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603Lerman-Garber I et al.
Evidence of a linkage between neurocardiogenic dysfunction and reactive hypoglycemia
. Rev Invest Clin 2000; 52 (6): 603-610
ARTÍCULO ORIGINAL
La Revista de Investigación Clínica / Vol. 52, Núm. 6 / Noviembre-Diciembre, 2000 / pp 603-610
Versión completa de este artículo disponible en internet: www.imbiomed.com.mx
Evidence of a linkage between neurocardiogenic
dysfunction and reactive hypoglycemia
Israel Lerman-Garber,* Jorge A. Valdivia López,* Armando Flores Rebollar,* Francisco Javier Gómez Pérez ,*
Juan Antonio Rull,* Antonio G Hermosillo**
* Departamento de Endocrinología y Metabolismo, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán.
** Departamento de Electrocardiografía y Electrofisiología, Instituto Nacional de Cardiología Ignacio Chávez.
ABSTRACT
Objective. Reactive hypoglycemia is a common medical problem
whose pathophysiology is not completely understood. The objec-
tive of this study was to investigate the prevalence of autonomic
nervous system abnormalities in patients with reactive hypogly-
cemia compared with controls. Methods. Six women, mean age
31 ± 5 years, with reactive hypoglycemia, and 5 healthy controls
women aged 24 ± 4 years were studied. We investigated the heart
rate variability and blood pressure changes after an upright tilt
with and without an isoproterenol infusion. A positive result was
defined as syncope or presyncope associated with bradycardia,
hypotension or both. Results. In response to the orthostatic
stress alone or in conjunction with a 4
µ
g isoproterenol infusion,
5 of 6 patients had a positive test as did one of the five control
subjects. Patients had a baseline hyperadrenergic tone, with a
sympathetic to parasympathetic ratio of 2.3 ± 0.8 under basal
conditions and 10.1 ± 4.1 during the isoproterenol infusion,
compared to 0.7 ± 0.3 (p = 0.06) and 0.5 ± 0.1 (p < 0.01) respec-
tively, in the control group. Conclusion. Patients with reactive
hypoglycemia may be at the extreme end of a spectrum of normal
biologic variability, they may have an hyperadrenergic tone and,
after a provocative stimulus, sympathetic nerve firing and or
synaptic release of NE may not be sufficient to maintain an ade-
quate vascular tone. Alternatively, the vascular response to NE
may be impaired. An excessive and paradoxic vasovagal or para-
sympathetic response was not observed.
Key words. Reactive hypoglycemia. Autonomic nervous system.
Upright tilt. Neurocardiogenic dysfunction.
RESUMEN
La hipoglucemia reactiva es un problema común en la práctica
clínica cuya patofisiología es motivo de controversia. El objetivo
del presente estudio fue investigar la prevalencia de anormalida-
des del sistema nervioso autónomo en pacientes con hipogluce-
mia reactiva comparada con controles sanos. Material y méto-
dos. Se incluyeron para el estudio a seis mujeres con hipogluce-
mia reactiva con edad media de 31 ± 5 años y 5 mujeres sanas
con edad media de 24 ± 4 años. Se investigó la variabilidad de la
frecuencia cardiaca y los cambios en la presión arterial después
de una prueba de inclinación con y sin isoproterenol. Se definió
como prueba positiva a la presencia de síncope o presíncope aso-
ciados a bradicardia, hipotensión o ambas. Resultados. En res-
puesta a la prueba de inclinación con o sin isoproterenol 5 de 6
pacientes comparado con 1 de 5 controles sanos presentaron una
prueba positiva. Las pacientes presentaron un tono hiperadre-
nérgico con una relación simpático/parasimpático de 2.3 ± 0.8
en condiciones basales y 10.1 ± 4.1 durante la infusión de iso-
proterenol, en comparación a 0.7 ± 0.3 (p = 0.06) y 0.5 ± 0.1 (p
< 0.01) respectivamente en el grupo control. Conclusiones.
Los pacientes con hipoglucemia reactiva pueden estar en un ex-
tremo de variabilidad biológica normal. Pueden cursar con un
tono hiperadrenérgico y después de un estímulo provocativo la
descarga simpática o la liberación sináptica de norepinefrina
pueden ser insuficientes para mantener un tono vascular ade-
cuado. Otra posibilidad es que la respuesta vascular a norepin-
efrina esté alterada. No se observó una respuesta vasovagal pa-
radójica o excesiva.
Palabras clave. Hipoglucemia reactiva. Sistema nervioso autó-
nomo. Prueba de inclinación. Disfunción neurocardiogénica.
Lerman-Garber I et al.
Evidence of a linkage between neurocardiogenic dysfunction and reactive hypoglycemia
. Rev Invest Clin 2000; 52 (6): 603-610604
INTRODUCTION
In clinical practice is common to encounter patients
with a variety of nonspecific postprandial complaints
similar to the signs and symptoms of hypoglycemia,
such as sweating, palpitations, irritability, dizziness,
tremor, fatigue, confusion, hunger and headaches.
1-4
A
diagnosis of reactive hypoglycemia is clearly establis-
hed when there is a relationship between food intake,
timing of symptoms, correlation of symptoms with low
blood glucose values, and reproducibility of symptoms
with the occurrence of hypoglycemia during a 5 hr oral
glucose tolerance test (OGTT).
3,5
However, approximately 95% of the patients refe-
rred for this condition, do not meet these diagnostic
criteria.
2,3,5-7
Consequently a new term was introdu-
ced, idiopathic postprandial syndrome or non-hypo-
glycemia, which has added more confusion about the
diagnosis and true nature of this disorder. Further-
more, in patients with reactive hypoglycemia, no clear
abnormalities have been observed in glucose homeos-
tasis, serum levels of insulin or counterregulatory
hormones.
6,8-11
Various hypotheses have been studied
and postulated; excessive vagal stimulation and/or
epinephrine response,
8,9
increased beta-adrenergic
sensitivity,
11
a state of dysinsulinism or innapropriate
late insulin secretion,
10
increased insulin sensitivi-
ty,
12
increased non oxidative metabolism of glucose
13
,
diminished glucagon response
14,15
an emotional or
psychiatric disorder,
1,16
a socially acceptable diagnosis
preferable to anxiety and/or depression.
1,2
Our belief is that reactive hypoglycemia is com-
mon and frequently improves with dietary modifica-
tions. The same symptoms described by the patients,
can in many cases also occur after eating, in stress-
ful situations, during hyperventilation, associated
with peptic disease or after a drop in blood pressure,
and are more prevalent when the individual is anxio-
us and/or depressed.
Two other clinical entities, postprandial hypoten-
sion in the elderly and neurocardiogenic syncope
17-20
share common clinical features with those observed in
these patients and are likely secondary to cardiovascu-
lar dysautonomia. This lead us in the present study, to
investigate by means of the tilt test and spectral analy-
sis of heart rate variability the prevalence of abnorma-
lities in the autonomic nervous system of patients with
reactive hypoglycemia as compared with controls.
The hypothesis was that individuals with reactive
hypoglycemia, have an hyperadrenergic tone or a lo-
wer threshold for autonomic activation in response
to physiologic stimuli that is related to an autonomic
dysfunction.
SUBJECTS AND METHODS
Subjects
Two groups of subjects were studied, six women,
mean age 31 ± 5 years, in whom a diagnosis of reacti-
ve hypoglycemia was established and organic hypogly-
cemia was ruled out (normal glucose/insulin ratios
baseline and during a 72 hr fasting, and normal corti-
sol and thyroid functions tests). All patients had a
history of repeated episodes of classical autonomic
symptoms in the postprandium relieved by food in-
take. None had gastrointestinal tract surgery, they
were otherwise healthy, and all reproduced their cli-
nical manifestations during an OGTT. In addition, we
studied 5 control subjects, healthy women of similar
age 24 ± 4 years, who had no history of postprandial
complaints and were asymptomatic during an OGTT.
Procedure
Power spectral analysis of heart rate (HR) variabili-
ty is a noninvasive method of estimating sympathetic
and parasympathetic contributions to sinus node acti-
vity. This technique, using the fast Fourier transform,
decomposes HR fluctuations into their component fre-
quencies. The power of HR fluctuations in physiologi-
cally relevant frequency bands can then be computed.
Analysis of heart rate variability: The two lead
ECG recorded by a Hewlett Packard New Wave Hol-
ter, was processed automatically by the predictor
HR variability software capable of classifying QRS
complexes of rejecting technical errors, interferences
and ectopic beats.
Frequency domain measures were analyzed in 60
seconds periods after 5 minutes of supine rest, follo-
wing 1 minute in a 70 degrees upright position, 2
and 1 minute before syncope, and finally, 1 and 5
minutes after syncope in the supine position. Power
spectral density was calculated by a Fast Fourier
Transform algorithm, producing a 512 points spec-
trum for the 0.01 to 1.0 Hz frequency band (total
spectrum). The low frequency ( 0.01 to 0.15 Hz) and
high frequency (0.15 to 0.4 Hz) bandwidth areas
were calculated and power values were expressed as
natural logarithm because they were not normally
distributed. Clinical studies have shown that the
power of the high frequency component (0.15 to 0.4
Hz) reflects the parasympathetic input to the sinus
node, whereas the low frequency band (0.01 to 0.15
Hz) is modulated mainly by sympathetic impulses.
Sympathovagal balance expressed as LF/HF ratio
was also calculated in arithmetic power to cancel the
605Lerman-Garber I et al.
Evidence of a linkage between neurocardiogenic dysfunction and reactive hypoglycemia
. Rev Invest Clin 2000; 52 (6): 603-610
influence of the parasympathetic activity on the LF
spectral power.
17
Head-up tilt protocol
Subjects were studied after a 12 hr fasting. An in-
travenous line was inserted and an infusion of saline
was begun at rate of 20 mL/h. Subjects remained in
the supine position for 15 minutes for stabilization.
Throughout the baseline period and the tilt test,
heart rate was continuously monitored and the blood
pressure recorded every two minutes using a stan-
dard sphygmomanometer. A solid state computeri-
zed two-lead Holter ECG was recorded during this
study.
After baseline measurements of heart rate and
blood pressure, each patient was positioned at a 70
degree angle from horizontal for up to 30 minutes on
a tilt table with a foot-board for weight bearing.
Blood pressure measurements were taken every
three minutes and continuing electrocardiographic
monitoring was performed. If severe autonomic
symptoms or syncope developed during the tilt, the
table was rapidly lowered to the supine position and
the study ended. If syncope did not occur during the
initial tilt, the patient was lowered to the supine po-
sition for five minutes.
An intravenous isoproterenol infusion was then
initiated at 4 µg/minute and continued for five minu-
tes with the subject supine. Upright tilt testing was
then performed, as previously, for a period of ten mi-
nutes. If the result of the test was negative, the pa-
tient was returned to the supine position. A positive
result was defined as syncope or presyncope associa-
ted with bradycardia (<40 heart beats per minute),
hypotension (<90/60 or decrements >30 mmHg in
systolic BP) or both. The five control individuals un-
derwent upright tilt table testing both with and
without the isoproterenol infusion.
Informed consent was obtained after the nature of
the procedure had been fully explained.
The protocol was approved by the Human Ethical
Committee of the INCMNSZ.
Statistical analysis
In each patient and control subject we determined
the maximal and minimal changes in heart rate and
blood pressure during the upright tilt or upright tilt
plus infusion of isoproterenol. Data are expressed as
mean ± SD or SE.
The ratio of sympathetic to parasympathetic
input was obtained (low frequency/high frequency
power). The value of high frequency and low fre-
quency spectral power, heart rate and blood pressu-
re were compared by the Mann-Whitney test for
unpaired observations. Statistical significance was
defined as p < 0.05. The log transformation of spec-
tral power was reported in arbitrary units.
RESULTS
There were no significant differences in age, basal
heart rates and systolic and diastolic blood pressures
between patients and controls. Patients were more
symptomatic and had more dramatic reductions in
systolic and diastolic blood pressure as compared to
controls during the tilt test with the isoproterenol
infusion.
Response to tilt table testing
In response to the head-up tilt test alone (baseli-
ne), one patient experienced syncope (Table 1), ano-
ther patient experienced autonomic symptoms and
almost fainted (presyncope) with associated hypo-
tension, and a third patient presented mild dizziness
with no significant hemodynamic changes. The re-
maining patients and all the controls were asympto-
matic with appropriate heart rate and blood pressu-
re responses.
During the response to the upright tilt table test
in conjunction with isoproterenol infusion, 4 of the 5
patients in whom the test was done developed synco-
pe or presyncope, as compared with only one of the
five control subjects.
Table 1. Signs and symptoms during the head-up tilt test.
Patients Saline Isoproterenol Hypotension
1 Yes (mild dizziness) Yes (mild dizziness) No
2 No Yes (syncope) Yes
3 Yes (presyncope) Yes (presyncope) Yes
4 No Yes (syncope) Yes
5 No Yes (presyncope) Yes
6 Yes (syncope) Not done Yes
Controls
1 No Yes (dark vision) No
2No NoNo
3No NoNo
4 No Yes (presyncope) Yes
5No NoNo
Lerman-Garber I et al.
Evidence of a linkage between neurocardiogenic dysfunction and reactive hypoglycemia
. Rev Invest Clin 2000; 52 (6): 603-610606
Each patient reported that the tilt induced initial
symptoms were similar to those experienced clinica-
lly in hypoglycemia. Five of the six patients had a
positive test compared to one of five healthy controls
(Table 1).
Changes in heart rate and systolic and diastolic
blood pressures during the upright tilt table testing
alone and with isoproterenol infusion are shown in
figures 1 and 2. Patients compared to controls had
non significantly higher maximal baseline and after
isoproterenol infusion heart rates (103 ± 21 vs. 87 ±
14, and 136 ± 28 vs. 115 ± 21 respectively). After
the isoproterenol infusion, patients HR response
was partially blunted and they had compared to con-
trols, lower minimal systolic (81 ± 21vs 101 ± 20, p
< 0.05) and diastolic (51 ± 17vs 65 + 11 p < 0.05)
blood pressures. These differences were not signifi-
cant under basal conditions.
Heart rate spectral power responses to tilt
table testing
To compare changes in spectral power during the
tilt table test, we examined baseline data in the supi-
ne position, at the moment the tilt was started, after
five minutes of orthostatism, one minute before
symptoms appeared and during symptoms in those
exhibiting a positive test.
Figures 3 and 4 show the changes in the different
bands of spectral power during the test under basal
conditions and under the isoproterenol infusion in
patients and controls.
As shown in these figures, spectral power output
is in all bands of frequencies diminished in patients
compared to controls. Shortly before the onset of
symptoms, patients had an increment in the values
of low frequency and high frequency spectral power.
During the isoproterenol infusion, patients showed a
reduction in the spectral power at the beginning of
the tilt test and had a similar sympathetic and pa-
rasympathetic response. During the isoproterenol
infusion, control subjects had a trend to increase
their sympathetic tone (LF) and to diminish the pa-
rasympathetic outflow (HF). Patients had a baseline
hyperadrenergic tone, with a sympathetic to pa-
rasympathetic ratio of 2.3 ± 0.8 under basal condi-
tions and 10.1 ± 4.1 during the isoproterenol infu-
sion, compared to 0.7 ± 0.3 (p = 0.06) and 0.5 ± 0.1
(p < 0.01), respectively in the control group. The
healthy subject who experienced syncope had the lo-
west sympathetic to parasympathetic baseline ratio
of 0.2 and most likely had a vasovagal reaction. It is
likely that this also occurred in the patient who ex-
perienced syncope without isoproterenol and had a
ratio of 0.6. During the tilt test an excessive vagal
response (significant reduction in the sympathetic/
parasympathetic ratio) was not observed.
Figure 1. Changes in heart rate and systolic and diastolic blood pressu-
re during the upright tilt table testing alone (baseline) in patient (open
circles) and controls (closed circles). Data are mean
±
SE. 0' = 0 min
during the tilt test, maximal = maximal response, minimal = minimal res-
ponse during the tilt test.
160
140
120
100
80
60
40
20
Prestudy 0 Maximal Minimal
TILT TEST
Heart rate (beats x min)
160
140
120
100
80
60
40
20
TILT TEST
Blood Pressure (beats x min)
Systolic
Diastolic
Prestudy 0 Maximal Minimal
607Lerman-Garber I et al.
Evidence of a linkage between neurocardiogenic dysfunction and reactive hypoglycemia
. Rev Invest Clin 2000; 52 (6): 603-610
DISCUSSION
This study demonstrates with the use of the tilt
test and spectral power analysis of heart rate varia-
bility, a significant dysautonomia in patients with
reactive hypoglycemia compared to healthy controls.
The diagnosis of reactive hypoglycemia has been
hampered by a lack of objective criteria. Patients
with reactive hypoglycemia have been described as
emotionally labile persons who complain of autono-
mic symptoms, such as weakness, faintness, nervo-
usness, palpitations and perspiration.
The majority of patients respond to diet therapy
and reassurance; others remain symptomatic and go
from one physician to another seeking relief of
symptoms. In every case endocrine, psychiatric, neu-
rologic and metabolic problems must be considered
and ruled out.
Since the clinical manifestations are not consisten-
tly associated with chemical hypoglycemia, several
authors have suggested naming this disorder idiopha-
tic postprandial syndrome or non-hypoglycemia, ins-
tead of reactive hypoglycemia.
1-5
About 15-30% of
normal individuals have whole blood glucose values
below 50 mg/dL without hypoglycemic symptoms du-
ring an OGTT.
Other diagnostic criteria have been proposed to
eliminate reliance on blood glucose levels or subjecti-
ve symptoms: the hypoglycemic index, which combi-
nes the rate of fall in blood glucose concentration
with the glucose nadir,
3
the cortisol response to the
glucose nadir
3
and the insulin and catecholamine le-
vels
9-11
during hypoglycemia.
Some aspects of disturbed autonomic function
have also been previously suspected as a possible fac-
tor in the etiology of reactive hypoglycemia.
21
Per-
mutt et al
8
measured the effect of cholinergic blocka-
de on glucose stimulated insulin release in normal
subjects and patients with reactive hypoglycemia
and concluded that excessive vagal activity may be
an important constituent of idiopathic hypoglyce-
mia. Berlin et al
11
studied heart rate, blood pressure,
plasma insulin, C-peptide and catecholamine respon-
ses during a 5-h oral glucose tolerance test and eva-
luated beta adrenergic sensitivity by the isoprotere-
nol sensitivity test. He concluded that patients with
suspected postprandial hypoglycemia have normal
glucose tolerance, increased beta adrenergic sensiti-
vity and emotional distress.
Food ingestion and oral glucose loading have been
shown to reduce systemic blood pressure in elderly
individuals (postprandial hypotension of the elderly)
and in patients with autonomic insufficiency.
18,22,23
Oral glucose loading induces specific vasodilation of
splanchnic vasculature, particularly in elderly and
hypertensive individuals, which may be incompletely
counterbalanced by activation of the sympathetic
nervous system, due to an age and blood pressure re-
Figure 2. Changes in heart rate and systolic and diastolic blood pressu-
res during the upright tilt table testing with isoproterenol infusion in pa-
tients (open circles) and controls (closed circles). Data are mean
±
SE.
*p < 0.05. 0' = 0' min during the tilt test, maximal = maximal response,
minimal = minimal response during the tilt test.
160
140
120
100
80
60
40
20
Prestudy 0 Maximal Minimal
TILT TEST
Heart rate (beats x min)
TILT TEST
Blood Pressure (mmHg)
Systolic
Diastolic
Prestudy 0 Maximal Minimal
160
140
120
100
80
60
40
20
*
*
Lerman-Garber I et al.
Evidence of a linkage between neurocardiogenic dysfunction and reactive hypoglycemia
. Rev Invest Clin 2000; 52 (6): 603-610608
lated reduction of baroreflex sensitivity. The eleva-
tions in circulating catecholamines in elderly pa-
tients with postprandial hypotension immediately
Figure 3. Baseline and post upright tilt table test alone (baseline) spectral
power responses in patients (open circle) and controls (closed circles). Data
are expressed as mean
±
SD, *p < 0.05,
< 0.01. Values are log transformed
arbitrary units. Spectral power band 2 is low frequency (0.04-0.15 Hz), spectral
power band 3 is high frequency (0.15-0.50 Hz). Band 2 represents mainly the
sympathetic response and band 3 the parasympathetic tone, BL = baseline, 0
= 0 min during the tilt test. 5' = 5 min during tilt test, 1BS = 1 minute before
symptoms, DS = during symptoms (only in those who developed symptoms).
Figure 4. Baseline and post upright tilt table test with isoproterenol infu-
sion spectral power responses in patients (open circles) and controls
(closed circles). Data are expressed as mean
±
SD,
*p < 0.05,
< 0.01.
Values are log transformed arbitrary units. Spectral power band 2 is low
frequency (0.04-0.15 Hz), spectral power band 3 is high frequency
(0.15-0.40 Hz). Band 2 represents mainly the sympathetic response and
band 3 the parasympathetic tone. BL = baseline, 0 = 0' min during the
tilt test. 5' = 5 min during tilt test, 1' BS = 1 minute before symptoms, DS
= during symptoms. (Only in those who developed symptoms).
before the appearance of the classical adrenergic
symptoms, suggest that catecholamine excess may
paradoxically enhance the susceptibility to bradycar-
7
6
5
4
3
2
1
0
SPECTRAL POWER (BAND 2)
SPECTRAL POWER (BAND 3)
BL 0 ¨5 1BS DS
Log transformed Arbitrary Units
7
6
5
4
3
2
1
0
BL 0 ¨5 1BS DS
7
6
5
4
3
2
1
0
SPECTRAL POWER (BAND 2)
SPECTRAL POWER (BAND 3)
BL 0 ¨5 1BS DS
Log transformed Arbitrary Units
7
6
5
4
3
2
1
0
*
*
*
BL 0 ¨5 1BS DS
609Lerman-Garber I et al.
Evidence of a linkage between neurocardiogenic dysfunction and reactive hypoglycemia
. Rev Invest Clin 2000; 52 (6): 603-610
dia and hypotension.
18
Neurocardiogenic syncope
usually occurs in the upright or sitting position. Tilt
(erect posture) serves as a stimulus for the induction
of vasovagal syncope. Upright posture causes a shift
of approximately 300 to 800 mL of blood from the
thorax to the lower extremities. The subsequent re-
duction in thoracic blood volume reduces the filling
pressure of the ventricles, and causes an immediate
fall in cardiac output. Maintenance of arterial pres-
sure in the upright posture is achieved by an increa-
se in total peripherical resistance. Thus the prime
determinant for circulatory failure is due to a dimi-
nution in the volume of blood available to the heart
as the result of venous pooling in the lower limbs. In
neurocardiogenic syncope, the autonomic compensa-
tory reflex fails to maintain arterial pressure.
24
In
addition, the combination of reduced ventricular vo-
lumes and raised sympathetic tone may result in an
increase in ventricular wall tension and may trigger
a depressor reflex for sympathetic activity initiated
by left ventricular receptors.
25
Upright tilt testing has been of increasing interest
as a diagnostic aid in patients with unexplained syn-
cope. Previous reports have suggested that upright
tilt testing is uncommonly (6-11% of cases) associated
with the development of symptoms in otherwise heal-
thy control subjects.
26,27
Weissler et al,
21
observed
neither significant bradycardia nor hypotension du-
ring isoproterenol infusion in healthy controls. Systo-
lic arterial pressure is usually maintained as a result
of increased cardiac output, but diastolic pressure fa-
lls, and mean arterial pressure may decrease slightly.
Consequently, it has been proposed that upright
posture, in conjunction with the administration of
an exogenous catecholamine (isoproterenol), may be
used to reproduce neurally mediated episodes of syn-
copal spells.
27
This study evaluated the usefulness of
combining the upright tilt test with isoproterenol in-
fusion to elicit symptomatic hypotension and/or bra-
dycardia and classical autonomic symptoms in pa-
tients with reactive hypoglycemia.
In our study, five of the six patients compared to
only one of the five healthy controls experienced
characteristic adrenergic symptoms and significant
hypotension during the tilt test. Thus patients with
reactive hypoglycemia may have an increased adre-
nergic tone. After a provocative stimulus, sympathe-
tic nerve firing and/or synaptic release of NE may
not be sufficient to maintain adequate vascular tone
as suggested by the power spectral studies of heart
rate variability. Alternatively, the vascular response
to NE may be impaired. An excessive and paradoxic
vagal or parasympathetic response was not obser-
ved. Interestingly, one patient and one control sub-
ject with low sympathetic to parasympathetic ratios
developed syncope. Therefore, in most patients, the
most likely neurocardiogenic dysfunction is a va-
sodepressor phenomenon and in others probably a
vasovagal reaction.
We believe that many healthy individuals share
these autonomic abnormalities, that could be a spec-
trum of normal biologic variations and are clinically
expressed only after a provocative stimulus as occu-
rred in one of the control subjects. It seems very at-
tractive to maintain that anxiety may trigger this
response and this explains why anxiety and depres-
sion are common in patients with reactive hypogly-
cemia, and why they respond to therapies that relie-
ve the state of anxiety.
Certainly, the present study was done in a small
group of subjects and the results can be viewed with
some reserve, however, as previously stated, clear diffe-
rences were observed between patients and controls.
The upright tilt test with the isoproterenol infu-
sion is an invasive test that produced syncope or
presyncope in most of the patients with reactive
hypoglycemia. Two patients felt very bad after the
study, they were very anxious and began to cry (they
never experienced such a severe episode before), rea-
son why the isoproterenol infusion should not be in-
cluded in the study protocol of these patients.
Regarding therapy, β1 adrenergic cardioselective
blocking agents could theoretically prevent reflex
hypotension-bradycardia, presumably due, in part,
to their negative inotropic action.
27
Other pharma-
cologic approaches have been discussed.
3,24,28
The
current recommended diet for patients with reactive
hypoglycemia is low in refined sugars combined with
mid morning and mid afternoon snacks. The conco-
mitant management of anxiety has given the best
therapeutic results.
We conclude that tilt table testing and spectral
power analysis of heart rate variability can be of help
in understanding the pathophysiology of reactive hypo-
glycemia. Wether the tilt test without isoproterenol,
should be recommended as a routine study in the eva-
luation of these patients, remains to be established.
Patients with reactive hypoglycemia may be at the ex-
treme end of the spectrum of normal biologic variabili-
ty. Further studies should be done to obtain responses
to the following questions: would we observe similar
findings in patients with idiopathic postprandial syn-
drome or non hypoglycemia; would this autonomic
changes be transient and improve with any therapy
that may reduce the increased baseline adrenergic
tone; do frequent episodes of hypoglycemia lead to the
Lerman-Garber I et al.
Evidence of a linkage between neurocardiogenic dysfunction and reactive hypoglycemia
. Rev Invest Clin 2000; 52 (6): 603-610610
autonomic imbalance observed in these patients or is
hypoglycemia just another from a large group of poten-
tial stimuli that trigger this response?
REFERENCES
1. Johnson DD, Dorr KE, Swenson WM, Service J. Reactive hypogly-
cemia. JAMA 1980; 243: 1151-5.
2. Nelson R. Hypoglycemia: Facts or fiction? Mayo Clin Proc 1985;
60: 844-50.
3. Lev-Ran A, Anderson RW. The diagnosis of postprandial hypogly-
cemia. Diabetes 1981; 30: 996-9.
4. Jones J. Reactive hypoglycemia. Br Medical J 1987; 295: 286-7.
5. Hogan MJ, Service FJ, Sharbrough FW, Gerich JE. Oral glucose to-
lerance test compared with a mixed meal in the diagnosis of reacti-
ve hypoglycemia. A caveat on stimulation. Mayo Clin Proc 1983;
58: 491-6.
6. Hofeldt FD. Reactive hypoglycemia. Endocrinol Metab Clin North
Am 1989; 18: 185-207.
7. Palardy J, Havrankova J, Lepage R et al. Blood glucose measure-
ments during symptomatic episodes in patients with suspected pos-
tprandial hypoglycemia. N Engl J Med 1989; 321: 1421-5.
8. Permutt M, Keller D, Santiago J. Cholinergic blockade in reactive
hypoglycemia. Diabetes 1977; 26: 121-7.
9. Chalew SA, Mc Laoghlin JV, Marsey JH. The use of the plasma
epinephrine response in the diagnosis of idiopathic postprandial
syndrome. JAMA 1984; 251: 612-5.
10. Hofeldt FD, Lufkin EG, Hagler L, Block MB. Are abnormalities in
insulin secretion responsible for reactive hypoglycemia? Diabetes
1974; 23: 589-96.
11. Berlin I, Grimaldi A, Landault C, Cesselin F, Puech AJ. Suspected
postprandial hypoglycemia is associated with beta-adrenergic hy-
persensitivity and emotional distress. J Clin Endocrinol Metab
1994; 79: 1428-33.
12. Tamburrano G, Leonetti F, Sbraccia P, Giaccari A, Locuratolo N,
Lala A. Increased insulin sensitivity in patients with idiopathic
reactive hypoglycemia. J Clin Endocrinol Metab 1989; 69: 885-90.
13. Leonetti F, Foniciello M, Lozzo P. Increased nonoxidative glucose
metabolism in idiopathic reactive hypoglycemia. Metabolism 1996;
45: 606-10.
14. Foá PP, Dunbar JC, Klein SP. Reactive hypoglycemia and A-cell
(‘Pancreatic’) glucagon deficiency in the adult. JAMA 1980; 244:
2281-5.
15. Ahmadpour S, Kabadi UM. Pancreatic α-cell function in idiopathic
reactive hypoglycemia. Metabolism 1997; 46: 639-43.
16. Anthony D, Dippe S, Hofeldt FD, Davis JW, Forsham PH. Personali-
ty disorder and reactive hypoglycemia. Diabetes 1973; 22: 664-75.
17. Ryan Sheila M, Goldberger Ary L, Ruthazer R, Mietus J, Lipsitz
LA. Spectral analysis of heart rate dynamics in elderly persons with
postprandial hypotension. Am J Cardiol 1992; 69: 201-5.
18. Lipsitz LA, Ryan SM, Parker JA, Freeman R, Wein JY, Goldberger
AL. Hemodynamic and autonomic nervous system to mixed meal in-
gestion in healthy young and old subjects and dysautonomic patients
with postprandial hypotension. Circulation 1993; 87: 391-400.
19. Jansen RWMN, Penterman BJM, Van Lier HJJ, Hoefnagels WHL.
Blood pressure reduction after oral glucose loading and its relation to
age, blood pressure and insulin. Am J Cardiol 1987; 60: 1087-91.
20. Guzmán Rodriguez CE, Sánchez MG, Márquez MF, Gonzáles Her-
mosillo JA, Cárdenas M. Differences in heart rate variability bet-
ween cardioinhibitory and vasodepressor responses to head-up tilt
table testing. Arch Med Res 1999; 30: 203-11.
21. Fabrykant M. The problem of functional hyperinsulinism or func-
tional hypoglycemia attributed to nervous causes. Metabolism
1955; 4: 469-90.
22. Robertson D, Wade D, Robertson RM. Postprandial alterations in
cardiovascular hemodynamics in autonomic dysfunctional states.
Am J Cardiol 1981; 48: 1048-52.
23. Robinson BJ, Johnson RH, Lambie DG, Palmer KT. Autonomic
responses to glucose ingestion in elderly subjects with orthostatic
hypotension. Ageing 1985; 14: 168-73.
24. Ibrahim MM, Tarazi RC, Dustan HP. Orthostatic hypotension: me-
chanisms and management. Am Heart J 1975; 90: 513-20.
25. Epstein SE, Stampfer M, Beiser GD. Role of the capacitance and re-
sistance vessels in vasovagal syncope. Circulation 1968; 37: 524-33.
26. Grubb BP, Temesy-Armos P, Hahn H, Elliot L. Utility of upright
tilt-table testing in the evaluation and management of syncope of
unknown origin. Am J Med 1991; 90: 6-10.
27. Almquist A, Goldenberg IF, Milstein S. Provocation of bradycardia
and hypotension by isoproterenol and upright posture in patients
with unexplained syncope. N Engl J Med 1989; 320: 346-51.
28. Jansen RWMM, Lipsitz LA. Postprandial hypotension: epidemiolo-
gy, pathophysiology and clinical management. Ann Intern Med
1995; 122: 286-95.
Address for correspondence:
Dr. Israel Lerman
Departamento de Endocrinología y Metabolismo,
Instituto Nacional de Ciencias Médicas y Nutrición
Salvador Zubirán.
Vasco de Quiroga 15, Tlalpan 14000,
Mexico City, Mexico.
55731200 ext. 2405, FAX 55130002.
E-mail: lerman@netservice.com.mx
Recibido el 15 de marzo de 2000.
Aceptado el 06 de julio de 2000.