Preliminary evidence for obesity-associated insulin resistance in adolescents without elevations of inflammatory cytokines

Cohen, Maayan Lawrence, Convit, Convit Antonio

Description

To ascertain whether the associations between obesity, inflammation, and insulin resistance established in human adult studies are found among adolescents. Methods We contrasted 36 obese and 24 lean youth on fasting glucose, insulin levels, lipid profile, hemoglobin A1C, markers of hepatic function, white blood cell count, C-reactive protein (CRP) and fibrinogen levels. The cytokines IL-6, TNF-α, IFN-γ, IL-10 and IL-4 and the adipokines leptin, resistin, and adiponectin were also compared between the two groups. The fasting glucose and insulin values were used to estimate the degree of insulin resistance with the homeostatic model assessment of insulin resistance (HOMA-IR). T-tests and correlations were run to examine group differences and associations between groups. In addition, regression analyses were used to ascertain whether the markers of inflammation were predictive of the degree of insulin resistance. Results Although obese adolescents had clear evidence of insulin resistance, only CRP, fibrinogen and leptin were elevated; there were no group differences in pro- or anti-inflammatory cytokines nor adiponectin and resistin. Anthropometric measures of obesity and level of insulin resistance were highly correlated to the acute phase reactants CRP and fibrinogen; however, the degree of insulin resistance was not predicted by the pro- or anti-inflammatory cytokine markers. Obese adolescents had higher white blood cell counts. In addition they had higher circulating alanine aminotransferase concentrations and lower circulating albumin and total protein than lean adolescents, possibly as a result of hepatocyte damage from fatty liver. Conclusion Unlike rodent or adult studies, we found that wide-spread systemic inflammation is not necessarily associated with insulin resistance among adolescents. This finding does not support the current paradigm that the associations between obesity and insulin resistance are, to a significant degree, mediated by low grade systemic inflammation. These data support the need for further adolescent studies to explore these associations.

Sujets

• Insulin resistance
• Cytokine
• Adipokine
• Adolescents (band)
• Obesity

Informations

• Publié par: biomed
• Publié le: 01 janvier 2012
• Nombre de lectures: 7
• Langue: English

Extrait

Cohen
etal.Diabetology&MetabolicSyndrome
2012,
4
:26
http://www.dmsjournal.com/content/4/1/26

RESEARCH

DMIEATBAEBTOOLLIOC GSYY N
&
D ROME

OpenAccess

Preliminaryevidenceforobesity-associated
insulinresistanceinadolescentswithout
elevationsofinflammatorycytokines
JessicaICohen
1
,LawrenceMaayan
1,3
andAntonioConvit
1,2,3*

Abstract
Background:
Toascertainwhethertheassociationsbetweenobesity,inflammation,andinsulinresistance
establishedinhumanadultstudiesarefoundamongadolescents.
Methods:
Wecontrasted36obeseand24leanyouthonfastingglucose,insulinlevels,lipidprofile,hemoglobin
A1C,markersofhepaticfunction,whitebloodcellcount,C-reactiveprotein(CRP)andfibrinogenlevels.The
cytokinesIL-6,TNF-
α
,IFN-
γ
,IL-10andIL-4andtheadipokinesleptin,resistin,andadiponectinwerealsocompared
betweenthetwogroups.Thefastingglucoseandinsulinvalueswereusedtoestimatethedegreeofinsulin
resistancewiththehomeostaticmodelassessmentofinsulinresistance(HOMA-IR).T-testsandcorrelationswererun
toexaminegroupdifferencesandassociationsbetweengroups.Inaddition,regressionanalyseswereusedto
ascertainwhetherthemarkersofinflammationwerepredictiveofthedegreeofinsulinresistance.
Results:
Althoughobeseadolescentshadclearevidenceofinsulinresistance,onlyCRP,fibrinogenandleptinwere
elevated;therewerenogroupdifferencesinpro-oranti-inflammatorycytokinesnoradiponectinandresistin.
Anthropometricmeasuresofobesityandlevelofinsulinresistancewerehighlycorrelatedtotheacutephase
reactantsCRPandfibrinogen;however,thedegreeofinsulinresistancewasnotpredictedbythepro-or
anti-inflammatorycytokinemarkers.Obeseadolescentshadhigherwhitebloodcellcounts.Inadditiontheyhad
highercirculatingalanineaminotransferaseconcentrationsandlowercirculatingalbuminandtotalproteinthan
leanadolescents,possiblyasaresultofhepatocytedamagefromfattyliver.
Conclusion:
Unlikerodentoradultstudies,wefoundthatwide-spreadsystemicinflammationisnotnecessarily
associatedwithinsulinresistanceamongadolescents.Thisfindingdoesnotsupportthecurrentparadigmthatthe
associationsbetweenobesityandinsulinresistanceare,toasignificantdegree,mediatedbylowgradesystemic
inflammation.Thesedatasupporttheneedforfurtheradolescentstudiestoexploretheseassociations.
Keywords:
Insulinresistance,Cytokines,Adipokines,Adolescents,Obesity

Introduction
thatmediatorsoflowgradechronicinflammation,such
Obesityisconsideredalow-gradechronicinflammatoryascytokinesandacutephasereactants,contributetothe
diseasethatmaycontributetothedevelopmentofinsu-developmentoftheseco-morbidconditions[6,7].Inthe
linresistance[1].Obeseadultsandadolescentsareatadulthuman,theveryhighco-occurrenceofobesity,
higherriskfordevelopingtype2diabetes,cardiovascularinflammationandinsulinresistancebolstersthehypoth-
disease,non-alcoholicfattyliverdisease(NAFLD)andesisthatobesity-associatedinflammationmayleadto
severalformsofcancer[2-5].Previousresearchsuggestsinsulinresistance[8,9].However,thereisnotcomplete
consensusonthismatter[10].Itisimportanttoimprove
*Correspondence:[e-mail]
ourunderstandingofthepathophysiologyinvolvedin
1
DepartmentofPsychiatry,NewYorkUniversitySchoolofMedicine,145East
theprogressionfromobesitytoinsulinresistance,
32ndSt,NewYork,NY10016,USA
2
DepartmentofMedicine,NewYorkUniversitySchoolofMedicine,145East
particularlyinyouthwhereobesityandinsulinresistance
32ndSt,NewYork,NY10016,USA
maystillbedissociated.
Fulllistofauthorinformationisavailableattheendofthearticle
©2012Cohenetal.;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative
CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and
reproductioninanymedium,providedtheoriginalworkisproperlycited.

Cohen
etal.Diabetology&MetabolicSyndrome
2012,
4
:26
http://www.dmsjournal.com/content/4/1/26

Overthelasttwodecades,ourviewofadiposetissue
wastransformedfromthatofan
“
inert
”
storagetissue
toanendocrineorganthatsecretesanumberofpro-
teins,suchasadiponectin,resistin,andleptin[11-14].
Adiponectinisanti-inflammatory,whileresistinispro-
inflammatory,andtheirimbalancecanresultinlow
gradeinflammation[15,16].Leptin,anotheradipokine
thatincreaseswithadiposity,isanimportantsatiety
signal,andobeseindividualsmaybecomeresistantto
leptinresultingingreaterproductionandsecretionof
thisprotein[8,17].Bothleptinandresistinarecorre-
latedwithinsulinresistanceandareconsideredkey
mediatorslinkinginsulinresistancewithhepaticstea-
tosis[18].
Asadipocytesstorelargerlipiddropletsandincrease
insize,thephysicalstressonthebloodvesselsthat
supplythemincreasesleadingtoacompromisedendo-
theliallining[19].Thisfacilitatesmacrophageinfiltra-
tion,whichinturnincreasescytokineproduction[6].
Anotherpossiblecauseofincreasedcytokineexpression
isdamagetospecificorgans,forexampletheliver.
Hepaticsteatosisisanimbalanceintriglycerideacquisi-
tionandremoval,resultinginthestorageofexcesstri-
glyceridesbyhepatocytes.Thiscanresultinthe
increasedproductionofinflammatorycytokines,such
astumornecrosisfactor(TNF)-
α
,byresidentmacro-
phages[3].Acutephasereactantsproducedintheliver,
suchasC-reactiveprotein(CRP)andfibrinogen,are
alsoelevatedinobeseadultsandareimplicatedinthe
developmentofcardiovascular,kidneydiseaseanddia-
betes[20-22].
Thepathophysiologyofinflammationamongobese
childrenandadolescentsislesswell-developed,andno
clearconsensusexistsinthepediatricliterature[23,24].
Mostpediatricstudiesshowconsistentincreasesin
CRP,butnotincreasesininterleukin(IL)-6andTNF
α
nordecreasesinIL-10orIL-4.Theseareimportant
issuestoconsidergiventhelargevariabilityinthede-
greeofinsulinresistanceamongobeseadolescents
[25,26].
Wehypothesizedthattheassociationsbetweenkey
biomarkersofobesityandinsulinresistanceinadoles-
centsmayexistatanorgansystemlevelbutperhapsnot
systemically,thusresultingintheinconsistentresults
reportedinthisagegroup.Totestthishypothesiswe
assessedmarkersoftheimmunesystem,livermarkers,
pro-andanti-inflammatorycytokines,adipokines,and
acutephasereactantsinagroupofleanandobeseado-
lescents.Basedonclearfastinghyperinsulinemiaamong
ourobeseadolescents,suggestingsignificantlevelsofin-
sulinresistance,wealsoascertainedwhetherobesity/in-
sulinresistanceisassociatedwithsystemicchangesin
adipokinesandelevationsinacutephasereactantsand
inflammatorycytokines.

Page2of7

Materialsandmethods
Participants
Sixtyadolescents,24leanand36obese,matchedonage,
gender,schoolgrade,ethnicity,andsocioeconomicsta-
tus(Table1)werestudied.Thesubjectswereconsecu-
tivecasesevaluatedaspartofanNIH-sponsoredstudy
attheBrain,Obesity,andDiabetesLaboratory,Depart-
mentofPsychiatry,NewYorkUniversitySchoolof
Medicine.ThestudywasapprovedbythelocalIRB.All
oftheparticipants(and,iftheywereunder18yearsof
age,theirparent)signedinformedconsentandreceived
compensationfortheirtimeandinconvenience.Partici-
pantswerescreenedtoruleoutexclusionarypreexisting
medicalandpsychiatricconditions.Hypertension,dysli-
pidemia,andinsulinresistancewereallowed.Noneof
thestudysubjectswerereceivinganypsychotropicmedi-
cations.Theoriginalparticipantpoolcontained117ado-
lescents.Ofthe117adolescents,19wereexcluded
becausetheyhadeitherCRP>10mg/L,whichmaybe
indicativeofanacuteinflammationorinfection[27],or
hadmissingCRPvalues.Additionally,18possibleparti-
cipantswereexcludedbecausetheywerereceivinganti-
Table1Groupdifferencesindemographicandbiological
parameters
LeanObesep-value
Gender(%female)58.355.60.832
Race/Ethnicity
χ
2
=1.02
White(%)33.338.9
Hispanic(%)25.027.8
AfricanAmerican(%)25.025.0
Asian(%)16.78.3
Age(yrs)17.2±0.417.5±0.30.396
Grade11.2±0.411.4±0.20.708
BMI(kg/m
2
)21.5±0.537.4±1.20.000**
WaistCircumference(cm)76.8±1.2112.2±2.80.000**
Waist:Height0.45±0.010.66±0.010.000**
Waist:Hip0.85±0.010.94±0.010.000**
Glucose(mg/dL)73.5±1.477.3±1.50.083
Insulin(IU/mL)7.4±0.618.4±2.00.000**
HOMA-IR1.3±0.13.5±0.40.000**
HemoglobinA1C(%)5.1±0.15.4±0.10.000**
Totalcholesterol(mg/dL)160.5±5.9164.1±5.30.662
LDL(mg/dL)91.5±5.1102.6±4.70.125
HDL(mg/dL)55.0±2.543.7±1.50.000**
Triglycerides(mg/dL)70.6±5.689.4±7.20.064
SystolicBP(mmHg)101.3±1.9115.3±2.00.000**
DiastolicBP(mmHg)63.2±1.768.0±1.50.036*
*Denotesap-valueof>0.05;**denotesap-valueof
≤
0.010.
Bodymassindex(BMI);homeostaticmodelassessmentofinsulinresistance
(HOMA-IR);lowdensitylipoprotein(LDL);highdensitylipoprotein(HDL);
bloodpressure(BP).

Cohen
etal.Diabetology&MetabolicSyndrome
2012,
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inflammatoryor
β
-agonistmedicationsand10hadahis-
toryofinflammatoryillnesses(e.g.,asthma).Lastly,10
participantsdidnothavestoredplasmaavailablefor
measurementofcytokineandadipokineconcentrations.
The57excludedand60evaluateddidnotdifferonage,
race,gender,orBMI.
Bloodcollection
Followinga10
–
12hourfast,bloodwascollecte