1/4/2016 Clinicalpresentationanddiagnosisofdiabetesmellitusinadults

OfficialreprintfromUpToDate
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Clinicalpresentationanddiagnosisofdiabetesmellitusinadults

Author SectionEditors DeputyEditor

DavidKMcCulloch,MD DavidMNathan,MD JeanEMulder,MD
JosephIWolfsdorf,MB,BCh

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Feb2016.|Thistopiclastupdated:Mar19,2015.
INTRODUCTIONThetermdiabetesmellitusdescribesseveraldiseasesofabnormalcarbohydratemetabolismthatarecharacterizedbyhyperglycemia.Itis
associatedwitharelativeorabsoluteimpairmentininsulinsecretion,alongwithvaryingdegreesofperipheralresistancetotheactionofinsulin.Everyfewyears,
thediabetescommunityreevaluatesthecurrentrecommendationsfortheclassification,diagnosis,andscreeningofdiabetes,reflectingnewinformationfrom
researchandclinicalpractice.

TheAmericanDiabetesAssociation(ADA)issueddiagnosticcriteriafordiabetesmellitusin1997,withfollowupin2003and2010[13].Thediagnosisisbasedon
oneoffourabnormalities:glycatedhemoglobin(A1C),fastingplasmaglucose(FPG),randomelevatedglucosewithsymptoms,orabnormaloralglucosetolerance
test(OGTT)(table1).Patientswithimpairedfastingglucose(IFG)and/orimpairedglucosetolerance(IGT)arereferredtoashavingincreasedriskfordiabetesor
prediabetes.(See'Diagnosticcriteria'below.)

Screeningforandpreventionofdiabetesisreviewedelsewhere.Theetiologicclassificationofdiabetesmellitusisalsodiscussedseparately.(See"Screeningfor
type2diabetesmellitus"and"Preventionoftype2diabetesmellitus"and"Preventionoftype1diabetesmellitus"and"Classificationofdiabetesmellitusand
geneticdiabeticsyndromes".)

CLINICALPRESENTATIONType2diabetesisbyfarthemostcommontypeofdiabetesinadults(>90percent)andischaracterizedbyhyperglycemiaand
variabledegreesofinsulindeficiencyandresistance.Themajorityofpatientsareasymptomaticandhyperglycemiaisnotedonroutinelaboratoryevaluation,
promptingfurthertesting.Thefrequencyofsymptomaticdiabeteshasbeendecreasinginparallelwithimprovedeffortstodiagnosediabetesearlierthrough
screening(see"Screeningfortype2diabetesmellitus").Classicsymptomsofhyperglycemiaincludepolyuria,polydipsia,nocturia,blurredvisionand,infrequently,
weightloss.Thesesymptomsareoftennotedonlyinretrospect,afterabloodglucosevaluehasbeenshowntobeelevated.Polyuriaoccurswhentheserum
glucoseconcentrationrisessignificantlyabove180mg/dL(10mmol/L),exceedingtherenalthresholdforglucose,whichleadstoincreasedurinaryglucose
excretion.Glycosuriacausesosmoticdiuresis(ie,polyuria)andhypovolemia,whichinturncanleadtopolydipsia.Patientswhorepletetheirvolumelosseswith
concentratedsugardrinks,suchasnondietsodas,exacerbatetheirhyperglycemiaandosmoticdiuresis.

Rarelyadultswithtype2diabetescanpresentwithahyperosmolarhyperglycemicstate,characterizedbymarkedhyperglycemiawithoutketoacidosis,severe
dehydration,andobtundation.Diabeticketoacidosis(DKA)asthepresentingsymptomoftype2diabetesisalsouncommoninadultsbutmayoccurundercertain
circumstances(usuallysevereinfectionorotherillness)andinnonCaucasianethnicgroups.(See"Diabeticketoacidosisandhyperosmolarhyperglycemicstatein
adults:Clinicalfeatures,evaluation,anddiagnosis"and"Syndromesofketosispronediabetesmellitus".)

Type1diabetesischaracterizedbyautoimmunedestructionofthepancreaticbetacells,leadingtoabsoluteinsulindeficiency.Type1diabetesaccountsfor

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approximately5to10percentofdiabetesinadults.DKAmaybetheinitialpresentationinapproximately25percentofadultswithnewlydiagnosedtype1diabetes.
Comparedwithchildren,thelossofinsulinsecretorycapacityusuallyislessrapidinadultswithtype1diabetes[4].Thus,adultswithtype1diabetestypically
havealongerestimatedperiodpriortodiagnosisandarelikelytohavealongerperiodwithsymptomsofhyperglycemia(polyuria,polydipsia,fatigue)thanchildren
[5].In2to12percentofadults,theclinicalpresentationissimilartothatoftype2diabetes(notinitiallyinsulindependent),withautoimmunemediatedinsulin
deficiencydevelopinglaterinthecourseofdisease[4].Thisissometimescalledlatentautoimmunediabetesofadults(LADA).(See"Classificationofdiabetes
mellitusandgeneticdiabeticsyndromes",sectionon'Latentautoimmunediabetesinadults(LADA)'.)

DIAGNOSTICCRITERIA

SymptomsofhyperglycemiaThediagnosisofdiabetesmellitusiseasilyestablishedwhenapatientpresentswithclassicsymptomsofhyperglycemia(thirst,
polyuria,weightloss,blurryvision)andhasarandombloodglucosevalueof200mg/dL(11.1mmol/L)orhigher.

AsymptomaticThediagnosisofdiabetesinanasymptomaticindividualcanbeestablishedwithanyofthefollowingcriteria:fastingplasmaglucose(FPG)
values126mg/dL(7.0mmol/L),twohourpostoralglucosechallengevaluesof200mg/dL(11.1mmol/L),andglycatedhemoglobin(A1C)values6.5percent(48
mmol/mol)(table1).Intheabsenceofunequivocalsymptomatichyperglycemia,thediagnosisofdiabetesmustbeconfirmedonasubsequentdaybyrepeat
measurement,repeatingthesametestforconfirmation.However,iftwodifferenttests(eg,FPGandA1C)areavailableandareconcordantforthediagnosisof
diabetes,additionaltestingisnotneeded.Iftwodifferenttestsarediscordant,thetestthatisdiagnosticofdiabetesshouldberepeatedtoconfirmthediagnosis[6].

Theimportanceofconfirmingthediagnosisbyrepeatmeasurementonasubsequentday,especiallywhenthediagnosisisbaseduponplasmaglucose
measurements,isillustratedbyareportfromtheNationalHealthandNutritionExaminationSurvey(NHANES)IIISecondExamination[7].Theprevalenceof
diabetesbaseduponeitherFPGortwohourpostOGTTplasmaglucoseconcentrationsignificantlydecreasedwhenthediagnosiswascontingentuponhavingtwo
abnormalmeasurementsratherthanasingleabnormalmeasurement.

IfmeasurementofA1Ctestiseitherunavailableoruninterpretable,forexampleowingtorapidredcellturnoverinapatientwithanemia,thepreviousdiagnostic
methodsandcriteria,usingglucosetesting(FPG,twohourOGTT),shouldbeused.TheA1Cassayandpotentialsourcesoferrorarereviewedseparately.(See
"Estimationofbloodglucosecontrolindiabetesmellitus",sectionon'Glycatedhemoglobin'.)

Thediagnosticcriteriahavebeendevelopedbasedupontheobservedassociationbetweenglucoselevelsandtheriskfordevelopingretinopathy.Fastingplasma
glucose(FPG)values126mg/dL(7.0mmol/L),twohourpostoralglucosechallengevaluesof200mg/dL(11.1mmol/L),andglycatedhemoglobin(A1C)values
6.5percent(48mmol/mol)areassociatedwithanincreasedprevalenceofretinopathy[3].Notsurprisingly,sincethedifferentmeasuresofglycemia(FPG,two
hourplasmaglucose,andA1C)representdifferentphysiologicphenomena,eachofthemeasureswillidentifydifferentproportionsofthepopulationwithdiabetes.
Forexample,theshiftfromusingtheFPGtousingA1Ctodiagnosediabetesmaydecreasetheproportionofpatientsidentifiedashavingdiabetes[6,810].Asan
example,inastudyof6890adultswithoutahistoryofdiabetesparticipatingintheNHANES(1999to2006),theprevalenceofdiabetesusingA1CversusFPG
criteriawas2.3versus3.6percent[8].Overall,theA1CandFPGcriteriaresultedinthesameclassificationfor98percentofthepopulationstudied.Similarly,the
oralglucosetolerancetest(OGTT)identifiesdifferentgroupsthananFPGlevel.

WHOcriteriaThe2006WorldHealthOrganization(WHO)criteriadefinediabetesasanFPG126mg/dL(7.0mmol/L)oratwohourpostglucosechallenge
value200mg/dL(11.1mmol/L).In2011,theWHOconcludedthatanA1Cvalueof6.5percent(48mmol/mol)canbeusedasadiagnostictestfordiabetes[11].
Avalueof<6.5percentdoesnotexcludediabetesdiagnosedusingplasmaglucoselevels.

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Impairedglucosetolerance(IGT)isdefinedasafastingglucose<126(7.0mmol/L),andatwohourglucose140mg/dL(7.8mmol/L)but<200mg/dL(11.05mmol/L)
[12].Impairedfastingglucose(IFG)isdefinedasafastingglucoseof110to125mg/dL(6.1to6.9mmol/L).

ADAcriteriaIn2003,theAmericanDiabetesAssociation(ADA)recommendedtheuseofFPGlevels(nocaloricintakeforatleasteighthours)or75goral
glucosetolerancetestfordiagnosingdiabetes[2].In2009,anInternationalExpertCommitteerecommendedusinganA1Cvalueof6.5percent(48mmol/mol)to
diagnosediabetes[13],andtheADA,EASD(EuropeanAssociationfortheStudyofDiabetes),andWHOaffirmedthedecision(table1)[3,11].(See'Glycated
hemoglobinfordiagnosis'below.)

ThefollowingdefinitionsarefromADAreports(table1andtable2)[2,3,6,14,15]:

NormalFPG<100mg/dL(5.6mmol/L).TwohourglucoseduringOGTT<140mg/dL(7.8mmol/L).

Categoriesofincreasedriskfordiabetes:

IFGFPGbetween100and125mg/dL(5.6to6.9mmol/L).

IGTTwohourplasmaglucosevalueduringa75goralglucosetolerancetestbetween140and199mg/dL(7.8to11.0mmol/L).

A1CPersonswith5.7to6.4percent(39to46mmol/mol),(6.0to6.4percent[42to46mmol/mol]intheInternationalExpertCommitteereport[13])are
athighestrisk,althoughthereisacontinuumofincreasingriskacrosstheentirespectrumofA1Clevelslessthan6.5percent(48mmol/mol).

DiabetesmellitusFPGatorabove126mg/dL(7.0mmol/L),A1C6.5percent(48mmol/mol),atwohourvalueinanOGTT(2hPG)atorabove200mg/dL
(11.1mmol/L),orarandom(or"casual")plasmaglucoseconcentration200mg/dL(11.1mmol/L)inthepresenceofsymptoms(table1).

GLYCATEDHEMOGLOBINFORDIAGNOSISTherehasbeenlongstandinginterestintheuseofglycatedhemoglobin(A1C)valuesforscreeningand
identificationofimpairedglucoseregulationanddiabetes[1619].A1CvalueswerenotpreviouslyrecommendedtodiagnosediabetesbecauseofvariationinA1C
assays.However,theNationalGlycohemoglobinStandardizationProgram(NGSP)hasstandardizedmorethan99percentoftheassaysusedintheUnitedStates
totheDiabetesControlandComplicationsTrial(DCCT)standard.AstrictqualitycontrolprogramhasimprovedprecisionandaccuracyofassaysintheUSand
manyinternationalassays.TherearealsoseveraltechnicaladvantagesoftheA1Cassayoverplasmaglucosetesting,increasedpatientconvenience(sincethere
isnospecialpreparationortimingrequiredfortheA1Ctest),andthecorrelationofA1Clevelswithmeanglucoseconcentrationsanddiabetescomplications
[3,13,20,21].(See"Estimationofbloodglucosecontrolindiabetesmellitus",sectionon'Assay'.)

InasystematicreviewofstudiesassessingtheaccuracyofA1Cinthedetectionoftype2diabetes,A1Candfastingplasmaglucose(FPG)werefoundtobe
similarlyeffectiveindiagnosingdiabetes[19].UsinganA1Ccutoffof>6.1percenttodiagnosediabetes,sensitivityrangedfrom78to81percentandspecificity79
to84percent,whencomparedwithdiabetesdiagnosedwithFPG.

A1Cvaluesalsocorrelatewiththeprevalenceofretinopathy[22,23].Asanexample,inthe2005to2006NationalHealthandNutritionExaminationSurvey
(NHANES),1066individuals40yearshadretinalfundusphotographyandmeasurementsofA1CandFPGconcentration[24].Theprevalenceofretinopathy
increasedaboveanA1Cof5.5percentandaFPGof104mg/dL(5.8mmol/L).A1CwasmoreaccuratethanFPGinidentifyingcasesofretinopathy.

A1C,FPG,ANDOGTTASPREDICTORSOFDIABETESAlthoughthelifetimeriskoftype2diabetesishigh,ourabilitytopredict(andsubsequentlyprevent)
type2diabetesinthegeneralpopulationislimited.Nevertheless,insomeindividualswithclinicalriskfactorsfordiabetes,itmaybehelpfultoperformglycemic

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testingtoidentifythoseathighestriskfordevelopingtype2diabetes,asthesepatientsmaybecandidatesforpreventivetherapy.Ourapproachtoidentifying
candidatesfordiabetespreventionisreviewedseparately.(See"Preventionoftype2diabetesmellitus",sectionon'Ourapproach'.)

Thereiscurrentlynoconsensusonusingoneglycemictestinpreferencetotheothertoidentifyindividualswithincreasedriskfordiabetes.Whilethetwohouroral
glucosetolerancetest(OGTT)isamoresensitivetestinmostpopulations,glycatedhemoglobin(A1C)andfastingplasmaglucose(FPG)aremoreconvenient
(table2).Althoughmostofthehighriskgroupshavebeendefinedcategorically(eg,impairedfastingglucose[IFG]orimpairedglucosetolerance[IGT]),theriskfor
developingtype2diabetesfollowsacontinuumacrosstheentirespectrumofsubdiabeticglycemicvalues.HigherfastingortwohourOGTTplasmaglucosevalues
orhigherA1Cvaluesconveyhigherriskthanlowervalues.(See"Riskfactorsfortype2diabetesmellitus",sectionon'Abnormalglucosemetabolism'.)

A1CcriteriaforidentifyingpatientswithimpairedglucoseregulationwerederivedusingdatafromtheNationalHealthandNutritionSurvey(NHANES),2005to2006
[3].Comparedwithothercutpoints,anA1Ccutpointof5.7percent(39mmol/mol)hadthebestsensitivity(39percent)andspecificity(91percent)foridentifying
casesofIFG(FPG100mg/dL[5.6mmol/L]).

AlthoughthenaturalhistoryofIFGandimpairedglucosetolerance(IGT)isvariable,approximately25percentofsubjectswitheitherwillprogresstotype2diabetes
overthreetofiveyears[14].Subjectswithadditionaldiabetesriskfactors,includingobesityandfamilyhistory,aremorelikelytodevelopdiabetes.

A1C,FPG,ANDOGTTASPREDICTORSOFCARDIOVASCULARRISKEpidemiologicanalyses(observationalstudiesorsecondaryanalysesoftrials)
suggestacorrelationbetweenchronichyperglycemiaandhigherratesofcardiovasculardisease(CVD).Thereisconsistentevidencethattherelationshipbetween
bloodglucoselevelsandcardiovascularriskextendsintothenondiabeticrange[2529].

Thefollowingobservationshavebeenmadeindifferentreports:

Inacohortof4662menaged45to79yearsfollowedfrom1995to1999,bothallcausemortalityandcardiovasculardeathsweresignificantlyhigheramong
thosewithglycatedhemoglobin(A1C)inthehighendofthenormalrangecomparedwiththosewhoseA1Cwas5.0percent(31mmol/mol)(figure1)[30].

DatafromtheAtherosclerosisRiskinCommunities(ARIC)studyshowarelationshipbetweenA1Clevelandcoronaryheartdisease(CHD)innondiabetic
individuals[31].Therelativeriskofacardiovasculareventwas1.38(95%CI1.221.56)foreveryonepercentagepointincreaseinA1Cforsubjectswithout
diabeteswhoseA1Cwas5.5percent(37mmol/mol)orgreater.Theincidenceofperipheralvasculardiseasealsocorrelatedwithglycemiccontrol[32].

Severalstudieshaveshownthat,comparedwithimpairedfastingglucose(IFG),impairedglucosetolerance(IGT)isabetterpredictorofcardiovascular
disease[33,34]andmortality[35,36].Ina10yearprospectivestudyofalmost6800nondiabeticsubjects,eachonestandarddeviationincreaseintwohour
plasmaglucoseconcentrationincreasedthehazardratioforbothcoronaryevents(1.17,95%CI1.051.30)andcardiovascularmortality(1.22,95%CI1.09
1.37)[37].Therespectivevaluesforaonestandarddeviationincreaseinfastingplasmaglucose(FPG)concentrationwerelower(1.05and1.13).These
observationssuggestthatpostprandial(oralglucosetolerancetest[OGTT])hyperglycemiaismorestronglyassociatedwithcardiovascularriskandmortality
thanFPG.

ThepredictivevalueofIFGandriskofCHDdependsuponthecriteriausedfordefiningIFG[38,39].Asanexample,intheFraminghamHeartStudy,therisk
ofdevelopingCHDoverafouryearperiodwasgreaterinwomenwithIFGbaseduponthe1997comparedwiththe2003criteria(oddsratios[ORs]2.2[95%
CI1.14.4]and1.7[95%CI1.03.0],respectively)[40].Incontrast,menwerenotatincreasedriskofdevelopingCHDbyeitherIFGdefinition.

Althoughthereisacorrelationbetweenmeasuresofglycemiaandcardiovascularrisk,theiradditiontoconventionalcardiovascularriskfactorsisnotassociated
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withaclinicallymeaningfulimprovementinpredictionofCVDrisk.Ananalysisofindividualpatientdatafrom73prospectivestudies(294,998participants)[41]
showedthattheadditionofA1Ctoprognosticmodelscontainingconventionalcardiovascularriskfactors(age,gender,bloodpressure,totalandhighdensity
lipoprotein[HDL]cholesterol,smoking)significantlyimprovedthemodelsabilitytopredictthedevelopmentofCVDhowever,theincrementalimprovementwas
smallandoflittleclinicalrelevance.TheimprovementprovidedbyA1Cwasatleastequaltoestimatedimprovementsformeasurementoffasting,random,or
postloadglucoselevels.ThesefindingssuggestthatinindividualswithoutknownCVDordiabetes,traditionalcardiovascularriskfactorsaremuchstronger
predictorsofCVDthanmeasuresofglycemia.Thecoincidenceofandrelationshipbetweenhyperglycemiaandtraditionalriskfactorsmakestheanalysisoftheir
individualcontributionsparticularlychallenging.

CLASSIFICATIONOFDIABETESType2diabetesaccountsforover90percentofcasesofdiabetesintheUnitedStates,Canada,andEuropetype1
diabetesaccountsforanother5to10percent,withtheremainderduetoothercauses(table3)[6].Theetiologicclassificationofdiabetes,includingdistinguishing
type2fromtype1diabetes,andmonogenicformsofdiabetes(formerlyreferredtoasmaturityonsetdiabetesoftheyoung[MODY])fromtype1andtype2
diabetes,isreviewedelsewhere.(See"Classificationofdiabetesmellitusandgeneticdiabeticsyndromes".)

DIFFERENTIALDIAGNOSISTherearefewcausesofpersistenthyperglycemiainadultsotherthandiabetesmellitus.Transienthyperglycemiamayoccur
duringsevereillnessinadultswithoutknowndiabetesmellitus.Thisissometimesreferredtoasstresshyperglycemiaandisaconsequenceofmanyfactors,
includingincreasedserumconcentrationsofcortisol,catecholamines,glucagon,growthhormone,whichleadstoincreasedgluconeogenesisandglycogenolysis,
andinsulinresistance.Uncontrolledhyperglycemiaassociatedwithcriticalillnesshasbeenassociatedwithpooroutcomes,potentiallybecausesuch
hyperglycemiaisanindexoftheseverityoftheunderlyingillness,butpossiblybecauseofperniciouseffectsofhyperglycemiaandhypoinsulinemia.Suchpatients
aretypicallytreatedwithinsulinduringhospitalization.(See"Glycemiccontrolandintensiveinsulintherapyincriticalillness".)

Stresshyperglycemiamaysimplybeamarkerofabnormalglucosetoleranceandincreasedriskfordevelopingdiabetes.However,notallpatientsdevelopdiabetes
[42,43].Inaprospectivestudyof2124patientswithoutknowndiabetesadmittedtoahospitalwithpneumonia,1418(67percent)hadvaryingdegreesofstress
hyperglycemia(admissionplasmaglucose110to360mg/dL[6.1to20mmol/L])[44].Overfiveyears,agreaterproportionofpatientswithstresshyperglycemia
subsequentlydevelopeddiabetes(14versus6percentofpatientswithnormalglycemia).Theriskofanewdiagnosisofdiabetesincreasedwithincreasingdegrees
ofstresshyperglycemia:7,18,and47percentformild(110to139mg/dL[6.1to7.7mmol/L]),moderate(140to198mg/dL[7.8to11.0mmol/L]),andsevere(200to
360mg/dL[11.1to20.0mmol/L])hyperglycemia,respectively.Inmostpatientswithseverestresshyperglycemia,diabetesmellituswasdiagnosedwithinoneyear.
Thus,patientswithstresshyperglycemiarequirefollowuptestingafterdischargetoidentifyunderlyingdiabetes.

INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,TheBasicsandBeyondtheBasics.TheBasicspatienteducation
piecesarewritteninplainlanguage,atthe5thto6thgradereadinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.
Thesearticlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.BeyondtheBasicspatienteducationpiecesare
longer,moresophisticated,andmoredetailed.Thesearticlesarewrittenatthe10thto12thgradereadinglevelandarebestforpatientswhowantindepth
informationandarecomfortablewithsomemedicaljargon.

Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthesetopicstoyourpatients.(Youcanalsolocatepatient
educationarticlesonavarietyofsubjectsbysearchingonpatientinfoandthekeyword(s)ofinterest.)

Basicstopics(see"Patientinformation:Type1diabetes(TheBasics)"and"Patientinformation:Type2diabetes(TheBasics)"and"Patientinformation:
HemoglobinA1Ctests(TheBasics)")

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BeyondtheBasicstopics(see"Patientinformation:Diabetesmellitustype1:Overview(BeyondtheBasics)"and"Patientinformation:Diabetesmellitustype
2:Overview(BeyondtheBasics)")

SUMMARYANDRECOMMENDATIONS

Type2diabetesisbyfarthemostcommontypeofdiabetesinadults(>90percent)andischaracterizedbyhyperglycemiaandvariabledegreesofinsulin
deficiencyandresistance.Themajorityofpatientswithtype2diabetesareasymptomaticandhyperglycemiaisnotedonroutinelaboratoryevaluation,
promptingfurthertesting.Classicsymptomsofhyperglycemiaincludepolyuria,polydipsia,nocturia,blurredvision,andinfrequently,weightloss.These
symptomsareoftennotedonlyinretrospect,afteranelevatedbloodglucosevaluehasbeendocumented.(See'Clinicalpresentation'above.)

Type1diabetesischaracterizedbyautoimmunedestructionofthepancreaticbetacells,leadingtoabsoluteinsulindeficiency.Diabeticketoacidosismaybe
theinitialpresentationinapproximately25percentofadultswithnewlydiagnosedtype1diabetes.Comparedwithchildren,thelossofinsulinsecretory
capacityusuallyislesspronouncedinadultswithtype1diabetesand,therefore,adultswithtype1diabetestypicallyhavealongersymptomaticperiod
(polyuria,polydipsia,weightloss,fatigue)priortodiagnosisthanchildren.Insomeadults,theclinicalpresentationissimilartothatoftype2diabetes(ie,they
arenotinitiallyinsulindependent),withautoimmunemediatedinsulindeficiencydevelopinglaterinthecourseofdisease.(See'Clinicalpresentation'above.)

Thediagnosisofdiabetesmellitusiseasilyestablishedwhenapatientpresentswithclassicsymptomsofhyperglycemia(thirst,polyuria,weightloss,blurry
vision)andhasarandomplasmaglucosevalueof200mg/dL(11.1mmol/L)orhigher.

Thediagnosisofdiabetesinanasymptomaticindividualcanbeestablishedwiththefollowingcriteria:Fastingplasmaglucose(FPG)values126mg/dL(7.0
mmol/L),twohourpostoralglucosechallengevaluesof200mg/dL(11.1mmol/L),andglycatedhemoglobin(A1C)values6.5percent(48mmol/mol)(table
1).Intheabsenceofunequivocalsymptomatichyperglycemia,thediagnosisofdiabetesmustbeconfirmedonasubsequentdaybyrepeatmeasurement,
repeatingthesametestforconfirmation.(See'Diagnosticcriteria'above.)

AccordingtoADAcriteria,thediagnosticthresholdsforcategoriesofincreasedriskfordiabetesareasfollows(table2):

Impairedfastingglucose(IFG)FPG100to125mg/dL(5.6to6.9mmol/L)

Impairedglucosetolerance(IGT)2hPG(75goralglucosetolerancetest[OGTT])140to199mg/dL(7.8to11.0mmol/L)

A1C5.7to6.4percent(39to46mmol/mol)(theInternationalExpertCommitteerecommended6.0to6.4percent[42to46mmol/mol])

(See'ADAcriteria'aboveand'A1C,FPG,andOGTTaspredictorsofdiabetes'above.)

Theetiologicclassificationofdiabetes,includingdistinguishingtype2fromtype1diabetes,andmonogenicdiabetes(formerlyreferredtoasmaturityonset
diabetesoftheyoung[MODY])fromtype1andtype2diabetes,isreviewedelsewhere.(See"Classificationofdiabetesmellitusandgeneticdiabetic
syndromes".)

Theevaluationandmanagementofpatientswithdiabetesisreviewedseparately.(See"Overviewofmedicalcareinadultswithdiabetesmellitus"and"Initial
managementofbloodglucoseinadultswithtype2diabetesmellitus"and"Managementofbloodglucoseinadultswithtype1diabetesmellitus".)

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16.PetersAL,DavidsonMB,SchrigerDL,HasselbladV.Aclinicalapproachforthediagnosisofdiabetesmellitus:ananalysisusingglycosylatedhemoglobin
levels.MetaanalysisResearchGroupontheDiagnosisofDiabetesUsingGlycatedHemoglobinLevels.JAMA1996276:1246.
17.RohlfingCL,LittleRR,WiedmeyerHM,etal.UseofGHb(HbA1c)inscreeningforundiagnoseddiabetesintheU.S.population.DiabetesCare200023:187.
18.BuellC,KermahD,DavidsonMB.UtilityofA1Cfordiabetesscreeninginthe19992004NHANESpopulation.DiabetesCare200730:2233.
19.BennettCM,GuoM,DharmageSC.HbA(1c)asascreeningtoolfordetectionofType2diabetes:asystematicreview.DiabetMed200724:333.
20.NathanDM,KuenenJ,BorgR,etal.TranslatingtheA1Cassayintoestimatedaverageglucosevalues.DiabetesCare200831:1473.
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diagnosisofdiabetes?Diabetologia200952:1279.
22.MiyazakiM,KuboM,KiyoharaY,etal.ComparisonofdiagnosticmethodsfordiabetesmellitusbasedonprevalenceofretinopathyinaJapanesepopulation:
theHisayamaStudy.Diabetologia200447:1411.
23.MassinP,LangeC,TichetJ,etal.HemoglobinA1candfastingplasmaglucoselevelsaspredictorsofretinopathyat10years:theFrenchDESIRstudy.
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25.CoutinhoM,GersteinHC,WangY,YusufS.Therelationshipbetweenglucoseandincidentcardiovascularevents.Ametaregressionanalysisofpublished
datafrom20studiesof95,783individualsfollowedfor12.4years.DiabetesCare199922:233.
26.LevitanEB,SongY,FordES,LiuS.Isnondiabetichyperglycemiaariskfactorforcardiovasculardisease?Ametaanalysisofprospectivestudies.Arch
InternMed2004164:2147.
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GRAPHICS

ADAcriteriaforthediagnosisofdiabetes
1.A1C6.5percent.ThetestshouldbeperformedinalaboratoryusingamethodthatisNGSPcertifiedandstandardizedtotheDCCTassay.*

OR

2.FPG126mg/dL(7.0mmol/L).Fastingisdefinedasnocaloricintakeforatleasteighthours.*

OR

3.Twohourplasmaglucose200mg/dL(11.1mmol/L)duringanOGTT.ThetestshouldbeperformedasdescribedbytheWorldHealth
Organization,usingaglucoseloadcontainingtheequivalentof75gramanhydrousglucosedissolvedinwater.*
OR

4.Inapatientwithclassicsymptomsofhyperglycemiaorhyperglycemiccrisis,arandomplasmaglucose200mg/dL(11.1mmol/L).

A1C:glycatedhemoglobinDCCT:diabetescontrolandcomplicationstrialFPG:fastingplasmaglucoseNGSP:nationalglycohemoglobinstandardization
programOGTT:oralglucosetolerancetest.
*Intheabsenceofunequivocalhyperglycemia,criteria1to3shouldbeconfirmedbyrepeattesting.

Reprintedwithpermissionfrom:AmericanDiabetesAssociation.StandardsofMedicalCareinDiabetes2011.DiabetesCare201134:S11.Copyright
2011AmericanDiabetesAssociation.

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Categoriesofincreasedriskfordiabetes(prediabetes)*

FPG100to125mg/dL(5.6to6.9mmol/L)(IFG)

2hourPGonthe75gOGTT140to199mg/dL(7.8to11.0mmol/L)(IGT)

A1C5.7to6.4percent(39to46mmol/mol)

A1C:glycatedhemoglobinFPG:fastingplasmaglucoseIFG:impairedfastingglucoseIGT:impairedglucosetoleranceOGTT:oralglucosetolerancetest
PG:postglucose.
*Forallthreetests,riskiscontinuous,extendingbelowthelowerlimitoftherangeandbecomingdisproportionatelygreaterathigherendsoftherange.

ReprintedwithpermissionfromtheAmericanDiabetesAssociation.Standardsofmedicalcareindiabetes2011.DiabetesCare201134:S11.Copyright
2011AmericanDiabetesAssociation.Tablealsopublishedin:AmericanDiabetesAssociation.Standardsofmedicalcareindiabetes2013.Diabetes
Care201336Suppl1:S11.

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A1Cconcentrationasapredictorofmortality

Inastudyofmenages45to79years,A1C,amarkerofbloodglucose
concentration,wascorrelatedwithcardiovascular(blackbars)andallcause(gray
bars)mortality,evenwithinthenondiabeticrange.

A1C:glycatedhemoglobinCVD:cardiovasculardiseaseDM:diabetesmellitus.

Datafrom:KhawKT,WarehamN,LubenR,etal.Glycatedhemoglobin,diabetes,and
mortalityinmeninNorfolkcohortofEuropeanProspectiveInvestigationofCancerand
Nutrition(EPICNorfolk).BMJ2001322:15.

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Etiologicclassificationofdiabetesmellitus

Type1diabetes(betacelldestruction,usuallyleadingtoabsoluteinsulindeficiency)
A.Immunemediated

B.Idiopathic

Type2diabetes(mayrangefrompredominantlyinsulinresistancewithrelativeinsulindeficiencytoa
predominantlysecretorydefectwithinsulinresistance)

Otherspecifictypes
A.Geneticdefectsofbetacellfunction

1.Chromosome12,HNF1alpha(MODY3)

2.Chromosome7,glucokinase(MODY2)

3.Chromosome20,HNF4alpha(MODY1)

4.Chromosome13,insulinpromoterfactor1(IPF1MODY4)

5.Chromosome17,HNF1beta(MODY5)

6.Chromosome2,NeuroD1(MODY6)

7.MitochondrialDNA

8.Others

B.Geneticdefectsininsulinaction

1.TypeAinsulinresistance

2.Leprechaunism

3.RabsonMendenhallsyndrome

4.Lipoatrophicdiabetes

5.Others

C.Diseasesoftheexocrinepancreas

1.Pancreatitis

2.Trauma/pancreatectomy

3.Neoplasia

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4.Cysticfibrosis

5.Hemochromatosis

6.Fibrocalculouspancreatopathy

7.Others

D.Endocrinopathies
1.Acromegaly

2.Cushing'ssyndrome

3.Glucagonoma

4.Pheochromocytoma

5.Hyperthyroidism

6.Somatostatinoma

7.Aldosteronoma

8.Others

E.Drugorchemicalinduced

1.Vacor

2.Pentamidine

3.Nicotinicacid

4.Glucocorticoids

5.Thyroidhormone

6.Diazoxide

7.Betaadrenergicagonists

8.Thiazides

9.Dilantin

10.AlphaInterferon

11.Others

F.Infections
1.Congenitalrubella

2.Cytomegalovirus

3.Others

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G.Uncommonformsofimmunemediateddiabetes
1."Stiffman"syndrome

2.Antiinsulinreceptorantibodies

3.Others

H.Othergeneticsyndromessometimesassociatedwithdiabetes

1.Down'ssyndrome

2.Klinefelter'ssyndrome

3.Turner'ssyndrome

4.Wolfram'ssyndrome

5.Freiderich'sataxia

6.Huntington'schorea

7.LaurenceMoonBiedlsyndrome

8.Myotonicdystrophy

9.Porphyria

10.PraderWillisyndrome

11.Others

Gestationaldiabetesmellitus
Patientswithanyformofdiabetesmayrequireinsulintreatmentatsomestageoftheirdisease.Suchuseofinsulindoesnot,ofitself,classifythe
patient.

Copyright2007AmericanDiabetesAssociationFromDiabetesCareVol30,Supplement1,2007.ReprintedwithpermissionfromTheAmerican
DiabetesAssociation.

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ContributorDisclosures
DavidKMcCulloch,MDNothingtodisclose.DavidMNathan,MDNothingtodisclose.JosephIWolfsdorf,MB,BChNothingtodisclose.JeanEMulder,MD
Nothingtodisclose.

Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvettingthroughamultilevelreviewprocess,
andthroughrequirementsforreferencestobeprovidedtosupportthecontent.Appropriatelyreferencedcontentisrequiredofallauthorsandmustconformto
UpToDatestandardsofevidence.

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