Is chronic toxoplasmosis a risk factor for diabetes mellitus? A systematic review and meta-analysis of case-control studies

w w w . e l s e v i e r . c o m / l o c a t e / b j i d

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

Original

article

Is

chronic

toxoplasmosis

a

risk

factor

for

diabetes

mellitus?

A

systematic

review

and

meta-analysis

of

case–control

studies

Hamidreza

Majidiani

_,

_Sahar

_Dalvand

_,

_Ahmad

_Daryani

_,

Ma

de

la

Luz

Galvan-Ramirez

_,

_Masoud

_Foroutan-Rad

a_{TarbiatModaresUniversity,FacultyofMedicalSciences,DepartmentofParasitology,Tehran,Iran} b_{KurdistanUniversityofMedicalSciences,SocialDeterminantsofHealthResearchCenter,Sanandaj,Iran} c_{MazandaranUniversityofMedicalSciences,ToxoplasmosisResearchCenter,Sari,Iran}

d_{UniversityofGuadalajara,HealthSciencesUniversityCenter,DepartmentofPhysiology,ResearcherofNeurophysiologyLaboratory,} Guadalajara,Mexico

e_{AhvazJundishapurUniversityofMedicalSciences,FacultyofMedicine,DepartmentofMedicalParasitology,Ahvaz,Iran}

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Received30July2016 Receivedinrevisedform 28August2016

Availableonline18October2016

Keywords: Toxoplasmagondii Diabetesmellitus Systematicreview Meta-analysis

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Introduction:Theglobalprotozoanparasite,Toxoplasmagondii,infectsmanywarm-blooded animalsandhumansbyemployingdifferenttransmissionroutes.Therehavebeensome recent studieson the probablerelevanceof infectiousagents and diabetes.Therefore, weconductedasystematicreviewandmeta-analysistoidentifythepossibleassociation betweenchronictoxoplasmosisanddiabetesmellitus.

Methods:Thisstudywasconductedfollowingthegeneralmethodologyrecommendedfor systematicreviewsandmeta-analysis.NineEnglishliteraturedatabases(Googlescholar, PubMed,Scopus,Webofscience,ScienceDirect,Ovid,ProQuest,IngentaConnect,andWiley OnlineLibrary) weresearched,up toJanuary2016. Randomeffectsmodelwasused to determineoddsratiosandtheir95%confidenceintervals.

Results:Ourreviewresultedinatotalofsevenpublicationsmeetingtheinclusioncriteria. Becauseofsignificantheterogeneity,weestimatedacommonORbyarandomeffectsmodel at1.10(95%CI=0.13–9.57)withp=0.929and2.39(95%CI=1.20–4.75)withp=0.013fortype 1andtype2diabetesmellitus,respectively.

Conclusion: Despitethelimitationssuchaslownumberofstudies,thismeta-analysis sug-gests chronictoxoplasmosisasapossibleriskfactorfortype2DM.However,basedon randomeffectsmodelnostatisticallysignificantassociationwasobservedbetweenT.gondii andtype1DM.Itishighlyrecommendedforresearcherstocarryoutmoreaccuratestudies aimingtobetterunderstandthisassociation.

©2016SociedadeBrasileiradeInfectologia.PublishedbyElsevierEditoraLtda.Thisisan openaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/ by-nc-nd/4.0/).

∗ _{Correspondingauthor.}

E-mailaddress:[email protected](M.Foroutan-Rad).

http://dx.doi.org/10.1016/j.bjid.2016.09.002

1413-8670/©2016SociedadeBrasileiradeInfectologia.PublishedbyElsevierEditoraLtda.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

The ubiquitous parasitic protozoan, Toxoplasma gondii, is one of the most successful microorganism on the planet owingtoquitealotofcompatibilitytomanyhostspecies, especially mammals, various transmission pathways (e.g. food,water,congenital,bloodtransfusion,organstransplant, etc.) and approximately involving one-third ofthe human population.1–4 _{Being the categoryB prioritypathogen with}

zoonoticsignificance,Toxoplasmahasfrequentlybeen asso-ciatedwithcongenitalcomplications(suchashydrocephalus, stillbirthandabortion)aswellasneuropathicanomalies, pre-dominantly in high risk populations, i.e. pregnant women and immunocompromised hosts.2,5–7 _{While unusual, there}

aresomeevidencethatT.gondiiparasitesmaypossiblyhave anundiscoveredroleintheputativepathogenesisof autoim-munediseases.8

A group of chronic metabolic disorders, specified as “Diabetes”,areofmedicalimportancewithwidespread dis-tribution,especiallyinpersonswithhigh-caloriediets.They aredistinguishedbyhyperglycemiaelicitedbythe deficien-ciesintheinsulinhormonerelease(type1diabetes)and/or failuretorespondproperlytoinsulinintargetcells(type2 dia-betes),andthisconditionisprobablyoverwhelmedbygenetic elements,autoimmuneprocesses,andenvironmentalfactors. Accordingtoscientificevaluations,itisanticipatedthatthe numberofdiabeticpatientswillreach522millionindividuals by2030.9_{Recently,somereportshavespotlightedthe}

proba-blerelevanceofdiabetesmellitus(DM)andinfectiousagents likeHelicobacterpylori10_{andCoxsakieB4virus.}11_Inthiscase,

theApicomplexanparasite,T.gondii,hasbeenproposedasa likelycauseofdiabetes,andexistinginformationnearly predi-cateonthisissue.12–16_{Hence,thisreviewwasintendedtoshed}

lightonthepossibleassociationbetweentoxoplasmosisand diabetes.

Methods

Asthisreviewdidnotinvolveanyhumanoranimalsubjects, thereforeethicalapprovalwasnotrequired.

Searchstrategy

A systematic review was premised on screening the liter-ature published online in English language up to January 2016,inordertoaddresstheassociationbetween toxoplas-mosis and diabetes. Thesearch was conductedon Google scholar, PubMed, Scopus, Web of science, Science Direct, Ovid, ProQuest, IngentaConnect, and Wiley Online Library (SupplementaryFig.1).Towardthatend,themedicalsubject headings (MeSH) terms in PubMed and Scopus databases usingthesearchkeywords“Toxoplasmosis”,“T.gondii”, “Tox-oplasma gondii”,“Diabetes mellitus”and “Diabetic patients” combined together using OR and/or AND. Also reference listsofthe primaryrelevance recordsfoundwere explored

manually.Corresponding authors ofpaperswere contacted formoredetails,ifdeemednecessary.

Studyselectionanddataextraction

Onlycase–controlstudies onseroepidemiologyof toxoplas-mosisindiabeticindividualsaroundtheworldwereincluded. Otherinclusioncriteriawereasfollows:diabetesasadisease and T. gondii as an exposure, presence of healthy individ-ualsascontrolgroup,andserologicdiagnostictest.Records wereevaluatedbytwoindependentreviewers.Theselected articles werescrutinizedand contradictionsamongstudies were obviatedbydiscussionandconsensus.Thedatawere extractedcarefullyfromdatabasesonthebasisoftitle,year ofpublication,firstauthor,diagnosticmethod,typeof inves-tigation,typeofdisease,aimofstudy,mainfindings,exact numberofparticipantsbothincaseandcontrolgroups,and details ofT. gondiipositiveindividuals aswell.ThePRISMA (preferredreportingitemsforsystematicreviewsand meta-analysis)guideline17_{wasfollowedinthereportingofcurrent}

systematicreview.

Meta-analysis

For each included study, the common odds ratio (OR) and respective 95% confidence interval (CI) on the association amongtoxoplasmosisanddiabeteswerecalculated.The out-comeofpoolestimatesofstudiesinadditiontotheir95%CIof independentrecordsweredepictedinaforestplot.Cochran’s QandI2_{statisticswereappliedtoassessheterogeneityand}

inconsistency,respectively.Furthermore,smallstudyeffects and their publication biaswere discerned bya funnelplot onthecornerstoneofEgger’sregressiontest.Tocomplywith the resultsof heterogeneity test, either DerSimonian and Laird’s random-effects method or Mantel-Haenszel’s fixed-effectswereemployedtopooltheapproximations.

Results

Basedoninclusioncriteria,atotalnumberof7outof1377 studieswerequalifiedtobeultimatelyincludedinthis sys-tematicreviewandmeta-analysis,12,14,18–22_{asdemonstrated}

inSupplementaryFig.1.Thespecificationsofeachstudy com-prisingthenumberofcasesandcontrolsaswellasthenumber ofIgGpositiveindividuals,theutilizedmethodandobtained p-value havebeen summarizedinTable1.Out of2248 per-sonstestedfortoxoplasmosisinfection,717werepositivefor T.gondiiinfection,202hadtype1,and1158hadtype2DM;out of888healthyindividuals280positiveforT.gondiiinfection. Theheterogeneitywasstatisticallysignificant,forbothtype 1,I2_{=94.7%andQ=38.09(p<0.001),andtype2DM,I}2_=88.1%

and Q=25.26(p<0.001)(Table2and Supplementary Fig.2). Accordingly,wecalculatedacommonORbyrandomeffects modelat1.10(95%CI=0.13–9.57)withp=0.929and2.39(95% CI=1.20–4.75)withp=0.013fortype1andtype2DM, respec-tively(Table2andSupplementaryFig.2).Alsothecalculated commonOR(randomeffectsmodel)forbothtype1and2 dia-betes was 1.86 (95% CI=0.93–3.74) withp=0.0796. Thetest of publication biaswas clearlynot significant inthis case,

Table1–PrevalenceofToxoplasmainfectionamongdiabetic(cases)andhealthyindividuals(controls)includedinthe systematicreview.

Reference Diabeticpatients (cases)

Healthyindividuals (controls)

Matching Method OR(95%CI) p-Value

n Toxoplasma IgG+_n(%) n Toxoplasma IgG+_n(%) Type1diabetes (14) 85 49(57.6) 85 18(21.1) Ageand gender ELISA (EUROIMMUN) 5.066(2.579–9.952) <0.001

(21) 57 3(5.2) 140 56(40) Unspecified Bio-Plex2200kits 0.083(0.025–0.279) <0.001

(20) 60 27(45) 60 14(23.3) Unspecified ELISA 2.688(1.226–5.895) 0.01 Type2diabetes (22) 807 457(56.6) 250 56(22.4) Ageand gender ELISA (EUROIMMUN) 4.523(3.257–6.281) <0.001 (19) 91 55(60.4) 93 36(38.7) Ageand gender ELISA(Pishtaz TebZamanCo.)

2.419(1.338–4.373) 0.003

(18) 150 79(52.6) 150 76(50.6) Gender ELISA(VIRO,

Germany). 1.083(0.689–1.704) 0.72 (12) 110 47(42.7) 110 24(21.8) Ageand gender ELISA(Biotech Co.England) 2.673(1.483–4.819) 0.001

n,numberofindividuals;IgG+_{,anti-Toxoplasmaantibody(immunoglobulinG);(%),percentage;ELISA,enzyme-linkedimmunosorbentassay;} OR,oddsratio;95%CI,95percentconfidenceinterval.

Table2–Subgroupanalysisaccordingtotypeofdiabetes.

Typeofdiabetes No.ofstudies OR(95%CI) I2_{% Heterogenietytest}

p Q

Type1 3 1.10(0.13–9.57) 94.7 38.09 <0.001

Type2 4 2.39(1.20–4.75) 88.1 25.26 <0.001

Overall 7 1.86(0.93–3.74) 90.2 61.35 <0.001

TestforheterogeneitybetweensubgroupQ:0.703,p-value:0.4.

p=0.335(SupplementaryFig.3).Also,thechartofforestplot hasbeen illustratedinsupplementary Fig.2. Thestatusof toxoplasmosisinfection wasbasedonELISAIgG,exceptfor onepaperinwhichtheBio-Plex2200kitswereemployed.

Discussion

ApossibleassociationbetweentoxoplasmosisandDMwould entail significant clinical consequences, shedding light on the complicated pathogenesis of DM. Overall, the current hypothesissuggests that toxoplasmosisincreases suscepti-bilitytoacquiringdiabetesand,ontheotherhand,diabetic patientsaremorevulnerabletoopportunisticinfectionssuch as toxoplasmosis.12–14,22–24 _{Subsequently, to elucidate this}

association,variousempiricalevidencehavebeenappraised andproposed asplausible pathophysiologicalmechanisms, including:(1)infectedwhitebloodcellsrepresentenhanced migratoryfeature,leadingtotheeasierspreadofToxoplasma inbody organs,e.g.pancreas13_{; (2) aclinicallyconspicuous}

autoimmuneprocesscould beignitedbyT.gondiiinfection, trending immune machinery toward autoantibody produc-tion,forinstance against␤-cellsofLangerhans islets13_{; (3)}

in light of ex vivo d-glucose and insulin dose-responsive experimentin3T3-L1cells,betterreplication ofToxoplasma occursininsulin-producing ␤-cells,leadingtoactivation of

autoimmunitypathwaysaswellasprovokingthe inflamma-tionofLangerhansislets(insulitis)andultimatelydeveloping diabetes23_{;(4)apossibility,isthatT.gondiiitselfmayinvade}

anddestroypancreatic␤-cellsdirectly,instigating pancreati-tisandmoreimportantly,diabetes25_{;(5)productionofreactive}

oxygen species (ROS) and nitric oxide (NO) is induced by diabetes, and these agents, as stimulant for intra-cellular pathogens, can re-activate latent, cysts ofparasites, again initiating acute infection26_{; (6) given the inability of}

neu-trophilstocorrectlyperformphagocytosisandintra-cellular killinginprogressivephaseofdiabetes,theremaybeincreased responsiveness tointra-cellularpathogens suchasCandida andToxoplasma,27_{and(7)theopsonizationactivityand}

leuko-cytecytotoxicityofdiabeticpatientsrequiredforelimination ofpathogensareconsiderablysubsided,hencetheywouldbe morepronetoopportunisticinfections.12,27,28

Intheincludedstudies(Tables1and2),theORintype1DM individualswas1.10(95%CI=0.13–9.57)withp=0.929,while thisratiointype2DMpatientswas2.39(95%CI=1.20–4.75) withp=0.013. Thus,therisk oftype1and 2diabeteswith previous Toxoplasma exposurewould be 1.10 and 2.39 fold higher,respectively,thanforunexposedpersons.However,no statisticallysignificantassociationbetweenchronic toxoplas-mosisandtype1DMwasheldonrandomeffectsmodel.In this case,the highestOR(5.066) wasreported inthestudy byGokceetal.14 _{(p<0.001)andthelowestOR(0.083)inthe}

study by Krause et al.21 _{(p<0.001). According to the}

esti-matedORbyKrauseetal.21_{thereisnoassociationbetween}

toxoplasmosisanddiabetesandit ishypothesizedthatthe patients’youngeragesaswellasuncommonrouteof infec-tionmayhaveremarkablybiasedtheirresults.Recently,some researchershavedemonstratedtheinfluenceofparasite geno-typesonbehavior,psychomotorperformance,physiology,and overallhealthoftheirhost.Hence,thestrainofToxoplasma shouldbeconsideredasaninfluentialparameterinrelation todiabetes.15,16,29–32

Despite of the lack of remarkable correlation between chronic toxoplasmosis and type 1 diabetes in the current meta-analysis,exvivostudiesstronglydemonstratethe pres-ence ofthis relationship.13,24 _{Therefore,furtherstudies are}

neededinthefuture.There wereseverallimitations inour study,including (1) small samplesizes inincluded studies andnofurtherdetailsaboutdiseaseconditionandduration incases;(2) thevariable quality ofreportingofstudies;(3) variablemethodologytodefineToxoplasmainfection;and(4) lackofrepresentativenessofcasesandcontrolsastheywere selectedfromrestrictedcommunities,thuslimitingexternal validityoftheresults.

Implications

for

research

Basedoncurrentlyavailableresults, nostatistically signifi-cantassociationwasobservedbetweenchronictoxoplasmosis andtype1DM;ofcoursethereremainmanyquestionstobe answeredinfutureinvestigations.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgments

The authors would like to thank all staff of the Depart-mentofMedicalParasitologyofTarbiatModaresandAhvaz JundishapurUniversitiesofMedicalSciences,Iran.Wearevery gratefultoDrJasemSaki(DepartmentofMedicalParasitology, FacultyofMedicine,AhvazJundishapurUniversityof Medi-calSciences,Ahvaz,Iran)andHassanNiksima(Department ofEpidemiology and Biostatistics, School of Public Health, TehranUniversityofMedicalSciences,Tehran,Iran)fortheir helpfulconsultations.

Appendix

A.

Supplementary

data

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.bjid.2016.09.002.

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