8 6 1.3 5.6 6 0.8 5.9 6 1.4 0.580
Fasting insulin, mU/L 4.7 6 1.7 6.8 6 4.2a* 5.3 6 0.8 5.5 6 1.9b 5.4 6 1.1 6.2 6 1.9a,b 5.4 6 2.1 5.4 6 2.3b 0.039
HOMA-IR 1.2 6 0.4 1.9 6 1.2a* 1.3 6 0.4 1.4 6 1.0b 1.3 6 0.3 1.6 6 0.9a,b 1.3 6 0.4 1.8 6 0.8b 0.021
ISI 4.2 6 1.4 4.7 6 1.1 3.6 6 1.4 3.5 6 1.2 3.8 6 1.9 3.7 6 2.2 4.0 6 2.5 3.7 6 2.1 0.851
AIRg 291 6 82 274 6 91 308 6 102 324 6 91 253 6 111 286 6 98 295 6 120 292 6 129 0.488
DI 1130 6 221 1206 6 311 1065 6 301 1068 6 319 916 6 301 945 6 410 1003 6 451 1017 6 399 0.990
Tertile 2
Fasting glucose, mmol/L 5.8 6 0.8 5.9 6 0.7 5.8 6 0.5 5.9 6 0.7 5.9 6 0.8 5.8 6 0.7 5.8 6 0.7 5.9 6 0.9 0.114
Fasting insulin, mU/L 9.3 6 1.7 8.7 6 2.2 9.3 6 1.3 9.2 6 1.9 9.5 6 1.3 9.4 6 1.9 9.4 6 1.9 8.7 6 2.2 0.835
HOMA-IR 2.4 6 0.3 2.3 6 0.9 2.4 6 0.2 2.5 6 0.8 2.4 6 0.2 2.4 6 0.9 2.4 6 0.2 2.3 6 0.9 0.878
ISI 2.8 6 1.4 2.8 6 1.1 2.9 6 1.3 3.2 6 1.2 2.8 6 1.3 2.7 6 1.8 2.5 6 1.5 2.6 6 1.9 0.913
AIRg 403 6 107 388 6 99 323 6 112 364 6 101 376 6 192 378 6 201 408 6 192 389 6 201 0.516
DI 1039 6 211 968 6 199 895 6 201 1007 6 219 885 6 201 1011 6 219 949 6 331 995 6 411 0.511
Tertile 3
Fasting glucose, mmol/L 6.4 6 0.9 6.3 6 0.8 6.2 6 0.9 6.1 6 0.8 6.3 6 0.8 6.2 6 1.4 6.5 6 0.9 6.4 6 1.1 0.405
Fasting insulin, mU/L 16.0 6 2.7 14.9 6 3.2a 15.4 6 3.3 13.1 6 2.9b* 15.7 6 4.3 14.8 6 5.9a,b 15.7 6 4.0 13.0 6 4.9b* 0.019
HOMA-IR 4.6 6 0.3 4.3 6 1.9a 4.2 6 0.2 3.5 6 0.8b* 4.4 6 1.2 3.9 6 1.8a,b 4.5 6 1.2 3.6 6 1.3b* 0.035
ISI 2.0 6 1.2 1.9 6 1.1 2.9 6 1.2 3.2 6 1.1 2.1 6 0.9 1.9 6 0.7 1.8 6 0.2 1.9 6 0.6 0.877
AIRg 466 6 95 520 6 88 433 6 112 450 6 101 413 6 98 452 6 99 450 6 98 457 6 99 0.806
DI 680 6 120 968 6 213 884 6 281 784 6 203 588 6 381 709 6 209 719 6 421 819 6 318 0.226
1
Values are means 6 SDs. Tertile 1: low HOMA-IR (,1.90); tertile 2: medium HOMA-IR (1.902.93); tertile 3: high HOMA-IR (.2.93). *Significant
changes between Post and Pre in each diet (P , 0.05). Means in a row without a common superscript letter differ significantly, P , 0.05. AIRg, acute insulin
response to glucose; DI, disposition index; HMUFA, high MUFA; HSFA, high SFA; LFHCC, low fat, high complex carbohydrate; ISI, insulin sensitivity
index; Post, postintervention; Pre, preintervention.
2
P , 0.05 (repeated-measures ANOVA): differences in D changes (Post 2 Pre = change over time by tertile) between diets.

between-person variation. The degree of IR is an important issue
in terms of defining potential responsiveness to lifestyle modi-
fications and, thus, developing a better understanding of per-
sonalized health. Interestingly, these MetS subjects, who were
classified by different HOMA-IR cutoffs, showed a differential
response to dietary SFA substitution. The removal of dietary
SFAs attenuated IR in those MetS subjects with the greatest
HOMA-IR (.2.93), who showed a decrease in fasting insulin
concentrations and HOMA-IR when they consumed the HMUFA
and LFHCC n3 diets, compared with those who consumed the
HSFA diet. However, markers related to insulin sensitivity and
secretion, such as ISI, AIRg, DI, or fasting glucose, were unaltered
in the 3 subgroups of MetS subjects. Different studies have at-
tempted to assess the relation between HOMA-IR and ISI and
have found discrepancies (32, 33), as occur in our results. A fea-
sible explanation for that could be that HOMA-IR is a fasting
index, as well as a measure of IR, whereas ISI is a dynamic index
that measures insulin sensitivity. The advantage of indexes based
on dynamic testing is that information about insulin secretion can
be obtained at the same time as information about insulin action.
However, if one is interested only in estimating insulin sensitivity/
resistance, fasting surrogates may be preferable to dynamic sur-
rogates because they are simpler to obtain (34, 35). On the other
hand, MetS subjects with the lowest HOMA-IR (,1.90) exhibited
an improvement in several MetS risk factors, including a decrease
in BMI after consumption of the LFHCC control and LFHCC n3
diets compared with the HSFA and HMUFA diets, a reduction in
blood pressure (both DBP and SBP), a reduction in LDL choles-
terol and triglyceride concentrations after consumption of the
LFHCC n3 diet compared with the other diets, and an increase in
HDL cholesterol and apolipoprotein A-I concentrations after
consumption of the HSFA and HMUFA diets compared with the
LFHCC control and LFHCC n3 diets. Moreover, IL-6 was the
only variable related to inflammation that responded to dietary fat
modification. Plasma IL-6 concentrations were only reduced after
consumption of the HMUFA and LFHCC n3 diets in MetS
subjects with low and medium HOMA-IR concentrations com-
pared with the other diets (,1.90 and 1.902.93, respectively).
Cross-sectional, intervention, and experimental data suggest
that high-fat diets promote obesity, IR, and inflammation, driving
the development of MetS, T2DM, and cardiovascular disease (36,
37). However, there is a large and increasing body of published
evidence from other human studies that shows no clear effects
from SFA consumption on vascular function, IR, diabetes, and
stroke, highlighting a need for further investigation of these
endpoints (3840). Conversely, different dietary intervention
studies have analyzed the effect of changes in dietary fat on
insulin sensitivity and secretion. The KANWU study found an
improvement in insulin sensitivity, but not in insulin secretion,
in healthy subjects when dietary SFAs were substituted by
MUFAs (41). Other authors have suggested a beneficial effect
from MUFA diets compared with SFA and high-carbohydrate
diets on insulin sensitivity and glycemic response in MetS
subjects (42, 43). However, the effects of n3 PUFAs on insulin
1514 YUBERO-SERRANO ET AL.
TABLE 3
Effect of dietary fat modification on anthropometric measurements, blood pressure, and plasma lipids according to tertiles of low, medium, and high HOMA-
IR status1
HSFA HMUFA LFHCC control LFHCC n3
diet (n = 39) diet (n = 38) diet (n = 41) diet (n = 44)

Pre Post Pre Post Pre Post Pre Post P2

Tertile 1
BMI 29.7 6 4.3 29.5 6 4.2a 30.3 6 4.1 30.2 6 4.1a 31.5 6 4.5 31.0 6 4.3b* 30.9 6 4.0 30.4 6 4.2b* 0.013
WC, cm 101.3 6 11.9 99.7 6 10.2a 101.3 6 11.8 101.2 6 10.3a 103.7 6 11.0 100.3 6 11.3b* 102.2 6 12.0 100.4 6 11.0b* 0.029
DBP, mm Hg 84 6 8 83 6 8a 85 6 9 83 6 8a 82 6 7 81 6 8a 84 6 7 81 6 9b* 0.033
SBP, mm Hg 135 6 14 134 6 14a 136 6 15 134 6 14a 134 6 11 132 6 15a 137 6 12 130 6 11b* ,0.001
LDL cholesterol, 3.1 6 0.9 3.0 6 0.9a 3.3 6 0.8 3.1 6 0.9a 3.0 6 1.0 2.9 6 0.9a 3.3 6 0.8 2.9 6 0.9b* 0.012
mmol/L
HDL cholesterol, 1.1 6 0.2 1.3 6 0.2a* 1.1 6 0.2 1.3 6 0.3a* 1.2 6 0.4 1.2 6 0.3b 1.2 6 0.2 1.2 6 0.3b 0.049
mmol/L
Total cholesterol, 5.2 6 0.8 5.3 6 0.9 5.4 6 1.0 5.2 6 0.9 5.1 6 0.8 5.0 6 0.9 5.3 6 0.8 5.1 6 1.0 0.234
mmmol/L
Triglycerides, 1.6 6 0.6 1.5 6 0.6a 1.4 6 0.5 1.4 6 0.6a 1.4 6 0.5 1.5 6 0.8a 1.4 6 0.5 1.1 6 0.5b* 0.030
mmol/L
ApoB, mmol/L 1.0 6 0.8 1.0 6 0.6 0.9 6 0.6 1.0 6 0.6 0.9 6 0.4 1.0 6 0.6 1.0 6 0.5 1.0 6 0.6 0.543
ApoA-I, mmol/L 1.3 6 0.2 1.5 6 0.3a* 1.3 6 0.1 1.6 6 0.3a* 1.4 6 0.4 1.5 6 0.3b 1.4 6 0.4 1.4 6 0.3b 0.012
Tertile 2
BMI 30.9 6 4.3 30.8 6 4.3a 32.7 6 4.1 32.6 6 4.0a 31.7 6 4.1 31.2 6 4.0b* 31.6 6 4.1 31.1 6 4.0b* 0.014
WC, cm 102.9 6 10.6 102.2 6 10.4 105.7 6 9.1 105.8 6 9.4 106.1 6 9.0 105.9 6 10.4 106.1 6 9.0 105.9 6 10.4 0.835
DBP, mm Hg 88 6 10 86 6 11 89 6 11 87 6 12 88 6 15 86 6 12 88 6 15 86 6 12 0.878
SBP, mm Hg 137 6 18 136 6 17 138 6 17 137 6 17 142 6 17 139 6 20 142 6 17 139 6 20 0.913
LDL cholesterol, 3.4 6 1.2 3.2 6 1.1 3.0 6 1.1 2.9 6 0.9 3.2 6 1.1 3.1 6 0.9 3.2 6 1.1 3.1 6 0.9 0.516
mmol/L
HDL cholesterol, 1.1 6 0.3 1.3 6 0.2a* 1.0 6 0.4 1.2 6 0.2a* 1.1 6 0.3 1.1 6 0.4b 1.1 6 0.3 1.1 6 0.4b 0.041
mmol/L
Total cholesterol, 5.6 6 1.1 5.4 6 1.0 5.2 6 1.2 5.1 6 1.0 5.3 6 1.2 5.3 6 1.1 5.3 6 1.2 5.3 6 1.1 0.765
mmmol/L
Triglycerides, 2.0 6 1.5 2.0 6 0.9a 2.0 6 1.5 2.0 6 0.9a 1.8 6 1.0 1.8 6 1.2a 1.9 6 1.0 1.7 6 1.2b* 0.039
mmol/L
ApoB, mmol/L 1.1 6 0.7 1.0 6 0.6 1.1 6 0.8 1.0 6 0.6 1.1 6 0.8 1.0 6 0.6 1.1 6 0.8 1.0 6 0.6 0.672
ApoA-I, mmol/L 1.4 6 0.2 1.4 6 0.3 1.4 6 0.1 1.4 6 0.3 1.4 6 0.5 1.4 6 0.3 1.4 6 0.5 1.4 6 0.3 0.511
Tertile 3
BMI 35.1 6 4.2 35.2 6 4.2 34.7 6 4.0 34.6 6 4.1 34.3 6 5.0 34.1 6 4.0 32.4 6 4.0 32.1 6 4.3 0.495
WC, cm 111.8 6 10.4 112.1 6 10.1 111.7 6 9.4 112.3 6 9.1 110.4 6 9.4 106.4 6 9.0 110.0 6 11.1 105.9 6 10.2 0.119
DBP, mm Hg 86 6 10 86 6 11 85 6 10 85 6 11 85 6 12 83 6 14 85 6 13 84 6 11 0.335
SBP, mm Hg 141 6 16 136 6 14 134 6 12 132 6 19 140 6 13 138 6 20 135 6 19 133 6 13 0.677
LDL cholesterol, 3.1 6 1.1 3.3 6 1.8 3.0 6 1.0 3.0 6 1.2 3.4 6 1.1 3.3 6 1.2 3.4 6 1.0 3.2 6 1.2 0.887
mmol/L
HDL cholesterol, 0.9 6 0.4 1.0 6 0.2 1.0 6 0.2 1.0 6 0.2 1.0 6 0.4 1.0 6 0.2 1.0 6 0.4 1.0 6 0.5 0.912
mmol/L
Total cholesterol, 5.1 6 1.2 5.3 6 1.4 5.1 6 1.0 5.0 6 1.4 5.3 6 1.0 5.2 6 1.3 5.4 6 1.0 5.3 6 1.1 0.435
mmol/L
Triglycerides, 2.2 6 1.8 2.1 6 0.4 1.8 6 0.4 1.7 6 0.4 1.9 6 0.5 2.0 6 0.4 1.9 6 0.5 1.8 6 0.4 0.423
mmol/L
ApoB, mmol/L 1.1 6 0.8 1.1 6 0.6 1.0 6 0.8 1.0 6 0.6 1.0 6 0.4 1.0 6 0.6 1.0 6 0.2 1.0 6 0.6 0.871
ApoA-I, mmol/L 1.4 6 0.2 1.3 6 0.5 1.4 6 0.2 1.4 6 0.5 1.4 6 0.2 1.3 6 0.5 1.4 6 0.2 1.3 6 0.5 0.626
1
Values are means 6 SDs. Tertile 1: low HOMA-IR (,1.90); tertile 2: medium HOMA-IR (1.902.93); tertile 3: high HOMA-IR (.2.93). *Significant
changes between Post and Pre in each diet (P , 0.05). Means in a row without a common superscript letter differ significantly, P , 0.05. Apo, apolipoprotein;
DBP, diastolic blood pressure; HMUFA, high MUFA; HSFA, high SFA; LFHCC, low fat, high complex carbohydrate; Post, postintervention; Pre, preintervention;
SBP, systolic blood pressure; WC, waist circumference.
2
P , 0.05 (repeated-measures ANOVA): differences in D changes (Post 2 Pre = change over time by tertile) between diets.

sensitivity and secretion are controversial, showing a neutral/
marginal effect in related indexes in healthy subjects (41) and in
both insulin-resistant and T2DM subjects (44).
The addition of n3 fatty acids influenced neither insulin sen-
sitivity nor insulin secretion.
In this sense, our results demonstrated that consumption of
both the HMUFA and LFHCC n3 diets reduced fasting insulin
concentrations and HOMA-IR, but consumption of other diets
did not; this occurred only in those MetS patients with the
greatest HOMA-IR, although the other variables related to in-
sulin sensitivity were not affected. On the other hand, con-
sumption of an HSFA diet produced an increase in fasting
insulin and HOMA-IR in MetS subjects with lower HOMA-IR.
Similarly, and in agreement with most dietary fat modification
 IR AND DIETARY FAT ON MetS RISK FACTORS 1515
TABLE 4
Effect of dietary fat modification on plasma cytokines, adipokines, and adhesion molecule concentrations according to tertiles of low, medium, and high
HOMA-IR status1
HSFA diet HMUFA diet LFHCC control diet LFHCC n3 diet
(n = 39) (n = 38) (n = 41) (n = 44)

Pre Post Pre Post Pre Post Pre Post P2

Tertile 1
Adiponectin, mmol/L 3.6 6 2.6 3.8 6 2.2 3.7 6 2.6 3.9 6 2.2 5.1 6 3.6 5.5 6 3.2 3.7 6 3.1 4.3 6 3.2 0.531
Leptin, mU/L 17.4 6 9.7 17.8 6 10.2 12.6 6 9.7 15.8 6 12.2 15.8 6 9.7 15.2 6 10.2 20.4 6 11.7 18.0 6 12.4 0.460
TNF-a, pg/mL 5.8 6 4.4 4.1 6 4.2 6.1 6 7.4 5.1 6 5.2 4.8 6 4.4 4.2 6 4.2 6.0 6 3.4 5.3 6 5.4 0.235
IL-6, pg/mL 4.8 6 1.4 4.7 6 2.3a 5.6 6 2.4 4.3 6 2.1b* 4.2 6 1.4 5.3 6 2.0a 5.7 6 2.0 4.1 6 2.1b* 0.031
VCAM-1, ng/mL 579 6 156 569 6 181 604 6 156 625 6 191 638 6 149 626 6 199 583 6 168 582 6 174 0.388
ICAM-1, ng/mL 273 6 68 278 6 69 273 6 69 281 6 71 268 6 77 276 6 75 272 6 81 264 6 88 0.590
Tertile 2
Adiponectin, mmol/L 4.5 6 3.0 4.5 6 3.2 3.9 6 3.1 3.9 6 3.0 3.5 6 2.7 3.5 6 2.2 3.4 6 2.7 3.8 6 2.5 0.714
Leptin, mU/L 19.4 6 10.7 18.0 6 9.2 20.6 6 10.7 19.7 6 10.2 16.5 6 10.7 15.0 6 10.0 20.2 6 11.7 18.2 6 10.3 0.435
TNF-a, pg/mL 4.8 6 2.8 4.9 6 3.2 4.3 6 2.9 4.2 6 3.1 5.0 6 2.9 5.1 6 3.1 5.4 6 2.9 5.6 6 3.1 0.678
IL-6, pg/mL 4.8 6 1.4 4.6 6 2.1a 6.2 6 1.1 4.6 6 2.0b* 5.5 6 4.1 4.9 6 2.0a 5.2 6 4.1 4.0 6 2.0b* 0.013
VCAM-1, ng/mL 572 6 293 605 6 311 597 6 311 589 6 322 562 6 311 575 6 174 567 6 311 581 6 174 0.519
ICAM-1, ng/mL 270 6 74 269 6 75 286 6 65 269 6 72 265 6 74 259 6 81 278 6 74 282 6 73 0.516
Tertile 3
Adiponectin, mmol/L 3.3 6 1.8 3.4 6 2.2 3.5 6 2.0 3.2 6 3.3 3.2 6 0.8 3.7 6 1.4 3.3 6 0.8 3.3 6 1.9 0.435
Leptin, mU/L 30.7 6 18.7 29.8 6 19.2 33.8 6 10.7 33.2 6 10.2 27.0 6 10.3 27.3 6 11.9 31.3 6 19.3 29.7 6 15.9 0.819
TNF-a, pg/mL 4.6 6 1.7 4.9 6 2.2 4.7 6 1.9 4.5 6 3.8 4.4 6 1.2 4.0 6 1.8 4.5 6 1.2 4.6 6 1.8 0.635
IL-6, pg/mL 4.2 6 1.4 4.5 6 2.1 5.2 6 3.1 5.0 6 3.0 4.5 6 2.9 5.2 6 1.9 5.2 6 3.9 4.8 6 1.8 0.807
VCAM-1, ng/mL 572 6 218 608 6 211 560 6 187 557 6 201 598 6 206 597 6 234 581 6 218 593 6 230 0.606
ICAM-1, ng/mL 314 6 81 317 6 87 311 6 70 317 6 81 326 6 81 323 6 89 289 6 81 290 6 91 0.226
1
Values are means 6 SDs. Tertile 1: low HOMA-IR (,1.90); tertile 2: medium HOMA-IR (1.902.93); tertile 3: high HOMA-IR (.2.93). *Significant
changes between Post and Pre in each diet (P , 0.05). Means in a row without a common superscript letter differ significantly, P , 0.05. HMUFA, high
MUFA; HSFA, high SFA; ICAM-1, intracellular adhesion molecule 1; LFHCC, low fat, high complex carbohydrate; Post, postintervention; Pre, preintervention;
VCAM-1, vascular cellular adhesion molecule 1.
2
P , 0.05 (repeated-measures ANOVA): differences in D changes (Post 2 Pre = change over time by tertile) between diets.

studies, we did not find an effect from reducing dietary SFAs on
insulin secretion in any MetS subject groups.
Interestingly, we observed that the LFHCC n3 diet signifi-
cantly reduced both SBP and DBP in MetS subjects with lower
HOMA-IR. Similarly, the hypotensive effect of the LFHCC n3
diet was also demonstrated in our MetS population (45). In
contrast, other studies that compared high-carbohydrate with
high-MUFA diets observed no differences in the blood pressure
response, or were even favorable to MUFA diets (46). However,
an independent inverse relation of total n3 PUFA intake to SBP
and DBP has been shown in a population-based study on food
n3 PUFA intake (47).
It has been well described that the potential hypertriglyceridemic
effect of an LFHCC diet could be ameliorated by long-chain
n3 PUFA supplementation (20). Although we previously
reported that an LFHCC n3 diet reduced plasma triglyceride
concentrations in MetS subjects, this effect was most striking
in men (17). In the current analysis, we demonstrated that
long-chain n3 PUFAs only effectively reduced plasma tri-
glyceride concentrations, in association with reduced LDL
cholesterol concentrations in MetS subjects with a low to
medium HOMA-IR.
HDL is a major risk factor for coronary artery disease and its
reduction is a very important risk factor for MetS. In our study,
HDL cholesterol concentrations were increased after the 2 high-
fat diets (HSFA and HMUFA), reflecting the well-characterized
impact of total fat on HDL metabolism. When specific types of
fatty acids were analyzed, SFA and MUFA intake, but not for
PUFA intake, were associated with higher HDL cholesterol
content (48). However, this increase in HDL cholesterol con-
centrations only occurred in MetS subjects with lower HOMA-
IR, which is in agreement with other intervention studies (41, 49).
In the full cohort, the LIPGENE intervention study showed no
significant effect from dietary fat modification on several markers
of inflammation, coagulation, lipid peroxidation, and oxidative
stress (50). Interestingly we observed that the HMUFA and
LFHCC n3 diets significantly reduced plasma IL-6 concen-
trations in MetS subjects with low-medium HOMA-IR. In
contrast, these diets had no impact on IL-6 in the subjects with
the greatest IR. It is difficult to modify the inflammatory phe-
notype of dietary fat modification alone in weight-stable MetS
individuals, particularly considering a situation of IR. A related
study showed that long-chain n3 PUFA supplementation re-
duced plasminogen activator inhibitor-1 concentrations, but not
leptin, adiponectin, IL-6, or TNF-a concentrations (19). How-
ever, there are several other studies that have shown little effect.
Despite the evidence, we should be cautious in the in-
terpretation of our results. The LIPGENE cohort is a very-well-
characterized population, and the multicenter origin of the
subjects allows extrapolation of the results to the European
population. A limitation is ensuring complete adherence to di-
etary instructions in a feeding trial. However, adherence to
recommended dietary patterns was good, as judged by dietary
assessment. Also, we have to point out that our study represents
1516 YUBERO-SERRANO ET AL.
a secondary analysis of the LIPGENE study. More studies would
be required specifically designed for this purpose.
In summary, MetS is a heterogeneous condition requiring targeted
and personalized dietary therapies for its different metabolic fea-
tures. Our data support earlier findings, from a cross-sectional study,
that reported a differential response to modifications in dietary fat in
MetS subjects divided according to different HOMA-IR cutoffs. We
could suggest that those MetS subjects with IR (greater HOMA-IR)
showed more metabolic complications and may be more susceptible
to the healthy effects of dietary SFA substitution, which favors the
HMUFA and LFHCC n3 diets. However, although MetS
subjects without IR (lower HOMA-IR) showed improvement
in other metabolic risk factors related to MetS, such as obesity,
blood pressure, and lipid markers, mainly after consumption
of the LFHCC n3 diet, they may be more responsive to the
detrimental effects of the HSFA diet.
However, a confirmation of this hypothesis would require
a study designed specifically to address this issue. More extensive
dietary fat modification studies are needed to extend the knowledge
about the quantity and quality of dietary fat on MetS risk factors
and to shed more light on nutrition based on therapeutic strategies
for IR on metabolic syndrome.
The authors responsibilities were as followsEMY-S, JD-L, PP-M,
AG-R, FJT, and FP-J: collected the data; CAD, CD, EEB, AD-K, UR, JAL,
HMR, and JL-M: designed and conducted the research and provided mate-
rials or participants; EMY-S, ACT, JFA-D, and JPC: analyzed the data;
EMY-S: wrote the manuscript; JD-L, ACT, CAD, and HMR: provided sig-
nificant advice and support in reviewing the drafting of the manuscript;
HMR and JL-M: had the main responsibility for the final content; and all
authors: read and approved the final manuscript. None of the authors re-
ported a conflict of interest related to the study.
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