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Evidence of a linkage between neurocardiogenic dysfunction and reactive hypoglycemia

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Reactive hypoglycemia is a common medical problem whose pathophysiology is not completely understood. The objective of this study was to investigate the prevalence of autonomic nervous system abnormalities in patients with reactive hypoglycemia compared with controls. 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. In response to the orthostatic stress alone or in conjunction with a 4 micrograms 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) respectively, in the control group. 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 adequate vascular tone. Alternatively, the vascular response to NE may be impaired. An excessive and paradoxic vasovagal or parasympathetic response was not observed.
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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, 1BS = 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 1BS DS
Log transformed Arbitrary Units
7
6
5
4
3
2
1
0
BL 0 ¨5 1BS DS
7
6
5
4
3
2
1
0
SPECTRAL POWER (BAND 2)
SPECTRAL POWER (BAND 3)
BL 0 ¨5 1BS DS
Log transformed Arbitrary Units
7
6
5
4
3
2
1
0
*
*
*
BL 0 ¨5 1BS 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?
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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.
... Tampoco es llamativo encontrar la presencia de síncope en enfermos diabéticos con episodios frecuentes de hipoglucemia. Pero el reciente trabajo de Lerman et al. 1 ...
... Tampoco es llamativo encontrar la presencia de síncope en enfermos diabéticos con episodios frecuentes de hipoglucemia. Pero el reciente trabajo de Lerman et al. 1 ...
Article
Full-text available
Objectives: Postprandial hypoglycemia in a nondiabetic patient is a frequent chief complaint across all medical specialties and represents a significant diagnostic challenge. Methods: We conducted an electronic and print literature search using PubMed for articles published in the last 40 years using the key words "postprandial hypoglycemia," "reactive hypoglycemia," and "hyperinsulinemic hypoglycemia." All available sources were reviewed, and publications were included based on clinical relevance. Results: Over the last century, the classification, etiologies, diagnosis, and management of hypoglycemia have evolved considerably. In the contemporary literature, the evaluation of hypoglycemia is divided into well-appearing and ill-appearing patients. Symptoms of hypoglycemia in the well-appearing patient may result from insulinoma, noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS), postbariatric surgery hypoglycemia, dumping syndrome, insulin autoimmunity, or postprandial syndrome. For each of these, the literature is lacking in randomized clinical trials investigating optimal diagnostic and treatment modalities, and this is due to the relatively recent description of some diseases and the rarity of cases. Conclusion: This review provides an overview of postprandial hypoglycemia and summarizes the proposed pathophysiologic mechanisms of postprandial hypoglycemia, with special attention paid to some of the more recently described syndromes, such as NIPHS and postbariatric surgery hypoglycemia. Diagnostic and management strategies are also discussed.
Article
Serum glucose, A-cell (IRGA) and total glucagon (IRGT), insulin, growth hormone, cortisol, triiodothyronine, and thyroxine values were measured in the fasting state and in response to oral glucose, intravenously administered arginine, and a meal of pan-broiled ground beef in 31 symptomatic patients and 11 normal subjects. Twenty-four patients and 11 control subjects had normal glucose tolerance (group 1); seven patients had reactive hypoglycemia (group 2). Under all conditions, serum IRGA value was significantly lower in group 2 than in group 1. Glucose, arginine, or meat increased serum IRGT levels. This response did not differ significantly in the two groups, nor did the secretion of the other measured hormones. We conclude that A-cell insufficiency can contribute to reactive hypoglycemia in the adult. (JAMA 244:2281-2285, 1980)
Article
Idiopathic reactive hypoglycemia (IRH) is a well-documented but overdiagnosed syndrome. The presence of transient hypoglycemia and enhanced insulin secretion and/or increased insulin sensitivity before the onset of IRH is well documented. However, the data regarding glucagon secretion are sparse. Therefore, this study assessed glucagon and insulin responses to (1) oral ingestion of 100 g glucose oral glucose tolerance test (OGTT) and (2) a 100-g protein meal after an overnight fast in a randomized sequence at intervals of 7 to 10 days in five subjects with previously well-documented IRH and six normal subjects. Basal plasma glucose and insulin levels were not significantly different in both groups. However, basal glucagon was significantly higher (P < .025) in IRH subjects (347 ± 83 ng/L) compared with normals (135 ± 20 ng/L). In IRH subjects during the OGTT, hypoglycemia (2.7 ± 0.11 mmol/L) occurred at 150 ± 16 minutes and was preceded by a markedly higher (P < .01) peak glucose concentration (11.7 ± 0.6 mmol/L) at 36 ± 6 minutes in comparison to normals (8.8 ± 0.4 mmol/L), indicating the presence of impaired glucose tolerance in these subjects. Similarly, the plasma insulin increase was significantly higher (P < .01) but delayed in IRH subjects compared with normals. In contrast, glucagon suppression was not significantly different in both groups, although glucagon failed to increase following hypoglycemia in IRH. During a protein meal, plasma glucose declined in both groups, with a significantly (P < .05) greater decrease in IRH subjects (−0.8 ± 0.2 mmol/L) compared with normals (0.5 ± 0.1 mmol/L). However, the glucagon increase was significantly (P < .01) blunted in IRH subjects (61% ± 15%) in comparison to normals (152% ± 39%). Thus, basal hyperglucagonemia with normal glucose concentration may suggest the presence of a hyposensitivity of the glucagon receptor in IRH. Moreover, the lack of appropriate suppression during the OGTT despite marked hyperglycemia, the lack of an increase at the onset of hypoglycemia, and the inhibited response to a protein meal in IRH subjects compared with normals denote altered glucagon secretion in IRH. Therefore, it is likely that glucagon receptor downregulation and impaired glucagon sensitivity and secretion may contribute to postprandlal hypoglycemia in IRH.
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The hypoglycemoses include a large category of distinctly unique entities. Guidelines for a clinical, physiological approach to these disorders is presented. Within this diagnostic spectrum of hypoglycemia lies the reactive hypoglycemic disorders that are characterized by their postprandial onset, adrenergic mediated symptoms, and relatively benign causes. The spectrum of reactive hypoglycemia includes early alimentary-reactive hypoglycemia, late diabetic-reactive hypoglycemia, hormonal deficiency states, and idiopathic hypoglycemia. A new postprandial hypoglycemic disorder, fructose 1–6 diphosphatase, can be added to this list.The frequent sampling of blood-glucose values in the postprandial state will frequently lead to the finding of a biochemically low blood-glucose value of below , and these individuals show no hypothalamic-pituitary-adrenal stress to the low blood sugar and do not manifest adrenergic symptoms. Their low blood-glucose value simply reflects the transition in intermediary metabolism between the fed and fasting state and provides a biochemical marker of this event. We refer to this asymptomatic biochemical event as transitional low blood-glucose state. It has no clinical implication and may frequently be confused with the bona fide reactive hypoglycemic disorders.Using a symptomatic, counter-regulatory model to define hypoglycemia as a bona fide disorder, findings are presented in patients with the varying types of reactive hypoglycemia, and their results are compared to normal controls and to a weight-matched and disease patient controls. Abnormalities in insulin secretion are discussed as relating to the pathophysiology causal in the hypoglycemia. An approach to therapy is presented based upon the classification of the patient as to the type of hypoglycemia and their abnormalities in insulin secretion.
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The effects of cholinergic blockade on the plasma glucose and insulin responses during oral and intravenous glucose administration were studied. Propantheline (30 mg.) was given by mouth 45 minutes before standard glucose tolerance testing to produce symptomatic cholinergic blockade. In 10 normal subjects a flattening of the over-all plasma glucose response to oral glucose was observed compared with the control test, whereas insulin secretion was not different. In seven patients with repeated episodes of symptomatic reactive hypoglycemia, cholinergic blockade eliminated both symptomatic and chemical hypoglycemia in each, raising the mean nadir glucose from 44 ± 4 mg./dl. to 84 ± 8 mg./dl. (p<0.01) and significantly reducing insulin secretion. In contrast, following intravenous glucose challenge, cholinergic blockade produced no significant difference in the rate of glucose utilization or insulin secretion in either group. These results are compatible with the hypothesis that excessive vagal stimulation may contribute to the hypoglycemia seen in patients with reactive hypoglycemia but suggest that the predominant effect is on the gastrointestinal tract rather than on pancreatic islets directly. These studies confirm that anticholinergic drugs may be useful adjuvants in treating these patients.
Article
There is no single drug that proved effective in the treatment of orthostatic hypotension. Oral sympathomimetics like ephedrine, wyamine, aramine, and similar drugs are generally prescribed but, in our experience, their effectiveness is unpredictable; however they should be given a trial. Mineralocorticoids have already been referred to, 9 α fluorohydrocortisone (Florinef) is the one we use. Besides producing salt and water retention and expanding the blood volume, an effect which helps venous filling of the heart, it may increase the responsiveness of arterioles to the neurotransmitter. Recently there are claims that tyramine rich foods combined with monoamine oxidase inhibitors are effective in the treatment of resistant cases of IOH, but results were not encouraging when this regimen was tried in two of our patients. All kinds of drug therapy carry the danger of precipitating hypertension. Frequent observation of arterial pressure at weekly intervals is recommended. When Florinef is prescribed one should start with a small dose (0.1 mg. per day) which can be increased gradually according to therapeutic response. In conclusion the treatment of orthostatic hypotension still presents a challenging problem. The aim should be to keep the patient active and ambulatory as long as possible.
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Vasovagally mediated hypotension and bradycardia are believed to be common, but difficult to diagnose, causes of syncope. Upright tilt-table testing has been proposed as a possible way to test for vasovagal episodes. This study investigated the clinical utility of this technique in the evaluation and management of patients with syncope of unknown origin. Twenty-five patients with recurrent unexplained syncope and six control subjects were evaluated by use of an upright tilt-table test for 30 minutes, with or without an infusion of isoproterenol (1 to 3 micrograms/minute given intravenously), in an attempt to provoke bradycardia, hypotension, or both. Of the 25 patients, there were 14 males and 11 females, with a mean age of 50 +/- 16 years. Six control patients with no history of syncope were also studied. All tilt-positive patients received therapy with either beta-blockers, disopyramide, transdermal scopolamine, or hydroflurocortisone, the efficacy of which was evaluated by another tilt-table test. Syncope occurred in six patients (24%) during the baseline tilt and in nine patients (36%) during isoproterenol infusion (total positives, 60%). None of the controls had syncope during the test. All patients who had positive test results eventually became tilt-table-negative by therapy, and over a mean follow-up period of 16 +/- 2 months no further episodes have occurred. From this study we conclude that upright tilt-table testing combined with isoproterenol infusion is clinically useful in the diagnosis of vasovagal syncope and the evaluation of pharmacologic therapy.
Article
Prior studies suggest that postprandial hypotension in elderly persons may be due to defective sympathetic nervous system activation. We examined autonomic control of heart rate (HR) after a meal using spectral analysis of HR data in 13 old (89 +/- 6 years) and 7 young (24 +/- 4 years) subjects. Total spectral power, an index of overall HR variability, was calculated for the frequency band between 0.01 and 0.40 Hz. Relatively low-frequency power, associated with sympathetic nervous system and baroreflex activation, was calculated for the 0.01 to 0.15 Hz band. High-frequency power, representing parasympathetic influences on HR, was calculated for the 0.15 to 0.40 Hz band. Mean arterial blood pressure declined 27 +/- 8 mm Hg by 60 minutes after the meal in elderly subjects, compared with 9 +/- 8 mm Hg in young subjects (p less than or equal to 0.0001, young vs old). The mean change in low-frequency HR power from 30 to 50 minutes after the meal was +19.4 +/- 25.3 U in young subjects versus -0.1 +/- 1.5 U in old subjects (p less than or equal to 0.02). Mean change in total power was also greater in young (19.0 +/- 26.6 U) subjects compared with old subjects (0.0 +/- 1.6 U, p greater than or equal to 0.02). Mean ratio of low:high-frequency power increased 3.1 +/- 3.3 U in young subjects vs 0.5 +/- 2.7 U in old subjects (p less than or equal to 0.01). The increase in low-frequency HR power and in the low:high frequency band ratio in young subjects is consistent with sympathetic activation in the postprandial period.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Reactive hypoglycemia is a relatively uncommon meal-induced hypoglycemic disorder. Most patients with adrenergic-mediated symptoms have a diagnosis other than reactive hypoglycemia. In many patients with this self-diagnosis, other disorders can be attributed as a cause for symptoms, especially neuropsychiatric disease. The continued use of the terminology "functional hypoglycemia" only contributes vagueness to our correct understanding of this metabolic condition. There are a number of conditions associated with postprandial hypoglycemia. One category is the reactive hypoglycemias, which occur in patients with diabetes mellitus (diabetes reactive hypoglycemia), gastrointestinal dysfunction (alimentary reactive hypoglycemia), hormonal deficiency states (hormonal reactive hypoglycemia), and a large patient group characterized as having idiopathic reactive hypoglycemia. Of these causes the alimentary, hormonal, and diabetic patients are less disputed, whereas the idiopathic reactive hypoglycemic group has been referred to as a "nondisease" group. Characteristic alterations in insulin secretion accompany each of these conditions. In bona fide patients, dysinsulinism or hyperinsulinism usually accounts for the hypoglycemia. Some patients may have increased insulin sensitivity, but this association is doubtful or very rare. Patients with this meal-related eating disorder are characterized as ingesting excessive quantities of refined carbohydrate. In the research setting, the disorder can easily be elicited with the oral glucose tolerance test. However, to establish clinical relevance, the hypoglycemia needs documentation in the home setting with measurements of blood glucose during a postpradial symptomatic episode. The reactive hypoglycemic patients are frequently confused with patients with underlying psychiatric illness. Both syndromes are similar, with adrenergic-mediated symptoms and a common characteristic personality as noted on Minnesota Multiphasic Personality Inventory (MMPI) testing. Patients with bona fide meal-related reactive hypoglycemia should be treated primarily with dietary restriction of refined carbohydrates; other patients may require medications.
Article
We performed a euglycemic hyperinsulinemic glucose clamp in 20 patients selected from a large number of subjects referred to our clinic with symptoms suggesting reactive hypoglycemia. Diagnosis was made on the basis of blood glucose measurements during symptoms in their daily life and confirmed by a 5-h oral glucose tolerance test. The patients were divided into the following groups: 8 patients with idiopathic reactive hypoglycemia (IRH), i.e. biochemical hypoglycemia associated with symptoms and plasma insulin concentrations in the normal range; 6 patients with nonhypoglycemia (NH), i.e. patients experiencing the symptoms evoking hypoglycemia at essentially normal plasma glucose levels; and 6 patients with alimentary hypoglycemia secondary to previous gastric surgery (GS). Eight normal volunteers formed the control group (N). Hypoglycemia in this study was considered to be present when plasma glucose concentrations were below 2.5 mmol/L. The peak cortisol levels after glycemic nadir were higher (2P less than 0.05) in IRH compared to GS and N. In the same group, a partially deficient glucagon response to hypoglycemia was noted. During the euglycemic clamp, the glucose uptake appeared to be significantly greater in the IRH group than in NH, GS, and N groups (8.13 +/- 0.49 vs. 7.02 +/- 0.35, 6.48 +/- 0.22, and 6.66 +/- 0.42 mg/kg.min, respectively; 2P less than 0.05). Therefore, our data suggest that increased insulin sensitivity represents a feature of idiopathic reactive hypoglycemia.