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  Elevated Levels of the Anti-Inflammatory Interleukin-1 Receptor Antagonist Precedethe Onset of Type 2 Diabetes The Whitehall II Study C HRISTIAN  H ERDER ,  PHD 1 E RIC  J. B RUNNER ,  PHD 2 W OLFGANG  R ATHMANN ,  MD, MSPH 3 K  LAUS  S TRASSBURGER ,  PHD 3 A DAM  G. T AB ´ AK  ,  MD 2,4 N ANETTE  C. S CHLOOT ,  MD 1,5 D ANIEL  R. W ITTE ,  PHD 2,6 OBJECTIVE — Interleukin-1receptorantagonist(IL-1Ra),anaturalinhibitorofinterleukin-1  , has been shown to improve  -cell function and glycemic control in patients with type 2diabetes. The aim of this study was to investigate whether baseline systemic levels of IL-1Ra areassociated with incident type 2 diabetes during more than 10 years of follow-up. RESEARCHDESIGNANDMETHODS — We measured serum IL-1Ra concentrationsin a nested case-control study (181 case and 376 age-, sex-, and BMI-matched normoglycemiccontrol subjects) within the Whitehall II cohort (U.K.). RESULTS — IL-1Ra concentrations were higher in case subjects ( P  0.0006) and associatedwithincidenttype2diabetes(oddsratiofora1-SDincreaseofIL-1Ra1.48[95%CI1.21–1.80]).This association remained significant after adjustment for multiple potential confounders butwas attenuated by adjusting for 2-h glucose. CONCLUSIONS — Our findings indicate that individuals who will develop type 2 diabetesare characterized by a complex immune activation that also includes upregulation of the anti-inflammatory cytokine IL-1Ra. Diabetes Care  32:421–423, 2009 S ystemic concentrations of severalacute-phase proteins, cytokines,and chemokines are elevated in in-dividuals who will subsequently developtype 2 diabetes compared with those inindividuals who remain disease free (1–3). Immune mediators such as interleu-kin-6 and monocyte chemoattractantprotein-1 have been shown to interferewith insulin signaling in fat, liver, andmuscle cells (1,4), whereas, in particular,the proinflammatory cytokine interleu-kin-1   inhibits   -cell function and pro-motes   -cell apoptosis (5). Therefore,low-grade inflammation may contributeto diabetes development both by induc-ing insulin resistance and reducing insu-lin secretion.The importance of interleukin-1  andinterleukin-1receptorantagonist(IL-1Ra) was emphasized by a randomized,double-blind, clinical trial; IL-1Ra im-proved  -cell function and glycemic con-trol in patients with type 2 diabetes (6). Itis thus tempting to speculate that highcirculating IL-1Ra concentrations couldindicate decreased risk of type 2 diabetesmuch like increased adiponectin levelsare associated with lower incidence of type2diabetes(7).SystemicIL-1Ralevelsareincreasedinpatientswithobesity,im-paired glucose tolerance, and the meta-bolic syndrome in cross-sectional studies(8–10). Longitudinal data on the rela-tionship between IL-1Ra and the risk of type 2 diabetes are not available. There-fore, the aim of the current study was toinvestigate whether systemic levels of IL-1Ra are associated with incident type 2diabetes in a nested case-control studywithin the prospective Whitehall II co-hort study. RESEARCH DESIGN ANDMETHODS — We present resultsfrom a nested case-control study withinthe Whitehall II cohort, which was estab-lished in 1985 and included 10,308 civilservants age 35–55 years (11). Phase 3(1991–1994) of the study was the firstphase where glucose tolerance was as-sessed by a 75-g oral glucose tolerancetest and is the baseline for the currentstudy ( n  7,537). Participants were fol-lowed through postal questionnaires at2.5-year intervals (phases 4–8) and fur-ther clinical examinations (including anoral glucose tolerance test) in 1997–1999(phase 5) and 2003–2004 (phase 7) (12).Individuals without type 2 diabetes atbaselineandwithincidenttype2diabetesduringthefollow-upperiodof11.5  3.0years served as case subjects ( n    181).The control subjects ( n  376), with nor-malglucosetoleranceatbaselineanddur-ing the follow-up, were frequencymatched to case subjects for age (5-yearbands), sex, and BMI (5 kg/m 2 bands).Furtherdetailsontheselectioncriteriaforthis nested case-control study and infor-mation on the collection of anthropomet-ric, metabolic, socioeconomic, andimmunologicalvariablesandonstatisticalanalysis are given in an online appendix(available at dc08-1161). ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● From the  1 Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, LeibnizInstitute for Diabetes Research, Du¨sseldorf, Germany; the  2 Department of Epidemiology and PublicHealth,UniversityCollegeLondon,London,U.K.;the 3 InstituteofBiometricsandEpidemiology,GermanDiabetes Center at Heinrich Heine University, Leibniz Institute for Diabetes Research, Du¨sseldorf, Ger-many;  4 Semmelweis University, Budapest, Hungary; the  5 Center for Internal Medicine, Heinrich HeineUniversity Du¨sseldorf, Du¨sseldorf, Germany; and the  6 Steno Diabetes Center, Gentofte, Denmark.Corresponding author: Christian Herder, 26 June 2008 and accepted 24 November 2008.Published ahead of print at on 10 December 2008. DOI: 10.2337/dc08-1161.© 2009 by the American Diabetes Association. Readers may use this article as long as the work is properlycited, the use is educational and not for profit, and the work is not altered. See for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be herebymarked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. E p i d e m i o l o g y / H e a l t h S e r v i c e s R e s e a r c h B R I E F R E P O R T D IABETES  C ARE ,  VOLUME  32,  NUMBER   3, M ARCH  2009  421  RESULTS — Characteristics of caseand control subjects are shown in Table A1 of the online appendix. The compari-sonoftheincludedandexcludeddiabeticcase subjects revealed only a few signifi-cant differences: selected case subjectswere less likely to be women and smok-ers, were more likely to be ex-smokers,and had a marginally lower BMI. Othercomparisons between the two groupswere not significant (data not shown).Characteristics of control subjects in ourselection mainly reflected the selectioncriteria (normal glucose tolerancethroughout the study and matching forage, sex, and BMI to case subjects): theywere slightly older and had a higher BMI,waist circumference, and diastolic bloodpressure but lower fasting and 2-h glu-cose compared with the rest of the cohortwhowerenondiabeticatbaselineandfol-low-up (data not shown).IL-1Ra concentrations at baselinewere higher in case subjects (median232.8 pg/ml [25th–75th percentiles180.7–342.2]) than in control subjects(207.6 pg/ml [159.3–274.8]) ( P   0.0006). A 1-SD increase of IL-1Ra(157.7 pg/ml) was associated with inci-dent type 2 diabetes in models that ad- justedformultiplepotentialconfounders,including age, sex, waist circumference,cardiovascular risk factors, socioeco-nomic status, proinflammatory media-tors, and fasting glycemia (Table 1).Further inclusion of BMI had virtually noimpact on odds ratio (model 2 plus BMIodds ratio 1.41 [95% CI 1.13–1.77];  P  0.0027). However, addition of 2-h glu-cose led to reduced effect sizes and loss of statistical significance (Table 1). CONCLUSIONS — Elevatedlevelsof IL-1Ra were associated with an increasedrisk of developing type 2 diabetes in thisnested case-control study. We found aslightattenuationofthisassociationwhenadjusting for waist circumference, whichis consistent with IL-1Ra production inadipose tissue (13). It is remarkable thatthe association was stable to adjustmentfor a range of further potential confound-ers, including fasting glucose and insulin.However, adjustment for 2-h glucose at-tenuated the association. This findingcould be interpreted to indicate that in-creasedIL-1Ralevelsareareactiontoandnot a cause of early postprandial hyper-glycemia before the onset of diabetes.Studies with measurements of glycemicmarkers and IL-1Ra at multiple timepoints and analysis of their trajectorieswill be needed to clarify this point.Our findings expand observationsfrom cross-sectional studies that reportedelevatedlevelsofIL-1Rainthecirculationofindividualswithobesityandinsulinre-sistance (8–10). Thus, individuals whowilldeveloptype2diabetesarecharacter-izednotonlybyanupregulationofproin-flammatory immune mediators (1–3) butalso by the upregulation of at least oneanti-inflammatory immune marker. Be-cause animal studies and a recent clinicaltrial indicated that administration of IL-1Ra attenuates subclinical inflammation,supports   -cell function/insulin secre-tion, and may also improve insulin sensi-tivity (6,14), it is tempting to speculatethat elevated IL-1Ra levels in individualsat risk of type 2 diabetes may be an at-tempt to counteract the proinflammatoryeffects of interleukin-1  and to preserveinsulin secretion and insulin sensitiv-ity—an effort that eventually fails. How-ever, our data cannot rule out thealternative interpretation that IL-1Ra hasadditional metabolic effects beyond theinhibitionofinterleukin-1  thatcouldleadto insulin resistance and type 2 diabetes. As a potential limitation of the study,it should be mentioned that point esti-mates and CIs are derived from non-weighted data from a nested case-controlstudyand,therefore,theirstatisticalinfer-ence may be restricted and may not rep-resent the best available estimate withinthe context of the srcinal cohort. Thus,further studies will be needed to supportour hypothesis that individuals with highrisk of type 2 diabetes are characterizedbythepresenceofanearlycompensatory,anti-inflammatoryresponsethatprecedesthe development of the disease. This hy-pothesiscouldbetestedbytheanalysisof further, mainly anti-inflammatory im-mune mediators, such as interleukin-10or transforming growth factor-  in addi-tional cohorts. Acknowledgments — TheWhitehallIIStudyis funded by the Medical Research Council;the Economic and Social Research Council;the British Heart Foundation; the Health andSafety Executive; the Department of Health(U.K.); the National Heart, Lung and BloodInstitute (HL36310), National Institutes of Health (NIH); the National Institute on Aging(AG13196), NIH; the Agency for Health CarePolicy and Research (HS06516); and the JohnD. and Catherine T. MacArthur Foundation.This case-control study was funded by a Med-ical Research Council New Investigator grant(G0501184), the Federal Ministry of Health Table 1—  Association between circulating concentrations of IL-1Ra and incident diabetes Model Covariables Odds ratio (95% CI)  P 1 Age and sex 1.48 (1.21–1.80) 0.00012 Age, sex, and waist circumference 1.39 (1.11–1.74) 0.00383 Those for model 2 plus cardiovascular risk factors (cholesterol, fastingtriglycerides, systolic blood pressure, smoking*, physical activity†,antihypertensive medication, and lipid-lowering medication)1.34 (1.05–1.72) 0.0214 Those for model 2 plus socioeconomic status (employment grade‡) 1.39 (1.10–1.75) 0.00595 Those for model 2 plus proinflammatory mediators (CRP and IL-6) 1.35 (1.06–1.70) 0.0136 Those for model 2 plus fasting glycemia (fasting glucose and fasting insulin) 1.39 (1.05–1.86) 0.0247 Those for model 2 plus 2-h glucose 1.24 (0.91–1.69) 0.178 Age, sex, waist circumference, and all covariables from models 3–6 1.43 (1.03–2.00) 0.0349 Age, sex, waist circumference, and all covariables from models 3–7 1.20 (0.84–1.71) 0.32 Data are odds ratio (95% CI) given for a 1-SD increase of IL-1Ra concentrations unless otherwise indicated. IL-1Ra, triglycerides, C-reactive protein (CRP),interleukin (IL)-6, and insulin entered the models as ln-transformed variables. *Smoking is coded in three classes (never smoked, former smoker, and currentsmoker).†Physicalactivityiscodedinthreeclasses(none/mild,moderate,andvigorous).‡Employmentgradeiscodedinsixclassesrunningfrom1(highestgrade)to 6 (lowest grade).  Anti-inflammatory IL-1Ra and type 2 diabetes 422  D IABETES  C ARE ,  VOLUME  32,  NUMBER   3, M ARCH  2009  (Berlin, Germany), and the Ministry of Inno-vation, Science, Research, and Technology of thestateNorthRhine-Westphalia(Du¨sseldorf,Germany).C.H. received a consulting honorariumfrom XOMA (Berkeley, CA). No other poten-tial conflicts of interest relevant to this articlewere reported. We thank Karin Ro¨hrig (German DiabetesCenter) for excellent technical assistance. References 1. KolbH,Mandrup-PoulsenT:Animmunesrcin of type 2 diabetes?  Diabetologia  48:1038–1050, 20052. Herder C, Baumert J, Thorand B, Koenig W, de Jager W, Meisinger C, Illig T, Mar-tin S, Kolb H: Chemokines as risk factorsfor type 2 diabetes: results from theMONICA/KORA Augsburg Study, 1984–2002.  Diabetologia  49:921–929, 20063. Herder C, Klopp N, Baumert J, Mu¨ller M,Khuseyinova N, Meisinger C, Martin S,Illig T, Koenig W, Thorand B: Effect of macrophage migration inhibitory factor(MIF) gene variants and MIF serum con-centrations on the risk of type 2 diabetes:results from the MONICA/KORA Augs-burg Case-Cohort Study, 1984–2002. Diabetologia  51:276–284, 20084. Sell H, Dietze-Schroeder D, Eckel J: Theadipocyte-myocyte axis in insulin resis-tance.  Trends Endocrinol Metab  17:416–422, 20065. Donath MY, Schumann DM, FaulenbachM, Ellingsgaard H, Perren A, Ehses JA:Islet inflammation in type 2 diabetes:from metabolic stress to therapy.  DiabetesCare  31 (Suppl. 2):S161–S164, 20086. LarsenCM,FaulenbachM,VaagA,Vølund A, Ehses JA, Seifert B, Mandrup-Poulsen T,DonathMY:Interleukin-1-receptorantag-onist in type 2 diabetes mellitus.  N Engl J Med  356:1517–1526, 20077. Lindsay RS, Funahashi T, Hanson RL,Matsuzawa Y, Tanaka S, Tataranni PA,Knowler WC, Krakoff J: Adiponectin anddevelopment of type 2 diabetes in thePima Indian population.  Lancet  360:57–58, 20028. Salmenniemi U, Ruotsalainen E, Pihlaj-ma¨kiJ,VauhkonenI,KainulainenS,Pun-nonenK,VanninenE,LaaksoM:Multipleabnormalities in glucose and energy me-tabolism and coordinated changes inlevels of adiponectin, cytokines, andadhesion molecules in subjects with met-abolic syndrome.  Circulation  110:3842–3848, 20049. Meier CA, Bobbioni E, Gabay C, Assima-copoulos-Jeannet F, Golay A, Dayer JM:IL-1 receptor antagonist serum levels areincreased in human obesity: a possiblelink to the resistance to leptin?  J Clin En-docrinol Metab  87:1184–1188, 200210. Ruotsalainen E, Salmenniemi U, Vauh-konen I, Pihlajma¨ki J, Punnonen K,Kainulainen S, Laakso M: Changes in in-flammatory cytokines are related to im-paired glucose tolerance in offspring of type2diabeticsubjects. Diabetes Care 29:2714–2720, 200611. MarmotM,BrunnerE:Cohortprofile:the WhitehallIIstudy. IntJEpidemiol 34:251–256, 200512. Kumari M, Head J, Marmot M: Prospec-tive study of social and other risk factorsfor incidence of type 2 diabetes in the Whitehall II study.  Arch Intern Med  164:1873–1880, 200413. Juge-AubryCE,SommE,GiustiV,Pernin A, Chicheportiche R, Verdumo C,Rohner-Jeanrenaud F, Burger D, Dayer JM, Meier CA: Adipose tissue is a majorsource of interleukin-1 receptor antago-nist: upregulation in obesity and inflam-mation.  Diabetes  52:1104–1110, 200314. 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