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Am J Clin Nutr 2013;98:1533–42. Printed in USA. Ó 2013 American Society for Nutrition 1533
a certain food product. Therefore, besides studying effects of nu- the Hoorn study were used. We combined these studies because
trients on inflammation and markers of glucose metabolism, it is they had followed a similar data-collection research protocol and
also important to study whether the overall diet is associated with had been used as a combined cohort in previous investigations
markers of glucose metabolism through its effects on low-grade (21–23). Of the 1397 participants with reliable measures of food
inflammation. A dietary index that reflects the quality of the diet, intake obtained from a food-frequency questionnaire (FFQ) (518
the alternative healthy eating index (AHEI), was associated with subjects from the CODAM; 879 subjects from the Hoorn study),
markers of low-grade inflammation and risk of type 2 diabetes (8, we excluded, in consecutive order, 138 participants with missing
9). However, this index was not designed to reflect the in- information on glucose metabolism status or inflammation
flammatory potential of the diet. To design an index that does markers, 105 participants with known diabetes, 22 participants
reflect the inflammatory potential of the diet, Cavicchia et al (10) with missing information on covariates used in the analysis, and
developed dietary inflammatory weights for a number of dietary 108 participants with a CRP concentration .10 mg/L. Partici-
components on the basis of a systematic review of available lit- pants with CRP concentrations .10 mg/L were excluded be-
erature on diet and inflammation. For instance, ethanol had an cause these higher concentrations reflect acute rather than
antiinflammatory weight of 20.53, whereas SFA had a proin- chronic inflammation (24). Finally, the population for analysis
flammatory weight of 0.25. The weights can be used to obtain comprised 1024 participants (420 subjects from the CODAM;
a dietary inflammatory index (DII) that reflects the inflammatory 604 subjects from the Hoorn study).
potential of the diet. To our knowledge, whether a DII is associated
with any inflammation-related health outcomes, such as markers Assessment of dietary intake
of glucose metabolism, has not been previously investigated.
Aims of this study were to investigate whether a DII is as- In both cohorts, dietary intake was assessed by using a self-
administered semiquantitative FFQ, which had been validated in
Study population
Calculation of adapted dietary inflammatory index
The study population consisted of participants from the fol-
lowing 2 Dutch cohorts: the Cohort study on Diabetes and Cavicchia et al (10) has developed literature-based dietary in-
Atherosclerosis Maastricht (CODAM) and the Hoorn study. flammatory weights that reflect the inflammatory potential of en-
Briefly, the CODAM started in 1999 and is an ongoing cohort ergy, 32 nutrients, 4 food products, 4 spices, and caffeine (Table 1).
study. It was designed to investigate the effects of disturbed glucose In line with Cavicchia et al (10), we obtained a DII by multiplying
metabolism, obesity, blood lipids concentrations, lifestyle factors, the dietary inflammatory weights of the dietary components by the
and genetic factors on cardiovascular disease and mortality (11–15). daily intake. Subsequently, these multiplications were summed.
The CODAM comprises 574 participants who were selected on the Details about the calculation of the DII are shown in Table 1.
basis of elevated risk of type 2 diabetes and cardiovascular diseases On the basis of a nutritional rationale, we also obtained an
from a large population-based cohort (n . 20,000) and had un- adapted dietary inflammatory index (ADII) by multiplying the
dergone a glucose metabolism screening test (n = 2715) (11, 16). dietary inflammatory weight of 26 nutrients, one food product,
Briefly, the Hoorn study started in 1989 with a sample of the one spice, and caffeine by the standardized energy-adjusted in-
general population of Hoorn, Netherlands (n = 2484) (17). The take. Subsequently, these multiplications were summed (Table 1).
Hoorn study is a population-based cohort study designed to We explain 1) why an energy-adjusted intake was used, 2) why
investigate the effect of disturbed glucose metabolism on car- the intake was standardized, and 3) why some dietary compo-
diovascular disease risk factors and complications (17). In 2000– nents were excluded. Other details are shown in Table 1.
2001, 822 participants were examined again (18, 19) [ie, 648
Energy-adjusted intake
surviving participants in the Hoorn study and an additional group
of 174 participants with type 2 diabetes from the Hoorn screening We adjusted all dietary components for energy by using the
study (20)]. residual method to reduce the between-person variation in dietary
Both studies obtained written informed consent from all intake resulting from differences in physical activity, body size,
participants and were approved by the local Ethics Committees and metabolic efficiency (29). Therefore, the ADII was used as
(CODAM: Medical Ethical Review Committee of the Maastricht a measure of diet quality.
University Medical Centre; Hoorn study: Ethical Review Com-
mittee of the VU University Medical Center Amsterdam). Standardized intake
To avoid that the variation in the ADII was solely driven by
a few dietary components with a large range in intake, we
Population for analysis standardized intake of all components. Standardization was done
For the current investigation, data from both the baseline by subtracting the mean intake of the population from the in-
examination of the CODAM and the follow-up examination of dividual intake and dividing the difference by the SD of the study
ADII, INFLAMMATION, AND GLUCOSE METABOLISM 1535
TABLE 1
Dietary components included in the DII and ADII1
Components IW2 Included in DII Included in ADII
population (z score) to equilibrate the intake of all nutrients to data-dependent 10 as Cavicchia et al (10) did (Table 1). We also
the same unit. Therefore, it was not necessary to divide intakes did not divide the overall ADII by 100 because division did not
of vitamin A and b-carotene by the arbitrary, data-dependent improve the interpretation of the results as it improved the in-
100 and multiply n23 and n26 fatty acids with the arbitrary, terpretation of the previously published DII (10).
1536 VAN WOUDENBERGH ET AL
FIGURE 1. Model used in the multiple mediation analysis of the association between the adapted dietary inflammatory index and markers of glucose
metabolism, including fasting glucose, 24-h glucose, HOMA-IR, and glycated hemoglobin [adapted from Preacher and Hayes (34)]. Paths a represent the regression
coefficient of the association between the adapted dietary inflammatory index and the summary score for low-grade inflammation (path a1) or BMI (path a2). Paths
b represent the regression coefficient of the association between the summary score for low-grade inflammation (path b1) or BMI (path b2) and markers of glucose
metabolism. In addition to other covariates, path b1 was adjusted for BMI and the adapted dietary inflammatory index, whereas path b2 was adjusted for the
summary score for low-grade inflammation and the adapted dietary inflammatory index. The product of regression coefficients of paths a and b represents the
mediated effect of inflammation (path a1 3 path b1) or BMI (path a2 3 path b2). Path c’ represents that part of the association that was not explained by low-grade
inflammation or BMI. This path is referred to as the direct association between the adapted dietary inflammatory index and markers of glucose metabolism.
1538 VAN WOUDENBERGH ET AL
TABLE 2
Characteristics of the study population by tertiles of the ADII (n = 1024)1
ADII
Range 212.0 to less than 21.27 21.27 to less than 1.15 1.15 to less than 15.7 —
Median 22.51 20.03 2.72 —
n 341 342 341 —
Age (y) 65.0 6 8.13 63.9 6 8.4 64.1 6 9.3 0.23
Sex (M) (%) 50.7 53.8 61.6 0.01
Study (% from the Hoorn study) 61.6 59.4 56.0 0.33
Smoking (current) (%) 12.3 18.1 23.5 0.01
Any physical activity (h/d) 4.2 6 2.8 4.2 6 2.9 3.8 6 3.0 0.20
BMI (kg/m2) 27.3 6 3.7 27.9 6 3.8 27.7 6 4.1 0.09
Waist circumference (cm)4 94.8 6 10.8 96.4 6 11.4 97.7 6 12.4 0.01
Diabetes category (% with NGM) 53.7 50.0 49.9 0.79
Family history of diabetes (%)5 27.9 27.5 27.0 0.61
Lipid-lowering medication (%) 15.3 18.7 15.0 0.34
Antihypertensive medication (%) 34.3 33.9 35.5 0.90
1
ADII, adapted dietary inflammatory index; NGM, normal glucose metabolism.
2
Chi-square test was used for categorical variables; ANOVA was used for continuous variables.
3
Mean 6 SD (all such values).
Low-grade inflammation and markers of glucose baseline examination. Of the 592 participants without type 2
metabolism diabetes at baseline and with follow-up data, 99 subjects had
The summary score for low-grade inflammation was associ- type 2 diabetes at follow-up. The ADII was not associated
ated with adverse concentrations of all markers of glucose me- with the incidence of type 2 diabetes [incidence proportion
tabolism (Table 5). An increment of 1 unit in the summary score ratiomodel 1= 1.00 (95% CI: 0.91, 1.09)].
for low-grade inflammation was associated with, on average,
a 4% (95% CI: 2%, 6%) higher fasting glucose concentration, a DISCUSSION
9% (95% CI: 4%, 14%) higher postload glucose concentration, The aims of this study were to investigate whether the in-
a 16% (95% CI: 11%, 22%) higher HOMA-IR, and a 0.21% flammatory potential of the diet as assessed with the ADII is
(95% CI: 0.13%, 0.29%) higher Hb A1c concentration (model 2). associated with 1) the summary score for low-grade in-
flammation and 2) markers of glucose metabolism. We observed
an adverse association between the ADII and summary score
ADII and markers of glucose metabolism
An increment of 1 SD in the ADII (ie, 2.88 units) was as- TABLE 3
sociated with, on average, a 0.9% (95% CI: 0.1%, 1.7%) higher Explained interindividual variance in the ADII and DII by dietary
fasting glucose concentration, a 2.3% (95% CI: 0.0%, 4.6%) components included in the index calculation (n = 1024)1
higher postload glucose concentration, and a 3.5% (95% CI: Components R2 Model R2
0.6%, 6.3%) higher HOMA-IR (Table 6, model 1). The ADII
was not associated with Hb A1c. After inclusion of the summary ADII
Magnesium (mg/d) 0.34 0.34
score for low-grade inflammation, all associations attenuated
Folate (mg/d) 0.25 0.60
[eg, HOMA-IR: b-model 1+inflammation= 2.2% (95% CI: Quercetin (mg/d) 0.16 0.76
20.6%, 5.0%)]. Additional adjustment of BMI attenuated the n23 PUFAs (g/d) 0.07 0.82
association further [eg, HOMA-IR: b-model 1+inflammation b-Carotene (mg/d) 0.04 0.86
+BMI (c#) = 1.4% (95% CI: 21.1, 3.9)] (Figure 1, Table 6). Ethanol (g/d) 0.04 0.89
When the summary score for low-grade inflammation and BMI Vitamin D (mg/d) 0.02 0.91
were simultaneously added to model 1, the summary score for Other components 0.09 1.00
low-grade inflammation, but not BMI, explained a significant DII
Tea (g/d) 0.55 0.55
proportion of the association between the ADII and HOMA-IR
SFAs (g/d) 0.17 0.72
(path a1 3 path b1 = 0.7% higher per SD through inflammation Beer (g/d) 0.13 0.85
independent of BMI) and between ADII and postload glucose Energy (kcal/d) 0.06 0.91
(path a1 3 path b1 = 0.5% higher per SD through inflammation Wine (g/d) 0.05 0.96
independent of BMI) (Figure 1, Table 6). ADII had no direct Magnesium (mg/d) 0.02 0.98
association (c#) with the 4 markers of glucose metabolism Other components 0.02 1.00
(Figure 1, Table 6). 1
Forward linear regression was used to calculate the R2 and model R2.
Part of our population for analysis (n = 720; 70%) was retested Components that explained .1% of the interindividual variation are shown.
with an oral glucose tolerance test, on average, 7.2 y after the ADII, adapted dietary inflammatory index; DII, dietary inflammatory index.
ADII, INFLAMMATION, AND GLUCOSE METABOLISM 1539
TABLE 4
b-Coefficients (95% CIs) of the association between dietary inflammatory indexes and markers of inflammation (n = 1024)1
Crude P Model 1 P Model 2 P
for low-grade inflammation, which suggested that the in- intakes, the ADII was less dependent on the intake range of
flammatory potential of the diet affects markers of inflammation. components in the study under investigation. Therefore, it is
The adverse association between the ADII and HOMA-IR likely that the results from the ADII will be more comparable
suggested that the inflammatory potential of the diet affects between populations. Second, the ADII also avoided an over-
insulin resistance. This effect was supported by the mediating estimation of the inflammatory effect of certain nutrients by
role of low-grade inflammation in this analysis on insulin re- excluding alcoholic beverages, total fat, and energy. Third, the
sistance. ADII was associated with the summary score for low-grade
On the basis of our results, it is likely that the adaptations in the inflammation, whereas the original DII was not associated with
DII calculation improved the estimation of the inflammatory the summary score for low-grade inflammation in our study. The
potential of the diet. First, the variation in the ADII was not solely previously published DII was not associated with CRP on a
driven by components with a large range in intake, in contrast to continuous scale, although it was concluded that diet can affect
the previously published DII. The intake of tea explained most of low-grade inflammation on the basis of the observed adverse
the variation in the original DII in our study because the intake of association between the DII and elevated CRP concentration
tea ranged from 0 to 1500 mL/d. With the use of standardized (.3 mg/L) (10).
TABLE 5
b-coefficients (95% CIs) of the association between the summary score for low-grade inflammation and markers of glucose metabolism1
Summary score for low-grade inflammation
Other diet-quality scores have been shown to be associated with the dietary antiinflammatory weights for ethanol (20.53) in
with chronic low-grade inflammation. The AHEI (8), the alter- the ADII. Even though the purpose of these diet quality scores
nate Mediterranean diet index (MEDI) (8), and the Mediterranean was not to assess the inflammatory potential of diet, these
diet score (35) were inversely associated with CRP, IL-6, and studies provided evidence that diet as a whole may play a role in
sICAM. If examined closely, these scores have some similarities chronic low-grade inflammation.
with the ADII. A low intake of cereal fiber and a high intake of The summary score for low-grade inflammation explained
trans fat are considered unhealthy in the AHEI, which is in line a significant proportion of the association between the ADII and
with the dietary inflammatory weights for total fiber (20.52) and HOMA-IR, even independent of BMI. This result supported the
trans fatty acids (0.26) in the ADII. Furthermore, the AHEI hypothesis that low-grade inflammation mediates, at least in part,
gives a preference to PUFAs and MEDI to MUFAs over SFAs. the association between diet and insulin resistance. As part of an
In the ADII, n23 PUFAs and MUFAs are considered antiin- inflammatory environment, a more proinflammatory diet could
flammatory, whereas SFAs are considered pro-inflammatory. In lead to an impaired action of insulin (7). This hypothesis was not
addition, the intake of ethanol is considered healthy in the further confirmed by an association between ADII and incidence
AHEI, MEDI, and Mediterranean diet score, which is in line of type 2 diabetes in our cohorts. However, the analysis was
ADII, INFLAMMATION, AND GLUCOSE METABOLISM 1541
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