The Role of Anxious Arousal and Inflammation

33 Pages·2016·0.38 MB·English

by  Kyle W. Murdock

Psychoneuroendocrinology71(2016)102–109

ContentslistsavailableatScienceDirect

Psychoneuroendocrinology
journal homepage: www.elsevier.com/locate/psyneuen

Executive functioning and diabetes: The role of anxious arousal and

inflammation
KyleW.Murdocka,AngieS.LeRoya,b,TamaraE.Lacourtc,DannyC.Duked,
Cobi J.H eijnenc,Ch ristop he rP.Fagun desa,c,e, ∗

aDepartmentofPsychology,RiceUniversity,BioscienceResearchCollaborativeRoom773,6100MainStreet,Houston,TX77005,UnitedStates
bDepartment of Psychology, Univ ersityofHo uston,369 5CullenB oulevardRoo m126 ,Hou ston, TX77 204,Un itedState s
cDepartment of SymptomRe search,The U niversity ofTex asMD Anderson Cancer Cen ter,1515 Hol combe Bouleva rd,Unit1450,Houston,TX77030,United

States
dDivisionofPsychology,InstituteonDevelopmentandDisability,OregonHealthandScienceUniversity,707SWGainesStreet,Portland,OR97239,United

States
eDepartmentofPsychiatry,BaylorCollegeofMedicine,OneBaylorPlaza–BCM350,Houston,TX77030,UnitedStates

a r t i c l e i n f o a b s t r a c t

Articlehistory: Individualswhoperformpoorlyonmeasuresoftheexecutivefunctionofinhibitionhavehigheranx-
Receiv ed28January2016 iousarousa linc ompariso ntoth ose withbett er perf ormance. Highanx iou sarousali sasso ciated with
RAeccceepivteedd i3n Mr eavyis2e0d1 f 6orm 2 May 2016 a pro -inflam ma tory respon se. Chron ically high anxious arous al and inflamm ation i nc rease one’s risk
ofdevelopingtype2diabetes.Wesoughttoevaluateanxiousarousalandinflammationasunderlying

mechanismslinkinginhibitionwithdiabetesincidence.Participants(N=835)completedmeasuresof
Keywords: cognitiveabi lities,a self-report meas ureofan xiousarou sal,anddona ted blood toassessi nterleukin -6
Executivefunctioning
(IL-6)andglycatedhemoglobin(HbA1c).Individualswithlowinhibitionweremorelikelytohavedia-
Inhibition
betesthanthosewithhighinhibitionduetotheserialpathwayfromhighanxiousarousaltoIL-6.Findings
Anxiousarousal
Inflamm ation remained when entering other indicators of cognitive abilities as covariates, suggesting that inhibition
Diabetes isauniquecognitiveabilityassociatedwithdiabetesincidence.Onthebasisofourresults,wepropose

severalavenuestoexploreforimprovedpreventionandtreatmenteffortsfortype2diabetes.

©2016ElsevierLtd.Allrightsreserved.

1. Introduction tions.Thepresentstudydrawsfromthepsychoneuroimmunology

literaturetoexaminehowcognitiveprocessesandimmunefunc-

Emotionalstressisariskfactorforpoorphysicalhealth.Indeed, tioning underlie the association between anxious arousal and

highanxietyisassociatedwithdiabetesincidence(Lietal.,2008). glycated hemoglobin (HbA1c), a well-known biomarker used to

A better understanding of the association between anxiety and estimatebloodglucoseduringthepreceding2–3months.

bloodglucoseisimportantgiventhatapproximately347million Theexecutivefunctionofinhibition(alsoknownasattentional

people worldwide have diabetes, which has imposed a growing controlorinhibitorycontrol)isassociatedwiththeexperienceof

economicstrainonhealthcaresystems(Zhangetal.,2010).More- stressfulemotionssuchasanxiety.Inhibitionistheabilitytorefrain

over, approximately 90% of all diabetes is type 2, which can be fromrespondingorattendingtotempting/distractinginformation,

preventedordelayedvialifestylechanges(e.g.,physicalactivity, objects,thoughts,oractivities.Indeed,thosewhohavelowinhi-

diet;TuomilehtoandWolf,1987;WHO,2014)thataremorediffi- bition are more likely to attend to anxious thoughts, and have

culttoachievewhenstressedoranxious(Stults-Kolehmainenand greaterdifficultyshiftingtheirattentionawayfromsuchthoughts,

Sinha,2014).Therefore,afurtherunderstandingoftheassociation thanthosewithhighinhibition(DeGutisetal.,2015;Joormannand

betweenanxietyandbloodglucoseisneededtoimproveinterven- Gotlib,2010;SchmeichelandTang,2015).Othershavearguedthat

betterinhibitionisassociatedwithlessanxietyviatheabilityto

flexiblyandadaptivelyrespondtoone’senvironmentusingopti-

malcopingstrategies(e.g.,Marteletal.,2007).Indeed,inflexibility

∗ inthinkingisassociatedwithincreasedanxiety(e.g.,Brittonetal.,
Correspondingauthorat:BioscienceResearchCollaborative,Rm773MS-142,
6100MainStreet,H ouston ,Un itedStates . 20 10),whic h mayexplai nwh ythosewi thbette rinh ibitionr ep ort

E-mailaddresses:[email protected],[email protected] lessanxietythanthosewithpoorinhibition.Theneurovisceralinte-
(C.P.Fagun des).

http://dx.doi.org/10.1016/j.psyneuen.2016.05.006
0306-4530/©2016ElsevierLtd.Allrightsreserved.
K.W.Murdocketal./Psychoneuroendocrinology71(2016)102–109 103

.09* (.02, .16)
Anxious Arousal Interleukin-6
-.12* (-.05, -.18) .26* (.03, .50)

.08 (-.16, .31)
-.08* (-.02, -.15)

-.01 (-.23, .21)
Inhibition Diabetes

Incidence

Fig.1. Amediationmodelofassociationsbetweeninhibition,anxiousarousal,interleukin-6,anddiabetesincidence.Standardizedregressioncoefficientsarerepresented

whenpredictinganxiousarousalandinterleukin-6,whilelogisticregressioncoefficientsarerepresentedwhenpredictingdiabetesincidence.95%confidenceintervalsare
depict edinparen theses.I ndirecte ffec tsusing5000b ootstr apsamp les:anxiou sarousal(0 .008 9,SE=0.0144 ,95% CI=−0.018 1,0.0407 ),interleuk in-6 (0.0220,SE= 0.0142,9 5%

CI=0.0023,0.0616),andserialmediation(i.e.,mediationinsequence;0.0028,SE=0.0022,95%CI=0.0003,0.0103).Controlvariablesincludedparticipantage,sex,ethnicity,

bodymassindex,useofinsulin,andsmokinghistory,aswellthetimelagbetweenassessments.*p<0.05.

grationmodel(e.g.,ThayerandLane,2009)alsoindicatesthatthose raldeclineofcognitiveskillsandincreaseininflammationnearthe

withpoorinhibitionarelessphysiologicallycapableofresponding endofhumanlife(Magakietal.,2007;Simenetal.,2011).Further-

and adapting to their environment in comparison to those with more,inhibitionistypicallycombinedwithothercognitiveabilities

betterinhibition.Asaresult,thosewithpoorinhibitionaremore instatisticalanalyses,limitingtheabilitytounderstandtheunique

likelytohaveapre-attentivebiastothreatinformationthanthose effectsofinhibition(Marslandetal.,2015).Specifically,indicators

withbetterinhibitionduetoaninabilitytoflexiblyrespond,and ofexecutivefunctioning(i.e.,workingmemory,cognitiveflexibil-

aremorelikelytoreportincreasedarousalduetothisbias(Thayer ity,andinhibition)areoftencombinedintoalatentconstructof

andFriedman,2004).Therefore,bothcognitiveandphysiological executive functioning as opposed to being evaluated as individ-

processes may link poor inhibition with increased anxiety. High ualpredictorsoftargetedoutcomes.Accordingly,itisimportantto

anxiety is associated with poor overall physical health in adults determineifinhibitionisassociatedwithdiabetesthroughanxious

(Needham et al., 2015), which is notable given that those with arousalandinflammation.

lowinhibitionaschildrenexhibitpoorphysicalhealthoutcomes Weexpectedthatlowinhibitionwouldbeassociatedwithhigh

inadulthood(Moffittetal.,2011). anxiousarousaland,inturn,highinflammation.Itwaspredicted

The underlying mechanisms linking low inhibition and poor that the serial pathway from anxious arousal to inflammation

healthhavenotbeenadequatelystudied.Inadditiontoincreased wouldexplaintheassociationbetweeninhibitionanddiabetesinci-

anxiety(SchmeichelandTang,2015),lowinhibitionisalsoarisk dence(i.e.,serialmediation).Furthermore,weexpectedthatthis

factor for poor diabetes management because of an inability to pathwaywouldremainsignificantaboveandbeyondotherindica-

consistentlyadheretoandcompletediabetesmanagementtasks torsofcognitiveabilities(i.e.,performanceondigitspan,backwards

(Wassermanetal.,2015).Therefore,itisimportanttogeneratea counting,andnumberseriesmeasures).

further understanding of how inhibition is linked to diabetes to

improvepreventionandinterventionefforts.

Inflammation may play an important role in linking inhibi-
tion and diabete s. Tho se w ith high stress dem on strate a greater 2. Materialandmethods

inflammatoryresponsethanindividualswhoarelessstressedat
themoderate effectsize level (i.e.,r=0.42 to0 .57; Fagu ndeseta l., 2.1. Participantsandprocedure

2013).Anxiety,aswellasstressmoregenerally,leadstoinflam-
mation viaactiv ati onof nu clearfa ctor-k appaB(N F-KB). Ac tivation DatawereobtainedfromtheMidlifeDevelopmentintheUnited
ofNF-K Bin creasespr od uctiono fpro-inflamm a torycyto kinessuch States (M IDU S) study in wh ich menta l and physica l h ealt h out-
as interle ukin-6(B ierhauseta l.,2 003).Further,chro nicinflam ma- comes wereexa mined am ongan ationall yrep resentati vesamp leof
tio n is a reliabl e predicto r o f d iabete s onset a t the s mall effect middle aged adults.Da tafrom t wotimepo intswereutili zedinth e
size le ve l (i.e., r= 0.28–0.33 ; C hen et a l., 200 9; Pert icone et al., present stud y.Speci ficall y,me asur esof cogniti veab ilitydesc ri bed
2008 ;We nget a l., 2010),asw ellas m orbi dityan dmortalit yw ith beloww ereco mpleteddur ingabase lin evisit.Al lother measures
smallt omod era tee ffectsi zes typi cal lyidentifie d(i.e .,r=0.10– 0.40; werec ompl etedatthe follow- up visit,wh icho ccu rreda naverage
Kieco lt- Glasereta l.,201 0).In addition toinflamm atio n b eingapre- of 23 .39 months (S D= 14.28) afte r par ticipan ts comple ted cogni-
dictor of diabe te s o nset, d ia betes pro gr ession is asso ciated w ith tiv e mea sures. A tota l of 451 2 pa rticipants co mpleted co gnitive
increa sed inflamm ationo vertime( Stehouwere ta l.,2002).Ch ronic asse ssments.O ft hose wh ocom pletedtheco gnitiveass essments,
elevated i nflammation is ass ociat ed with inc re ase d risk of heart 1255agreed top artici patea ndwereid enti fiedasbe ingmedically
disease ( OR=1.45; Han ss on, 2005), a maj or complic ation o f dia- safet otravel to Madison,W I,L osAn geles,CA,o rW ashi ngton,DC,
betes(G rund y etal. ,1999).Ind icators o fanxio usarousal(e.g .,ra cing fort he follow -u passessm ent. Com pleteda taw as obtainedfro ma
heart, chestpa in) ar estron gerpredict or sofinfla mmatio ntha ncog- tot alof 835partic ipants(Mage= 57.62,SD =11. 60).S ignifican tmea n
nitive anxie ty(e.g .,fe arfulof dyingorlo sin gcontrol)at thes mall differ en ces were not id entified amo ng th ose w ith comple te vs.
effects sizelev el(r= 0.12;D ui viset al., 2013), possibly du eto acti- incomplete dataf orth evastmaj orityof study variab les(i.e.,in hi-
vation ofth esym p at hetic nervou ss yst em(Jan ig,2014 ). bition,anxio usa rou sal, inter leukin-6, dia betes incidence ,age ,sex,
Asl ow inh ibitionisass ociatedw ithhig hanxio usarousalatthe ethnici ty, body mass in dex, and time lag betw een asses smen ts);
mediu me ffectsizele ve l(r=0.38; DeGu tiset al.,201 5),lowi nh ibi- however, partic ipant s with inco mplet e d ata were older (t=2.34,
tionmay alsob eass ociat ed w ithh ighinfla mm at ion;ho wev er,itis p=0.02) a nd more lik ely to have a his tory of sm oking (t = 2.84,
uncl earif inhi bit ionisassoc iated with inflammation inthegen er al p = 0.01) in c ompar ison to th ose w i th comp let e data, co n si stent
populat io nasthelite ra turehaspr imar ilybeenfocuse do nth enatu- w it hthe ne edtobemedi cal lysafe totra veltothef ollow -upassess-
ment .
104 K.W.Murdocketal./Psychoneuroendocrinology71(2016)102–109

Table1

Participantcharacteristics.

Variable Metcriteriafordiabetes(n=103)Mean(SD)or Didnotmeetcriteriafordiabetes(n=737)

number(%) Mean(SD)ornumber(%)

Participantageatbiologicalassessment 62.55(10.88) 57(11.58)

Participantsex

Male 54(52.4) 319(43.6)

Female 49(47.6) 413(56.4)

Participantethnicity

White 93(90.3) 686(93.8)

Non-white 10(9.7) 46(6.2)

Bodymassindex 32.51(7.57) 28.69(5.65)

Eversmokedcigarettesregularly?

Yes 51(49.5) 428(58.4)

No 52(50.5) 304(41.6)
Inhib ition −0 .21(2. 02) 0.35 (1.94)

Logtransformedinterleukin-6 0.45(0.31) 0.30(0.32)

HemoglobinA1cpercentage 7.53(1.35) 5.73(0.36)

Fastingglucosemg/dL 133.22(49.19) 95.16(10.40)

Digitspan 4.71(1.27) 5.08(1.42)

Backwardscounting 36.51(11.45) 39.80(10.82)

Numberseries 2.01(1.40) 2.64(1.50)

Note.Inhibitionreflectsthez-standardizationandcombinationofaveragereactiontimeandnumberoferrorsonthereversedandmixedconditionsofthego-nogotask.

Allcognitivetestswereadministeredoverthetelephoneinthe conditionoftheSGSTwasmoderatelycorrelated(i.e.,r=0.52)with

MIDUSstudy(TunandLachman,2006).Thereliabilityandvalidity TaskSwitchingfromtheBostonCognitiveBattery,a90mininper-

ofconductingthecognitivemeasuresoverthephoneintheMIDUS sonassessment,usingasubsampleofMIDUSparticipants(n=299)

study was recently evaluated and excellent test-retest reliability who also participated in the Boston Longitudinal Study (BOLOS;

wasidentified(Lachmanetal.,2014).Moreover,moderatetolarge Miller and Lachman, 2000). The SGST was also tested in person

correlations ranging from 0.55 to 0.95 were identified between among a subsample (n=30) of participants who had also com-

atelephoneadministrationandanin-personadministrationina pletedthemeasureoverthetelephone.Thecorrelationbetween

subsampleof30participants.Inaddition,moderatetolargecorre- thetelephoneandinpersonadministrationsoftheSGSTwas0.71

lationsrangingfrom0.42to0.54wereidentifiedbetweenmeasures (Lachmanetal.,2014).

onthetelephoneadministrationandparticipantperformancefor

similarmeasuresontheBostonCognitiveBattery(Lachmanetal., 2.2.2. Anxiousarousal
2014)w hichisad mi niste redin person. Th e62item versionoftheMoodandAnxietySymptomQues-

tionnaire(MASQ;ClarkandWatson,1991)wasutilizedtomeasure

2.2. Measures anxiousarousal.OntheMASQ,individualsreportedthedegreeto
whichth eyexpe rien ced variou sfeelingso rsensatio ns( e.g.,“w as

2.2.1. Inhibition shortofbreath”)duringthepreviousweekonascalerangingfrom1
Th estopandgoswitchtask(SGST)wasdesignedtomeasure (very sli ghtlyorn otata ll)to 5(extre mely) .A to talof 16item scom -
inhibiti on an d a tten tion sh ifting (Lachm an et al., 201 4; Tun and prise theanxi ou sar ou sals ca le ,withtherem a ining it em sasse ssing
Lachman, 2006 ,2008)an dconsis tsofthree con dit ions.In the first gener ald istressa ndanhe donia .Inth epr esentstud y,the reliability
condition (i.e.,n ormal) ,par ticipants w ereas kedtorespo nd bys tat- coefficie ntforth ean xiousarous al sca lewasac ceptab le( (cid:2)=0.75).

ing“stop”whenpresentedwiththestimulusword“red”or“go”
wh enpres entedw iththesti mulus wo rd“green ”acros s20tr ials .For 2.2.3. Interleukin-6
these condcond ition (i.e. ,reverse) ,part icipants werei nst ructed to Se rumIL-6levelswereevaluatedviahigh-sensitivityenzyme-
stat ethew ord“go”w hen presente dwiththest imulu sword“re d” linked im mun osorbe nt as say (ELISA ) (Q uantikine, R&D Systems,
and“ stop ”whe npre sente dwiththe stimu lus word“gr een”a cross Minne apolis,MN)witha sensi tivityof detectionat0 .16pg .mL.Val-
20t rials.In thet hirdandfin alco ndi tion(i.e., mixed ),partic ipants ueswerelog trans form e dtonorma liz ethedist rib utio nofsco res.
we re pro vid ed with a cu e of e ither “nor mal” or “rev erse” before IL-6 was sele cted as an in dic ator of infl am mation as it ha s been
being presente dwith astim u luswo rdacross 32 trials.For exam- linke dwi thanxiou sa rou sal(O’Don ov anetal.,2010) an dt ype 2dia-
ple,if aparticipa ntwa s provided witht hecue of “norm al”a ndthe betes( Doyl eetal.,2 013).Se rumIL-6is als oa mark erof acut e and
stim u lu s word “gre en,” the corre ct re spo nse wa s “go”; h owe ver, chron icstres s( Kiec olt-Gla sereta l.,2 00 3).M o reover, an imalw ork
iftheyw erepr esentedw ith thecue of“rever se”a ndthe stimulus hasdem onstr atedthatvagus ne rve stimu lation,wh ichisas soci-
w ord“ green ,”thecorre ctres pon sew as “stop.”Res pon sela tencyfor ated with improve d in hibitio n (Tha yer and Lane , 2009 ), r educes
theSG STinth ep resents tudyrefl ects theave ragetime ittook to prod uction of tumor necrosis f actor (TN F)-a lpha a nd IL-6 (Wang
corr ectly res pon dtoeach stimu lusinth ere versean dmix ed cond i- etal.,2004) .O therim munebio marke rsthatwere anal yzed during
tion.Inth enorma lc ondit ion,inhib iti ons killsare not utilize d,and th eM IDUSs tudy(i .e.,C-Rea ctiveprotei n,IL- 6rece ptor,E-se lectin,
assu ch ,res ponsela tencyinth enormalc ondit ionw as notinclu ded inte rcellula radhe sion molecule1 (ICAM-1 ))ar enotstron glylinked
in prese ntstudya nalyses .D urin gfollow -upanaly ses, we included with vagus n erve stim ulation a n d stress r egu latio n, two i mpor-
th enumbe rofer rorsfrom eachc onditiona saddition alin dicators tant mecha nisms fortheassoc iatio nbetw eeninhibit iona ndIL-6
ofin hibition to determ ine ifthe rewerean ys peed/error tradeoffs. (Step toeetal.,200 7; Wan getal.,200 4).

Indicatorsofinhibitionwerereversecodedsuchthathigherscores

indicatedbetterinhibition. 2.2.4. HemoglobinHbA1c

Usingresponselatencyastheprimaryindicatorofinhibition, AnHbA1cassaywasperformedbyMeriterLabsinMadison,WI
Lachman etal.(201 4)dem ons trat edexcell entpsych om etricchar- using theCob asInt egra ®analyzer (Ro cheDia gnost ic s,Indiana po-

acteristicsfortheSGST.Forinstance,responselatencyforthemixed lis, IN). Percent HbA1c, which is represented in the descriptions
K.W.Murdocketal./Psychoneuroendocrinology71(2016)102–109 105

Table2

Bivariatecorrelationsbetweenstudyvariables.

Variable 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

1.Inhibition-reverse –

2.Inhibition-mixed 0.61* –
3. AA −0.11 * −0.13* –
4. IL-6 −0.14* −0.13* 0.14* –
5. Diab etes −0.08* −0.08 0.10* 0.16* –
6. HbA1c −0.09 −0.14 * 0.12* 0.17* 0.57* –
7. Age −0.19 * −0.25* 0.02 0.25* 0.16* 0.18* –
8. Sex 0.04 −0.07 0.10 * 0.04 −0.06 0.01 −0.03 –
9. Ethn icity 0.03 −0.06 0.04 0.04 0.05 0.07 −0.11 * 0.02 –
10 .Bodymassindex −0.0 1 −0.06 0.12 * 0.31 * 0.18 * 0.19 * −0.05 −0.0 7* 0.06 –
11. Smok ingH istory −0.04 −0.05 0.11* 0.07 0.05 0.03 0.11* −0.08* 0.03 0.02 –
12. Currenti nsulinu se −0.10 * −0.11 * 0.10* 0.10 * 0.59 * 0.38 * 0.09* −0.06 0.02 0.20 * −0.01 –
13. Timelag 0.07* 0.13* −0.03 0.09* −0.11 * −0.12 * −0.04 0.12* 0.01 −0.09 * −0.06 −0.11* –
14. Digit spa n 0.23* 0.18* −0.08 * −0.07 * −0.09* −0.06 −0.15 * 0.05 −0.0 3 −0.08* 0.07* −0.08* 0.09* –
15. Backw ards counting 0.37* 0.41* −0.06 −0.13* −0.11* −0.09 * −0.38* −0.1 1* −0.06 −0.05 −0.07 * −0.07 0.08* 0.28* –
16. Numberse ries 0.24* 0.27* −0.15 * −0.10* −0.13* −0.13* −0.21* −0.09* −0.11 * −0.02 −0.05 −0.09 * 0.05 0.32* 0.40*

Note.Pearsoncorrelationsarepresentedforcorrelationsbetweencontinuousvariables;Spearman’scoefficientsarepresentedforcategoricalvariables.AA=anxiousarousal;

IL–6=interleukin6.Participantgendercodedas1=maleand2=female.Participantethnicitycodedas0=non-whiteand1=white.Smokinghistorycodedas0=neversmoked

cigarettesregularlyand1=havesmokedcigarettesregularly.Currentinsulinusecodedas0=noand1=yes.*p<0.05.

and analyses below, is determined by the quotient of HA1C by oncognitivemeasuresassociatedwithagingthatisseparate,but

totalhemoglobin.Higherscoresrepresentworseglycemiccontrol. related,toinhibition(e.g.,Baudouinetal.,2009).

ConsistentwiththeInternationalExpertCommittee’ssuggestions

for using HbA1c to diagnose diabetes (The International Expert 2.2.8. Numberseriestask

Committee,2009),scoresabove6.5%wereconsideredtobecon- Participantscompletedanumberseriestask(SalthouseandPrill,

sistent with a diagnosis of diabetes; however, the committee 1987)whichwasutilizedasacovariate.Forthistask,participants

suggestedthatarepeatmeasurementofHbA1cisneededfordiag- werepresentedfive-numberseries,oneatatime,andwereasked

nosis of diabetes if clinical symptoms and blood glucose levels toindicatethecorrectnumberthatshouldappearnextintheseries.

below200mg/dl(11.1mmol/l)areidentified.Asecondmeasure- Total scores reflected the number of series completed correctly

mentwasnotconductedforsuchindividualsinthepresentstudy. after a five trials. It has been argued that measures of fluid rea-

In the analyses described below, diabetes incidence was defined soning,suchasnumberseriestasks,arerelatedtothemajorityof

aswhetherornotparticipantsdemonstratedHbA1clevelsgreater measuresofexecutivefunctioningandintelligence(e.g.,Unsworth

than 6.5% and/or self-reported using medication to manage dia- etal.,2009).Asaresult,thismeasurewaschosenasacovariate

betes. todetermineifbroadcognitiveskillsexplainhypothesizedassoci-

ations.Thisisimportantgiventhatanxietysymptomsassociated

2.2.5. Demographics withpost-traumaticstresshavebeenfoundtobespecifictoinhi-

Participantsprovidedself-reportedage,sex,ethnicity,smoking bitionasopposedtogeneralexecutivedysfunction(DeGutisetal.,

history,andcurrentuseofinsulin.Participantheightandweight 2015).

wasmeasuredinordertocalculatebodymassindex(BMI).

2.3. Analyticstrategy

2.2.6. Digitspan

ThebackwarddigitspantaskfromtheWechslerAdultIntelli- SPSSstatisticalsoftware(IBM,2012)wasutilizedforallanal-

genceScale,ThirdEdition(WAIS-III;Wechsler,1997)wasalsoused yses.Moreover,themodelrepresentedinFig.1wastestedusing

asacovariateinthepresentstudy.Thedigitspantaskinvolvedthe thePROCESSmacroforSPSS(Hayes,2013)whichallowsforeval-

participant listening to a series of numbers ranging from two to uation of serial mediation. Indirect effects were evaluated using

eight digits that increased in length as they progressed through 5000bootstrapsamples.Anindirecteffectissignificantifthe95%

thetrials.Afterlisteningtotheseriesofnumbers,theparticipants confidence interval does not contain zero (Hayes, 2013). Media-

wereaskedtorepeateachseriesinthereverseorder.Participants tionmodelsreflectthatonevariable(i.e.,themediator)explains,

weregiventwoseparateopportunities,usingadifferentorderof orpartiallyexplains,anassociationbetweenanindependentand

digits,toprovidethecorrectresponseforagivenserieslength.The dependent variable. Of note, mediation models can be tested

taskwasdiscontinuediftheparticipantdidnotprovidethecorrect without longitudinal data if hypotheses are theoretically driven

responsetoatrialaftertwoattemptsforagivenserieslength.The (MacKinnon,2008).Furthermore,inserialmediationmodels,itis

numberofdigitsinthelongestseriescorrectlyrecalledwasuti- hypothesizedthatonemediatorisseriallyassociatedwithanother

lizedasanindicatorofdigitspanability.Thebackwarddigitspan

taskwaschosenasacovariateinthepresentstudyasitisrelated
Table3
totheexecutivefunctionofupdating/monitoringofinformationin Logist icregressionanalysespredictingdiabetesincidence.
wo rki ngmemor y(Hilber te tal.,2015).
Variable Model1 Model2 Model3

2.2.7. Backwardscountingtask Inhibition −0.11 −0.01 −0.04

AnxiousArousal 0.08 0.07 0.04
For30s,participantswereaskedtocountbackwardsfrom100
Interleukin-6 0.44* 0.26* 0.42*
asquicklyaspossible.Thenumberofcorrectresponseswasuti-
liz edasan ind icatorof proc essingsp ee d,acova riateinthe pre sent Note. Values represent logistic regression coefficients (i.e., odds ratios). Model
1=unadjusted.Model2=adjustedforage,sex,ethnicity,bodymassindex,smok-
study.Thenumberoferrorsduetorepeatingorskippingnumbers
wassu btra ctedfrom t hetota lsco re .Thismea su rewasch osenasa i3n=g ahdijsutostreyd, afonrd ptehref otirmmea nlacge boentwdiegeitns cpoagnn,ibtaivcek wanadrd bsiocloougnictianl gasasnedssnmuemnbtse.r Mseordieesl

covariategiventhatprocessingspeedisapredictorofperformance tasks.*p<0.05
106 K.W.Murdocketal./Psychoneuroendocrinology71(2016)102–109

.10* (.03, .17)

Anxious Arousal Interleukin-6

-.12* (-.05, -.18) .06* (.01, .12)

-.01 (-.07, .04)
-.08* (-.01, -.15)

.02 (-.03, .08)

Inhibition HbA1c Percentage

Fig.2. Amediationmodelofassociationsbetweeninhibition,anxiousarousal,interleukin-6,andHbA1c.Valuesrepresentstandardizedregressioncoefficientsand95%
confi de nc eintervals aredep ict edinparenth eses.Ind irecteffects using50 00boots trapsamples: anxi ousarou sal(−0 .0015,SE= 0.0038,95%CI =−0.0111, 0.0047),inte rleu kin-

6(.0049,SE=0.0034,95%CI=0.0005,0.0154),andserialmediation(i.e.,mediationinsequence;0.0007,SE=0.0006,95%CI=0.0001,0.0028).Controlvariablesincluded

participantage,sex,ethnicity,bodymassindex,smokinghistory,insulinuse,aswellthetimelagbetweenassessments.*p<0.05.

mediator, and that this chain explains, or partially explains, an inhibition.Allsignificantpaths,aswellasindirecteffects,remained.

associationbetweenanindependentanddependentvariable(e.g., Moreover,betternumberseriesperformancewasassociatedwith
Hayes,2012 ).Import ant ly,thePROCE SSm acroautom aticallyi den- lower anx ious ar ousal ((cid:3) =−0.1 3, p<0.05) a nd d ecreased l ikeli-
tifiesd ichotom ousdepend ent variables, sucha sdiabetesincid ence hoodo fmeetin gcriteria for diabete s (B =−0. 35,p <0.05);ho wever,

in the present study, and utilizes logistic regression. Participant further analysis revealed that number series performance was

age,sex,ethnicity,BMI,smokinghistory,andthetimelagbetween not associated with diabetes incidence through anxious arousal
asse ssme ntswere utiliz edasco variates. Add itio nally ,pa rticipant (−0 .0082,SE=0 .0163 ;95%CI= −0.0434, 0.0224)o rIL-6(− 0.0113,
performance onth ecognit ive tasksrepre sentingdigit span,back- SE=0.0122 ;9 5 %CI=−0 .045 2, 0. 0051).Mo reover,i nh ibitio nwasthe

wardscounting,andnumberserieswereenteredascovariatesin onlycognitiveskilldirectlyassociatedwithIL-6.

follow-upanalyses.

4. Discussion

3. Results

Ourfindingsindicatethatthosewithbetterinhibitionevidence

Descriptive statistics are presented in Table 1 and bivariate lower anxious arousal, IL-6, and HbA1c, in addition to a lower

correlations are presented in Table 2. As expected, better inhi- likelihood of meeting criteria for diabetes, than those with poor

bition was associated with less anxious arousal, IL-6, diabetes inhibition. Additionally, those with higher anxious arousal had

incidence,andHbA1c.Moreover,allindicatorsofcognitiveability higher IL-6. As expected, higher IL-6 was associated with higher

weresignificantlypositivelyassociated.Furthermore,inlinewith HbA1candlikelihoodofdiabetesincidence.Inthefullmodel(see

hypotheses,higheranxiousarousalwasassociatedwithgreaterIL- Fig. 1), poor inhibition was associated with increased diabetes

6.Asexpected,higherIL-6wasassociatedwithagreaterlikelihood incidencethroughtheserialpathwayfromanxiousarousaltoIl-

of diabetes incidence and higher HbA1c. Interestingly, increased 6 as hypothesized. These findings were unique to inhibition as

anxiousarousalwasassociatedwithahigherBMIandlikelihood outcomesdidnotchangewhenotherindicatorsofcognitiveabil-

of reporting a history of regular cigarette use. Moreover, greater itywereincludedinthemodel.Findingsextendtheliteratureby

IL-6wasassociatedwithhigherBMI,andworseperformanceonall demonstratingthatlowinhibitionisariskfactorfordiabetesinci-

measuresofcognitiveability. dence as opposed to being a consequence of disease processes

AsseeninFig.1,lowerinhibitionwasassociatedwithgreater (e.g.,Bottirolietal.,2014;Tranetal.,2014).Betternumberseries

anxious arousal and plasma IL-6. Higher anxious arousal was performance was independently associated with lower anxious

also associated with greater IL-6. Furthermore, serial mediation arousalanddecreasedlikelihoodofmeetingcriteriafordiabetes,

wassupported,indicatingthatthesequentialpathwayfromanx- suggestingthatnumberseriesperformanceandinhibitionshould

iousarousaltoIL-6explainedtheassociationbetweeninhibition bedifferentiatedwithinmodelsofdiabetesincidence.
and diabete s i ncide nce. Logis tic regression analyses predicting Parasympathe tic ner vous sy st em and NF-(cid:4)B activation are

diabetes incidence are presented in Table 3. Covariates signifi- potentialmechanismslinkinginhibitionwithanxiousarousaland

cantlyassociatedwithdiabetesincidenceincludedparticipantage inflammation.Indeed,thosewithpoorinhibitionaremorelikely

(B=0.53,p<0.05)andBMI(B=0.54,p<0.05),aswellasthetime tohavestressfulthoughtsenterandcontinuetooccupyworking
lag betw ee n asses sme nttim e p oints (B =−0.2 8,p <0.0 5) .Pri mary me mory thantho sewithb etteri nhib ition(Joo rm an,2010 ).More-

findingsremainedconsistentwhenexaminingHbA1casacontin- over, those with poor inhibition are more likely to demonstrate

uousdependentvariablewithinsulinuseincludedasacovariate maladaptivephysiologicalandpsychologicalresponsestostress-

(Fig. 2), in addition to when adding the number of errors made orsthanthosewithbetterinhibition(Lackschewitzetal.,2008).

duringthereverseandmixedtasksasadditionalindicatorsofinhi- Therefore,asaresultofbeingunabletoblockstressfulthoughts

bition.Furthermore,serialmediationwasnotsupportedwhenthe frombeingattendedto,andaninabilitytoshiftattentionawayfrom

sequencewasreversedsuchthatIL-6ledtoanxiousarousal(.0013, distressingthoughts,thosewithpoorinhibitionmaybemorelikely
SE=0.001 3;95 %CI=−0 .0005 ,0.00 54) .We al soexam inedifd iabetes toexperien ceanxious arous alan ddem onstrate heigh te nedin flam-

incidencewasassociatedwithinflammationthroughthepathway mationwhenexposedtostressorsthanthosewithbetterinhibition.

fromanxiousarousaltoinhibitiongiventhatmanagementofdia- Althoughinhibitionisahypothesizedprecursortoanxiousarousal

betes is associated with potentially anxiety providing situations andinflammation,furtherresearchisneededtoevaluateifinhi-

(DukeandHarris,2014).Resultsdidnotsupportthisserialmedia- bitionisassociatedwithageneralarousalsystemasopposedto
tional path way(0 .0004,S E=0.00 06; 95% CI=−0. 0001 ,0.00 27). being ap recursorto anxi ou sarousa landin flamma tio ngiventh is

Infollow-upanalyses,digitspan,backwardscountingandnum- speculativehypothesis.

berseriesperformancewereexaminedascovariatesinthemodel Maladaptive health behaviors associated with poor inhibition

depictedinFig.1todetermineifprimaryfindingswereuniqueto mayalsoexplaintheassociationbetweeninhibitionanddiabetes.
K.W.Murdocketal./Psychoneuroendocrinology71(2016)102–109 107

Indeed,individualswithpoorinhibitionarelesslikelytoeathealthy etal.,2014),supportingpresentstudyfindings.Moreover,asstudy

foods (Limbers and Young, 2015; Segerstrom and Nes, 2007) or variableswerenotassessedovermultipletimepoints,directional-

engage in healthy amounts of physical activity than those with ityofassociationscannotbedetermined.Longitudinaldesignscan

highinhibition,evenwhentheyhavetheintentionofdoingso(Hall addressthislimitationinfuturework.

etal.,2008).Thosewithpoorinhibitionarelesslikelytoconsume

fruits/vegetables(AllomandMullan,2014),adheretoaweightloss 5. Conclusions

plan(Pauli-Pottetal.,2010),utilizesunscreen(Allometal.,2013),

or demonstrate adaptive sleeping habits than those with better Consistent with theoretical models linking inhibition, stress,

inhibition(KorandMullan,2011).Impairedinhibitionalsoleads andhealth,poorinhibitionisassociatedwithincreaseddiabetes

to alcohol relapse following treatment (Garland et al., 2012). As incidencethroughtheserialpathwayfromhighanxiousarousalto

highanxietyandpoorhealthbehaviorsareknownriskfactorsfor highinflammation.Thesefindingshaveimportantimplicationsfor

type2diabetes(Lietal.,2008;WHO,2014),futureworkshouldtar- thepreventionandtreatmentofdiabetesbyidentifyingunderlying

gethealthbehaviorsasanunderlyingmechanismlinkinginhibition mechanismscontributingtoelevatedbloodglucose.

withtype2diabetes.

Findings point to several intervention opportunities that Contributors

may reduce diabetes incidence. Mindfulness-based therapeutic

techniquescanimproveneuralnetworksassociatedwithpoorinhi- K.W.M was involved in data analysis and manuscript writing
bition, such as in the an terior cingulate cortex (AC C; G ard e t al., forthepre sent study.A. S.L ,T.E.L .,D.C.D, C.J.H ,andC.P.F.p rovided
2012) which fa cil itate sexecuti veattenti onbyd etecti ngand m it- crit ical feedbac kande dited them anuscr ipt.
igating distra cting tho ughts (Van Veen an d Carter, 20 02). Low

inhibitionisalsoimprovedviastimulantmedication(Roschetal.,
Roleofthefundingsource
2015). Anxious arousal is reduced through cognitive behavioral

therapy,andinparticular,exposureandresponseprevention(Arch
DatacollectionforthepresentstudywasfundedbytheNational
etal.,2013).Useofanti-inflammatorymedicationmayalsoreduce
InstituteonAging(P01-AG020166).Preparationofthemanuscript
riskofdiabetesgivenpresentstudyfindings(Serhanetal.,2008).
wassupportedbyagrantfromtheNationalHeart,Lung,andBlood
Further research is needed to determine if implementing such
Institute(1R01HL127260-01)toC.P.F.
interventions can reduce diabetes incidence among at risk indi-

viduals.
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