Elevation of 1-Hour Plasma Glucose During Oral Glucose Tolerance Testing Is Associated With Worse Pulmonary Function in Cystic Fibrosis.

0.15 MB·English

by  Brodsky, Jill

Clinical Care/Education/Nutrition/Psychosocial Research
O R I G I N A L A R T I C L E
Elevation of 1-Hour Plasma Glucose
During Oral Glucose Tolerance Testing
Is Associated With Worse Pulmonary
Function in Cystic Fibrosis
JILL BRODSKY, MD1 RONALD C. RUBENSTEIN, MD, PHD2 sincetheearly1990s(2).CFRDisassoci-
SHAYNE DOUGHERTY, CRNP1 ANDREA KELLY, MD, MSCE1 atedwithworseclinicalstatus,asindicated
RAMKRISHNA MAKANI, MBBS, MPH1 byreducedpulmonaryfunction;increased
frequency of pulmonary exacerbations;
increasedprevalenceofimportantsputum
OBJECTIVE—Cysticfibrosis(CF)-relateddiabetes(CFRD)isassociatedwithdecliningpul- pathogenssuchasPseudomonasaeruginosa
monaryfunctionandincreasedmortality.Duringoralglucosetolerancetesting(OGTT),CFRD
and Burkholderia cepacia; and worsening
isdefinedby2-hplasmaglucose(PG2).WehypothesizedPGelevationsduringOGTTresolving
by2h,notmeetingCFRDcriteria,influencepulmonaryfunctioninCF.Thusweinvestigated nutritionalstatus,amongothers(3).Fur-
therhighlightingitsclinicalsignificance,
thefrequencyofelevated1-hOGTTPG(PG1)anditsrelationshipwithpulmonaryfunction.
CFRD is associated with increased mor-
RESEARCHDESIGNANDMETHODS—RetrospectivereviewofOGTTswasperformed bidityanduptoasixfoldgreatermortal-
between August 2005 (annual screening initiation) and June 2008 at Children’s Hospital of ityrate(2,4).
PhiladelphiaCFCenter.First-time,wellstateOGTTs(PG0,PG1,PG2)wereanalyzed.Additional CFRD is hypothesized to result pri-
datacollectedwere:percentpredictedforcedexpiratoryvolumein1s(FEV1),BMIpercentile, marily from insulin deficiency, although
lungbacterialcolonization,age,andsex.OGTTswerecategorizedasnormal(PG2,140mg/dL),
some element of insulin resistance is
impairedglucosetolerance(IGT)(PG2140–199mg/dL),CFRD(PG2 $200mg/dL), andin-
determinateglycemia(INDET)(PG1$200mg/dLandPG2,140mg/dL).FrequencyofPG1 likelypresentaswell.Beforethedevelop-
$140but,200mg/dLwasalsonoted.Multivariablelinearregressionwasusedtoassessasso- ment of frank diabetes, insulin secretion
ciationsbetweenpercentpredictedFEV ,BMIpercentile,andOGTTPG. is delayed and blunted (5). The earliest
1
changesinglucosetoleranceinvolvevari-
RESULTS—OGTTs (101) were available (59 male/42 female; age 5.8–22 years, percent able postprandial hyperglycemia. Pro-
predictedFEV =94.5618%,BMIpercentile=52625%).WiththeuseofPG2,91OGTT
1 gressive decline in insulin secretion leads
werenormal,eightwereIGT,andtwowereCFRD.WiththeuseofPG1(n=89),39OGTT
to impaired glucose tolerance (IGT) and,
were normal, 36 were PG1 $140 ,200 mg/dL, and 14 were PG1 $200 mg/dL. PG1 was
negativelyassociatedwithpercentpredictedFEV ,adjustingforBMIpercentile(P=0.009,R2 ultimately,CFRD.
1 The oral glucose tolerance test
0.13).PercentpredictedFEV wasnotassociatedwithPG0,PG2,age,sex,orlungbacterial
1
colonization. (OGTT) is recommended for screening
purposes (6), and the diagnostic criteria
CONCLUSIONS—PG elevations at nontraditional OGTT times are common in CF. The for CFRD are similar to those for other
associationofincreasingPG1withworsepulmonaryfunctionsuggestsearlyPGabnormalities formsofdiabetes.However,theappropri-
maybedeleteriousoranearlymarkerforworseningdiseaseandwillbemissedifCFRDdiagnosis
ateness of using conventional thresholds
focusesonPG2.
derived from epidemiologic studies in
DiabetesCare34:292–295,2011 non-CF patients for the diagnosis of
CFRD has been questioned (7). In type
W 2 diabetes, glycemic thresholds defining
ith improved survival among in- care centers, reports that 20% of indi-
diabetesarebasedonglucoseconcentra-
dividualswithcysticfibrosis(CF), viduals with CF will haveCF-related di-
tionsassociatedwithmicrovascularcom-
diabetesmellitushasemergedasa abetes (CFRD) by the third decade (1). plications, such as diabetic retinopathy
significant comorbidity. The CF Founda- Higher prevalence of 40–50% has been andnephropathy(8).Althoughmicrovascu-
tion Patient Registry 2008 Annual Data reported in adults with CF followed at larcomplicationsarerelevantinCF(9),the
Report, which reflects data from over the University of Minnesota, where rou- paradigmfordefiningglucoseabnormalities
25,000 patients at U.S.-accredited CF tine annual screening has been in place inCFisshiftingtofocusonoutcomesmore
immediately relevant to CF, such as nutri-
tionalstatusandpulmonaryfunction.This
c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c
paradigm shift is underscored by a recent
Fromthe1DivisionofPediatricEndocrinologyandDiabetes,TheChildren’sHospitalofPhiladelphia,Phil- randomized control trial in which insulin
adelphia,Pennsylvania;andthe2CysticFibrosisCenter,DivisionofPulmonaryMedicineandCysticFi-
brosisCenter,TheChildren’sHospitalofPhiladelphia,UniversityofPennsylvaniaSchoolofMedicine, treatmentwasassociatedwithimprovednu-
Philadelphia,Pennsylvania. tritionalstatusinadultswithCFRDwithout
Correspondingauthor:JillBrodsky,[email protected]. fastinghyperglycemia(10).
Received19August2010andaccepted24October2010. In 2009, the North American CFRD
DOI:10.2337/dc10-1604
Consensus Committee restructured glu-
©2011bytheAmericanDiabetesAssociation.Readersmayusethisarticleaslongastheworkisproperly
cited,theuseiseducationalandnotforprofit,andtheworkisnotaltered.Seehttp://creativecommons.org/ cosetolerancecategoriesinCF,basedon
licenses/by-nc-nd/3.0/fordetails. thefastingand1-and2-hplasmaglucose
292 DIABETESCARE,VOLUME34,FEBRUARY2011 care.diabetesjournals.org
BrodskyandAssociates
duringanOGTT(6):normalglucosetol- performed on spontaneously expecto- Table1—Patientcharacteristics
erance (NGT), IGT, CFRD, and indeter- rated sputum (when available) or by
minate glycemia (INDET). This new cough swabs. All of these evaluations
Characteristic All(n=101)
category of INDET occurs in individuals wereperformedaspartofstandardclini-
with normal fasting and 2-h plasma glu- calcareatthetimeoftheOGTT. Female/male 42/59
cose but who have 1-h plasma glucose OGTT results were categorized ac- Age(years) 12.563.9
concentrations greater than 200 mg/dL cording to PG2 as normal (PG2 ,140 White 99(98%)
(6).Theclinical relevance ofthis INDET mg/dL),IGT(PG2140–199mg/dL),and BMIpercentile 52%625
category with regard to clinical outcome CFRD(PG2$200mg/dL),aswellasac- PercentpredictedFEV1 94.5%618.3
inCFisnotknown. cording to PG1 as INDET (PG1 $200 PercentpredictedFVC 98.7%616.8
The goals of this study were to in- mg/dL but PG2 ,140 mg/dL or PG1 MSSAorMRSA 23
vestigate the frequency of abnormal 1-h $140mg/dLbut,200mg/dL). Burkholderiacepacia 4
plasma glucose during an OGTT and to Pseudomonasaeruginosa 24
exploretherelationshipbetweenthe1-h Statistical methods Data are mean 6 SD. MSSA, methicillin-sensitive
plasmaglucose (PG1), percent predicted Means and SD were calculated for con- Staphylococcus aureus; MRSA, methicillin-resistant
forced expiratory volume in 1 s (FEV1), tinuousvariables;proportionswereused Staphylococcusaureus.
andBMIpercentileinapediatricCFpop- to characterize categorical data. Simple
ulation.Wehypothesizedthatelevations linear regression was used to test the additional 36 had PG1 $140 but ,200
inPG1wouldbebothcommonandneg- mg/dL.
associationsbetweenOGTTPG,asacon-
atively associated with percent predicted Simplelinearregressionanalysiswas
tinuousvariable,andpulmonaryfunction
FEV and BMI percentile. Our data sug- performed to test for associations be-
1 tests, BMI percentile, and other clinical
gestthatelevationsofPG1areinfactas- factors such as sex, age, and sputum tween percent predicted FEV1, percent
sociated with worse clinical outcomes in predicted FVC, and BMI percentile and
bacterial colonization. Multivariable lin-
CF and provide a foundation for further age, sex, PG0, PG1, and PG2 as well as
ear regression was then used to test the
investigation regarding optimal manage- between BMI percentile and pulmonary
associations between OGTT PG and
mentofCFRD. functiontests.AsshowninTable2,per-
percentpredictedFEV afteradjustment
1 cent predicted FEV and percent pre-
forBMIpercentile.Theregressionmod- 1
RESEARCH DESIGN AND dicted FVC were associated with both
els were assessed further through the
METHODS BMI percentile and PG1 but not age,
Shapiro-Wilktestofnormalityofthere-
sex, PG0, PG2, or colonization status in
siduals and the Cook-Weisberg test for
Subjects this unadjusted analysis. BMI percentile
InAugust2005,TheChildren’sHospitalof heteroscedasticity. wasalsoassociatedwithPG1.
Data analysis was performed using
Philadelphia CF Center initiated annual We performed multivariable linear
CFRD screening in children over age 6–8 Stata 9 (Stata Corporation, College Sta- regressionanalysestoadjustforpotential
tion, TX). Two-sided tests of hypotheses
years using a standard OGTT (75 g/kg confounders (Table 2); PG1 remained
wereused,andaP,0.05wasconsidered
dextrose, maximum dose 75 g) after an negatively associated with percent pre-
statisticallysignificant.
overnightfast.Thisretrospectivechartre- dicted FEV even after adjustment for
1
This study was approved by the In-
viewislimitedtoOGTTperformedforthe BMIpercentile.Thisrelationshipdidnot
first time in individual subjects between stitutionalReviewBoardatTheChildren’s persistforpercentpredictedFVCafterad-
HospitalofPhiladelphia.
August 2005 and June 2008 in the well justmentforBMIpercentile.Accordingto
state, defined as no hospitalizations or theregressionmodel,afteradjustmentfor
RESULTS—During 2005 through
oral or intravenous glucocorticoid ex- BMI percentile, percent predicted FEV
2008, first-time OGTT were performed 1
posure within 6 weeks before OGTT. was reduced by 1% for every 10 mg/dL
in101childrenwithCF.CompleteOGTT
Patients that had undergone lung trans- increaseinPG1.
data (PG0, PG1, PG2) were available in
plant or had a previous diagnosis of
CFRD were excluded. Patients who were 89subjects. CONCLUSIONS—In children with
unabletocooperatewithpulmonaryfunc- Clinical characteristics of the 101 CF undergoing routingOGTTforCFRD
tion testing because of young age or (42F) are listed in Table 1. Mean age screening, the 1-h PG is commonly ele-
behavioral/developmentalissueswereex- was12.563.9years.MeanBMIpercen- vated despite normal fasting and 2-h PG
cludedfromtheanalysesexaminingasso- tile was 52 6 25%, and mean percent concentrations. In fact, until the recent
ciations between OGTT and pulmonary predicted FEV1 was 94.5 6 18%. Mean introduction of the INDET category of
function. PG0,PG1,andPG2were8669mg/dL, glucose tolerance in CF, ;10% of our
148651 mg/dL,and 102 632mg/dL, center’s pediatric CF population would
Data respectively. have been labeled as having normal glu-
Datawerecollectedfromclinicalrecords Ofthe101whounderwentOGTT,14 cosetolerancedespiteanelevatedPG1,or
andPortCFandincludedOGTTplasma (14%) had PG1 $200 mg/dL. Of this 1-hPG.Moreimportantlyandlikelyclin-
glucoseconcentrations,percentpredicted group, nine (64%) had normal PG2 ically relevant, our data suggest that the
FEV and percent predicted forced vital (,140mg/dL)and,untilrecently,would 1-h OGTT PG is negatively associated
1
capacity (FVC) according to the Wang- have been labeled as having normal glu- with percent predicted FEV even after
1
Hankinson reference equations (REF), cosetolerance.Twoofthese14hadCFRD adjustment for BMI percentile. In con-
and BMI percentile. Sputum cultures (PG2 $200 mg/dL), and an additional trast, fasting and 2-h PG concentrations,
to assess bacterial colonization were three of these 14 had IGT (Fig. 1). An parametersuponwhichwetypicallyrely
care.diabetesjournals.org DIABETESCARE,VOLUME34,FEBRUARY2011 293
One-hourplasmaglucoseandpulmonaryfunction
ElevationsofPG1arealsoassociated
with abnormalities in inflammatory
markers and metabolic characteristics
in patients without a diagnosis of diabe-
tes. Adults with PG1 .155 mg/dL had
significant increases in inflammatory
markers and lipid ratios, higher white
blood cell count and fibrinogen levels,
andworseinsulinsensitivity(14).More-
over,subjectswithnormalglucosetoler-
anceasdefinedbyfastingand2-hPG,but
whohadPG1.155mg/dL,hadafivefold
greaterriskoftype2diabetesthanthose
subjects with PG1 ,155 mg/dL (15).
These findings further highlight the im-
portanceofunderstandingtheroleofhy-
perglycemia that occurs earlier than the
2-hmark.
Both CFRD and IGT are associated
withgreaterdeclinesinpulmonaryfunc-
tion (16). Glucose abnormalities occur-
ring earlier than 2 h during a OGTT
Figure1—PlasmaglucoseexcursionsduringOGTT. have also been associated with declines
in weight in the year preceding the
to define abnormal glucose,were related and Adverse Pregnancy Outcome study OGTT (17). More concerning, CFRD is
toneitherBMIpercentilenorpulmonary identified an association between mater- associated with increased mortality (2).
Recent data from the University of Min-
function. These data suggest that clini- nalglucoseconcentrationsandmarkersof
nesota suggest, however, that early diag-
cally important abnormal PG elevations perinatal complications, even at glucose
nosisandtreatmentofCFRDcanimprove
maybemissedifglucosetolerancetesting concentrations below those traditionally
survival(2).Ina1-yearrandomizedcon-
omitsevaluationofPG1andoptimalther- accepted as diagnostic of gestational di-
apymayrequireadditionalfocusonnor- abetes (11). Additionally, the finding of troltrialofCFRD withoutfastinghyper-
glycemia, insulin treatment improved
malizingPG1. improvedpregnancyoutcomeswithtreat-
BMI percentile, and, although not statis-
Asimilarmodelforredefiningglucose mentofmildgestationaldiabetes(12)em- tically significant, trends in reversing
abnormalitiespredicatedonnontraditional phasizes importance of the 1-h PG. An
declinesinpulmonaryfunctionweresug-
outcomes can be seen with gestational abnormalPG1predictspostpartummeta-
gested.
diabetes. The original definitions of glu- bolicdysfunction(13)andhasbeenasso-
Current recommendations for the
cose abnormalities acquired during preg- ciatedwithincreasedriskforadversefetal
treatmentofbloodglucoseabnormalities
nancy were based upon subsequent outcomessuchaslargeforgestationalage,
in CF rely on the 2-h blood glucose
development of diabetes and not upon neonatal hypoglycemia, increased rate of concentration,whichisdefinedasabnor-
predictive value for adverse pregnancy cesarean section, and shoulder dystocia
mal based upon its ability to predict
outcomes. Recently, the Hyperglycemia (11).
developmentofmicrovascularcomplica-
tions. In the setting of CF, worsening
Table2—Unadjusted associationsbetweenOGTTandpulmonaryfunction andBMI pulmonaryfunctionandpoornutritional
status are the more clinically relevant
causes of significant morbidity and mor-
Variable tality. Given that current median pre-
Dependent Independent Partialb-coefficient(95%CI) Pvalue R2 dicted survival for people with CF is
only ;37 years, pulmonary function
Unadjusted andnutritionalstatuseclipsemicrovascu-
PercentpredictedFEV1 PG1 20.11(20.18to20.04) ,0.0003 0.10 lar disease as clinically significant causes
BMIpercentile 0.19(0.05–0.33) 0.007 0.07 of morbidity and mortality in CF. Thus
PercentpredictedFVC PG1 20.06(20.13to0.005) 0.07 0.04 our findings of worse percent FEV in
BMIpercentile 0.19(0.06–0.32) 0.004 0.08 the setting of increasing PG1 but1not
BMIpercentile PG1 20.11(20.21to20.005) 0.04 0.05 PG2 suggest earlier and not typically as-
AdjustedforBMIpercentile sessed glucose abnormalities may have
PercentpredictedFEV1 0.13 implications for pulmonary status and
PG1 20.10(20.17to20.02) 0.009 thatrelianceonPG2maymissanimpor-
BMIpercentile 0.14(20.01to0.29) 0.067 tantimpetusforintervention.
PercentpredictedFVC 0.1 In this study, a negative association
PG1 20.05(20.11to0.02) 0.2 between PG1 and baseline percent FEV
BMIpercentile 0.18(0.04–0.32) 0.01 was identified; however, this association1
294 DIABETESCARE,VOLUME34,FEBRUARY2011 care.diabetesjournals.org
BrodskyandAssociates
doesnotdifferentiatebetween1)acausal todiscussion,wrotethearticle,andreviewed fibrosis-relateddiabetes.DiabetesCare2007;
effect and 2) glucose abnormalities and andeditedthearticle. 30:1056–1061
worsening percent FEV , both arising as TheauthorsthankTheChildren’sHospital 10. MoranA,PekowP,GroverP,etal;Cystic
1
manifestations of worsening CF disease. of Philadelphia Cystic Fibrosis Center, Di- Fibrosis Related Diabetes Therapy Study
visionofPulmonaryMedicine,andDivisionof Group.InsulintherapytoimproveBMIin
Infact,PG1mayonlybeanearlymarker
EndocrinologyandDiabetes. cystic fibrosis-related diabetes without
of pulmonary decline. It is important to
fastinghyperglycemia:resultsofthecystic
also note that although the model is sta- fibrosis-relateddiabetestherapytrial.Di-
tistically significant, the R2 was low; an References abetesCare2009;32:1783–1788
association between glucose abnormali- 1. Cystic Fibrosis Foundation. Patient Reg- 11. Metzger BE, Lowe LP, Dyer AR, et al;
tiesisthereforesuggested,buttheclinical istry 2008 Annual Data Report. Bethesda, HAPOStudyCooperativeResearchGroup.
impact of this association has yet to be MD,2008. Hyperglycemia and adverse pregnancy
determined. The finding of increasing 2. Moran A, Dunitz J, Nathan B, Saeed A, outcomes.NEnglJMed2008;358:1991–
PG1 predicting worse percent FEV in Holme B, Thomas W. Cystic fibrosis- 2002
1
subsequentyearswouldprovidesupport relateddiabetes:currenttrendsinpreva- 12. Landon MB, Spong CY, Thom E, et al;
for this causal effect, while an interven- lence, incidence, and mortality. Diabetes EuniceKennedyShriverNationalInstitute
Care2009;32:1626–1631 ofChildHealthandHumanDevelopment
tionstudytargetingthe1-hOGTTblood
3. Marshall BC, Butler SM, Stoddard M, Maternal-FetalMedicineUnitsNetwork.A
glucosewouldprovideimportantinsights
MoranAM,LiouTG,MorganWJ.Epide- multicenter,randomizedtrialoftreatment
into the role of glucose/insulin in nutri- miologyofcysticfibrosis-relateddiabetes. formildgestationaldiabetes.NEnglJMed
tionalstatusandpulmonaryfunction. JPediatr2005;146:681–687 2009;361:1339–1348
We have identified a significant asso- 4. Moran A, Hardin D, Rodman D, et al. 13. RetnakaranR,QiY,ConnellyPW,Sermer
ciation between elevated PG1 and de- Diagnosis,screeningandmanagementof M, Zinman B, Hanley AJ. Glucose in-
creased percent predicted FEV in cystic fibrosis related diabetes mellitus: tolerance in pregnancy and postpartum
1
childrenwithCF.Thesefindingssupporta a consensus conference report. Diabetes risk of metabolic syndrome in young
newparadigmfortheapproachtoPGab- ResClinPract1999;45:61–73 women. J Clin Endocrinol Metab 2010;
normalities in CF by defining PG abnor- 5. LanngS,ThorsteinssonB,RøderME,etal. 95:670–677
Pancreas and gut hormone responses to 14. BardiniG,DicembriniI,CresciB,Rotella
malities by risk of pulmonary function oral glucose and intravenous glucagon CM.Inflammationmarkersandmetabolic
declineandnutritionalstatuscompromise in cystic fibrosis patients with normal, characteristicsofsubjectswith1-hplasma
rather than microvascular complications,
impaired,anddiabeticglucosetolerance. glucose levels. Diabetes Care 2010;33:
as well as support further investigation of Acta Endocrinol (Copenh) 1993;128: 411–413
glycemiccontroldefinedbyPG1inCF. 207–214 15. Abdul-GhaniMA,Abdul-GhaniT,AliN,
6. Moran A. Evidence based guidelines for Defronzo RA. One-hour plasma glucose
cystic fibrosis related diabetes. Diabetes concentration and the metabolic syn-
Acknowledgments—This study was sup- throughout the lifespan symposium. In drome identify subjects at high risk for
portedbygrantsfromtheNationalInstitutes 23rdAnnualNorthAmericanCysticFibrosis future type 2 diabetes. Diabetes Care
of Health (NIH K23-RR021973 to A.K.) and Conference. Minneapolis, MN, 15–17 Oc- 2008;31:1650–1655
the Cystic Fibrosis Foundation (to A.K. and tober2009 16. MillaCE,WarwickWJ,MoranA.Trends
R.C.R.). 7. MoranA.Cysticfibrosis-relateddiabetes: in pulmonary function in patients with
Nopotentialconflictsofinterestrelevantto an approach to diagnosis and manage- cystic fibrosis correlate with the degree
thisarticlewerereported. ment.PediatrDiabetes2000;1:41–48 of glucose intolerance at baseline. Am J
J.B. wrote the article, contributed to dis- 8. AmericanDiabetesAssociation.Diagnosis Respir Crit Care Med 2000;162:891–
cussion,andresearcheddata.S.D.researched and classification of diabetes mellitus. 895
data and contributed to discussion. R.M. re- Diabetes Care 2009;32(Suppl. 1):S62– 17. HameedS,MortonJR,JafféA,etal.Early
searcheddata.R.C.R.researcheddata,contrib- S67 glucoseabnormalitiesincysticfibrosisare
uted to discussion, and reviewed and edited 9. SchwarzenbergSJ,ThomasW,OlsenTW, preceded by poor weight gain. Diabetes
thearticle.A.K.researcheddata,contributed etal.Microvascularcomplicationsincystic Care2010;33:221–226
care.diabetesjournals.org DIABETESCARE,VOLUME34,FEBRUARY2011 295