Glucose Metabolism in 105 Children and Adolescents After Pancreatectomy for Congenital Hyperinsulinism.

0.56 MB·English

by  Beltrand, Jacques

Clinical Care/Education/Nutrition/Psychosocial Research
O R I G I N A L A R T I C L E
Glucose Metabolism in 105 Children and
Adolescents After Pancreatectomy for
Congenital Hyperinsulinism
JACQUES BELTRAND, MD, PHD1 JACQUES RAHIER, MD, PHD6 Thefrequentresistanceofcongenital
MARYLÈNE CAQUARD, MD1 FRANCIS BRUNELLE, MD, PHD7 hyperinsulinismtomedicaltreatmentsof-
JEAN-BAPTISTE ARNOUX, MD2 CLAIRE NIHOUL-FÉKÉTÉ, MD, PHD8 tenleadsto surgery, which has for a long
KATHLEEN LABORDE, MD, PHD3 JEAN-MARIE SAUDUBRAY, MD, PHD2 time consisted of near-total pancreatec-
GVIIRLGBEINRITEOVVEERLKHAOR,REM,DM,DPH, DPH4D5 JPEAASNC-AJLAECQDUEELSORNOLBAEYR,TM,DM,DP,HPDH2D1 tdoimabye,twesit(h4a–7h)ig.hHroiswkeovfeirn,suthlien-ddieffpeernendteina-t
tion between two formsdthe diffuse
form with no histological anomalies but
OBJECTIVEdTodescribethelong-termmetabolicoutcomeofchildrenwithcongenitalhy- signsofb-cellhyperfunctionandtheade-
perinsulinismafternear-totalorpartialelectivepancreatectomy.
nomatouslocalizedhyperplasiadhascon-
RESEARCH DESIGN AND METHODSdPatients (n = 105: 58 diffuse and 47 focal siderably changed the surgical treatment
congenitalhyperinsulinism)receivedoperationsbetween1984and2006.Follow-upconsisted and the prognosis of the disease (8,9).
ofperiodicmeasurementsofpre-andpostprandialplasmaglucoseover24h,OGTT,andIVGTT. Thefocalformscanindeedbedefinitively
Cumulativeincidenceof hypo-orhyperglycemia/insulintreatment wasestimatedbyKaplan- curedofhypoglycemiawithpartialelective
Meieranalysis.
pancreatectomy(10).Thepreoperativedis-
RESULTSdAfternear-totalpancreatectomy,59%ofchildrenwithdiffusecongenitalhyper- tinctionbetweenthetwoformswasinitially
insulinismstillpresentedmildorasymptomatichypoglycemiathatrespondedtomedicaltreat- established using selective pancreatic ve-
ments and disappeared within 5 years. One-third of the patients had both preprandial nous catherization (11,12), which has re-
hypoglycemiaandpostprandialhyperglycemia.Hyperglycemiawasfoundin53%ofthepatients centlybeenabandonedforthelessinvasive
immediatelyaftersurgery;itsincidenceincreasedregularlyto100%at13years.Thecumulative positron emission tomography with [18F]
incidenceofinsulin-treatedpatientswas42%at8yearsandreached91%at14years,butthe fluoro-L-DOPA(13).
progressiontoinsulindependencewasveryvariableamongthepatients.Plasmainsulinrespon- The long-term outcome of patients
sestoIVGTTandOGTTcorrelatedwellwithglycemicalterations.Infocalcongenitalhyperin-
suffering from congenital hyperinsulin-
sulinism,hypoglycemiaorhyperglycemiawererare,mild,andtransient. ismhasnotbeenwelldescribed(4,5,14–
CONCLUSIONSdPatientswithfocalcongenitalhyperinsulinismarecuredofhypoglycemia 17).Fewstudieshaveclearlydifferentiated
afterlimitedsurgery,whiletheoutcomeofdiffusecongenitalhyperinsulinismisveryvariable diffuseandfocalformsofinsulinhyperse-
afternear-totalpancreatectomy.Theincidenceofinsulin-dependentdiabetesisveryhighinearly cretion. If the incidence of postoperative
adolescence. recurrent hypoglycemia was often docu-
mented, the follow-up was often short
DiabetesCare35:198–203,2012 anddatauponglucosetoleranceandinsu-
C linsecretionwererarelyavailable,making
ongenital hyperinsulinism is the theneonatalformsofcongenitalhyper- itdifficulttoevaluatetheincidenceofpost-
most common cause of persistent insulinism, the most common genetic surgical diabetes, although the risk seems
severehypoglycemiaatbirthorin mutations (in ABCC8 and KCNJ11 tobehighbeforetheseconddecadeoflife
early infancy, requiring early intensive genes) cause alterations of the ATP- afternear-totalpancreatectomy(4,5,16).
multidisciplinary management to pre- dependentK+channels(SUR1andKir6.2 We report the long-term follow-up
vent brain damage (1,2). The inappro- subunits) in the b-cells, which play a study of glucose and insulin metabo-
priatesecretionofinsulinbytheb-cells critical role in the regulation of insulin lism in 105 children who underwent sur-
has heterogeneous genetic origins. In secretion(3). geryforeitherafocaloradiffuseformof
congenital hyperinsulinism. The study
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 clearly confirms the contrast between the
From1PediatricEndocrinologyandDiabetes,HôpitalNecker–EnfantsMalades,UniversitéParisDescartes evolutionofthetwoformsbutalsoshows
SorbonnePariscité,Paris,France;2InheritedMetabolicDiseases,HôpitalNecker–EnfantsMalades,Uni- the great variability in the incidence of
versitéParisDescartesSorbonnePariscité,Paris,France;the3DepartmentofPhysiology,HôpitalNecker– hypoglycemia and hyperglycemia within
EnfantsMalades,UniversitéParisDescartesSorbonnePariscité,Paris,France;4INSERMU695,Hôpital the diffuse form and contributes to char-
Bichat,UniversitéParisDiderot,Paris,France;the5DepartmentofPathology,HôpitalNecker–Enfants
Malades,UniversitéParisDescartesSorbonnePariscité,Paris,France;the6DepartmentofPathology,Clinique acterizing insulin secretion and sensitivity
Saint-Luc,Louvain,Belgium;7PediatricRadiology,HôpitalNecker–EnfantsMalades,UniversitéParis and to determining the investigations
Descartes,Paris,France;and8PediatricSurgery,HôpitalNecker–EnfantsMalades,UniversitéParisDes- neededforanoptimalfollow-up.
cartesPariscitéSorbonne,Paris,France.
Correspondingauthor:Jean-JacquesRobert,[email protected].
Received8July2011andaccepted25October2011. RESEARCH DESIGN AND
DOI:10.2337/dc11-1296 METHODSdFrom 1984 to 2006, 105
©2012bytheAmericanDiabetesAssociation.Readersmayusethisarticleaslongastheworkisproperly
cited,theuseiseducationalandnotforprofit,andtheworkisnotaltered.Seehttp://creativecommons.org/ patientsreceivedoperationsforcongenital
licenses/by-nc-nd/3.0/fordetails. hyperinsulinismatHôpitalNecker–Enfants
198 DIABETESCARE,VOLUME35,FEBRUARY2012 care.diabetesjournals.org
BeltrandandAssociates
Table1dCharacteristics of105 childrenwhounderwent near-totalorpartialelective A1C 2.2) (National Glycohemoglobin
pancreatectomyforcongenital hyperinsulinism Standardization Program: normal values
4.2–5.6%).
Insulin secretion indices were com-
Neonates Infants
putedastheratiosofareaunderthecurve
Diffuse Focal Diffuse Focal (AUC) to AUC and of
insulin glucose
Patients 52 35 6 12 Dinsulin30–0 min to glucose30 min during
OGTTandasthesumofinsulinlevelsat
Boys/girls 22/30 10/15 2/4 0/12
Term(weeks) 37.262.5 39.461.2 37.560.4 39.561.4 19and39duringIVGTT(20).Insulinsen-
Birthweight(kg) 3.960.8 3.760.7 3.860.8 3.560.4 sitivitywasassessedbythecompositein-
Ageatsurgery(years) 0.560.7 0.360.5 1.261.1 0.760.5 sulin sensitivity index (21). Homeostasis
model assessment (HOMA) indices of
Secondoperation 10 1 0 1
Delaysecondoperation(years) 0.360.3 1.9 d 0.5 b-cell function and insulin sensitivity
werecomputedfrombaselinefastinglev-
Geneticstudy* 32 20 1 6
ABCC8mutation 27 20 1 5 els of glucose and insulin and expressed
KCNJ11mutation 2 0 0 1 as percentage of average values found in
youngfitsubjects(22).
Dataareeithermean6SDforthequantitativedataorthen(ofoperation,patient,ormutation).*Genetic
studycouldnotbeperformedin20neonateswithdiffusecongenitalhyperinsulinismorin15withfocal
Statistical analysis
congenitalhyperinsulinism.
Dataaregivenasmeans6SDunlessother-
wise indicated. The evolution ofhypogly-
Maladesandwerefollowedoverthelong thefocallesion.Whensampleswereavail- cemia and hyperglycemia or initiation of
term (Table 1). The first symptoms oc- able, mutations of the ABCC8, KCNJ11, insulin treatment was estimated using
curredin87neonates(,1week),andaf- andtheglucokinasegenesweresearched Kaplan–Meieranalysis.Giventhesmallvar-
ter1month(to1year)ofagein18cases. for on blood leukocytes of the patients iationsintheageofsurgery,itwasconsidered
Thepatientspresentedwithsevere(,0.3 and their parents, using PCR and direct moreappropriatetopresenttheseresultsin
mmol/L)pre-andpostprandialhypoglyce- sequencing(Table1). relationtoageratherthantimeaftersurgery.
mias, with no ketones, concomitant with Glucose metabolism and insulin se- Average values of glycemic control,
relatively high plasma insulin levels (.3 cretion were evaluated immediately after glucose tolerance, insulin secretion, and
mU/L)andaglycemicresponsetosubcu- surgeryandthenperiodicallyforamean insulinsensitivitythroughoutthefollow-
taneous glucagon. Syndromic or hyper- durationof6.362.1years(range1–19) upwerecomparedbetweenchildrenwith
ammonemichyperinsulinismsandatypical in the diffuse forms and 2.6 6 4.1 years focal or diffuse forms of congenital hy-
histological forms of hyperinsulinism (0–17) in the focal forms. The following perinsulinism.Totakeintoaccountthata
were not included in the study. In most tests were used: HbA , plasma glucose, different number of tests was performed
1c
patients, the distinction between diffuse insulin and C-peptide concentrations indifferentindividualsandinordertouse
and focal hyperinsulinism was based on over 24 h (before and after each meal alltheavailabledatatomaximizeresults,
transhepaticportalcatheterization(11,15) and at 0 and 4 h; 168 24-h cycles in 49 we compared data between groups as
or onresults ofapositronemissiontomo- childrenwithdiffuseand67cyclesin39 standardleastsquarescomputedinmixed
graphyscanwith[18F]fluoro-L-DOPA(13). childrenwithfocalcongenitalhyperinsu- regression models with random effects,
Surgery was indicated in all patients linism), oral glucose tolerance test including as covariables sex, the duration
withafocalformandinthosewithadiffused (OGTT)(77 tests in23children withdif- of follow-up when the parameter was
form of congenital hyperinsulinism that fuseand50in27childrenwithfocalcon- measured, and the subject identification
resistedmedicaltreatmentswhereresection genital hyperinsulinism), and intravenous number. Statistics were performed with
wasalwaysidentical.Forthechildrenwho glucosetolerancetest(IVGTT)(41testsin JMP software (SAS Institute, Inc., Cary,
requiredasecondsurgery(persistenthypo- 15childrenwithdiffuseand21in11chil- NC).
glycemia),theevaluationoffollow-upstar- dren with focal congenital hyperinsulin-
tedfromthesecondintervention. ism). Hypoglycemia was defined as a RESULTS
During surgery, biopsies were taken value ,3 mmol/L during the 24-h cycle
in various areas of the pancreas and an- (1). Hyperglycemia was defined as an ab- Focal hyperinsulinism
alyzed extemporaneously to confirm the normalOGTT(WorldHealthOrganization Among47childrenwhounderwentoper-
form, localize the focal lesion, and de- criteria),aplasmaglucoselevel.11mmol/L ationsforfocalcongenitalhyperinsulinism,
terminetheextentofthepancreatectomy duringthe24-hcycle,orHbA .6%.In- none received any antidiabetes treatment.
1c
(8,18,19). For focal lesions, surgery was sulin treatment was generally initiated Four children presented persisting but
limitedtotheheadofthepancreasin13 basedontwomaincriteria:permanenthy- asymptomatic hypoglycemias (three neo-
patients, thebodyin6,andthetailin5; perglycemia (pre- and postprandial) and natalandoneinfantform)duringthe24-h
the head and body of the pancreas in 4 elevated HbA (.7%). Plasma glucose cycles immediately after surgery. In only
1c
patients, the head and tail in 4, and the wasmeasuredbyaglucoseoxidasetech- one case, asymptomatic hypoglycemias
bodyandtail in4;and two-thirdsof the nique and plasma insulin by radioim- werealso foundattheageof4 years, but
pancreasin3(notspecifiedin3cases). munoassay (Bi-Insulin IRMA Ciis-Bio this patient showed no abnormalities at 3
If a sample was taken, pancreatic International; Gif-sur-Yvette, France). or5yearsofage.
DNAwasextractedtosearchforthespe- HbA wasdeterminedbyhigh-pressure As for hyperglycemia, minor and
1c
cific loss of allele in the 11p15 region in liquidchromatography(TosohBioscience transitoryanomalieswerefound.Achild
care.diabetesjournals.org DIABETESCARE,VOLUME35,FEBRUARY2012 199
Long-termoutcomeofcongenitalhyperinsulinism
had a plasma glucose of 8.8 mmol/L at the children after surgery, could persist HbA intheevaluationofthemetabolic
1c
120minoftheOGTTatage4years,but until5yearsofage(Fig.1). statusindiffusehyperinsulinism,whenat
theOGTTwasnormalatage6years.Four One-half of the patients (53%) with least two tests were performed on the
children showed plasma glucose values diffuse congenital hyperinsulinism pre- same day: 72 pairs with OGTT and
between 11.5 and 14.4 mmol/L at 30 or sented with hyperglycemia in the days HbA , 95 with the 24-h cycle and
1c
60minofOGTTspostoperativelyandat aftersurgery.Theincidenceofhypergly- HbA ,and56withOGTTandthe24-h
1c
2,4,and10yearsofage,buttheyshowed cemiaincreasedregularlywithage,reach- cycle. When the OGTT was normal, the
normal 24-h glucose cycles and no ab- ing 100% at the age of 13 years (Fig. 1). othertestswerealsonormalinmostcases.
normalitiesatallotherages.Inthesefive The incidence of insulin therapy in- When the OGTT showed criteria of dia-
patients,HbA remainedinnormalrange creased from 19% postoperatively to betes,hyperglycemiawasalsofounddur-
1c
forthewholedurationofthefollow-up. 42%at8yearsandthenmorerapidlyto ingthe24-hcyclein81%ofthepatients
reach91%at14yearsofage.However,it and an HbA .5.6% in 58% of the pa-
1c
Diffuse hyperinsulinism doesnotdepictthegreatvariabilityofthe tients. With criteria of impaired glucose
Of58childrenwhounderwentnear-total postoperative progressiontowarddefini- tolerance at the OGTT, hyperglycemia
pancreatectomyfordiffusecongenitalhy- tiveneedforinsulininthe33treatedpa- wasfoundin18%andanHbA .5.6%
1c
perinsulinism, 59% were still suffering tients. Insulin therapy was started in 36% of the patients. When the 24-h
from hypoglycemias immediately after immediatelyaftersurgeryanddefinitively cycle showedhyperglycemia, HbA was
1c
surgery (after first surgery, 48 children; (follow-up 5.4 6 3.8 years [range 0.5– .5.6%in56%ofthepatients.Relativeto
aftersecondsurgery,10children).How- 11]) in eight children. It was initiated that of the OGTT, the sensitivity of the
ever, hypoglycemias did not have the afteradelay,between5monthsaftersur- 24-hglucosecyclewasgreaterthanthatof
severityofthosebeforesurgery and they geryand14.8yearsofage(age8.464.2 HbA (81 vs. 58%,respectively) for dia-
1c
occurred principally in the preprandial years), and definitively in 13 patients betescriteria,butitwasverylowwithboth
periods,especiallyattheendofthenight. (Fig.2).Forthelast12patients,theevolu- tests (18 and 36%) for impaired glucose
They could be controlled by dietetic ad- tion was more erratic. Five patients re- tolerance. The specificity varied from
justments(rawcornstarchatbedtimein quired insulin immediately after surgery 69%(HbA )to80%(24-hcycle)fordi-
1c
16 children) and medical treatments butforashortperiodoftime(1–16days); abetesandfrom 79to75% forimpaired
(in15patients:diazoxidein10,octreotide four of these five children remained hy- glucosetolerance.
in6,oralsteroidsin11,andnifedipinein perglycemic but untreated (follow-up
2 and diazoxide-octreotide, diazoxide- 5.5 6 4.1 years [1–11]), while the last CONCLUSIONSdThe aim of this
steroids,octreotide-steroids,ordiazoxide- onedidnotshowanyabnormalityinglu- workwastoextendthedescriptionofthe
nifedipine in 2–3 patients each). The cose tolerance up to 6 years of age. Four metabolic evolution of patients who were
incidence of hypoglycemia decreased patients received insulin immediately pancreatectomizedforcongenitalhyper-
slowly, in some cases persisting until after surgery for a longer period of time, insulinism. We previously reported the
5yearsofage(Fig.1). 2–21months(Fig.2),butithadtobein- general evolution of 52 neonatal forms
Averypeculiarandunusualsituation terruptedforrecurrenthypoglycemia;the ofcongenitalhyperinsulinismafternear-
was observed in 19 patients who pre- first three remained hyperglycemic but totalorpartialelectivepancreatectomy(15).
sented fasting persisting hypoglycemia untreated until 1–3 years of age, while The greater number of patients followed
(value,3mmol/Lonthe24-hcycle)as- the fourth again received insulin when 9 for a longer period of time after surgical
sociatedwithpostprandialhyperglycemia yearsold.Forthelastthreepatients,insu- treatmentbasedonwell-identifiedlesions
(.11 mmol/L on the 24-h cycle or im- lin was started several months after sur- makestheseupdatedresultsofinterest.
paired glucose tolerance or diabetes at gery, but it had to be stopped after 8–11 Thepresentresultsillustratethedra-
the OGTT). This association, in 35% of months for recurrent hypoglycemia; one matic contrast in metabolic outcome
childremaineduntreateduntil7.9yearsof between the two forms of congenital
age,whiletwowereagaintreatedwithin- hyperinsulinism. The follow-up of 47
sulinbefore6yearsofage. focal forms of hyperinsulinism strongly
confirmsthatthechildrenwhounderwent
Insulin secretion and sensitivity partial elective pancreatectomy were
In the fasting state, plasma insulin was cured of hypoglycemia. Our previous
significantlyhigherinthediffusethanin results and those of other teams led to a
the focal forms, and this was associated 2000 European consensus on the man-
withslightlylowerplasmaglucosevalues. agement of persistent congenital hyper-
Bycontrast,allindicesofglucose-stimulated insulinism, which recommended a
insulinsecretionweresignificantlylower, conservativesurgicalattitudeinthefocal
whichwasassociatedwithpostprandial forms (1). Thedevelopmentoftheposi-
(orpostglucose)hyperglycemiainthedif- tron emission tomography scan with
Figure1dCumulativeincidenceofhypoglyce- fuseforms.Indicesofinsulinsensitivitydid [18F]fluoro-L-DOPA (23), a less invasive
notdifferbetweenthetwoforms(Table2). alternativetothetranshepaticpancreatic
mia (-), hyperglycemia (○), association hy-
pohyperglycemia(◇),andinsulintherapy(C) catheterization,shouldhelptogeneralize
Metabolic follow-up after near-total these recommendations and prevent pa-
in 58 patients pancreatectomized for diffuse
pancreatectomy tients from undergoing an unnecessary
congenital hyperinsulinism. Patients with both
hypo- and hyperglycemia are a subset of both Comparisonsweremadebetweenresults extended pancreatectomy leading to a
hypo-andhyperglycemiagroups.yr,years. oftheOGTT,the24-hglucosecycle,and progression toward insulin-dependent
200 DIABETESCARE,VOLUME35,FEBRUARY2012 care.diabetesjournals.org
BeltrandandAssociates
abnormal function of the pancreatic
residual tissue and, indeed, renders even
more complex the postoperative meta-
bolicevaluationofthepatients.Pancreatic
endocrinefunctionofthesepatients,using
metabolictests,haspreviouslybeeneval-
uated in one study, showing the altered
butvariableinsulinresponsetoanIVGTT
and its poor correlation with later evolu-
tion(24).Resultsinourpatientsillustrate
thatinsomecases,thedramaticreduction
ofb-cellmasscannotcompensateforthe
excessive insulinsecretionoftheremain-
ing cells. Remarkably, dysfunction of the
residual pancreatic tissue associates in
most cases an excessive fasting secretion
asasequeloftheb-cellsdysfunctionand
anexpectedlowerinsulinsecretorycapac-
ityinresponsetoglucoseasasequelofthe
extended resection. This clearly explains
theverynovelassociationoffastinghypo-
glycemiaandpostprandialhyperglycemia
observedinanumberofthesepatientsin
Figure 2dIllustration of changes over time of insulin requirements in 20 of the 33 patients theearlyyearsaftersurgery.
pancreatectomizedfordiffusecongenitalhyperinsulinism.Fourupperbars:Patientswithinsulin Mechanisms of progression toward
immediatelyaftersurgerybuttransiently.Thethreefollowingbars:Patientswithinsulinafter diabetescannotbedefinitelystatedfrom
adelaybuttransiently.Thirteenlowerbars:Patientswithinsulinafteradelayanddefinitively. this study. Some authors havesuggested
Theotherpatientsarenotpresented:eightwithinsulinimmediatelyaftersurgeryanddefinitively, that mutation of the ATP-dependent K+
withnoinsulintreatment(includingfivewhoreceivedinsulinimmediatelyaftersurgeryfor1–16 channels could increase b-cell apoptosis
days).Darkbars,timeofinsulintherapy;graybars,timeoffollow-up,withhyperglycemiabut
(25). However, the few data available
withoutinsulin.yr,years.
report a lower incidence of diabetes in
adulthood in diffuse congenital hyperin-
diabetes. However, one must keep in is astonishing, such as the case of one sulinism medically treated than that re-
mindthattheexistenceofraremultifocal 19-year-oldpatient,whowasfreeofinsulin ported here. If involution of the b-cells
andcomplexfocalforms(23)ofhyperin- withnormalHbA andOGTTaftera95% in the remaining tissue of the patients
1c
sulinismjustifiesthesystematicandregu- pancreatectomyinthefirstmonthsoflife. could contribute to the progressive de-
lar evaluation of the surgery-treated Indeed,thisstudyclearlyshowsthatpost- clineofinsulinsecretionandthedevelop-
patients until complete disappearance of operative evolution is unpredictable and ment of diabetes, the removal of 95% of
hypoglycemia.Eveninthepresentseries, sometimes complex, with a recurrence of thepancreasisthemostprobablecauseof
twopatientsrequiredasecondsurgerybe- bothhypo-andhyperglycemia.Theageat developingdiabetes.
cause all the hypersecreting hyperplasia institution of insulin also varied greatly. These results also have implications
had not been resected. In contrast, al- These characteristics are noteworthy, as for the various tests used to follow the
though the rare and mild hyperglycemia theymayseem unexpectedinviewofthe patients (1). The 24-h glucose cycle is
observed during follow-up in some pa- extentofthepancreaticresection,butalso necessary to screen for hypoglycemia
tients did not show any predictive value unusualcomparedwithwhatisknownof and must thus be used in all focal and
oflaterdeteriorationofthemetabolicsta- thedevelopmentofanyothertypeofdia- diffuse forms as long as there is no cer-
tus,theablationofalimitedbutsignificant betes.However,whateverthevariabilityof taintythatthereisnomoreriskofhypo-
partofthepancreascouldaddtolaterag- this evolution, the final result is insulin glycemia.Thisisgenerallythecaseduring
gravatingfactors,suchaspregnancy,obe- therapythatwasstartedbeforepubertyin the first months in the focal formsdthe
sity, or aging, and confer on these morethanone-halfofthecases.Thesere- timetomakesurethatthereisnotarare
subjects a risk of developing long-term sultsthusconfirm previousreports inthe complexormultifocalform.Thiscanlast
anomalies inglucose tolerance. A regular literature,with33–40%ofrecurrenthypo- up to 5 years in the diffuse forms at an
and long-term follow-up, with periodic glycemiarisk,andtheriskofbeingtreated annual or biannual rate. For hyperglyce-
evaluation of glucose tolerance, is thus with insulin was estimated to be between mia,theOGTTremainsthemostsensitive
stronglyrecommendedforthesepatients. 14 and 69% in studies enrolling enough testtodetectearlyimpairmentofglucose
Forthe58operateddiffuseforms,the patientstoappreciatetheincidenceofthis toleranceand should bedone everyyear
cumulative incidence of hyperglycemia complication (4,5,16). However, they starting the year after surgery. During
was 100% at 13 years of age and the allowanicedetaileddescriptionofthisevo- OGTT, plasma insulin and glucose mea-
incidence of insulin therapy reached lution based on a clear definition of the surementsat30and60minoftheOGTT
91% a year later. As opposed to this in- histologicalformofthedisease. arenotinformativeandcanbeomitted,as
evitableevolution,theveryslowprogres- Suchunpredictableevolutiontoward theyhaveshownlittleimpactforthede-
sion toward insulin-requiring diabetes diabetes seems to reflect the persistent tection of impaired glucose tolerance.
care.diabetesjournals.org DIABETESCARE,VOLUME35,FEBRUARY2012 201
Long-termoutcomeofcongenitalhyperinsulinism
Table2dInsulinsecretion andsensitivityinchildrenwhounderwentnear-totalorpartial of the neonate? J Pediatr Surg 1997;32:
electivepancreatectomy forcongenital hyperinsulinism 342–346
6. ThomasCGJr,CuencaRE,AzizkhanRG,
Underwood LE, Carney CN. Changing
Diffuse Focal P conceptsofisletcelldysplasiainneonatal
and infantile hyperinsulinism. World J
HbA /subjects 156/40 61/25
1c Surg1988;12:598–609
HbA (%) 6.060.2 5.060.2 ,0.001
1c 7. Thomas CG Jr, Underwood LE, Carney
OGTT/subjects 76/25 48/24
CN,DolcourtJL,Whitt JJ.Neonataland
Fastinginsulinsecretion infantile hypoglycemia due to insulin
Plasmaglucose(mmol/L) 4.260.2 4.560.2 0.06 excess:newaspectsofdiagnosisandsur-
Plasmainsulin(pmol/L) 34.763.2 28.463.7 0.04 gical management. Ann Surg 1977;185:
HOMAofb-cellfunction(%) 190632 60635 0.01 505–517
Glucose-stimulatedinsulinsecretion 8. SempouxC,GuiotY,DahanK,etal.The
Glucose120min(mmol/L) 11.160.7 5.560.8 ,0.0001 focal form of persistent hyperinsulinemic
hypoglycemia of infancy: morphological
AUC -to-AUC ratio
insulin glucose
(pmolinsulin/mmolglucose) 8.961.4 16.861.7 ,0.001 andmolecularstudiesshowstructuraland
DInsulin30–0min-to-glucose30minratio fDuinacbteitoensa2l00d3if;f5e2re:7n8ce4s–7w94ith insulinoma.
(pmolinsulin/mmolglucose) 5.561.8 14.562.2 ,0.001
9. Jack MM, Walker RM, Thomsett MJ,
Insulinsensitivity Cotterill AM,Bell JR.Histologicfindings
HOMAofinsulinsensitivity(%) 203628 292631 NS in persistent hyperinsulinemic hypogly-
IVGTT/subjects 39/15 23/11 cemia of infancy: Australian experience.
Glucose-stimulatedinsulinsecretion: PediatrDevPathol2000;3:532–547
IVGTT,19+39(pmol/L) 203628 292631 0.01 10. FékétéCN,deLonlayP,JaubertF,Rahier
Dataaren/normeans6SEM(averagevaluesoftheparametersthroughoutthefollow-upcomparedbetween J,BrunelleF,SaudubrayJM.Thesurgical
groupsasstandardleastsquarescomputedinmixedregressionmodelswithrandomeffects,includingas management of congenital hyperinsuline-
covariatessex,thedurationoffollow-upwhentheparameterwasmeasured,andsubjectidentificationno.). michypoglycemiaininfancy.JPediatrSurg
Statisticsrefertocomparisonsperformedwithlog-transformeddata. 2004;39:267–269
11. Brunelle F, Negre V, Barth MO, et al.
Pancreatic venous samplings in infants
IVGTT is not recommended during the and,assuch,hadfullaccesstoallthedatainthe and children with primary hyperinsu-
follow-up,asitdoesnotprovideanyper- studyandtakesresponsibilityfortheintegrityof linism. Pediatr Radiol 1989;19:100–
tinent supplemental information. HbA thedataandtheaccuracyofthedataanalysis. 103
1c
is of less interest for screening but be- The authors thank Dr. Bellane-Chantelot 12. Doppman JL, Miller DL, Chang R,
(Unitéfonctionnelledegénétiquedesmaladies Shawker TH, Gorden P, Norton JA. In-
comesimportantwhenthepatientsreach
métaboliquesetdesneutropéniescongénitale, sulinomas: localization with selective in-
the state of diabetes for the decision to
groupehospitalierPitié-Salpétrière,Paris,France), traarterialinjectionofcalcium.Radiology
startinsulintherapy. whoperformedthegeneticanalysis.Theauthors 1991;178:237–241
In conclusion, hypoglycemia due to
areverygratefultoAlanDelamater(Department 13. de Lonlay P, Simon-Carre A, Ribeiro MJ,
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