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Livingwithreactivehypoglycemia.com
POSTPRANDIAL REACTIVE HYPOGLYCEMIA SUMMARY - Postprandial reactive hypoglycemia (PRH) can be di- ´ SUME´ - Hypoglycémie réactionnelle post-prandiale.
agnosed if sympathetic and neuroglucopenic symptoms develop concur-
Le diagnostic d’hypoglycémie réactionnelle (HR) nécessite l’observation
rently with low blood sugar (< 3.3 mmol). Neither the oral glucose toler-
simultanée d’une glycémie basse (< 3,3 mmol/l) et des signes sympathi-
ance test (OGTT) nor mixed meals are suitable for this diagnosis, due to
ques et neuroglucopéniques. L’hyperglycémie provoquée per os et les
respectively false positive and false negative results. They should be
repas tests mixtes entraînant respectivement de fréquents faux positifs
replaced by ambulatory glycemic control or, as recently proposed, an
et faux négatifs n’ont aucune valeur pour le diagnostic et sont à rempla-
hyperglucidic breakfast test. PRH patients often suffer from an associ-
cer par l’autocontrôle glycémique ou, comme récemment proposé, par
ated adrenergic hormone postprandial syndrome, with potential patho-
un petit déjeuner hyperglycémique. Les HR s’associent souvent à une
logic consequences such as cardiac arrhythmia. PRH could result from
hypersensibilité adrénergique postprandiale. Les HR s’expliquent par (a)
(a) an exaggerated insulin response, either related to insulin resistance
une décharge excessive d’insuline, due à une insulino-résistance ou au
or to increased glucagon-like-peptide 1; (b) renal glycosuria; (c) defects
glucagon-like-peptide 1, (b) des glycosuries, (c) une déficience de ré-
in glucagon response; (d) high insulin sensitivity, probably the most fre-
ponse du glucagon, et (d) une sensibilité élevée à l’insuline (mécanisme
quent cause (50-70%), which is not adequately compensated by hypoin-
probable de 50-70 % des HR). Cette dernière non compensée par un hy-
sulinemia and thus cannot be measured by indices of insulin sensitivity
poinsulinisme est indétectable par les index basés sur l’insulinémie à
such as the homeostatic model assessment. Such situations are frequent
jeun. Les HR sont fréquentes en cas de forte maigreur, d’adiposité gy-
in very lean people, or after massive weight reduction, or in women with
noïde modérée, ou d’amaigrissement important. Les habitudes alimen-
moderate lower body overweight. PRH is influenced by patient’s alimen-
taires influençant la survenue des HR, le régime est la thérapeutique de
tary habits (high carbohydrate-low fat diet, alcohol intake). Thus, diet
remains the main treatment, although α-glucosidase inhibitors and some
Key-words: hypoglycemia, insulin sensitivity, exercise, glucagon,
Mots-clés : hypoglycémie, insulino-sensibilité, exercice, glucagon,
✍ : J.F. Brun, Service Central de Physiologie Clinique,Centre d’Exploration et de Réadaptation des Anomalies duMétabolisme Musculaire (CERAMM), CHU Lapeyronie 34295Montpellier Cedex 5, France. E-mail : [email protected]Service Central de Physiologie Clinique, Centre d’Exploration et deRéadaptation des Anomalies Métaboliques et Musculaires (CERAMM),Received : June 23rd, 2000 ; revised : September 5th, 2000
Lapeyronie Hospital Montpellier, France.L owvaluesofbloodglucose,reachingthe cosetolerancetest(OGTT)shouldnotbeemployed
can be observed, are not unfrequent [1-2].
This conference provided thus the basis for a novel
While the differential diagnosis with “or-
approach of this disease on better defined bases. Since
ganic” causes of hypoglycemia [3] should
that time, several interesting advances have been per-
always be carefully discussed, most of these cases
formed in the understanding and treatment of the dis-
reflect a situation on the boundaries of physiology
ease. It is the purpose of this review to discuss post-
where glucose counterregulation becomes unable to
totally balance glucose disposal [1]. This situation was
pathogenesis, diagnosis, and treatment. Another usual
first evidenced by Harris [4] who reported in 1924 five
situation very close from reactive hypoglycemia is
cases of hypoglycemia following a meal, that he
exercise hypoglycemia, which is also “functional” in
called reactive hypoglycemia. Harris postulated that
nature and is frequently associated with an increased
reactive hypoglycemia was some kind of counterpart
occurrence of reactive postprandial decrease in blood
to diabetes mellitus: while the latter was considered to
glucose. It will not be reviewed in this article since we
result from hypoinsulinism, or at least impaired insu-
lin action, hypoglycemia was expected to be due tohyperinsulinism or dysinsulinism. Symptoms fullysimilar to those occurring during insulin-induced hy-
m WHICH ARE THE BOUNDARIES
poglycemia were observed at blood-glucose values
BETWEEN HYPOGLYCEMIA AND NORMOGLYCEMIA?
Later, this issue became for decades a matter of
While in his initial description Harris [4] reported
considerable controversy [5-6], due to a lack of con-
that symptoms of hypoglycemia occurred at blood-
sensus in definitions and to the unappropriate use of
glucose values below 0.7 g/l (3.9 mmol/l) the blood
the oral glucose tolerance test [7-8]. In addition, hy-
glucose value defining hypoglycemia has fluctuated
poglycemia has become a fashionable and overdiag-
since this time [10-13]. Some authors defined hy-
nosed disorder in several countries, due to its popular-
poglycemia as a decrease of more than 0.2 g/l [10] or
ization in the lay literature, so that a host of patients
10% to 20% [12-13] below the fasting blood glucose
used to describe signs suggestive for hypoglycemia
level. Such definitions are no longer accepted since
without any clinical evidence for low blood glucose, a
the rate of relative decrease does not modify physi-
situation that Cahill [5] and Yager [6] proposed to call
ological responses [14-17] which are set at fixed val-
ues, so that hypoglycemia should be defined on a level
Charles [9] who found that such patients never exhib-
of blood glucose [11, 18]. Physiological studies aim-
ited hypoglycemia after a mixed meal concluded that
ing at more closely defining “normoglycemia” in ev-
this situation has no relation to glycemia and should
eryday life [2] can help to define this level. Marks [2]
rather be termed “post prandial idiopathic syndrome”.
studied 30 healthy volunteers (aged 25-55 years), in
The number of terms applied to reactive hypoglyce-
whom he determined capillary blood glucose levels
mia have added to the confusion: these included func-
17-18 times a day during the ordinary everyday life,
tional hyperinsulinism, essential hypoglycemia, func-
i.e., a total of 498 values. The crude mean of all blood
tional hypoglycemia, dysinsulinism, hypoglycemic
glucose values was 4.2 ± 0.8 (S.D.) mmol/l, but there
fatigue, insulinogenic hypoglycemia, and relative hy-
was a physiological nadir at 17.00 hours (3.9 ±
0.6 mmol/l) while the highest level was found insamples collected at 14.00 hours which averaged 4.9 ±
Consensus conferences were held to clarify this
1.0 mmol/l. This study demonstrated that 5% of blood
question. Chairmen of the Third International Sympo-
glucose values of this sample were below 3.0 mmol/l
sium on Hypoglycemia (22-23 September 1986) in
and 2.8% below 2.8 mmol/l (0.5 g/l). Values < 3 mmol
Rome [8] published a consensus statement indicating
were found in 33% of subjects and values < 2.8 in
that, although the disease was generally overdiag-
17% of them. Since ninety-five percent of all blood
nosed, there was no doubt that “some patients exhibit
glucose values were above 3 mmol/l (0.54 g/l) hy-
postprandial symptoms suggesting hypoglycemia in
poglycemia could be defined biochemically as a blood
everyday life and that, if these symptoms are accom-
glucose level below this level [2]. However, consen-
panied by blood glucose levels between 2.8 and 2.5
sus statements proposed a lower cut-off value at 0.4
mM or below (determined by a specific method on
g/l (= 2.2 mmol/l) on whole blood and 0.5 g/l
capillary or arterialized venous blood, respectively)
(= 2.8 mmol/l) on plasma [8]. This definition was
the diagnosis of postprandial, or reactive, hypoglyce-
questionable since it did not take into account the fact
mia may be correct. In these patients, every effort
that symptoms physiologically occur at threshold val-
should be made to document hypoglycemia under
ues comprised between 3 and 3.5 mmol [19-23].
their everyday-life conditions.”. Another important
These thresholds have been carefully described on
conclusion of that conference was that the oral glu-
arterialized blood by Mitrakou et Cryer [24] who
found at 3.7 mmol the onset of counterregulatory
First, diagnosis based upon symptoms, (including
hormonal response (glucagon, epinephrine, norepi-
the usual self-diagnosis by patients themselves), is
nephrine and growth hormone), at 3.2 mmol the onset
seldom confirmed by accurate investigations [30]. Re-
of the sympathetic response and at 2.8 mmol/l the
cent consensus statements [8] emphasize the impor-
onset of neuroglucopenic symptoms. Deterioration in
tance of interpretating the patient’s symptoms in re-
cognitive function tests began at 2.7 mmol/l. In
spect to the blood glucose determination.
venous blood, thresholds are less precisely defined,
Despite their lack of specificity, symptoms could
but are interesting to assess since blood glucose is
be analyzed with a questionnaire [24] and quoted from
usualy measured on venous blood. Consistent with
0 to 5 (Table I). If clinical exploration reproduces the
this literature [20-24], we found on whole venous
hypoglycemic event, it is interesting to compare
blood that symptoms occur as soon as 3.5 mmol, with
symptoms of the laboratory event and the self-
a mean value at 3 mmol for adrenergic symptoms and
reported symptoms. Note that more recently the clas-
neuroglucopenic symptoms [25]. This value of
sification of these symptoms has been readdressed
3 mmol/l is the same as that reported by PJ Lefèbvre
with a multifactorial analysis [31] leading to a slightly
[1] in a paper reviewing studies performed in healthy
different list of symptoms. According to these authors,
volunteers in whom mild hypoglycemia was induced
signs of hypoglycemia cluster into three sets: auto-
with an insulin infusion. At this precise value of
nomic (sweating, palpitation, shaking and hunger),
3 mmol/l, the symptoms included weakness, difficulty
neuroglucopenic (confusion, drowsiness, odd behav-
in thinking and concentrating, diaphoresis, palpita-
ior, speech difficulty and incoordination), and malaise
tions and tremor. Values at which neurophysiological
(nausea and headache). However, this description has
testing is impaired range between between 2.2 and
not, as far as we know, resulted in a new standardized
3.5 mmol/l while objective electrophysiological test-
questionnaire and the classical one is still employed
ing has been demonstrated to already show alterations
already at 4 mmol/l [26]. More recently, studies on
However, unusual clinical presentations are not
driving performance when blood glucose levels de-
rare. For instance, in the study of Lev Ran [32], there
crease have also given evidence for early disturbances
was one of the patients who suffered from arthritis of
in several neurological functions at levels of blood
the hip with a sharp increase in pain after meals rich in
glucose higher than 3 mmol. For instance, Cox [27]
sugar. He did not suspect he was hypoglycemic, but
evidences important alterations between 3.3 and
during glucose tolerance testing he recorded hip pain
2.8 mmol, but also finds that between 4 and 3.3 mmol
when his plasma glucose reached a nadir of 0.44 g/l. A
there is already a significant disturbance of driving
low carbohydrate diet significantly decreased his pain
performance at high speed and a higher feeling of
during the 18 months that he was followed [32]. Due
difficulty in this task. These values are defined on
to this lack of specificity of symptoms, blood glucose
venous blood. Thus, in contrast to the classical state-
measurement should be performed in association with
ments defining hypoglycemia below 2.8 mmol, there
is a large body of evidence that indicates important
Permutt [33] recommended that the reproduction of
alterations, that may disturb everyday life, in the range
symptoms of hypoglycemia occurring in the home
of 3-4 mmol. Although these values are not likely to
situation during an OGTT at the time of plasma glu-
be at risk for neurological damage, they could result in
cose level of less than 0.50 g/l (2.8 mmol) is sufficient
marked uncomfort and difficulties for intellectual or
for the diagnosis of reactive hypoglycemia. However,
psychomotor tasks. Thus, defining hypoglycemia as a
it has been obvious since more than twenty years that
blood glucose value below 2.8 mmol (0.5 g/l), asclassically done [10], is probably too restrictive [3]. Based upon these physiological data a cut-off valuearound 3.3 (onset of counterregulatory responses)
Standardized list of symptoms of hypoglycemia. Each signcould be quoted from 0 to 5 allowing the calculation of a “score”. After[20, 24, 26].
m HOW TO PERFORM THE POSITIVE Sympathetic signs Neuroglucopenic signs DIAGNOSIS
Most of the confusion on reactive hypoglycemia is
clearly related to the diagnostic procedure [1, 5-8,9-11]. Usually, patients are referred to the endocri-
nologist with such a diagnosis made on the basis of
either an OGTT showing a low post-challenge bloodglucose value, or a rather imprecise description of
postprandial symptoms: obviously, none of these two
informations is conclusive for the diagnosis [28-30].
this could lead to most cases of misdiagnosis [11],
of no value in the diagnosis of functional hypoglyce-
since plasma glucose nadirs below 2.8 mmol are usual
mia [34] and should thus not be recommended.
in healthy persons after OGTT, while symptoms arenot specific [1, 7, 8, 11]. Therefore, the OGTT hasbeen repeatedly demonstrated to be not suitable at all
The golden standard (?): ambulatory glucose sam-
for this diagnosis, although it surely remains the most
widely employed procedure in this context. The prob-
Clearly, accurate diagnosis of hypoglycemia re-
ably most convincing demonstration of this was given
quires that symptoms develop concurrently with low
by Lev Ran and Anderson [32] who studied the de-
blood sugar and that they are absent at other times.
crease in blood glucose after OGTT in 650 patients
Low plasma glucose must be considered only if it
who were entirely free from hypoglycemic symptoms,
occurs in correlation with symptoms. By the past, this
either before and during testing. They found that 10%
diagnosis needed to be performed in an hospital unit.
of the patients had plasma glucose nadirs of 0.47 g/l
Nowadays, ambulatory glycemic control may give the
(2.6 mmol/l) or below and 2.5% had values of 0.39 g/l
means to measure glycemia in everyday life and to
(2.15 mmol/l) or less. Similarly, in a large group of
confirm, when symptoms occur, whether or not they
military draftees tested 2 h after glucose challenge,
are associated to a low blood glucose value. Palardy et
Fariss [34] found plasma glucose concentrations be-
al [38] investigated 28 patients referred for suspicion
low 0.49 g/l (2.7 mmol/l) in 7.4%, and below 0.29 g/l
of this disorder with ambulatory glycemic control and
(1.6 mmol/l) in 14%. Since most nadirs occur later
found at the time when symptoms occurred values of
than 2 h after glucose load, it is probable that their
blood glucose < 3.3 mmol in 46% of the subjects, and
true incidence is even higher than Fariss reports. In
< 2.8 mmol in 18% of them. This study provided a
another study [10], Hofeldt noted that 48% of normal
milestone in the history of PRH since it first demon-
subjects had nadirs below 0.50 g/l (2.8 mmol/l). Oc-
strated a rather high (46%) occurrence of bona fide
casionally, values as low as 0.35 g/l (1.9 mmol/l) are
hypoglycemia in patients referred for this diagnosis,
found in healthy persons. [11, 35]. Thus, reactive
and proposed the accurate tool for performing the
hypoglycemia is quite a “normal” finding after OGTT,
diagnosis. Patients have to be carefully educated to the
whether or not subjects suffer hypoglycemia after
use of glucose analyzers and should be asked to write
meals during their everyday life. Pure glucose appears
their blood glucose values, their association with
to be an unphysiologic stress, seldom encountered
signs, and whether sugar ingestion reverses them [19].
outside the clinical laboratory [7], and that induces a
However, this procedure is not always conclusive and
rather different glucose kinetics than a mixed meal
it is sometimes difficult to affirm that signs are due to
[36]. It is clear that a 75-g glucose load is a much
low blood glucose values. Presumably, when signs
stronger stimulus to insulin secretion and, therefore, is
occur, counterregulation has already started to operate
much more likely to provoke reactive hypoglycemia
and glycemia is not as low as expected because it is
than any meal [7]. Although the upper limits of nor-
increasing in order to recover from the hypoglycemic
mal for glucose tolerance testing are standardized in-
event. Thus, although considered as the “gold stan-
ternationally, there is no agreement concerning the
dard” for diagnosis of PRH, glycemic control is prob-
clinical significance of lower values obtained during
ably not devoid of false negative results and there is
testing. Clearly, considering nadirs below 0.50 g/l
room for an alternative approach as indicated below.
(2.8 mmol/l) abnormal leads to overdiagnosis of PRH[11]. All consensus statements emphasize that the glu-cose tolerance test alone is not a reliable means for
The breakfast test
diagnosing reactive hypoglycemia.[8] By contrast, itis suggested that this test could still be employed for
Theoretically, a standardized breakfast test could
further investigation (insulin response, glucose toler-
be a more accurate test than OGTT since it mimics
ance, relationships between symptoms and blood glu-
everyday life habits. If a patient undergoes hypogly-
cose values, counterregulation) after the diagnosis has
cemia after such a meal, this is not likely to be an
artifact as for the OGTT. On the other way about, sucha response would demonstrate that hypoglycemia canoccur in the patient’s everyday life. However, this
“The hypoglycemic index”
issue was extensively studied at the beginning of the1980 [9, 39-44] and all studies concluded that after a
The hypoglycemic index [37] is the drop of plasma
mixed meal patients referred for PRH almost never
glucose during the 90 min preceding the nadir divided
demonstrate a fall in blood glucose. Charles [9] con-
by the nadir value. It is reputedly above 0.8 in all
cluded that PRH actually did not exist or at least
symptomatic patients, and was said to be especially
should be considered as a “postprandial syndrome”
valuable for patients with nadirs below 0.65 g/l
that had nothing to do with glycemia. In fact all
(3.6 mmol/l). Lev Ran, consistent with Johnson and
authors used rather equilibrated mixed meals which
others [11] concluded that the hypoglycemic index is
reproduce the dietary correction of the PRH rather
than the hyperglucidic meal that induced the fall in
and is based upon the 48 to 72 hr fast test [19, 47].
glycemia. It is very likely that, in contrast to OGTT
Due to the low frequency of insulinoma, it is thus
which is too sensitive, mixed breakfast test are too
questionable in terms of health cost policy to perform
balanced, and that this is the reason why they almost
a prolonged fast in all patients referred for suspicion
never evidence hypoglycemia in subjects referred for
of hypoglycemia, and even more when this hypogly-
cemia is typically reactive and occurs after a meal
We thus developed [45] a new “hyperglucidic
[48]. However, there remains probably in some cases
breakfast test” which mimics more closely than the
a possibility to fail to detect an insulinoma if the 48 hr
above the dietary habits of people prone to PRH. This
fast is not performed. This is clearly demonstrated by
meal is composed of bread (80 g), butter (10 g), jam
a recent case report of insulinoma presenting as a late
(20 g), skimmed concentrated milk (80 ml), sugar (10
post-prandial hypoglycaemia in a patient who had
g) and powder coffee (2.5 g), which corresponds to
previously undergone subtotal gastrectomy [49]. This
2070 kilojoules with 9.1% proteins, 27.5% lipids, and
case report supports the use of the fasting test in some
63.4% carbohydrates. Thus, the test provides an al-
cases of PRH, when they appear to be severe and to
most equivalent amount of carbohydrates as the stan-
resist to dietary prescription. However, in our opinion,
dard OGTT (75g) and gives similar increases in blood
the fasting test should not be initially applied to the
glucose than standard OGTT in patients with impaired
subjects referred with a typical tableau of PRH.
glucose tolerance [46]. However, it proved to be suit-able for the diagnosis of hypoglycemia [45]. Usingthis hyperglucidic breakfast test we compared 43 con-
m PSEUDOHYPOGLYCEMIA AND
trols, 38 individuals referred for suspicion of post-
ADRENERGIC POSTPRANDIAL
prandial reactive hypoglycaemia and 1193 asymptom-
SYNDROME: A DIFFERENTIAL DIAGNOSIS OR AN ASSOCIATED
glycoregulation. We found that blood glucose levels
DISTURBANCE?
< 3.3 mmol/l were rare in subjects with no complaintof hypoglycemia (2.2% of control subjects and 1% of
Another explanation of the past confusion concern-
asymptomatic subjects) while they were found in
ing PRH is the disturbed psychological background
47.3% of subjects with suspected postprandial reactive
most often found in patients. The psychiatric literature
hypoglycaemia. This frequency is similar to that re-
related hypoglycemia to life situations, emotions, ten-
ported by Palardy in such patients explored with am-
sion, depression, neurosis, and asthenic syndromes
bulatory glycemic control, i.e., 46% of his 28 patients
and to a condition of pernicious inertia [10]. Subse-
exhibiting blood glucose levels < 0.6 g/l (3.3 mmol/l).
quently, reactive hypoglycemia became associated
It should be pointed out that values < 2,8 mmol/l were
with a number of disease states that included behav-
rare and were not found more frequently in patients
ioral disturbances, criminal behavior, alcoholism, al-
referred for PRH compared to the other two groups.
lergies, rheumatoid conditions, neurological distur-
Thus, the breakfast test evidences in almost half of the
patients a significant, albeit moderate decrease in
syndromes [10]. In addition, in a recent report [50]
blood glucose which is neither found in the controls
Kurlan suggests that postprandial reactive hypoglyce-
nor in the general population. This markedly higher
mia and restless leg syndrome might be related disor-
frequency of (moderately) low blood glucose values in
subjects with postprandial symptoms compared with
Harris, in his initial publication, also observed low
control and asymptomatic subjects suggests that this
blood-pressure readings in all but two of the nondia-
test detects a tendency to hypoglycemia after a stan-
betic patients who had symptoms of reactive hypogly-
dardized hyperglucidic breakfast. Since this test more
cemia and postulated that there may be an association
closely mimics the spontaneous situation in which
between the altered insulin secretion and abnormali-
hypoglycemia may occur during everyday life, these
ties in secretory disorders of the thyroid, pituitary, or
results suggest that the patients may also undergo such
adrenal gland [4]. A mild deficiency in adrenal or
symptoms in their day to day life. We thus proposed
pituitary counterregulatory response was then sug-
the hyperglucidic breakfast test as a simple alternative
gested, leading to some treatments with gland extracts
to ambulatory glucose sampling for diagnosis of post-
which were clearly not recommended by experts [10].
prandial reactive hypoglycaemia [45].
Hypoglycemia shoud also be distingued from Me-niere’s syndrome, idiopathic hypertrophic subaorticstenosis, migraine, functional bowel disorder, mitral
m A STILL IMPORTANT DIFFERENTIAL
valve prolapse, factitious thyrotoxicosis [32]. In fact,
DIAGNOSIS: INSULINOMA
the nonspecific symptoms of reactive hypoglycemiacan be seen in a host of paroxysmal disorders that
The diagnosis of insulinoma, a rather rare tumor,
present as adrenergic mediated syndromes: anxiety
the incidence of which is estimated to be four cases
neurosis, seizure disorders, pheochromocytoma, carci-
per 1 million person-years [47] is generally difficult
noid syndrome, hyperthyroidism, cardiac arrhythmias,
dumping syndrome, and beta-adrenergic hyperrespon-
3.1; nausea 3; headache 3; hunger 2.9 [25]. By con-
sive state (De Costa’s syndrome) [10].
trast, when symptoms are quoted during a PRH repro-
PJ Lefevre [1] proposes the term of “Adrenergic
duced with the hyperglucidic breakfast test, these
hormone postprandial syndrome” to describe auto-
thresholds are not at the same levels: respectively: 4;
nomic symptoms (anxiety, palpitations, sweating, irri-
4; 4; 3.9; 3.9; 3.8; 4.7; 4; 4.1 mmol. Thus, symptoms
tability, tremor.) that are experimentally observed
of PRH are reported at a higher blood glucose levels
after insulin infusion, at plasma glucose levels of
than symptoms of hypoglycemia artificially induced
about 3.7 mmol/l. It is likely that, in some individuals,
by insulin in non PRH prone individuals. Adrenergic
after a meal, such autonomic counterregulation may
symptoms are found at 4 ± 0.1 vs 3 ± 0.1 mmol and
occur. This counterregulatory response induces symp-
neuroglucopenic symptoms at 4 ± 0.2 vs 3 ± 0.1
toms but also prevents biochemical hypoglycemia be-
ing achieved [19]. In such cases, since low blood
(p < 0.001) [25]. Clearly, thresholds of appearance of
glucose levels do not occur, the term “postprandial” or
hypoglycemic symptoms are shifted towards higher
“reactive” hypoglycemia should thus be avoided.
blood glucose levels in patients with bona fide PRH. This is even more striking for the autonomous signs.
However, it is clear that patients with bona fide
Thus, pseudo-hypoglycemia may be associated with
reactive hypoglycemic states may manifest an abnor-
true PRH, so that the diagnosis of PRH could not be
mal personality profile as determined, for instance, by
fully excluded in patients with an obvious tableau of
the Minnesota Multiphasic Personality Inventory
pseudo-hypoglycemia and adrenergic hormone post-
(MMPI) [11]. These patients’ personality profiles are
characterized by hypersomatization and hypochon-
This adrenergic hormone postprandial syndrome is
driacal complaints. Therefore, it would surely be erro-
likely to be of clinical relevance, since Rokas and
neous to consider as fully different syndromes the true
coworkers [52] published a case report of a patient
postprandial or reactive hypoglycemia and this adren-
with refractory atrioventricular nodal reentry tachycar-
ergic hormone postprandial syndrome. Several lines of
dia in whom it was possible to document that reactive
evidence suggest that these mechanisms frequently
hypoglycemia was the trigger for aggravation of ar-
coexist, explaining to some extent the specific psycho-
rhythmia. Over a period of 6 years, a series of elec-
logical and behavioural pattern of the bona fide PRH
trophysiological studies revealed that, when the pa-
prone patients. This issue has been investigated by
tient was in a hypoglycemic state, initiation of
Berlin [51] who studied eight patients with suspected
tachycardia was easy and most importantly that tachy-
postprandial hypoglycemia in whom he evaluated
cardia termination by extra-stimulus pacing always
beta-adrenergic sensitivity with the isoproterenol sen-
failed. Furthermore, atrial fibrillation was inducible or
sitivity test. While plasma epinephrine and norepi-
spontaneously occurred only when the blood glucose
nephrine responses after OGTT were similar than
level was reduced by IV insulin administration [52].
those of controls, both heart rate and systolic bloodpressure were significantly higher (albeit remainingwithin the normal range) compared to controls. More-
m PHYSIOLOGICAL BASIS
over, after glucose intake, seven patients had symp-toms (palpitations, headache, tremor, generalized
Hypoglycemia is basically an unbalance between
sweating, hunger, dizziness, sweating of the palms,
glucose influx to the circulation (from endogenous
flush, nausea, and fatigue), whereas in the control
glucose production or exogenous glucose delivery)
group, one subject reported flush and another palpita-
and glucose efflux [53]. While external losses may be
tions, tremor, and hunger. Psychological analysis
a cause of hypoglycemia in the case of massive renal
showed that patients had emotional distress and sig-
glycosuria [54], glucose efflux is generally almost
nificantly higher anxiety, somatization, depression,
equivalent to glucose utilisation by tissues. This bal-
and obsessive-compulsive scores than controls. This
ance between glucose influx and efflux is controlled
study shows that such patients with suspected post-
by a complex equilibrium of glycoregulatory hor-
prandial hypoglycemia most often exhibit an in-
mones that may undergo various disturbances.
creased beta-adrenergic sensitivity and emotional dis-
Normoglycemia is physiologically maintained by a
complex set of regulatory mechanisms, which are thus
We investigated [25] this association between bona
likely to be impaired in various situations. First, insu-
fide PRH and postprandial adrenergic syndrome by
lin suppresses hepatic glucose production and, at
determining at which levels of venous blood glucose
higher levels, stimulates glucose utilisation by insulin-
adrenergic and neuroglucopenic symptoms were
sensitive tissues. Glucagon and epinephrine stimulate
found in subjects either complaining of PRH or with-
both glycogenolysis and gluconeogenesis. Insulin,
out this complaint. When hypoglycemia is artificially
glucagon, and epinephrine act rapidly (in minutes).
induced by an insulin infusion, symptoms occur at the
Over a longer time frame (3-4 h), cortisol and growth
following levels: vertiges 3.5 mmol; sweating 3.3;
hormone both limit glucose utilisation and stimulate
tremor: 3.3; blurred vision 3.2; anxiety 3.2; weakness
glucose production. Among the counterregulatory hor-
mones, glucagon initially plays a primary counter-
On the whole mechanisms by which blood glucose
regulatory role. Epinephrine is not normally critical
returns after 2-3 hours to a steady state value after a
unless glucagon secretion is deficient, so that hypogly-
meal appear to be a remarkably integrated mechanism
cemia will occur in situations where both glucagon
which results in a smooth transition from exogenous
and epinephrine are deficient while insulin is present,
glucose delivery to endogenous glucose production.
even when all other glucose counterregulatory sys-
The complexity of this coordinated process explains
tems are intact [55]. While glucagon, in terms of
why some degree of unbalance among insulin release,
effects on glucose metabolism, acts mostly on hepatic
insulin sensitivity and counterregulatory response may
glucose production, epinephrine decreases glucose
result in a fall of blood glucose concentration below
Therefore decrements in insulin and increments in
glucagon and, in the absence of glucagon, epineph-
m MECHANISMS OF PRH
rine, play important roles in the prevention and cor-rection of hypoglycemia. This has been demonstrated
Although some aspects require further investiga-
in the postprandial state, after overnight and 3-day
tion, most of the pathophysiology of PRH is nowadays
fasts, and during moderate physical exercise in hu-
elucidated and it is no longer correct to state that this
mans. Hypoglycemia develops over the short term
is an undefined entity whose mechanisms (and exist-
under all of these conditions when both glucagon and
epinephrine are deficient and insulin is present. Theroles of growth hormone and cortisol in the preventionof hypoglycemia are less easy to understand because
Exaggerated insulin response
they are rather long-lasting (12 hr). Thus they are not
A role for exaggerated insulin response was sus-
likely to impair recovery from hypoglycemia [47]
pected until the first reports by Harris [4]. The term
while some roles can be inferred from the fact that
“functional hyperinsulinism” (proposed by Conn [69])
fasting hypoglycemia sometimes develops in patients
has been utilized for describing the syndrome. With
(particularly young children) with chronic deficiencies
the appearance of extensive utilisation of methods for
the assay of plasma insulin, studies have been under-
Besides, there is evidence that glucose autoregula-
taken to confirm this hypothesis. Consistent with clas-
tion modulates hepatic glucose production as an in-
sical assumptions, a study conducted by Luyckx and
verse function of plasma glucose concentration inde-
Lefebvre [54] on forty-seven patients demonstrated to
pendent of hormonal and neural regulatory factors in
suffer from reactive hypoglycemia (< 45 mg/100 ml)
humans [53]. Autoregulation appears to be important
evidenced an exaggerated insulin response as the ma-
only during severe hypoglycemia (1.7 mmol/l) and not
jor abnormality explaining hypoglycemia, either in
during more moderate hypoglycemia (2.8 mmol/l) in
obese with impaired glucose tolerance or in isolated
PRH. A characteristic pattern was when the release ofinsulin is sluggish and the insulin peak delayed with
Skeletal muscle has also been reported to contrib-
respect to the peak value for blood glucose.
ute to defense against hypoglycemia. During hypogly-
While the most usual cause of an increased insulin
cemia, muscle markedly decreases (80%) its rate of
response is most often assumed to be insulin
glucose uptake [56-58], via a reduction in glycogen
resistance-related hyperinsulinemia [10, 54], there
synthase activity [56, 59] and in fractional velocity for
may be other mechanisms for hyperinsulinemia. For
glycogen synthase [60]. Epinephrine has been shown
example there has been an anecdotic report of reactive
hypoglycemia (0.34 g/l) with an unusually exagger-
adrenergic receptors [61] and this effect is mostly due
ated insulin secretion (more than 1000 µU/ml) which
to a reduction in nonoxidative glucose utilization via
seems to be explained by an exaggerated response of
an inhibition of insulin-mediated glycogenogenesis
glucagon-like-peptide-1 (GLP-1) [70].
[62]. Therefore, it is likely that muscular insulin resis-
Interestingly, hyperinsulinemia has been reported
tance in muscle during hypoglycemia is an important
to enhance epinephrine, norepinephrine and cortisol
defense against hypoglycemia and is to some extent
secretion in response to hypoglycemia [71], while it
due to catecholamines. This mechanism has been re-
does not modify glucagon and GH responses. Thus,
ported to be more prominent during prolonged hy-
excess insulin may be a factor involved in the post-
poglycemia, while stimulation of glucose production
prandial adrenergic syndrome whose link with PRH is
is predominant initially [53]. By contrast, this mecha-
nism is limited by the fact that glucose transportacross the muscular cell membrane, which is critical
Alimentary hypoglycemia
in insulin action [63-65] is up-regulated in situationsof hypoglycemia [66-67], and is not reduced by epi-
The PRH due to accelerated stomach emptying has
been proposed to be termed alimentary hypoglycemia
[72-73]. It is frequent in totally or partially gastrecto-
A major cause of PRH is surely high insulin sensi-
mized patients [54, 72-73]. Most generally this variety
tivity [1, 29, 30, 54]. This mechanism was postulated
of hypoglycemia is related to an excess insulin re-
many years before the tools for demonstrating it were
sponse [54]. Recent advances in the understanding of
made available [4]. It has been demonstrated by Tam-
this specific cause of hypoglycemia should be briefly
burrano [79] using the glucose clamp procedure. In 10
mentioned here. A study of gastric emptying in in 27
of 16 patients in whom PRH was diagnosed with
tumor-free totally gastrectomized patients provided
ambulatory glucose testing, the clamp evidenced an
convincing evidence that a rise in GLP-1 inducing
elevated insulin-stimulated glucose uptake. Further,
both insulin release and inhibition of pancreatic glu-
the same team [80] evidenced an increased nonoxida-
cagon explains the reactive hypoglycemia encountered
tive glucose metabolism that appears to explain most
in some patients following gastric surgery. The peak
of this increased glucose disposal as evidenced in
postprandial concentration of GLP-1 averaged 44
clamp experiments. They investigated eight patients
pmol/l in controls, 172 in gastrectomized patients
with PRH compared to eight controls during an
without reactive hypoglycemia, and 502 in patients
euglycemic-hyperinsulinemic clamp associated with
whose glucose fell below 3.8 mmol/l during the sec-
indirect calorimetry and found a similar rate of glu-
ond postprandial hour. Rapid emptying seems to be
cose oxidation in PRH subjects and controls, either in
one causative factor for the exaggerated response of
basal conditions and during the clamp studies, but the
gastro-intestinal insulin-stimulating hormones [74].
nonoxidative glucose disposal was significantly higher
This issue has been more recently investigated by Toft
(± 63%) in PRH than in controls. They also report a
Nielsen [75] who reproduced the glucose and hor-
lower rate of fat oxidation during insulinization in
mone profiles of the patients with reactive hypogly-
PRH, while the glucagon response to clamp (that is
caemia in healthy volunteers with an i.v. infusion of
normally found in controls) is blunted in PRH pa-
glucose, associated or not with i.v. GLP-1 infusion, or
tients. Thus, increased insulin-mediated glucose dis-
alternatively the other incretin hormone, glucose-
posal appears to be due to an increase in nonoxidative
dependent insulinotropic polypeptide (GIP). These
glucose metabolism. For these authors, it is clear that
procedures after termination of i.v. glucose achieved
an increase in insulin sensitivity associated with a
different glucose concentrations. Clearly the lowest
deficiency in glucagon secretion can widely explain
was after GLP-1 (2.4 mmol/l) while they were 3.7
the occurrence of hypoglycemia in the late postpran-
with low GIP, 3.3 with high GIP and 4.5 for glucose
alone. Thus, the exaggerated GLP-1 response to nutri-
We investigated this question with the minimal
ents in patients with accelerated gastric emptying is
model technique [81] and also found a high insulin
very likely to be responsible for their high incidence
sensitivity explaining more than 50% of our cases of
of postprandial reactive hypoglycaemia [75].
confirmed PRH. Interestingly, only the insulin-dependent component of glucose disposal was in-
PRH without hyperinsulinism: renal glycosuria, in-
creased, while the non-insulin dependent component
creased insulin sensitivity, or defects in counter-
of glucose effectiveness termed glucose effectiveness
regulation
at zero insulin was not significantly increased. Thiscontrasts with exercise hypoglycemia where this pa-
Abnormalities in circulating plasma insulin do not
rameter mostly explains the increased glucose dis-
explain all cases of reactive hypoglycemia, and about
half of patients in all published series have normalinsulin response [54, 76]. This led several authors to
It should be reminded that GLP-1 stimulates gly-
speculate on the existence of an inadequate counter-
cogen storage in muscle, [82] i.e., a component of
regulation in these subjects or of a possibility of a
nonoxidative glucose disposal that has been shown to
relatively exaggerated sensitivity to insulin [1, 29, 30,
be increased in patients with PRH [79-80]. Thus this
gastro-intestinal hormone may also play a role in this
The first well-defined mechanism of reactive hy-
poglycemia without hyperinsulinism has been renal
Thus, it seems well demonstrated by two different
glycosuria [77-78]. In some series it could represent
teams and with the two most accurate techniques that
15% of the patients [54]. Actually, an excess insulin
increased insulin sensitivity is the most usual mecha-
response during OGTT has been described in certain
nism of PRH. It probably explains fifty to seventy per
cases of renal glycosuria [77-78]. This hyperinsulin-
cent of the cases [79, 81]. However, it is not likely that
ism is apparently not involved in the pathogenesis of
increased insulin sensitivity alone can induce hy-
reactive hypoglycemia [54]. An excess renal loss of
poglycemia, since high values like those found in
glucose is likely to result in a slight unbalance be-
PRH are found in young, lean people who never
tween glucose production and disappearance, since the
report suffering PRH. The team of RN Bergman has
insulin response is related to the amount of the carbo-
developped the concept of an homeostatic balance
hydrate load while an important part of this load is
between insulin sensitivity and insulin secretion, so
that when insulin sensitivity increases, insulin levels
decrease in order to avoid excess insulin action [83].
cose clamp. When only insulin and glucose were in-
This relationship is a hyperbola: SIxI = constant [84]
fused the PRH patients required 20% higher glucose
where SI is insulin sensitivity and I insulin plasma
infusion rates to maintain euglycemia than controls.
levels. In our study, we analyzed this feedback loop
However this difference disappeared during second
and found that SIxI was actually increased in most
step of the clamp when basal glucagon was restored
PRH patients [81]. Thus, high insulin sensitivity is
by a glucagon perfusion. Thus, the glucagon defect
generally compensated by a decrease in insulin secre-
seems to play a role in the increased glucose disposal.
tion, and may generally not result in hypoglycemia
Glucagon may protect againt hypoglycemia via some
unless another abnormality is associated, leading to a
degree of insulin resistance that it induces [90].
disruption of the feedback loop SIxI = constant [84].
The abnormality of glucagon in PRH seems to
Whether a blunted glucagon response as described by
include also some degree of glucagon resistance, as
Leonetti [80] is involved by some way in this dis-
shown by Ahmadpour [91] who reported 2.5 fold
rupted feedback remains to be clarified.
higher values of basal glucagon in PRH subjects than
This finding of a loss of the homeostatic loop
in controls while, during a protein meal, its response
between insulin sensitivity and insulin secretion has
was 2.5 fold lower. This basal hyperglucagonemia
also practical consequences. It is useful in many clini-
with normal glucose concentration may suggest the
cal situations to measure insulin sensitivity with sim-
presence of a hyposensitivity of the glucagon receptor
plistic indices derived from baseline glucose and insu-
in PRH while the blunted response to hypoglycemia
lin, such as the homeostatic model assessment insulin
and to a protein meal reflected an altered glucagon
resistance index (HOMA-IR) [85] or the simple index
secretion. These authors conclude that in PRH sub-
SI= 40/Ib where Ib is basal fasting insulin and 40 the
jects both glucagon sensitivity and secretion are im-
average value of the constant SIxIb if Ib is expressed
paired and that these mechanisms are involved in the
in µU/ml and SI in min– 1/(µU/ml). 10– 4. [86]. The
validity of these indices is based on the assumption
A case of severe PRH with hyperinsulinaemia and
that insulin levels are a mirror of insulin resistance,
absent glucagon response to hypoglycaemia due to a
due to that feedback loop [84]. If the feedback loop is
defect in hepatic glucose-6-phosphatase enzyme sys-
disrupted, these indices do no longer mirror insulin
tem has been reported by Pears [92] who considers
sensitivity. This is clearly the case in PRH [87] where
this case as an example of disordered pancreatic islet
HOMA-IR and other related indices cannot predict
increased insulin sensitivity and should thus be
On the whole, the importance of a defect in gluca-
gon secretion in reactive hypoglycemia now appears
On the other hand, this picture of high insulin
well demonstrated. By contrast, very little his known
sensitivity as a prominent aspect of PRH sharply con-
about abnormalities of other counterregulatory hor-
trasts with the insulin resistance that characterizes
Defects in counterregulation
m INFLUENCE OF BODY COMPOSITION
Defects in counterregulatory response resulting in a
Very lean people are prone to hypoglycemia, a
lack of compensation of the hypoglycemic effect of
condition that could trigger accidents at work through
insulin has been long suspected. In a series of nineteen
errors in judgment by impairing cognitive function in
patients Mirouze [89] reported that postprandial reac-
some countries: this is clearly shown in a study on 77
tive hypoglycaemia is associated with a low response
“healthy” volunteers conducted in India [93]. In this
in glucagon to OGTT while this response is high in
study 22.4% of the 76 subjects experienced biochemi-
people who no not suffer from this symptom. In addi-
cal hypoglycemia (less than 3.3 mmol/l) as demon-
tion, he found that treatment with pectin protected
strated by multiple blood glucose determinations. This
against falls in blood glucose after OGTT, by increas-
underestimated situation may have important conse-
ing the glucagon response in the late period of the test
quences in occupational health in developing coun-
Consistent with this work, more recent reports sup-
Similarly, slimming increases insulin sensitivity
port the involvement of a defect in glucagon in the
[94-95]. Since fat mass (mostly intraabdominal) lin-
pathogenesis of PRH. As indicated above, Leonetti
early decreases insulin sensitivity in either diabetics or
[80] demonstrated a blunted response of glucagon to
nondiabetics [96] it is not suprising to observe that
the glucose clamp in PRH patients, suggesting that a
massive weight reduction increases the occurrence of
deficiency in glucagon secretion, associated to high
reactive hypoglycemia. After massive weight reduc-
insulin sensitivity, explained the occurrence of post-
tion, rates of insulin-stimulated nonoxidative glucose
prandial hypoglycemia. In a further paper [90] she
disposal accounted for the majority of the improve-
performed in 12 PRH subjects (compared with 12
ment in insulin sensitivity [95]. Interestingly, above a
controls) a two-step hyperinsulinemic euglycemic glu-
certain threshold of weight loss, improvement in insu-
lin sensitivity does not bear a linear relationship to the
[105], and this pattern is frequently found in PRH
magnitude of weight loss [95]. An additional mecha-
patients. In addition, two-weeks very-low-energy diets
nism of hypoglycemia in this circumstance could be a
alter some aspects of the counterregulatory response
persisting blunted glucagon secretion as suggested by
to falling plasma glucose concentrations as mostly
Tremblay [97]. Thus, very lean people, as well as
evidenced by growth hormone peaks. This results in
those who have successfully acheived an important
an accelerated decline in plasma glucose. Therefore,
body weight reduction, are prone to hypoglycemia.
patients on a very-low-energy diet may be at risk for
The major influence of body fat stores on SI [96] is
abnormally low plasma glucose concentrations when
likely to be the main explanation of high SI in people
ingesting high carbohydrate loads [106]. Clearly, there
is very few literature on this subject.
Another situation where reactive hypoglycemia is
frequently found is women with moderate lower body
A lot of literature has been devoted to the role of
overweight. In contrast to upper body overweight
alcohol in the occurrence of hypoglycemia. While it is
which is well known to decrease SI, lower body over-
well known that alcohol intake at fast inhibits hepatic
weight is associated with values of SI within the upper
glucose output (via a blunting of gluconeogenesis)
range [98]. This situation seems to be associated with
[107], there is also a large body of literature indicating
a lower incidence of diabetes [99] and high values of
that ethanol may induce hypoglycemia in the post-
HDL cholesterol [100], suggesting a possible protec-
prandial period [108]. An experiment by O’Keefe and
tive effect of tight fat [100]. We measured insulin
Marks [109] in ten volunteers shows that alcohol in-
sensitivity by the minimal model procedure in lower-
take (equivalent of three gin-tonics) increases insulin
body overweight women and compared matched
response to sucrose, resulting in a lower nadir of
women with a similar degree of upper-body obesity
glycemia (when compared to sucrose alone). In four
and control women. Insulin sensitivity averaged 11.2
subjects the nadir was below 2.5 mmol/l and signs of
min– 1/(µU/ml) × 10– 4 in lower-body obesity vs 2.6 in
neuroglucopenia were reported in three subjects. Simi-
upper-body obesity and 6.1 in controls. This finding
larly the association of glucose (50 g) and ethanol
was assumed to be explained by the fact that lower-
(50 g) induces a higher insulin response which may
body obesity could be associated with a reduced free
result in hypoglycemia while glycemia does not de-
fatty acids-induced inhibition of insulin action by the
crease below 4 mmol/l if ethanol is associated to corn
Randle mechanism [98]. In addition, the marked ef-
starch instead of glucose [110]. Note that other works
fects of the balance between estrogens and progester-
confirm the increase in insulin response but not the
one on insulin sensitivity may explain some of this
reactive hypoglycemia [111] after an association of
specific aspect, since it has been demonstrated twice
that insulin sensitivity is twofold higher in follicularthan in luteal phase [101-102]. Thus, lower body over-
These effects are due to the stimulatory effect of
weight seems to have a metabolic pattern opposite to
ethanol on insulin response to both sucrose and glu-
upper body obesity [100] and to be beneficial for
cose [108, 112-117]. This effect is found with either
carbohydrate and fat metabolism [98-100]. However,
oral [112-115] or intravenous [116-117] glucose. In
these women frequently describe hypoglycemic symp-
addition ethanol blunts hepatic glucose output [118]
toms late in the morning [98] which seem to result in
by inhibiting both glycogenolysis and gluconeogen-
carbohydrate craving and further weight gain [98].
esis and induces a peripheral insulin resistance [119-
Dietary advice generally counteracts this tendency.
120]. Effects on glucose counterregulation are more
It is interesting to remind that, on the whole,
controversial: Kolaszynski [121] reported that ethanol
women have been classically reported to be frequently
reduced the response of cortisol, epinephrine, GH and
prone to marked decreases in glycemia in situations
glucagon to hypoglycemia. However, insulin resis-
such as prolonged fasting. In approximately 40% of
tance seems to limit the consequences of this effect
women, blood glucose levels decrease to less than 0.4
[121]. Other investigators failed to report a defect in
g/l (2.22 mmol/l) in a 72-hr fast. Of these, one third
counterregulation [122] but a recent paper [123] con-
had values as low as 0.3 g/l (1.7 mmol/l) [103-104].
firms that in otherwise healthy individuals a combina-tion of gin and regular tonic can induce reactive hy-poglycemia, due to an inhibiting effect of acute
m INFLUENCE OF DIET
ethanol ingestion (0.5 g/kg) on epinephrine andgrowth hormone response to a fall in blood glucose
There is no doubt that patient’s alimentary habits
levels. After the ingestion of three gin tonics, the
have a major role in the occurrence of hypoglycemia.
blood glucose nadir (3.35 mmol/l) was lower com-
However, we are not aware of specific studies on
pared to that with tonic alone without alcohol alone
nutritional habits of these patients, and well-conducted
(3.87 mmol/l) and after gin, subjects reported typical
studies on this subject appear to be almost lacking.
hypoglycemic symptoms. Partial prevention of these
Some physiological literature indicates that high
alcohol-induced postprandial hypoglycemias can be
carbohydrate-low fat diet increases insulin sensitivity
obtained by a reduction of glucose or saccharose in
these drinks, or, alternatively, by replacing these car-
m PHARMACOLOGIC APPROACH
Some old literature also suggests an association of
When symptoms persist despite a correctly pre-
reactive hypoglycemia with calcium status. Reactive
scribed (and adequately followed .) diet, a pharma-
hypoglycemia has been reported to be frequent in
cological approach is justified [29]. The treatment of
hypocalcemic patients [10, 125], to be corrected by
choice seems to be intestinal alpha-glucosidase inhibi-
calcium infusion [126], and to be unrelated to gluca-
tors which delay starch and sucrose digestion and
therefore reduce the insulin response to sugar or to amixed meal [128, 129]. Satisfactory results in reactivehypoglycemia have been reported for both acarbose[130-133] and miglitol [134], the latter being poorly
m DIETARY TREATMENT
tolerated. However their long-term use in this indica-tion has not been firmly established by controlledstudies [128]. Acarbose can also be employed in the
Harris, in his first paper [4], advocated treating
dumping syndrome [135-137] and in PRH related to
PRH with a low-carbohydrate diet and frequent small
split meals. This dietary approach remains the first
Biguanides have been shown to alleviate PRH [10,
treatment of this disorder [1, 10, 28-30, 73].
139]. Metformin can be useful associated to diet at a
The first important point is to add small meals at
dose of 500 to 850 mg orally taken with the meals
the middle of the morning and of the afternoon, when
[29]. There are also reports on the anticholinergic
glycemia would start to decrease. If adequate compo-
drugs Atropine (0.25 mg) and Probanthine (7.5 mg),
sition of the meal is found, the fall in blood glucose is
taken before the meals [29, 140]. Phenytoin has been
shown to improve also PRH [141-142]. Calcium glu-
The second cornerstone of this diet is that patients
conate infusions [126-127] have also been shown to
should avoid rapidly absorbable sugars and thus avoid
modify the OGTT curve, suppressing the postload fall
popular soft drinks rich in glucose or sucrose. They
in blood glucose [127] and thus to be of some effi-
should also be cautious with drinks associating sugar
ciency in PRH. Supplemental chromium, which exerts
and alcohol, mainly in the fasting state.
some insulin-sensitizing effects, has also been pro-
If the breakfast is hyperglucidic, adding proteins to
posed 143]. By down-regulating beta-cell activity,
it frequently reduces its insulin response and thus its
chromium may be assumed to increase glucagon se-
power to induce further excessive falls in blood glu-
Diazoxide is a major treatment of organic hypogly-
cemia [144] that can also be employed in some very
Addition of soluble dietary fibers that lower the
severe cases of reactive hypoglycemia [145]. Since it
glycemic and the insulinemic index has a similar ef-
is generally not well tolerated (water retention, hyper-
fect and has thus been recommended. Soluble fibers as
trichosis, digestive disorders) its use remains limited
pectin and guar delay gastric emptying and prolong
in PRH [144-145] but it could sometimes provide an
the intestinal transit time. Mirouze [89] reported in a
efficient alternative in the case of failure of other
series of nineteen patients that treatment with pectin
protected against falls in blood glucose after OGTT by
In execeptional cases, somatostatin analogues can
increasing the glucagon response in the late period of
be interesting, as first shown in 1981 by Mirouze
the test [89]. The addition to the meal of 5 to 10 g
[146] who demonstrated that an infusion of somatosta-
hemicellulose, guar or pectin often improves postpran-
tin in PRH patients slowed down the initial rise in
dial hypoglycemia. Dietary fibers are mainly interest-
blood sugar and thus delayed the occurrence of hy-
ing when PRH is associated with decreased glucose
poglycemia. Given the increase in glycemia that
tolerance or occurs after gastric surgery [29].
reached 13 mmol, this drug appeared to be frankly
As shown above, the risk of reactive hypoglycemia
diabetogenic. However, somatostatin analogues gave
is markedly enhanced by the simultaneous ingestion
more interesting results in cases of PRH resisting to
of ethanol and sucrose or glucose, mainly in the fast-
all other treatments [147]. Somatostatin controls the
ing state. Decreasing the amount of sucrose (glucose)
secretion of gastrointestinal hormones and lowers in-
ingested or replacing it with either saccharin or the
sulin levels in both basal and stimulated conditions
noninsulinotropic carbohydrate fructose has been
[147]. In a case of severe PRH due to a defect in
shown to prevent this kind of hypoglycemia [108].
hepatic glucose-6-phosphatase [92], a good response
In most patients with idiopathic-reactive hypogly-
to a single dose (100 micrograms IM) of the soma-
cemia, diet alone is sufficient; but one should be
tostatin analogue octreotide was found. In fact this
alerted for the aggravation of symptoms on a low-
treatment, given its cost and its side effects, should be
carbohydrate diet. If this occurs, one should suspect
fructose 1-6 diphosphatase enzyme deficiency, and the
Other drugs proposed in PRH include propranolol
diet should be increased in carbohydrates [10].
and calcium antagonists such as nifedipine, diltiazem,
and nicardipine but controlled studies appear to be
4 Harris S. Hyperinsulinism and dysinsulinism. J Amer Med Ass, 1924,
still lacking to assess their interest [10]. Since a low
adrenal activity was initially assumed to explain the
5 Cahill GF, Soeidner JS. A non-editorial on non-hypoglycemia. NEngl J Med, 1974, 291, 905-906.
disease, its treatment by adrenal extracts got some
6 Yager J, Young RT. Non-hypoglycemia is an epidemic condition. N
popularity, leading the American Diabetes Association
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and the American Medical Association to issue a joint
7 Lefèbvre PJ. Heurs et malheurs de l’hyperglycémie provoquée par
statement on the necessity of critical evaluation of
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8 Lefèbvre PJ, Andreani D., Marks V, Creutzfeld W. Statement on
the biologically inactive adrenocortical extracts as
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m CONCLUSION
10 Hofeldt FD. Reactive hypoglycemia. Metabolism, 1975, 24, 1193-
The so-called functional hypoglycemic states have
11 Johnson DD, Door KE, Swenson WM, Service FJ. Reactive hypogly-
cemia. JAMA, 1980, 243, 1151-1155.
suffered from the past difficulty to diagnose and the
12 Gyland SP. Functional hyperinsulinism in general practice. JAMA,
lack of knowledge regarding their mechanisms. They
thus are still considered by many physicians as ex-
13 Salzer HM. Relative hypoglycemia as a cause of neuropsychiatric
amples of “non disease” [148]. However, there are
illness. JAMA, 1966, 58, 12-13.
now both standardized tools to perform the diagnosis
14 DeFronzo RA, Andres R, Bledsoe TA, Boden G, Faloona GA, Tobin
JD. A test of the hypothesis that the rate of fall in glucose concen-
and pathophysiological data explaining the mecha-
tration triggers counterregulatory hormonal responses in man. Dia-
nisms. These states represent minor disturbances of
betes, 1977, 26, 445-452.
the remarkably integrated mechanisms that maintain
15 Santiago JV, Clarke WL, Shah SD, Cryer PE. Epinephrine, norepi-
the balance between glucose utilization and glucose
nephrine, glucagon and growth hormone release in association withphysiological decrements in the plasma glucose concentration in
supply in situations like meals or exercise which sud-
normal and diabetic man. J Clin Endocrinol Metab, 1980, 51, 877-
denly disturb carbohydrate homeostasis. Most gener-
ally, these hypoglycemias occur in situations of high
16 Karam JH. Reactive hypoglycemia: Mechanism and management.
insulin sensitivity, ie, the opposite of syndrome X and
Calif Med, 1971, 114, 64-71.
17 Lilavivathana U, Brodows RG, Woolf RD, Campbell RG. Counter-
diabetes. While this metabolic situation is potentially
regulatory hormonal responses to rapid glucose lowering in diabetic
beneficial, a fall of blood glucose below the usual
man. Diabetes, 1979, 28, 873-877.
levels will result in rather uncomfortable symptoms
18 Amiel SA, Simonson DC, Tamborlane WV, DeFronzo RA, Sherwin
(palpitation, tremor, sweating, dizziness, blurred vi-
RS. Rate of glucose fall does not affect counterregulatory hormoneresponses to hypoglycemia in normal and diabetic humans. Diabetes,
sion) and in dangerous disturbances in reaction time in
some usual tasks like driving a car or performing a
19 Chalew SA, Mc Laughlin JV, Mersey JH, Adams AJ, Cornblath M,
specific exercise. Generally, the patient is disturbed by
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Journal of Perinatology (2006) 26, 31–36r 2006 Nature Publishing Group All rights reserved. 0743-8346/06 $30ORIGINAL ARTICLEHood versus mask nebulization in infants with evolvingbronchopulmonary dysplasia in the neonatal intensive care unitA Kugelman1, I Amirav2, F Mor1, A Riskin1 and D Bader11Department of Neonatology, Bnai Zion Medical Center, Haifa, Israel and 2Department of Pediatrics,
Dr. Ike Okorie Inland Family Practice Center LLC118 s. 10th ave Hattiesburg, MS 39401 Phone: 6015447012 Patient Education PHENTERMINE - ORAL IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your healt