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ORIGINAL

ARTICLES

Enhoncedodrenomedullory response
ond increosedsusceptibility to
neuroglycopenio : Mechonisms
underlyingthe odverseeffects of sugor
i n g e s t i o ni n h e o l t h yc h i l d r e n
TimothyW. Jones,vo, Wolterp. Borg,vo. SusonD. Boulwore.
uo.
GregoryMcCorthy,pno.RobertS.Sherwin,vo, ond
WilliomV. Tomborlone,MD
Fromthe Deportmentsof Pediotrics,
InlernolMedicine,ond Neurosurgery
ond the Generol
centers,yole university
clinicolReseorch schoolof Medicine,New Hoven,connecticut

oblecllve: Eoling simple sugors hos been suggesled os hoving odverse behov-
lorol ond c.ognlllve ellecls in children, buf o physiologic me-chonism hos not
been esloblished. rhis srudy wos performed to oddresJ thls lssue.
Deslgn: Metobollc, hormonol, ond symptomofic responEes lo o slonctqrd orol
glucose lood (1.75 gm/kg; moxlmum, r20 gm) were compqred In 25 heolthy
children ond 23 young odults, ond lhe hypoglycemlc clomp, logether wilh
meosuremenls of p300 oudlfory evoked polenliols, wqs used fo ossesswhether
chlldren ore more vulneroble lhon odulls to neuroglycopenlo.
SettlngzChlldren's Cllnicol ReseorchCenler, Yole UniversltySchool ot Medtcine.
Pesults|Bosellne ond olol glucose-siamuloted plosmo glucose ond insulin lev_
els were simllor in bofh groups, including fhe nodir glucose level 3 to s hours of-
ler orql odmlnlslrollon ol glucose (3.4 -r 0.1 mmol/t (6,1r l.g mg/dl) in children
ond 3.5 r- 0.t mmol/t (63 -* l.E mg/dtt in odulfs). rhe lole glucose decleose
sllmuloted o lise ln plosmo epln6phrlne levets thol wos fwololJ hlgher In chlldren
lhon fn odulls (2260 t 269 vs t03t + 147 pmo'/L l4o7 -r 52 vs tg6 + 26 pg/mll, p
<0.0{) ond o slgniflconl increose in hypoglycemic symplom scores in chlldren
(p <0.0f )' bul nol ln qdulls. During conlrol experimenls, In which stx ot the heolthy
chlldren Ingesfed q sugor-tree drlnk, lhere were no slgnlficont chonges In
ploimo glucose levels, hormone concenlrollon!, or hypoglycemlc sympfom
scores. Durlng lhe hypoglycemic clomp, p300 polenilols dld not chonge In ony
ot eighl odull sublecls unlll lhe plosmo glucose concenlrollon wos lowered to
3.0 mmol/L (54 mg/dl), whereos similor chonges ln p300 polenilqls were ob-
served ln slx of seven chlldren of glucose levels 3.6 lo 4.2 mmol/l (65 fo 75
m9/dl).
concluslon: Enhonced odrenomedullory responses lo modest reducllons in
plosmo glucose concenlrolion ond Increosed suscepilblllty fo neuroglycope-
nlo moy be impoilonl conltlbuting locfors lo qdverse behqvlorol ond Jognlfive
eftecls ofler sugor ingesllon in heolthy children. (J peoren ig95;126:ll1-71

Supportedby grants RR06022, RR00125, DK20495, and Reprint requests:William V. Tamborlane,MD, Departmentof
HD3067l from the NationalInstitutesof Healthand by a grant Pediatrics,Yale University Schoolof Medicine, 333 Cedar St..
fromthe JuvenileDiabetesFoundationInternational. New Haven,CT 06510-8064.
Copyrighto 1995by Mosby-Year Book, Inc.
Submitted
for publicationSept.6, 1994;acceptedOcr,.26,1994. 0022-3476lesl$3.00
t + 0 9/2o/6rs76
I
I
I
I
t7l
172 Joneset al. The Journal of Pediatrics
Februarv 1995

The question of whether refined sugar adverselyaffects the healthy, taking no medications, and have no history of di-
behavior or cognitive functions of healthy children is a con- abetesor carbohydrate intolerance. The children included
tinuing source of controversy. Whereas parents and clini- eight boys and 17 girls between 8 and 16 years of age; the
cians have frequently reported that even healthy children adults included 9 men and 14 women between 20 and 30
are prone to the development of behavioral changes and years of age. Subjects with attentional, behavioral, or psy-
cognitive defectsafter eating simple sugars,the outcomesof chiatric problems or with a history of unusual sensitivity to
research studies have been complex and discrepant.l-aIn sugar were excluded from the study. All subjectswere con-
addition, possible physiologic mechanisms for enhanced suming weight-maintaining diets containing at least 115
sensitivity to dietary sugar during childhood have not been gm/mz body surface area of carbohydratesper day before
clear. The presumed negative reactionsto sugar have been the study. Ofthe 25 children, eight were prepubertal (Tan-
attributed to an early rise or late fall in the plasma glucose ner stage I), and the other l7 had Tanner stage II to IV de-
concentration, and to an immunologic responseto sucrose.5 velopment.Bodymassindex(mean + SD)averaged18.2 +
Unfortunately, given the lack of consistentobjectivedata to 2.2kglm2 in the children and22.6 -r 2.8 in the adults. The
substantiatetheseassumptions,all thesehypothesesremain study was approvedby the Yale University School of Med-
open to questron. icine Human Investigation Committee, and informed writ-
The results of our previous studies of counterregulatory ten consentwas obtained from all subjectsand their parents
respons€sto hypoglycemia in children6'7 prompted us to (for the children).
propose a new hypothesis to explain the mechanisms Procedures.All subjectswere admitted to the Yale Gen-
underlying adverseeffectsof sugar ingestionin children. We eral Clinical ResearchCenter, where a history was obtained
hypothesizedthat, although the changesin plasma glucose and a physical examination performed. The studies were
levels after sucrose ingestion do not differ between adults started between8 and 8:30 epr, after the subjectshad been
and children, the children would show enhanced adreno- fasting for l0 to 12 hours overnight. With all procedures,
medullary and symptomatic responsesto these changesin an intravenouscatheter was inserted in a vein of a hand or
comparison with those of adults. Several lines of evidence distal portion of a forearm for blood sampling, and that
"arterial-
hand was kept in a heated box (60o to 65" C) to
ize" the blood.
See related article, p. l7E.
Oral glucose loading. All subjects took part in the oral
glucose loading study. They were allowed to rest for at least
support this hypothesis.Although sugar ingestion does not 30 minutes after insertion of the blood sampling catheter
normally causeseverereductionsin plasma glucoselevelsin
before baselinemeasurementswere obtained. Glucosewas
the late postprandialperiod in children,s'eour previous
ingestedin a dosageof 1.75 gm/kg body weight to a max-
study showed that plasma epinephrineresponsesto identi- imum of 120 gm (actual amount, I l0 + 5 gm in adults and
cal, modest insulin-induced reductions in plasma glucose 86 + 6 gm in children [mean + SD]) with a decaffeinated
are twofold greater in healthy children than in healthy cola preparation (General Medical Corp., Richmond, Va.).
adults.6 In addition, the plasma glucoselevel that triggers Blood sampleswere obtained every l0 minutes from -30 to
epinephrinereleaseand symptoms is substantiallyhigher in 300 minutes for measurementof the plasma glucose con-
children than in adults,T reaching values (plasma glucose centration, and every 30 minutes for measurement of
levels4.4 to 3.4 mmol/L [80 to 6l rng/dl]) that are com- plasma levels of insulin, catecholamines,and other coun-
monly observed 3 to 5 hours after oral glucose ingestion. terregulatory hormones (growth hormone, cortisol, and
To test our hypothesis,we compared the metabolic, hor- glucagon).
monal, and symptomatic responsesof healthy children and Each of the subjectsrated a list of symptoms before and
healthy young adults with a standardized, large glucose every 60 minutes after glucose ingestion, as previously de-
load. In addition, the hypoglycemic clamp technique was scribed. Symptoms (recorded on a lap-top computer) were
combined with serial measurementsof cortical auditory rated on a scale of I (not at all) to 7 (extreme). The eight
evokedpotentials to assesswhether young subjectsare more hypoglycemic symptoms included pounding heart, feeling
susceptibleto the adverseeffectsof reduced glucoseavail- shaky, feeling weak, having difficulty concentrating, head-
ability on cognitive function. aches,feeling anxious, slowed thinking, and feeling sweaty.
The sum of these symptoms at each observation point con-
METHODS stituted the total hypoglycemic symptom score at that time.
Subjects. Forty-eight nonobesesubjects(25 children' 23 In addition, four filler items (earache, pain in joints, watery
adults) were studied. To be eligible, the subjectshad to be eyes,and ringing in ears) were included to account for non-
The Journal of pediatrics
Volume126,Number 2 Joneset al. 173

specificeffects not referable to glucoseand antiinsulin hor-


electrode.The proportion ofsoft clicks varied between l0Zo
mones.
aad 20Vaof 200 clicks, and subjectsreported their count of
Control experiments were also performed in three boys
soft clicks at the end of each run. Two replicationswere ob-
and three girls, aged 10 + 3 years (mean r- SD), who had tained at each baseline(before insulin infusion) and at each
participated in the oral glucoseloading studies.These con_ plasma glucose plateau.
trol experiments were performed as describedabove; how_ f)eterminations.Plasma glucose was measuredin dupli_
ever, the oral glucoseload was replacedby an equal volume cate at the bedsidewith a glucose analyzer (Beckman In_
of sugar-free decaffeinatedcola drink (Coca-Cola Co., At_ struments Inc., Fullerton, Calif.). Epinephrine and norepi_
lanta. Ga.). nephrine were measured with a radioenzymatic assay
Hypoglycemic clamping. Eight of the children, aged (Amersham Corp., Arlington Heights, Ill.), glucagon (ICN
ll + 2 years (mean + SD), and eight of the adults,aged Biomedicals,Inc., Costa Mesa, Calif.), cortisol (Diagnostic
24 -t 2 years, who had taken part in oral glucose loading Products Corp., Los Angeles, Calif.), and growth hormone
experiments participated in the clamp protocol. However, (Kallestad Diagnostic Inc., Chaska, Minn.) were deter_
the cortical evoked potentials of one of children could not mined by radioimmunoassay.The intraassaycoefficientsof
be analyzed becauseof technical problems and was not rn- variation for these assayswere as follows: for epinephrine,
cluded in the analysis of electrophysiologicdata. 20.2Voat 175 pmol/L (31.5 pg/ml) and 6.j%oat l168
The methods used for the hypoglycemicclamp have been pmol/L (210 pg/ml); for growth hormone, 6.2Voat 3.5
describedin detail elsewhere.l0For this procedure,a second pg/L (3.5 nglml); for glucagon,9Vaat t22 ng/L (t22 pgl
cathcter was inserted in an antecubital vein in the arm op- ml); and for cortisol, l2go.Plasma insulin was measuredby
posite to the blood-sampling hand for administration of ex- double-antibody radioimmunoassay (Binax Inc., South
ogenous glucose and insulin. Portland, Maine).
After a 30-minute rest period, three blood sampleswere Statistical methods and analyses. Glucose and hormone
obtained during a 40-minute interval for measurementof responsesto orally administered glucoseand during clamp
baselinc glucose and hormone levels.A primed continuous studies were compared betweon groups by analysis of var!
infusion of rapid-acting human insulin (Novolin; Novo ance with repeated measures design. Other comparisons
Nordisk, Princeton, N.J.) was then begun at a continuous were made by analysisof variance,unpaired Student , test,
rate of 480 pmol . m-2 . min-I. and chi-square analysis where appropriate. The p values
After the insulin infusion was begun, the desired plasma (0.05 are reported as significant.
glucose level was achieved by varying the rate of 20Vogltt- Group differencesin symptom scores after glucose in-
cose infusion on the basis of measurementsof plasma glu- gestion were examined with time and at the plasma glu-
cose obtained at S-minute intervals. Blood samples for cosenadir. For the latter comparison,the symptom assess-
measurementof insulin and epinephrinewere taken at 20- ment that occurred at or immediately after the nadir
minute intervals throughout the study. In all subjects, plasma glucoselevel in each subject was used. During the
plasma glucosewas initially maintained at fasting euglyce- hypoglycemicclamp procedure,the plasma glucosethresh-
mic levelsfor 60 minutes and then reducedin hourly -Q.J6 old for epinephrine releasein each individual subject was
mmol/L (10 mg/dl) steps to a nadir of 3.0 mmol/L (54 defined as the glucoselevel at which a sustainedelevation
mg/dl). The subjectswere masked to plasma glucoselevels of >410 pmol/L Qa pg/ml\ above basal values was ob-
during the study. served, as previously described.TThe glycemic threshold
Electrophysiologic recordings were obtained during the for changesin P300 potentials in individual subjectsduring
last l0 to 15 minutes of each glycemicplateau.Scalp elec- the clamp procedure was defined as the plateau plasma
trodes were placed at the C, and P, positions,with a refer- glucoselevel at which a 30Voor greater reduction in p300
ence electrode placed on one ear and the ground electrode amplitude was observed.Demographic data are presented
placed on the opposite ear. A bipolar pair of electrodeswas as mean + SD, whereas other data are presented as
placed above and below the right eye to monitor for ocular mean + sEM.
artifacts. The P300 evokedpotentialswere obtained with an
auditory categorization ("oddball") task in which subjects RESULTS
were required to count silently the number of soft clicks de- Glucose ingestion. Basal plasma glucose levels and plas-
livered in a train consistingof a random mix of frequent loud ma insulin levels (55 + 5 pmol/L [8.8 t 0.8 pUlm|
and infrequent soft clicks. The loud clicks were presentedto in children;60 {- 5 pmol/L [9.6 + 0.E pUlm[ in adults)
the ear ipsilateral to the reference electrode, and the soft were similar in both groups, and the glucose and insu-
clicks wcre deliveredto the ear contralateral to the reference lin profiles were similar in children and adults after glucose

,,,t,rRU
11 4 Jones et al The Journal of Pediatrics
Februarv 1995

Ioble l. Basal and nadir plasma glucoseand basal and Toble ll. Total hypoglycemic and filler (control)
peak hormone concentrations (mean -r SEM) after symptom scoresat baselineand at the postprandial
glucose load glucose nadir

Chlldren Adults Children Adulfs


P l a s m a / g l u c o s e( m m o l / L ) Glucose Glucose
Basal 4.6 + 0.1 4.8+ 0.1 Boseline nodir Soieline nodll
Peak ?.5 + 0.3 8.1 + 0.4
Nadir 3.4 + 0.1 3.5+ 0.1 Total hypoglycemic scores
P l a s m a e p i n e p h r i n e( p m o l / L ) Mean 12.8 22.O' l0.o l 3.o
Basal 229 + 27 I9l + 27 sE 1.0 3.0 0.5 1.7
Peak 2260 + 289* l03l + 147 Filler (control) scores
Plasma growth hormone (pg/L) Mean 5.0 5.5 5.0 5.2
Basal 1.7+ 0.3 l.l + 0.2 sE 0.5 0.6 0.4 0.5
Peak 1 9 . 5+ 2 . 5 1 8 . 3+ 2 . 8 tp <0.01 versus baseline.

Plasma glucagon (ng/L)


Basal 94+12 1 2 0+ l 8
Peak 2 0 1+ 3 l 180 + 25 0.5), or weak (1.9 + 0.3 to 3.8 + 0.5), or having a
To convert to metric units: multiply glucosevalue by 18. epinephrinevalue pounding heart I ."7+ 0.2 to 2.5 + 0.5) (p (0.05 vs base-
by 0.I8. growth hormone value by 1.0, and glucagon value by L0. line).
tp <0.01 versus adults.
ln contrast to the response to glucose ingestion, no
changesin plasma epinephrine levels were observedafter
ingestion (data not shown). Peak and nadir plasma glu- the sugar-free cola drink. As a result, plasma epinephrine
cose levels observed in the postprandial period in individ- levelswere significantly higher after glucoseingestion ver-
ual subjects determined by frequent sampling (every 10 suscontrol valuesat 240 minutes and 270 minutes (p <0.05)
minutes) were virtually identical in children and adults in these subjects (Fig. l). Total hypoglycemic symptom
(Table I). scoresalso did not change from baseline values (ll + 2)
Baseline plasma epinephrine levels were similar, and during the control study, in contrast to the increasein hy-
mean epinephrine concentrationsrose in both groups in re- poglycemicsymptomsin thesesubjects( I I -r 2 to 25 + 4)
sponseto the late postprandial fall in plasma glucose (Ta- after glucoseingestion.
ble I). However, the rise in the plasma concentration of Hypoglycemic clamp studies. As shown in Fig. 2, the
epinephrinewas significantly greater in the children, reach- plasma glucose concentration was gradually reduced in
ing peak values that were nearly twofold higher in the chil- nearly identical 0.56 mmol/L (10 mg/dl) stepsfrom 4.8 to
dren than in the adults (p <0.01) (Table I). On the oth-er 3.0 mmol/L (86 mg/dl to 54 mgldl) in both children and
hand, peak postprandial plasma growth hormone and glu- adults during the 240-minute hypoglycemic clamp proce-
cagon levelsdid not differ betweenthe groups.Basal plasma dure. As expected,Tthis controlled reduction in the plasma
concentrationsof cortisol and norepinephrinewere similar glucoseconcentrationstimulated an exaggeratedrise in the
in healthy children and adults, and levelsof thesehormones plasma epinephrineconcentration in children, in compari-
did not change significantly in either group after oral glu- son with that in adults (e.9.,4830 -t 334 vs 2365 t 3ll
cose (data not shown). Results of subgroup analysesfailed pmol/L [870 -r 60 vs 426 -r- 56 pg/ml] at 240 minutes; p
to demonstrate a significant effect of gender or pubertal <0.011. The plasma glucoselevel that stimulated a rise in
stageon the rise in epinephrinelevelsafter glucoseingestion epinephrinewas also significantly higher in children than in
by the 25 healthy children. adults (3.6 + 0.1 vs 3.0 -r 0.1 mmol/L [65 + 1.8 vs 54 +
Total hypoglycemic and filler (control) symptom scores 1.8 mg/dll; p <0.01), even though steady-stateplasma in-
were similar in both groups at baseline(Table II), and the sulin levelsachievedduring the insulin infusion were sim-
symptom scores remained unchanged in the adults after ilar in both groups (903 + 48 pmol/L [144.5 t 7.6 pU/
glucoseingestion. In contrast, total hypoglycemicsymptom mll in childrenvs 857 * 42pmollL [137 + 6.7 pUlml] in
scoresrose sharply in the children in associationwith the adults).
late fall in plasma glucoseconcentration (p <0.01 vs base- At baseline(before the start of the insulin infusion) the
line). As in the adults, filler (control) symptom scoresdid P300 amplitude was not significantly greater in the children
not changein the children throughout the study. The change than in the adults (l 1.7 t 1.5 vs 9.7 + 1.4, respcctively),
in hypoglycemic symptom scoresin the children was mainly and no change in either group was observed at thc cnd of
due to significantly increased reporting of feeling shaky the initial euglycemic period (plasma glucose level, 4.E
(from 1.7 + 0.2 to 3.2 + 0.6), sweaty(1.5 + 0.2 to 2.8 + mmol/L [86 mgi dl]) (Fig. 3). Most important, no change
The Journal of Pediatrics
volume 126,Number Z Jones et al. I 75

2 10 0

18 0 0

15 0 0
Plasma
12 0 0
Ep r n e p n n n e
(mmo/L) eoo
500

300

0 60 120 180 240 300


TIME (minutes)
Flg' {. Plasma epinephrinelevels(mean + SEM) in six of the healthy children
before and after ingestionof oral glucose
(a) and a sugar-free cola drink (L). Asterisk indicates
significant difference in values between oral glucoseand control
e x p e r i m e n t sI < 0 . 0 5 ) . T o c o n v e r t t o m e t r i c u n i t s , m u l t i p l y e p i n e p h r i n e
value by 0.1g.

Plasma
Glucose
(mmol/L)

Plasma
Epinephrine
(pmol/L)

o 50 240 3oo
,,i? ,-,",,:::
Fig. 2. Plasma glucoseand epinephrinelevels (mean + SEM) during hypoglycemic
clamp studies in children (tr) and
adults (I). Asrerisk indicates significant difference (p <0.01) versuscorrespondingvalue
in adults. To convert to metric
units, multiply glucosevalue by 18, and e p i n e p h r i n ev a l u e b y 0 . 1 8 .

in P300 potentials was observedin any of the adults until glucoseconcentrationwas lowered to 4.2 mmol/L (75 mg/
the plasma glucose concentration was lowered to the last dl) (p <0.05 vs baseline)and the p300 amplitude remained
step (3.0 mmol/L [5a mg/dl]). In contrast,in the children significantly reduced throughout the remainder of the
the P300 amplitude was significantly reduced when the study. All but one of the children had alterations in cortical

.,*--
I 76 Jones et al
The Journal of Pediatrics
February 1995

- l

-2
A of P3O0
Amplitude -3

@v) -4

-5

-6

-7

8
6A5AL 4.E 4.2 3.0 3.0

cLyCEutCLEVEL (mmal/L)

Fig.3. Deltaof P300amplitudeduringeachglycemicplateauinchildren(O)andadults(I). Asterisksindicatesignif-


icant differences versus euglycemia in the children (rp <0.05). Dagger (l\ indicates significant difference versus eugly-
cemia in adults (p <0.01).

evoked potentials at glycemic levels greater than 3.0 propriate term to describethesephenomena.To excludethe
mmol/L (5a mg/dl) (p <0.002 vs adult values). possibility that the findings reported above might have been
caused by nonspecific effects not connected with the oral
DISCUSSION
glucose load, we performed control experiments with a sug-
Our findings indicate that the late postprandialrise in the ar-free drink on a subgroup of the healthy childrcn wbose
plasma epinephrineconcentration was markedly greater in responses to glucose ingestion were typical of the cntire
children than in adults, whereasthe responsesof other an- group of children studied, and no changes in plasma
tiinsulin, counterregulatory hormones were not different. hormone concentrations or hypoglycemic symptom scores
Epinephrine r€sponseswere exaggeratedin children, even were noted.
though a glucoseload larger than the standard 75 to I 00 gm The P300 evoked potential is a neuroelectrophysiologic
was given to adults and, more important, the peak and na- measureof cognitive function produced when a subject at-
dir plasma glucose levels were nearly identical in the two tends to and discriminates a given stimulus.l3 The cortical
groups. auditory evoked potential has been shown to be adversely
Enhanced adrenomedullary responsesin the children affected by modest reductions in plasma glucose levelsl4 and
were associatedwith an increasein symptoms,such as feel- may therefore provide a sensitiveindex of neuroglycopenia.
ing shaky and sweaty, that are commonly attributed to During controlled reductionsin the plasma glucoseconcen-
stimulation of th€ sympatheticnervoussystem,lI' l2 whereas tration, cortical potentials are normally maintained until a
the scoreson filler items included to control for nonspecific critical threshold glucosevalue is reduced.r5In this study,
fatigue effects did not change. Moreover, adults who had P300 potentials were markedly altered in almost all the
blunted epinephrine responsesremained free of symptoms children when the plasma glucose concentration was low-
throughout the study, even though the lowest plasma glu- ered to values that were equal to or higher than the nadir
cose level in the postprandial period, as determined by fre- plasma glucose level seen after glucose ingestion in this
quent measurements,was nearly identical in the two groups. group. On the other hand, in adults P300 potentials were
These data suggestthat discrepanciesin symptom aware- preserved until the plasma glucose concentration was low-
nessof the late fall in the plasma glucoseconcentrationaf- ered to 3.0 mmol/L (5a mg/dl), values rarely observedin
ter an oral glucoseload are more likely related to differences either group after glucose ingestion. These data suggestthat
in epinephrine responses than to the absolute plasma healthy children are more vulnerable to the effects of hypo-
glucose level achieved. The plasma glucose concentration glycemia on cognitive function than are adults. Becausere-
fell to only 3.4 + 0.1 mmol/L (61 + 1.8 mg/dl) in the lease of epinephrine in responseto a fall in the plasma glu-
children, so "enhanced adrenomedullary responsiveness," cose concentration appears to be mediated through the
rather than "reactive hypoglycemia," might be a more ap- central nervous system,l6' l7 increased susceptibility to neu-

ril
The Journal of Pediatrics
Jones et al. 177
Volume 126, Number 2

roglycopenia may, in turn, account for the higher plasma 6. Amiel SA, Simonson DC, Sherwin RS, Lauritano AA, Tam-
glucose level that triggered release of epinephrine in the borlane WV. Exaggerated epinephrine responsesto hypogly-
children. cemia in normal and insulin dependent diabetic children. J
PEDTATR 1 9 8 7 ; ll 0 : 8 3 2 - 7
The putative adverseeffectsofdietary sugar on behavior
7. JonesTW, Boulware SD, Kraemer DT, Caprio S, Sherwin RS,
and cognitive function in children have been the subject of Tamborlane WV. Independent effects of youth and poor dia_
marked controversy.lE-20 Previous studies in this area that betes control on responsesto hypoglycemia in children. Diabe-
have been focused on children with attention deficit disor- tes l99l;40:358-63.
der have tended to make exaggeratedclaims regarding the 8. RosenbloomAL, Wheeler L, Bianchi R, Chin FT, Tiwary CM,
Gorgic A. Age-adjusted analysis of insulin rcsponses during
global effectsof sugar and other food additives on their be-
normal and abnormal glucosetests in normal children and ad-
havioral problems. Kinsbourne2l noted that the problems olescents.Diabetes 1975t24:820-8.
caused by dietary sugar appear to be much less severeor 9. Grant DB. Serum-insulin levelsin children during glucosetol-
prevalent than some studiessuggest.On the other hand, we erance tests. Acta Paediatr Scand 1968;57:297-9.
10. Amiel SA, Simonson DC, Tamborlane WV, DeFronzo RA,
have shown in this study that consumption of glucosein an
Sherwin RS. Rate of glucose fall does not affect counterreg-
amount roughly equivalent in carbohydrate content to two ulatory hormone responsesto hypoglycemia in normal and di-
l2-ounce cans of Coca-Cola is followed by a fall in the abetic humans. Diabetes 1987;36:518-22.
plasmaglucoseconcentrationsufficient to induce hormonal, I l. Cryer PE, Binder C, Bolli GB, et al. Hypoglycemia in IDDM.
symptomatic, and neurophysiologic changes in healthy D i a b e t e s1 9 8 9 ; 3 8I: 1 9 3 - 9 .
12. Heller SR, Herbert M, MacDonald IA, Tattersall RB. Influ-
children. However, the rise in the plasma epinephrinecon-
enceof sympathetic nervoussystemon hypoglycemic warntng
centration and in associated adrenergic symptoms was s y m p t o m s .L a n c e t I 9 8 7 ; 2 : 3 5 9 - 6 3 .
acute and self-limited, and occurred only in the late post- 13. Sutton S, Tueting P, Zubin J, John ER. Information delivery
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plasma glucoseconcentrationscauseearly impairment in cog-
phasizethat most children could benefit from eating mixed
1 nitive function and later activation of glucose counterregula-
mealsthat include protein, fat, complex carbohydrate,and tion in the absenceof hypoglycemic symptoms in normal man.
fiber to limit postprandial reductions in plasma glucose lev- J Clin Invest 1988;82:436-44.
cls and increasesin plasma epinephrine levels. [n keeping 15. JonesTW, McCarthy G, Tamborlane WV, et al. Mild hypo-
I with this conclusion,Wolraich et al.l were unableto dem- glycemia and impairment of brain stem and cortical evoked
I onstrate any effects on behavior and cognitive function in
potentials in healthy subjects.Diabetes I 990;39:I 550-5.
I preschooland school-agechildren by adding or subtracting
16. Borg WP, During MJ, Sherwin RS, Borg MA, Brines ML,
Ii sucrosefrom a balanced diet.
Shulman GI. Ventromedial hypothalamic lesionsin rats sup-
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I vest 1994;93:1677-82.
i 17. Biggers DW, Myers SR, Neal D, et al. Role of brain in coun-
R EF E R E N C E S
terregulation of insulin-induced hypoglycemia. Diabetes
L WolraichML, LindgrenSD, StumboPJ,SteginkLD, Appel- I 9 8 9 ; 3 8 : 7I -6 .
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aspartame
on the behaviorand cognitiveperformanceof chil- Drabman RS. Effects of sugar (sucrose)on children's behav-
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:. Milich R, Wolraich M, Lindgren SD. Sugar and hyperactiv- 19. Goldman JA, Lerman RH, Contois JM, Udall JN. Behavioral
rty: a critical review of empirical findings.Clinical Psychology
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L Crook WG. Food allergy: the great masquerader.Pediatr Clin 20. Wender EH, Solanto MV. Effects of sugar on aggressiveand
! N o r t h A m 1 9 5 1. 2 2 : 2 2 1 - 3 8 .
I. Rapp DJ. Does diet affect hyperactivity? Journal of Learning
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swcetenersand b€havior. In: Diet and behavior. Washington, I 994;330:355-6.
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80.
Yolume126 FEBRITARY1995 Number 2

TFIE JOLIRNAL OF
PEDIffiRICS Medlcol progress 261 Sweat chlorides in Mauriac syndrome polack er al.

163 Allergic colitis in inltnts Odze et al.


263 Transformation of neutropenia into leukemia in child treated
with G-CSF Weinblatt et al.
Orlglnot orilctes
l7l Adrenomedullery responseand susceptibility to neuroglvcopenia 266 Keratoderma and photophobia in tyrosinemia type II
efter suglr ingestion Jones et al. Rabinowitz et al.

178 Effects of hyperglycemig on mental efficiency in adolescentswith 269 Loss of antibody to hepatitis B in immunized patients with
diebetes Gschwend et al. hemophilia Maris, Butler, and Cohen

lE5 Subsequentinsect stings in Hymenoptera hypersensitivity-


Felol oncl neonolql medlclne
Hauk et al.

l9l Relotion between infent feeding and infections 212 EfIect of maternal glucocorticoids on intraventricular
Eeaudry, Dufour, and Marcoux hemorrhage in preterr4 infa.nts Garland, Buck, and ltviton

l9E Effect of neonetel immunization with DT toxoids on responsesto 2E0 Reducing blood donor exposures by use of older red blood cells
Haemophilus conjugete vlccines Lieberntan et al. Lee et al.

20,6 Antibody responses after different sequencesof Haemophilus 2E7 Effects of L-carnitine on fat metabolism in premrture neonates
conjugate vaccinesGreenberget al. Bonner et al.

212 Risk fectors and outcomes in patients hospitalizedwith RSV


infection l|/ang et al. 293 Congenital CMV infection causedby nonprimary diseasein
mother with AIDS Sclueb&e el a/.

220 Hmpitelizrtion rNtes for lower respirrtory tract illness in infants


McConnochre, Roghmann, and Liptak Phormqcology ond lheropeullct

230 Binding oI Pseudomonosto respiratory cells in cystic fibrosis


297 Growth and growth holmone axis in children treated for asthma
Zar et al.
Crowley et al.

23.f Spectrum of herpes simplex encephalitisSthlesinger et al.


304 Corticosteroid therapy for ventricular tachycardia in lymphocytic
myocarditis Ino et al.
242 Lipid rbnormelities in Turner syndrome Ross et al.

246 Lysinuric protein intolennce with bone marrow abnormalities 309 Granisetron vs chlorpromazine plus dexametha$ne to prevent
Parenti et al. ifosfamide-inducedemcsis Hiihlen et al.

252 Reduction in bone mess after severe bttns Klein et al. 313 Amoxicillin-clavulanatcduring URI for preventionof otitis media
Heikkinen et al.
Edllor'r column
Currenl lllelqlule ond cllnlcol lrsues
257 Venom immunotherapy Eierman

317 Antenatal corticosteroid therapy to prevent RDS Ryan and Finer


llons

*"5l,gPlls,*k*"o."9M 327 Acknowledgmenl ol reylewe]3


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