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a
c
Food Security Research Center, b Department of Community Nutrition, School of Nutrition and Food Science, and
Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
Key Words
Moderate carbohydrate restriction Metabolic syndrome
Inflammation C-reactive protein Adipocytokines
Endothelial function
Abstract
Background and Aims: Despite the efficacy of low-carbohydrate diets in the management of metabolic syndrome
(MetS), it remains unknown if these favorable effects are mediated through changes in inflammation and endothelial
dysfunction. We aimed to assess the effects of moderate
substitution of dietary fats for carbohydrates on serum levels
of adipocytokines, inflammatory indices, and biomarkers of
endothelial function among women with the MetS. Methods: In a randomized cross-over clinical trial, 30 overweight
or obese (BMI >25) women with the MetS were randomly allocated to follow either a high-carbohydrate (HC) (6065%
carbohydrates, 2025% fats) diet or a moderately restricted
carbohydrate (MRC) (4347% carbohydrate, 3640% fats)
diet, each for 6 weeks. After a 2-week washout period, individuals were switched to the alternate diet for an additional
6 weeks. In a fasted state, markers of inflammation [highsensitivity C-reactive protein (hs-CRP), high-sensitivity inter-
Introduction
Rajaie/Azadbakht/Saneei/Khazaei/
Esmaillzadeh
Run-in period
n = 39
HC diet
n = 19
MRC diet
n = 20
Dropouts (n = 5)
Pregnancy (n = 1)
Dropouts (n = 4)
Surgery (n = 1)
Hip fracture (n = 1)
Washout period
n = 30
Traveling (n = 1)
Personal reasons (n = 2)
Personal reasons (n = 1)
HC diet
n = 16
MRC diet
n = 14
completed by 30 women. All participants provided written informed consent. The study wasapproved by the ethical committee
of the Isfahan University of Medical Sciences, Isfahan, Iran, and
is registered (IRCT201105131485N3) at the Iranian website for
registration of clinical trials (www.irct.ir).
activity and supplement use throughout the study. Anthropometric and biochemical measurements were done in the fasting state
in both study arms at baseline and after 6 weeks.
Study Design
At baseline, we collected information about demographic characteristics, medical history, and medication/supplement use. Prior
to the dietary intervention, all participants underwent a 2-week
run-in period during which they continued their habitual dietary
intakes and physical activity levels. All subjects were educated on
how to record their dietary intakes and physical activities. Threeday food records (2 weekdays and 1 weekend day) and 2-day physical activity records were taken from each subject throughout this
period. Following the run-in period, participants were randomly
assigned to consume either a high-carbohydrate (HC) diet or a
moderately restricted carbohydrate (MRC) diet (explained below),
according to a random-order cross-over design, for 6-weeks duration each. Treatment assignments were separated by a 2-week
washout period. Dietary and physical activity records were completed by each participant once every 2 weeks during the study.
Subjects were asked not to change their habitual levels of physical
Diets
Since all participants were overweight or obese, both diets were
designed to be calorie restricted (350700 kcal less than the computed energy requirement for each participant). The calorie requirements of each subject were estimated based on resting energy expenditure (using the Harris-Benedict equation) and physical activity
levels. The main difference between the two diets was the percent of
energy from fats and carbohydrates. The macronutrient composition of the HC diet was designed to be similar to that in Iranian
usual diets [18], i.e. 6065% of the energy from carbohydrates and
2025% from fats. The MRC diet was composed of 4347% of total
calories as carbohydrates and 3640% as dietary fats. Indeed, in the
MRC diet 1520% of the energy from carbohydrates was replaced
by nonhydrogenated vegetable oils. The protein content of both diets
was 1517% of the total energy. A 7-day cycle menu was provided
for each participant. To facilitate compliance, subjects were given an
exchange list of food groups and individually instructed about the
goals of each phase as well as the exchange list. Compliance with the
diets was assessed by the investigators by asking subjects to record
161
their dietary intakes once every 2 weeks. Dietary records were analyzed for their energy and macronutrient content using NutritionistIV software which was modified for Iranian food items.
Biochemical Assessment
After a 12-hour overnight fast, 10 ml venous blood samples
were collected and immediately centrifuged at 2,500 g for 10 min.
The obtained serum was stored frozen at 70 C until later analysis.
Serum concentrations of inflammatory biomarkers [including hsCRP, high-sensitivity interleukin-6 (hs-IL-6), high-sensitivity tumor necrosis factor- (hs-TNF-), and serum amyloid A (SAA)]
and adipocytokines (leptin and adiponectin), as well as markers of
endothelial function [including E-selectin, serum intercellular adhesion molecule 1 (sICAM-1), and serum vascular cell adhesion
molecule 1 (sVCAM-1)], were quantified by means of an enzymelinked immunosorbent assay using commercially available kits.
Both inter- and intra-assay coefficients of variation for all biomarkers were less than 10%.
Results
Age, years
Weight, kg
Height, cm
BMIa, kg/m2
Waist circumference, cm
Hip circumference, cm
Waist-to-hip ratio
Fat mass, kg
Body fat, %
Lean body mass, %
Categorical variables, %
Married
Family history of diabetes
Family history of stroke
Current supplement use
Regular physical activityb
Postmenopause
an
Mean
Standard
deviation
Range
42.4
80.8
157.6
33.0
107.2
116.1
0.91
32.4
39.5
60.5
7.2
14.8
5.6
4.6
15.7
10.3
0.06
8.7
3.9
3.9
2457
55.9104.8
147172
2541.1
88154
100140
0.801.03
18.848.9
30.747.0
53.069.3
96.7
53.3
70.0
33.7
46.7
26.7
= 29.
bHaving
HC dieta
Food groups (servings/day)
Dairy products
Vegetables
Fruits
Grains
Meats and alternatives
Fats and oils
Nutrients
Macronutrients
Energy, kcal
Carbohydrate, %
Protein, %
Fat, %
Micronutrients
Cholesterol, mg
Fiber, g
Calcium, mg
Phosphorus, mg
Sodium, mg
Potassium, mg
Zinc, mg
Folic acid, g
Vitamin B6, mg
MRC dietb
Differencec
pd
1.630.10
3.690.26
5.110.31
9.160.40
2.820.19
5.240.31
1.650.12
3.230.23
3.310.15
7.460.23
3.560.15
9.720.56
0.220.12
0.460.24
1.800.30
1.700.43
0.740.17
4.470.48
0.86
0.07
<0.01
<0.01
<0.01
<0.01
1,740.258.0
57.80.6
15.60.3
27.70.6
1,729.951.6
45.90.7
15.60.3
39.50.8
10.350.2
12.00.9
0.00.4
11.80.9
0.84
<0.01
0.96
<0.01
165.415.8
22.71.2
1,093.555.4
1,156.253.5
1,198.6148.2
3,563.5180.4
7.60.4
335.123.4
1.60.1
163.014.9
18.50.9
1,028.148.5
1,149.545.6
1,046.4115.6
3,114.1113.5
8.00.4
285.714.3
1.60.1
2.414.3
4.21.3
65.450.2
6.748.4
152.298.5
449.4164.2
0.50.5
49.422.1
0.00.1
0.87
<0.01
0.20
0.89
0.13
0.01
0.26
0.03
0.91
40
p = 0.17
38
36
MET h/day
34
37.8
35.6
36.5
37.2
32
30
28
26
24
Run-in
HC diet
Washout
MRC diet
163
Table 3. Effect of an MRC diet on weight, serum levels of inflammatory indices and adipocytokines among women with the MetS
Variables
Weight, kg
BMI, kg/m2
hs-CRP, mg/l
hs-TNF-, ng/ml
hs-IL-6, ng/ml
SAA, g/ml
Leptina, ng/ml
Adiponectina, ng/ml
HC dietb (n = 30)
pf
baseline
6th week
changed
pe
baseline
6th week
changed
pe
80.914.5
32.25.0
1.381.29
0.211.91
0.151.90
2.611.39
78.35.5
10.60.3
79.214.5
31.55.1
1.151.24
0.461.42
0.042.28
6.621.13
67.26.1
8.90.3
1.700.36
0.670.14
1.090.43
0.132.03
0.050.24
3.271.22
11.144.47
1.682.30
<0.001
<0.001
0.42
0.16
0.21
<0.01
0.02
<0.001
79.714.4
31.75.0
1.401.28
0.182.01
0.102.00
4.011.15
71.05.6
10.30.3
78.013.5
31.34.8
1.081.26
0.511.58
0.161.90
4.571.12
73.34.4
9.80.2
1.720.40
0.960.16
0.290.48
0.102.12
0.110.17
0.200.79
2.685.30
0.462.17
<0.001
<0.001
0.11
0.19
0.70
0.38
0.62
0.25
0.96
0.90
0.24
0.99
0.57
0.04
0.09
0.08
Reported values for baseline and the 6th week are geometric means SEM and those for changes are means SEM.
aReported values are means SEM.
b
Energy-restricted diet that contained 6065% of energy from carbohydrates, 2025% from fats, and 1520% from proteins.
cEnergy-restricted diet that contained 4347% of energy from carbohydrates, 3640% from fats, and 1520% from proteins.
d
Calculated by subtracting values at the 6th week from values at baseline.
e
Within-group changes by paired t test.
fBetween-group changes by paired t test.
Table 4. Effect of an MRC diet on circulating levels of biomarkers of endothelial function among women with the MetS
Variables
HC dieta (n = 30)
baseline
sICAM-1, ng/ml
sVCAM-1, ng/ml
E-selectinf, ng/ml
6th week
193.75.7
219.38.2 25.609.08
1,159.472.8 1,233.251.9 73.8392.76
24.531.13
18.171.10 8.713.92
pe
pd
baseline
0.01
0.43
0.02
188.75.5
211.78.7
23.009.57 0.02
1,155.480.8 1,302.946.5 147.4783.60 0.09
24.531.10
18.171.08 9.163.87 0.01
6th week
changec
pd
0.87
0.62
0.94
Discussion
The major finding of the present study was that consumption of an MRC diet had more favorable impacts on
SAA and adiponectin concentrations compared to an HC
diet; however, we failed to find a significant effect on othRajaie/Azadbakht/Saneei/Khazaei/
Esmaillzadeh
er inflammatory biomarkers. To the best of our knowledge, this study is the first to examine the effect of moderate variation in the dietary carbohydrate intake on surrogate measures of inflammation in a cross-over design.
Earlier studies have mostly applied parallel designs [14
16]. Moreover, this study was conducted among women
with the MetS. This is of particular importance given that
the MetS is the underlying condition for diabetes and cardiovascular disease [2], particularly in Middle Eastern
countries where the syndrome is highly prevalent with its
unique pattern. Furthermore, unlike most previous studies [1517], we used moderate carbohydrate restriction in
order to increase the possibility of long-term adherence
to carbohydrate-restricted diets. Identical protein contents in both diets is another point of this study.
Low-grade systemic inflammation has been recognized as a potent trigger for the pathogenesis and development of atherosclerosis, diabetes, neurodegenerative
disorders, cardiovascular disease, and MetS [79]. Finding the optimal dietary macronutrient composition to
modulate the inflammatory response would, therefore, be
of great importance. In the current study, we hypothesized that moderate replacement of dietary carbohydrates
by fats would improve circulating markers of inflammation, endothelial function, and adipocytokines. We found
that SAA and adiponectin levels were more significantly
affected by the MRC diet than that by the HC diet. Furthermore, our previous investigation in this population
of women showed a greater improvement in central obesity, atherogenic dyslipidemia, and hypertension with the
MRC diet than that with the HC diet [24]. These findings
are in line with previous studies [14, 25, 26]. In a parallel
randomized clinical trial, Forsythe et al. [14] indicated
that a very-low-carbohydrate diet (12% of energy from
carbohydrate) resulted in a greater reduction in some inflammatory biomarkers compared to a low-fat diet. In another clinical trial among insulin-resistant patients, moderate carbohydrate restriction led to lower serum E-selectin concentrations compared to fat restriction [25].
We found that the changes in most proinflammatory
cytokines and adhesion molecules were not significantly
different between the two diets. In agreement with our
observations, several previous studies have also shown
that carbohydrate restriction, for 2 weeks to 6 months,
leads to similar changes in serum hs-CRP [15, 17, 19, 27,
28], TNF- [17, 20, 28], IL-6 [17, 20, 28], and sICAM-1
[17, 28] levels compared to a low-fat diet. These findings
suggest that the magnitude of weight loss, not dietary
macronutrient composition, should be considered as the
primary determinant of inflammation modulation.
Contrary to our expectations, some inflammatory indices were significantly increased despite weight loss.
Others have also reached such findings [16, 29]. In the
context of weight loss diets, Seshadri et al. [30] showed
that consumption of a very-low-carbohydrate diet for
6months among patients with an initial low to moderate
level of hs-CRP (3 mg/dl) resulted in a significant increase in serum CRP levels [30]. It seems that baseline
levels of serum hs-CRP are a major determinant of the
inflammatory response to weight loss [29, 30]. Increased
levels of inflammation following weight loss have mostly
been reported among those with a normal baseline level
of hs-CRP; however, among individuals with high serum
hs-CRP levels at baseline, weight loss has resulted in reduced levels of inflammatory biomarkers [30]. In the current study, when the data were analyzed based on baseline
serum levels of hs-CRP, we reached the same findings.
Increased inflammation despite significant weight loss in
the current study needs further investigation. It seems
that factors other than weight loss might influence systemic inflammation.
Several underlying mechanisms for the effects of carbohydrates on the surrogate inflammatory biomarkers
have been postulated [3135]. Hyperglycemia and hypertriglyceridemia induced by excessive dietary carbohydrate intake increase oxidative stress via the activation of
enzymes responsible for reactive oxygen species production [31, 32]. A growing body of evidence indicates that
glucose intake activates several proinflammatory transcription factors like nuclear factor (NF)-B, activator
protein 1 (AP-1), and early growth response 1 (Egr-1) and
consequently upregulates the expression of systemic inflammation mediators (such SAA and adiponectin) [33,
34]. Moreover, activation of leukocytes, particularly T
lymphocytes and monocytes, as well as complement systems by triglyceride-rich lipoproteins might be involved
in the pathogenesis of inflammation [35]. Numerous
studies have also hypothesized that the carbohydrate intake might affect inflammation by interfering with the
normal insulin activity [34].
Our findings must be interpreted while considering
some limitations. We used the single measure of proinflammatory status to achieve serum levels of inflammatory biomarkers, while markers of systemic inflammation
fall and rise from day to day. Repeated measurements of
these biomarkers would be required for a better reflection
of inflammation. Furthermore, despite having MetS, just
4 cases were insulin resistant [36] at baseline. Some studies have shown that hypocaloric diets reduce inflammation only in insulin-resistant patients, not in other obese
165
Acknowledgments
The authors would like to thank the Clinical Research Council of the Isfahan University of Medical Sciences as well as the
Food Security Research Center for their financial support of this
study.
Disclosure Statement
The authors have no personal or financial conflicts of interest.
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