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Adapted dietary inflammatory index and its association with a summary

score for low-grade inflammation and markers of glucose metabolism:


the Cohort study on Diabetes and Atherosclerosis Maastricht (CODAM)
and the Hoorn study1–4
Geertruida J van Woudenbergh, Despoina Theofylaktopoulou, Anneleen Kuijsten, Isabel Ferreira,
Marleen M van Greevenbroek, Carla J van der Kallen, Casper G Schalkwijk, Coen DA Stehouwer, Marga C Ocke´,
Giel Nijpels, Jacqueline M Dekker, Ellen E Blaak, and Edith JM Feskens

ABSTRACT and diet (3). Nutrients assumed to have an antiinflammatory ef-


Background: Diet may be associated with the development of type fect, eg, fiber and moderate amounts of ethanol (3), may be as-
2 diabetes through its effects on low-grade inflammation. sociated with lower risk of diabetes (5, 6). In contrast, nutrients

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Objectives: We investigated whether an adapted dietary inflamma- assumed to have a proinflammatory effect, eg, SFAs and trans
tory index (ADII) is associated with a summary score for low-grade fatty acids (3), may be associated with higher risk of diabetes (7).
inflammation and markers of glucose metabolism. In addition, we Therefore, it could be hypothesized that certain nutrients may
investigated the mediating role of inflammation in the association influence markers of glucose metabolism through their effect on
between ADII and markers of glucose metabolism. chronic low-grade inflammation. However, nutrients are not con-
Design: We performed cross-sectional analyses of 2 Dutch cohort sumed as individual components but with others present within
studies (n= 1024). An ADII was obtained by multiplying standard-
ized energy-adjusted intakes of dietary components by literature-
based dietary inflammatory weights that reflected the inflammatory 1
From the Division of Human Nutrition, Wageningen University, Wage-
potential of components. Subsequently, these multiplications were ningen, Netherlands (GJvW, DT, AK, and EJMF); the CARIM School for
summed. Six biomarkers of inflammation were compiled in a sum- Cardiovascular Diseases (IF, MMvG, CJvdK, CGS, and CDAS), the Depart-
mary score. Associations of the ADII (expressed per SD) with the ment of Human Biology (EEB) and the NUTRIM School for Toxicology,
summary score for inflammation and markers of glucose metabo- Metabolism, and Nutrition (EEB), Maastricht University, Maastricht Nether-
lism were investigated by using multiple linear regression models. lands; the Departments of Internal Medicine (IF, MMvG, CJvdK, CGS, and
Inflammation was considered a potential mediator in the analysis CDAS) and Clinical Epidemiology and Medical Technology Assessment
(IF), Maastricht University Medical Center, Maastricht, Netherlands; the
with markers of glucose metabolism.
National Institute for Public Health and the Environment, Bilthoven, Nether-
Results: A higher ADII was associated with a higher summary lands (MCO); and the Departments of General Practice (GN) and Epidemiology
score for inflammation [b-adjusted = 0.04 per SD (95% CI: 0.01, and Biostatistics (JMD), EMGO Institute for Health and Care Research, Vrije
0.07 per SD)]. The ADII was also adversely associated with insulin Universiteit University Medical Center, Amsterdam, Netherlands.
resistance [homeostatic model assessment of insulin resistance 2
Funding sources were not involved in the conduct of this study or writing
(HOMA-IR): b-adjusted = 3.5% per SD (95% CI: 0.6%, 6.3% per of the manuscript.
3
SD)]. This association was attenuated after the inclusion of the The Hoorn study was supported by grants from the Dutch Diabetes Re-
summary score for inflammation [b-adjusted+inflammation = search Foundation, the Dutch Organization for Scientific Research, the Neth-
2.2% (95% CI: 20.6%, 5.0%)]. The ADII was also adversely as- erlands Heart Foundation, and the Health Research and Development
sociated with fasting glucose and postload glucose but not with Council of the Netherlands. The Cohort study on Diabetes and Atheroscle-
rosis Maastricht was supported by grants from the Netherlands Organization
glycated hemoglobin.
for Scientific Research (940-35-034) and the Dutch Diabetes Foundation (98.
Conclusion: The significant mediating role of low-grade inflammation
901). IF is supported by the Dutch Heart Foundation (senior postdoc research
in the association between the ADII and HOMA-IR suggests that in- grant 2006T06).
flammation might be one of the pathways through which diet affects 4
Address reprint requests and correspondence to GJ van Woudenbergh,
insulin resistance. Am J Clin Nutr 2013;98:1533–42. Division of Human Nutrition, Wageningen University, PO Box 8129, 6700
EV Wageningen, Netherlands. E-mail: truus.vanwoudenbergh@wur.nl.
5
INTRODUCTION Abbreviations used: ADII, adapted dietary inflammatory index; AHEI, al-
Chronic low-grade inflammation is characterized by slightly ternative healthy eating index; CODAM, Cohort study on Diabetes and Ath-
erosclerosis Maastricht; CRP, C-reactive protein; DII, dietary inflammatory
elevated concentrations of circulating proinflammatory markers,
index; FFQ, food-frequency questionnaire; Hb A1c, glycated hemoglobin;
including C-reactive protein (CRP)5, IL-6, and TNF-a. These MDS, multiarray detection system; MEDI, alternate Mediterranean diet index;
markers have been associated with higher risk of type 2 diabetes SAA, serum amyloid A; sICAM, soluble intercellular adhesion molecule-1.
in observational studies (1, 2) and can be induced by risk factors Received December 12, 2012. Accepted for publication September 30, 2013.
for type 2 diabetes, such as overweight (3), physical inactivity (4), First published online October 23, 2013; doi: 10.3945/ajcn.112.056333.

Am J Clin Nutr 2013;98:1533–42. Printed in USA. Ó 2013 American Society for Nutrition 1533

Supplemental Material can be found at:


http://ajcn.nutrition.org/content/suppl/2013/11/14/ajcn.112.0
56333.DCSupplemental.html
1534 VAN WOUDENBERGH ET AL

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

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sociated with 1) a summary score for low-grade inflammation
and 2) markers of glucose metabolism in a Dutch population. In a Dutch population (25). Intakes of all food items were converted
addition, we investigated whether the association between the into intakes of energy and nutrients by using an extended version
DII and markers of glucose metabolism is mediated by chronic of the Dutch Food Composition table 2001. The caffeine content
low-grade inflammation. of food items was not included in the Dutch Food Composition
table. Therefore, the caffeine content was estimated to be 68 mg/
100 mL coffee (26), 20 mg/100 mL tea (27), and 8 mg/100 mL
SUBJECTS AND METHODS cola soft drink (27).

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

Energy (kcal/d) 0.230 Included Not included3


Protein (g/d) 20.050 Included Included
Total fat (g/d) 0.323 Included Not included3
SFAs (g/d) 0.250 Included Included
MUFAs (g/d) 0.050 Included Included
trans Fatty acids (g/d) 0.260 Not included4 Included
n23 PUFAs (g/d) 20.384 Included Included
n26 PUFAs (g/d) 0.016 Included Included
Cholesterol (mg/d) 0.210 Included Included
Carbohydrate (g/d) 0.346 Included Included
Fiber (g/d) 20.520 Included Included
Ethanol (g/d) 20.534 Included Included5
Wine (g/d) 20.480 Included Not included3
Beer (g/d) 20.200 Included Not included3
Liquor (g/d) 20.100 Included Not included3
Caffeine (g/d) 20.035 Included Included
Vitamin A (mg/d) 20.580 Included Included
b-Carotene (mg/d) 20.725 Included Included
Thiamin (mg/d) 20.050 Included Included

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Riboflavin (mg/d) 20.160 Included Included
Niacin (mg/d) 20.260 Included Included
Vitamin B-6 (mg/d) 20.286 Included Included
Folate (mg/d) 20.214 Included Included
Vitamin B-12 (mg/d) 0.090 Included Included
Vitamin C (mg/d) 20.367 Included Included
Vitamin D (mg/d) 20.342 Included Included
Vitamin E (mg/d) 20.401 Included Included
Iron (mg/d) 20.029 Included Included
Magnesium (mg/d) 20.905 Included Included
Selenium (mg/d) 20.021 Included Included
Zinc (mg/d) 20.316 Included Included
Tea (g/d) 20.552 Included Included6
Quercetin (mg/d) 20.490 Included Included
Genistein (mg/d) 20.680 Not included7 Not included7
Epicatechin (mg/d) 20.120 Not included7 Not included7
Luteolin (mg/d) 20.430 Not included7 Not included7
Daidzein (mg/d) 20.170 Not included7 Not included7
Cyanidin (mg/d) 20.130 Not included7 Not included7
Garlic (g/d) 20.270 Included Included
Ginger (g/d) 20.180 Not included7 Not included7
Saffron (g/d) 20.180 Not included7 Not included7
Turmeric (g/d) 20.774 Not included7 Not included7
Total DII for a participant8 — + (intakei 3 IWi) O 100 —
Total ADII for a participant — — + (energy-adjusted standardized intakei 3 IWi)
1
ADII, adapted dietary inflammatory index; DII, dietary inflammatory index; IW, inflammatory weight.
2
Dietary components with a positive IW were considered proinflammatory. Dietary components with a negative IW were considered antiinflammatory.
3
Energy was excluded in the ADII because all macronutrients were already included. Total fat was excluded in the ADII because all fatty acids were
already included. Alcoholic beverages beer, wine, and liquor were excluded in the ADII because the intake of ethanol was already included.
4
trans Fatty acids were not included in the previously published DII because the intake of trans fatty acids could not be calculated in the study by
Cavicchia et al (10).
5
Dietary IW for ethanol was assumed to be zero when the intake of ethanol was .40 g/d because the intake of ethanol is not likely to be antiin-
flammatory when an intake is .40 g/d (29).
6
Intake of tea was still included because the intake of epicatechin could not be calculated from our food-frequency questionnaire.
7
These dietary components were not taken into account in our DII and ADII calculations because intakes of these components could not be calculated
from our food-frequency questionnaire.
8
Intake of n23 and n26 PUFAs were multiplied by 10 because intakes were low and expressed as grams per day. Intakes of vitamin A and b-carotene
were divided by 100 to equilibrate the range of intake to other micronutrients according to Cavicchia et al (10).

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

Exclusion components Calculation summary score for low-grade inflammation


We excluded several components when we calculated the ADII A summary score for low-grade inflammation was calculated
to avoid an overestimation of inflammatory effects of ethanol, fat, to cluster conceptually related markers of low-grade inflam-
and energy. To reduce the impact of ethanol on the ADII, separate mation and improve statistical efficiency. To obtain this summary
antiinflammatory effects of the alcoholic beverages beer, wine, score, a z score for each marker of low-grade inflammation was
and liquor were not taken into account. Antiinflammatory effects calculated because the markers of low-grade inflammation were
of these beverages are likely to be attributable to ethanol (3). expressed on different scale units. Subsequently, these z scores
Energy was excluded because it is likely that the inflammatory were averaged to obtain a summary score for low-grade in-
effect of energy is the sum of the inflammatory effects of all flammation for each participant as follows:
energy-providing macronutrients. Total fat was also excluded
because it was assumed that the inflammatory effect of total fat is Summary score ¼ ½z scoreðloge CRPÞ þ z scoreðloge IL  6Þ
the sum of the inflammatory effects of all separate fatty acids. þ z scoreðloge IL  8Þ þ z scoreðTNF  aÞ
þ z scoreðloge SAAÞ þ z scoreðsICAMÞO6 ð1Þ

Markers of glucose metabolism


This summary score for low-grade inflammation had been used
Venous blood samples were drawn from all participants at the
in previous investigations (14, 31, 32).
research center after an overnight fast (.10 h) to be able to
measure, eg, the fasting glucose concentration, fasting insulin
concentration, and glycated hemoglobin (Hb A1c). A 2-h post- Covariates
load glucose concentration was determined after a standard 75-g

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In both cohorts, the participant completed a self-administered
oral glucose tolerance test except in participants with established questionnaire that, among other things, included questions about
diabetes or a very high fasting plasma glucose concentration age, sex, smoking behavior, family history of diabetes in first-
(CODAM: .10 mmol/L; Hoorn study: .8.0 mmol/L). Fasting degree relatives, and use of medications (eg, antihypertensive,
and 2-h postload glucose concentrations were measured in plasma lipid-lowering, glucose-lowering medications). On the basis of
by using glucose hexokinase methods [CODAM: ABX Diagnostics the questions about smoking behavior, the participant was cat-
Glucose HK125 (Horiba-ABX); Hoorn study: Roche Diagnostics]. egorized as a never, former, or current smoker. Family history of
Hb A1c was analyzed by ion-exchange HPLC (CODAM and diabetes was defined as a parent, a sibling, or both with diagnosed
Hoorn study: Bio-rad). The insulin concentration was measured diabetes. Height was measured to the nearest centimeter, and
in plasma by a 2-site immunoradiometric assay by using paired weight was measured to the nearest 100 g by trained personnel.
monoclonal antibodies (CODAM and Hoorn study: Medgenix The participant was weighed in a standing position wearing light
Diagnostics). Insulin resistance was estimated from fasting indoor cloths and no shoes. BMI (in kg/m2) was calculated as
plasma glucose and plasma insulin concentrations by using the weight divided by height squared. Waist circumference (cm)
homeostasis model assessment calculator (HOMA2) (30). was obtained at levels halfway between the lateral lower rib
margin and the spina iliaca anterior superior. Habitual physical
activity was assessed by using a validated short physical activity
Markers of low-grade inflammation questionnaire (short questionnaire to assess health-enhancing
In both cohorts, concentrations of 6 biomarkers of low-grade physical activity), which measured the duration and intensity of
inflammation [ie, CRP, IL-6, IL-8, TNF-a, serum amyloid A different activities (min/wk 3 intensity) (33).
(SAA), and soluble intercellular adhesion molecule-1 (sICAM)]
were measured in plasma by using a multiarray detection system
(MDS) on the basis of electro-chemiluminescence detection Statistical analysis
(SECTOR Imager 2400; MesoScaleDiscovery). All measure- Summary statistics were used to describe population charac-
ments were performed at the Research Laboratory, Department teristics by tertiles of the ADII. To get more insight into the
of Internal Medicine, Maastricht University Medical Centre contribution of the individual dietary components to the total
(head: CGS). In the CODAM, CRP was also measured in serum ADII, the contribution of the different dietary components to the
by using a high-sensitivity immunoturbidimetry assay (Latex; variation between participants in the ADII was assessed by using
Roche Diagnostics Netherlands BV), and IL-6, SAA, sICAM forward linear regression. Before additional analyses, 7 skewed
were also measured in EDTA plasma by using an ELISA (IL-6: variables were loge transformed to improve their distribution
R&D Systems; SAA and sICAM: Biosource; Invitrogen). These toward normal (CRP, IL-6, IL-8, SAA, fasting plasma glucose,
measurements were done at the Laboratory of Toxicology, Ge- postload glucose, and HOMA-IR).
netics and Pathology of the National Institute for Public Health First, the association between the ADII and markers of low-
and the Environment, Bilthoven, Netherlands. Values obtained grade inflammation was investigated by using linear regression.
by using the immunoturbidimetry assay or ELISA were cali- Model 1 included, as the main independent variable, the ADII
brated on the values obtained by using the MDS in the CODAM. (expressed per SD) and the covariates age (y), sex, cohort
Subsequently, the calibrated and MDS values were averaged and (CODAM or Hoorn), smoking (never, former, or current),
used for CODAM participants in the current analysis. Intraassay physical activity (min/wk 3 intensity, family history of diabetes
CVs ranged from 0.6% to 6.4%, and interassay CVs ranged from (yes, no, or missing), use of lipid-lowering medication (yes or
1.9% to 17.5%. More information about measurements has been no), having hypertension (yes or no), and the intake of energy
shown elsewhere (12, 13, 31). (kcal/d). Except for cohort, these covariates were included
ADII, INFLAMMATION, AND GLUCOSE METABOLISM 1537
because of their association with inflammation and diabetes subjects were men, 26% of subjects had a normal weight, 18%
observed in the literature. In model 2, BMI was added to model of subjects were current smokers, and 51% of subjects had
1 because we were also interested in the effect of the ADII on normal glucose metabolism. The Hoorn study, compared with
inflammation independent of BMI. Waist circumference was not the CODAM, included participants with an older age (68 6 7
included as an additional covariate because its inclusion did not compared with 58 6 7 y, respectively), more women (49%
change the conclusions, and waist circumference was missing compared with 37%, respectively), and fewer current smokers
for 8 participants. Effect-measure modification by sex was in- (16% compared with 20%), respectively. The mean BMI was
vestigated by adding an interaction term between the ADII and comparable (27 6 4 in the Hoorn study; 28 6 4 in the CODAM).
sex to model 2 when the summary score for low-grade in-
flammation was studied as a dependent variable.
Second, to investigate whether this study also confirmed the ADII and its components
well-known adverse associations between low-grade inflammation The ADII ranged from 212.0 to 15.7 (range: 27.7 units)
and markers of glucose metabolism, the association between the (Table 2). Participants with a high ADII smoked more and were
summary score for low-grade inflammation and the 4 markers of more often men than were participants with a low ADII (Table
glucose metabolism was studied. Model 1 of the linear regression 2). Intakes of SFAs, MUFAs, and trans fatty acids were higher in
model included age (y), sex, cohort (CODAM or Hoorn), smoking participants with a high than low ADII. Intakes of protein, n23
(never, former, or current), physical activity (min/wk 3 intensity), PUFA, and n26 PUFA were lower in participants with a high
family history of diabetes (yes, no, or missing), use of lipid-lowering than low ADII (see Supplemental Table 1 under “Supplemental
medication (yes or no), and having hypertension (yes or no). Model data” in the online issue). The Spearman’s correlation between
2 included BMI in addition to model 1. the ADII and energy was low (r = 0.10, P = 0.02). The intake of

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Third, the association between the ADII and 4 markers of magnesium explained most of the variation (34%) between
glucose metabolism (ie, fasting plasma glucose, postload glucose, participants in the ADII, followed by intakes of folate (25%),
HOMA-IR, and Hb A1c) was investigated by using linear re- quercetin (16%), and n23 PUFA (7%) (Table 3). Regarding
gression. Model 1 included the ADII and other covariates as in the DII, which ranged from 220.7 to 6.3 (range: 27.0 units)
model 1. To investigate the mediating role of low-grade inflam- (see Supplemental Table 2 under “Supplemental data” in the
mation, the summary score for low-grade inflammation was in- online issue), the intake of tea explained most of the variation
cluded in addition to covariates included in model 1 (model 1 + (55%) between participants in the DII, followed by intakes
inflammation). To investigate whether the association of the ADII of SFA (17%), beer (13%), energy (6%), and wine (5%)
with markers of glucose metabolism was attributed to inflammation (Table 3).
independent of BMI, the summary score for low-grade inflammation
and BMI were simultaneously added to model 1. For this purpose,
we also used the multiple-mediation analysis as described by ADII and low-grade inflammation
Preacher and Hayes (34). This mediation analysis provides an effi-
cient way to quantify the independent mediating effects of low-grade An increment of 1 SD in the ADII (ie, 2.88 units) was as-
inflammation and BMI (Figure 1). sociated with a 0.04-unit (95% CI 0.01, 0.07-unit) higher sum-
All analyses were performed with the SAS statistical software mary score for low-grade inflammation in model 2 (P = 0.01)
package (version 9.2; SAS Institute Inc). P # 0.05 was con- (Table 4). This association was mainly driven by 4 of 6 markers
sidered statistically significant. of inflammation (ie, CRP, IL-6, TNF-a, and sICAM). The
original DII was not associated with the summary score for
low-grade inflammation [model 2: b = 20.002 (95% CI: 20.03,
RESULTS 0.03)] (Table 4). The association between the ADII and sum-
The mean (6SD) age of the population of analysis was 646 9 y, mary score for low-grade inflammation did not differ between
59% of subjects were participants from the Hoorn study, 55% of men and women (P-interaction = 0.80).

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

Tertile 1 Tertile 2 Tertile 3 P2

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).

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4
Missing for 8 participants.
5
Missing for 122 participants.

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

ADII (per SD of 2.88)


Inflammation score2 0.04 (0.01, 0.08) 0.01 0.04 (0.02, 0.07) ,0.01 0.04 (0.01, 0.07) 0.01
CRP3 0.07 (0.02, 0.13) 0.01 0.06 (0.01, 0.12) 0.02 0.05 (20.01, 0.10) 0.08
IL-63 0.06 (0.03, 0.10) ,0.01 0.05 (0.01, 0.08) 0.01 0.04 (0.01, 0.08) 0.02
IL-83 20.03 (20.08, 0.01) 0.16 20.01 (20.03, 0.02) 0.64 20.01 (20.03, 0.02) 0.63
TNF-a 0.15 (20.03, 0.32) 0.10 0.17 (20.00, 0.33) 0.05 0.16 (20.01, 0.33) 0.07
Serum amyloid A3 0.00 (20.04, 0.04) 0.97 0.02 (20.03, 0.06) 0.44 0.01 (20.03, 0.05) 0.67
sICAM 5.28 (1.81, 8.75), 0.01 4.57 (1.32, 7.81) 0.01 3.96 (0.76, 7.15) 0.02
DII (per SD of 2.07)
Inflammation score2 20.05 (20.08, 20.01) 0.01 0.02 (20.01, 0.05) 0.28 20.002 (20.03, 0.03) 0.90
CRP3 0.05 (20.00, 0.11) 0.06 0.08 (0.02, 0.13) 0.01 0.03 (20.02, 0.09) 0.21
IL-63 0.02 (20.02, 0.06) 0.29 0.01 (20.03, 0.05) 0.63 20.003 (20.04, 0.03) 0.90
IL-83 20.16 (20.21, 20.12) 0.01 -0.03 (20.06, 0.00) 0.06 20.03 (20.06, 0.00) 0.05
TNF-a 20.23 (20.40, 20.05) 0.01 20.01 (20.18, 0.17) 0.93 20.03 (20.20, 0.15) 0.75
Serum amyloid A3 20.02 (20.07, 0.02) 0.30 0.03 (20.02. 0.07) 0.21 0.01 (20.03, 0.05) 0.68
sICAM 21.62 (25.10, 1.86) 0.36 1.61 (21.77, 5.00) 0.35 20.06 (23.30, 3.42) 0.97
1
Median (25th–75th percentiles) or mean (6SD) of the inflammation markers were as follows: inflammation score, 20.1 6 0.5; CRP (mg/L), 1.7 (0.97–
3.4) ; IL-6 (ng/L), 1.4 (1.1–2.9); IL-8 (ng/L), 2.2 6 0.7; TNF-a (ng/L), 7.9 6 2.9; serum amyloid A (mg/L), 1.5 (0.97–2.4); and sICAM (mg/L), 239.5 6 56.7.
b-Coefficients (95% CIs) were obtained by using linear regression. Model 1 included age, sex, cohort, physical activity, smoking, family history of diabetes,

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use of lipid-lowering medication, and hypertension as covariates. The ADII was also adjusted for the intake of energy. In addition to model 1, model 2
also included BMI as a covariate. ADII, adapted dietary inflammatory index; CRP, C-reactive protein; DII, dietary inflammatory index; sICAM, soluble
intercellular adhesion molecule.
2
Summary score for low-grade inflammation was obtained by the following formula: [z score(logeCRP) + z score(logeIL-6) + z score(logeIL-8) + z score
(TNF-a) + z score(logeserum amyloid A) + z score(sICAM)] O 6.
3
For the analysis, these markers of inflammation were loge transformed to improve their distribution toward normal. Therefore, when the DII or ADII was
1 SD higher, these markers of low-grade inflammation were, on average, b 3 100% higher or lower.

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

n Crude P Model 1 P Model 2 P

Fasting glucose (mmol/L) 2


1022 0.07 (0.05, 0.09) ,0.01 0.05 (0.04, 0.07) ,0.01 0.04 (0.02, 0.06) ,0.01
Postload glucose (mmol/L)2 907 0.12 (0.08, 0.16) ,0.01 0.12 (0.07, 0.17) ,0.01 0.09 (0.04, 0.14) ,0.01
HOMA-IR2 1003 0.21 (0.15, 0.26) ,0.01 0.28 (0.22, 0.34) ,0.01 0.16 (0.11, 0.22) ,0.01
Hb A1c (%) 1008 0.27 (0.21, 0.34) ,0.01 0.23 (0.16, 0.31) ,0.01 0.21 (0.13, 0.29) ,0.01
1
Median (25th–75th percentiles) or mean (6SD) of markers of glucose metabolism were as follows: fasting glucose (mmol/L), 5.7 (5.3–6.4); postload
glucose (mmol/L), 6.6 (5.3–8.6); HOMA-IR, 1.1 (0.8–1.6); and Hb A1c (%), 5.9 6 0.6. b-coefficients (95% CIs) were obtained by using linear regression. The
summary score for low-grade inflammation was obtained by using the following formula: [z score(logeC-reactive protein) + z score(logeIL-6) + z score
(logeIL-8) + z score(TNF-a) + z score(logeserum amyloid A) + z score(soluble intercellular adhesion molecule)] O 6. Model 1 included age, sex, cohort,
physical activity, smoking, family history of diabetes, use of lipid-lowering medication, and hypertension as covariates. In addition to model 1, model 2 also
included BMI. Hb A1c, glycated hemoglobin.
2
For the analysis, these markers of glucose metabolism were loge transformed to improve their distribution toward normal. Therefore, when the summary
score for low-grade inflammation was 1 unit higher, these markers of glucose metabolism were, on average, b 3 100% higher.
1540 VAN WOUDENBERGH ET AL
TABLE 6
b-coefficients (95% CIs) of the association between the ADII and markers of glucose metabolism1
ADII (per SD of 2.88) P
2
Fasting glucose (n = 1022) (mmol/L)
Crude 0.008 (20.002, 0.017) 0.10
Total effect (model 1)3 0.009 (0.001, 0.017) 0.03
Model 1 + BMI 0.007 (20.001, 0.015) 0.08
Model 1 + inflammation 0.007 (20.002, 0.0156) 0.11
Direct effect [model 1+ BMI and inflammation (c#)] 0.006 (20.002, 0.014) 0.16
Indirect effect through BMI (a2 3 b2)4 0.001 (0.000, 0.003) —5
Indirect effect through inflammation (a1 3 b1)6 0.002 (0.001, 0.004) —5
Postload glucose (n = 907) (mmol/L)2
Crude 0.019 (20.004, 0.042) 0.10
Total effect (model 1)3 0.023 (0.000, 0.046) 0.05
Model 1 + BMI 0.019 (20.003, 0.041) 0.09
Model 1 + inflammation 0.017 (20.006, 0.039) 0.14
Direct effect [model 1 + BMI and inflammation (c#)] 0.015 (20.007, 0.037) 0.18
Indirect effect through BMI (a2 3 b2)4 0.003 (20.000, 0.008) —5
Indirect effect through inflammation (a1 3 b1)6 0.005 (0.002, 0.010) —5
HOMA-IR (n =1003)2
Crude 0.037 (0.007, 0.067) 0.02
Total effect (model 1)3 0.035 (0.006, 0.063) 0.02

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Model 1 + BMI 0.020 (20.005, 0.045) 0.12
Model 1 + inflammation 0.022 (20.006, 0.050) 0.12
Direct effect [model 1 + BMI and inflammation (c#)] 0.014 (20.011, 0.039) 0.28
Indirect effect through BMI (a2 3 b2)4 0.014 (20.001, 0.028) —5
Indirect effect through inflammation (a1 3 b1)6 0.007 (0.003, 0.014) —5
Hb A1c (n = 1008) (%)
Crude 0.010 (20.027, 0.048) 0.05
Total effect (model 1)3 0.011 (20.025, 0.046) 0.13
Model 1 + BMI 0.007 (20.029, 0.042) 0.06
Model 1 + inflammation 0.000 (20.035, 0.036) 0.05
Direct effect [model 1+ BMI and inflammation (c#)] 20.001 (20.037, 0.034) 0.10
Indirect effect through BMI (a2 3 b2)4 0.002 (0.000, 0.008) —5
Indirect effect through inflammation (a1 3 b1)6 0.010 (0.003, 0.019) —5
1
Median (25th–75th percentiles) or mean (6SD) of markers of glucose metabolism were as follows: fasting glucose
(mmol/L), 5.7 (5.3–6.4); postload glucose (mmol/L), 6.6 (5.3–8.6); HOMA-IR, 1.1 (0.8–1.6); and Hb A1c (%), 5.9 6 0.6.
b-coefficients (95% CIs) were obtained by using linear regression. See Figure 1 for the interpretation of c#, a1, a2, b1, and b2.
ADII, adapted dietary inflammatory index; Hb A1c, glycated hemoglobin.
2
For the analysis, these markers of glucose metabolism were loge transformed to improve their distribution toward
normal. Therefore, when the ADII was 1 SD (SD: 2.88) higher, these markers of glucose metabolism were, on average, b 3
100% higher or lower.
3
Model 1 was adjusted for age, sex, cohort, physical activity, smoking, family history of diabetes, use of lipid-
lowering medication, hypertension, and intake of energy.
4
When the ADII was 1 SD higher, the marker of glucose metabolism was b 3 100% higher or lower through the effect
of the ADII on BMI.
5
Multiple mediation analysis described by Preacher and Hayes did not provide P values (34).
6
When the ADII was 1 SD higher, the marker of glucose metabolism was b 3 100% higher or lower through the
effect of the ADII on 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
limited because information about the exact time of diagnosis 2. Kolb H, Mandrup-Poulsen T. An immune origin of type 2 diabetes?
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a clinical application of the ADII is considered. Nutr 2011;106(suppl 3):S5–78.
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First, in addition to CRP, 5 other markers of inflammation were 5. Schulze MB, Schulz M, Heidemann C, Schienkiewitz A, Hoffmann K,
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6. Baliunas DO, Taylor BJ, Irving H, Roerecke M, Patra J, Mohapatra S,
participants for 10 of the nutrients included in the ADII (25).
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based instead of data-driven nature. However, despite the use of 7. Kolb H, Mandrup-Poulsen T. The global diabetes epidemic as a con-
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Besides these strengths, the study had limitations as well. First, markers of inflammation and endothelial dysfunction. Am J Clin Nutr
our results were limited by the cross-sectional nature of our study, 2005;82:163–73.
which did not allow conclusions to be made about causality. We 9. Fung TT, McCullough M, van Dam RM, Hu FB. A prospective study
of overall diet quality and risk of type 2 diabetes in women. Diabetes
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participants with known diabetes who may have changed their 10. Cavicchia PP, Steck SE, Hurley TG, Hussey JR, Ma Y, Ockene IS,
diet recently. Second, the external validity of our study might Hebert JR. A new dietary inflammatory index predicts interval changes
have been low because all participants were white, and the in serum high-sensitivity C-reactive protein. J Nutr 2009;139:2365–72.
11. Kruijshoop M, Feskens EJ, Blaak EE, De Bruin TW. Validation of
CODAM included participants with high risk of impaired glucose capillary glucose measurements to detect glucose intolerance or type 2
metabolism. However, the inclusion of a high-risk population diabetes mellitus in the general population. Clin Chim Acta 2004;341:
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Blaak EE, Feskens EJ, Jansen EH, Schalkwijk CG, Stehouwer CD.
previously published DII, such as of ginger and saffron, could not Low-grade inflammation can partly explain the association between the
be calculated from our FFQ (Table 1). However, the variation in metabolic syndrome and either coronary artery disease or severity of
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MM, Van der Kallen CJ, Feskens EJ, Blaak EE, Schalkwijk CG,
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potential confounders could have been measured with error. sociated with adaptive immune activation: the CODAM Study. Obesity
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potential of the diet, as assessed with the ADII, with low-grade 14. Wlazlo N, Van Greevenbroek MM, Ferreira I, Jansen EJ, Feskens EJ,
Van der Kallen CJ, Schalkwijk CG, Bravenboer B, Stehouwer CD.
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We thank each staff member who contributed to the data collection of the Bruin TW, Blaak EE. Study on lifestyle-intervention and impaired
CODAM and the Hoorn study. We also acknowledge the contributions of all glucose tolerance Maastricht (SLIM): design and screening results.
participants in the studies. Diabetes Res Clin Pract 2003;61:49–58.
The authors’ responsibilities were as follows—GJvW: prepared data for 17. Mooy JM, Grootenhuis PA, de Vries H, Valkenburg HA, Bouter LM,
analyses, performed the analysis, and drafted the manuscript; DT and EJMF: Kostense PJ, Heine RJ. Prevalence and determinants of glucose in-
contributed to the interpretation of data; IF, MMvG, CJvdK, CGS, CDAS, tolerance in a Dutch caucasian population. The Hoorn Study. Diabetes
Care 1995;18:1270–3.
EEB, and EJMF: participated in the design and coordination of the CODAM;
18. Snijder MB, Dekker JM, Visser M, Bouter LM, Stehouwer CD,
CDAS, GN, and JMD: participated in the design and coordination of the Yudkin JS, Heine RJ, Nijpels G, Seidell JC; Hoorn study. Trunk fat
Hoorn study; and DT, AK, IF, MMvG, CJvdK, CGS, CDAS, MCO, GN, and leg fat have independent and opposite associations with fasting
JMD, EEB, and EJMF: critically revised the manuscript and agreed to be and postload glucose levels: the Hoorn study. Diabetes Care 2004;
listed as authors. None of the authors had a conflict of interest. 27:372–7.
19. van Dam RM, Snijder MB, Dekker JM, Stehouwer CD, Bouter LM,
Heine RJ, Lips P. Potentially modifiable determinants of vitamin D
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