Baltic 55’ “ELUSIVE” Page 1 of 6 53 America’s Cup Avenue 401-846-0300 firstname.lastname@example.org Newport, RI 02840 401-846-5757 web address: www.balticyachts.com BUILDER: DESIGNER: Perkins 4.236M, diesel , 78 hp; 8000 hrs BALLAST: HULL MATERIAL: ACCOMMODATIONS & LAYOUT: The forward most compartment is watertight with a commercial water
Australian people can buy antibiotics in Australia online here: http://buyantibioticsaustralia.com/ No prescription required and cheap price!
Jeanfrederic.brun.free.frPOSTPRANDIAL 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@example.com 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  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 . This situation was pathogenesis, diagnosis, and treatment. Another usual first evidenced by Harris  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
Later, this issue became for decades a matter of While in his initial description Harris  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  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  and Yager  proposed to call ological responses [14-17] which are set at fixed val- ues, so that hypoglycemia should be defined on a level Charles  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  can help to define this level. Marks  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  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 . 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 . 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  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 . Re- of the sympathetic response and at 2.8 mmol/l the cent consensus statements  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  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 . 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  leading to a slightly  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 . 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 , 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  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 . 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  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 , is probably too restrictive .
Based upon these physiological data a cut-off valuearound 3.3 (onset of counterregulatory responses) Standardized list of symptoms of hypoglycemia. Each sign could be quoted from 0 to 5 allowing the calculation of a “score”. After[20, 24, 26]. m HOW TO PERFORM THE POSITIVE
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 , of no value in the diagnosis of functional hypoglyce- since plasma glucose nadirs below 2.8 mmol are usual mia  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  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  found plasma glucose concentrations be- al  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 , 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 .
outside the clinical laboratory , 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 . 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 . 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. All consensus statements emphasize that the glu-cose tolerance test alone is not a reliable means for The breakfast test
diagnosing reactive hypoglycemia. 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  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  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  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  a new “hyperglucidic . 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 . 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 . However, it proved to be suit-able for the diagnosis of hypoglycemia . 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 . 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 . In addition, in a recent report  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 . 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 .
prandial reactive hypoglycaemia .
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 . 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  is generally difficult noid syndrome, hyperthyroidism, cardiac arrhythmias, dumping syndrome, and beta-adrenergic hyperrespon- 3.1; nausea 3; headache 3; hunger 2.9 . By con- sive state (De Costa’s syndrome) .
trast, when symptoms are quoted during a PRH repro- PJ Lefevre  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 . In such cases, since low blood (p < 0.001) . 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) . 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  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  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 .
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 . 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 , 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  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 . 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  pected until the first reports by Harris . The term while some roles can be inferred from the fact that “functional hyperinsulinism” (proposed by Conn ) 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  on forty-seven patients demonstrated to pendent of hormonal and neural regulatory factors in suffer from reactive hypoglycemia (< 45 mg/100 ml) humans . 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 . Epinephrine has been shown example there has been an anecdotic report of reactive hypoglycemia (0.34 g/l) with an unusually exagger- adrenergic receptors  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) .
. 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 , 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 . 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 . Recent advances in the understanding of made available . It has been demonstrated by Tam- this specific cause of hypoglycemia should be briefly burrano  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  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 .
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  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  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 .
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,  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 . 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 . 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 .
cose clamp. When only insulin and glucose were in- This relationship is a hyperbola: SIxI = constant  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 . 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 .
disruption of the feedback loop SIxI = constant .
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  is involved by some way in this dis- shown by Ahmadpour  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)  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. . 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 . 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  who considers sensitivity. This is clearly the case in PRH  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  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 . 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  demonstrated a blunted response of glucagon to nondiabetics  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  she disposal accounted for the majority of the improve- performed in 12 PRH subjects (compared with 12 ment in insulin sensitivity . 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 , and this pattern is frequently found in PRH magnitude of weight loss . 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 . 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  is abnormally low plasma glucose concentrations when likely to be the main explanation of high SI in people ingesting high carbohydrate loads . 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 . This situation seems to be associated with , there is also a large body of literature indicating a lower incidence of diabetes  and high values of that ethanol may induce hypoglycemia in the post- HDL cholesterol , suggesting a possible protec- prandial period . An experiment by O’Keefe and tive effect of tight fat . We measured insulin Marks  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 . In addition, the marked ef- starch instead of glucose . 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  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  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  toms late in the morning  which seem to result in by inhibiting both glycogenolysis and gluconeogen- carbohydrate craving and further weight gain .
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  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 . Other investigators failed to report a defect in g/l (2.22 mmol/l) in a 72-hr fast. Of these, one third counterregulation  but a recent paper  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 . The treatment of hypocalcemic patients [10, 125], to be corrected by choice seems to be intestinal alpha-glucosidase inhibi- calcium infusion , 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 , the latter being poorly m DIETARY TREATMENT
tolerated. However their long-term use in this indica-tion has not been firmly established by controlledstudies . Acarbose can also be employed in the Harris, in his first paper , 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 . 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  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  that can also be employed in some very Addition of soluble dietary fibers that lower the severe cases of reactive hypoglycemia . 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  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 . The addition to the meal of 5 to 10 g  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 .
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 . 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 . In a case of severe PRH due to a defect in shown to prevent this kind of hypoglycemia .
hepatic glucose-6-phosphatase , 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 .
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 . Since a low adrenal activity was initially assumed to explain the 5 Cahill GF, Soeidner JS. A non-editorial on non-hypoglycemia. N Engl 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 Engl J Med, 1974, 291, 907-908.
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 voie orale. In: Journées Annuelles de Diabétologie de l’Hôtel-Dieu,1987. Flammarion Médecine-Sciences, Paris, 313-322.
hypoglycemic states and to discourage the usage of 8 Lefèbvre PJ, Andreani D., Marks V, Creutzfeld W. Statement on the biologically inactive adrenocortical extracts as postprandial a or reactive a hypoglycaemia (Letter). Diabetes Care, 9 Charles MA, Hofeldt F, Shackelford A. Comparison of oral glucose tolerance tests and mixed meals in patients with apparent idiopathicpost-absorptive hypoglycemia. Diabetes, 1981, 30, 465-470.
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” . 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 Kowarski A. The use of the plasma epinephrine response in the the recurrence of these events and many physicians diagnosis of idiopathic postprandial syndrome. JAMA, 1984, 251,612-615.
will rather consider him as as neurotic send him to the 20 Boyle PJ, Schwartz NS, Shah SD, Clutter WE, Cryer PE. Plasma psychiatrist. However, we have seen that the specific glucose concentrations at the onset of hypoglycemic symptoms in patients with poorly controlled diabetes and in nondiabetics. N EnglJ Med, 1988, 318, 1487-1492.
which is mostly characterized by an increase in sym- 21 Stevens AB, McKane WR, Bell PM, King DJ, Hayes JR. Psychomo- pathetic tone, is also found in bona fide hypoglycemia, tor performance and counterregulatory responses during mild hy- probably in part because this is a very stressful situa- poglycaemia in healthy volunteers. Diabetes Care, 1989, 12, 12-17.
tion. In fact, just like the other metabolic diseases, 22 Blackman JD, Towle VL, Lewis GF, Spire JP, Polonski KS. Hy- poglycemic thresholds for cognitive dysfunction in humans. Diabe- postprandial hypoglycemia can now be approached tes, 1990, 39, 828-835.
scientifically and thus treated, so that the patient’s 23 Jones TW, McCarthy G, Tamborlane WV, Caprio S, Roessler E, Kraemer D, Starick-Zych K, Allison T, Boulware SD, Sherwin RS.
Mild hypoglycaemia and impairment of brain stem and corticalevoked potentiels in healthy subjects. Diabetes, 1990, 39, 1550-1555.
24 Mitrakou A, Ryan C, Veneman T, Modan M, Jenssen T, Kiss I, REFERENCES
Durrant J, Cryer P, Gerich J. Hierarchy of glycemic thresholds forcounterregulatory hormone secretion, symptoms, and cerebral dys-function. Am J Physiol, 1991, 260 (Endocrinol Metab 23), E67-E74.
1 Lefebvre PJ. Hypoglycemia or non-hypoglycemia. In: Rifkin H, 25 Brun JF, Baccara MT, Blachon C, Orsetti A. Niveaux de glycémie Colwell JA, Taylor SI (eds) Diabetes 1991. Proceedings of the 14th International Diabetes Federation Congress, Washington DC, June d’hypoglycémie. Comparaison avec des hypoglycémies réaction- 1991. Excerpta Medica Amsterdam London New York Tokyo, 1991, nelles. ALFEDIAM Montréal 7-9 Juin 1995. Diabetes Metab, 1995, 2 Marks V. Glycaemic stability in healthy subjects: fluctuations in 26 De Feo P, Gallai V, Mazzotta G, Crispino G, Torlone E, Perriello G, blood glucose concentration during the day. In: Andreani D, Marks V, Ventura MM, Santeusanio F, Brunetti P, Bolli GB. Modest decre- Lefèbvre PJ, eds. Hypoglycemia. Raven Press, New York, 1987, ments in plasma glucose concentration cause early impairment in cognitive function and later activation of glucose counterregulation 3 Virally ML, Guillausseau PJ. Hypoglycemia in Adults. Diabetes in the absence of hypoglycemic symptoms in normal man. J Clin Metab, 1999, 25, 477-490.
Invest, 1988, 82, 436-444.
27 DJ Cox, LA Gonder-Frederick BP Kovatchev, DM Julian, WL 52 Rokas S, Mavrikakis M, Iliopoulou A, Moulopoulos S. Proarrhyth- Clarke. Progressive hypoglycemia’s impact on driving simulation mic effects of reactive hypoglycemia. Pacing Clin Electrophysiol, performance. Diabetes Care, 2000, 23, 163-170.
28 Lefèbvre PJ, Luyckx AS, Gérard J. Le syndrome d’hypoglycémie 53 Cryer PE, Binder C, Bolli GB, Cherrington AD, Gale EAM, Gerich réactionnelle: mythe ou réalité In: Journées Annuelles de Diabétolo- JE, Sherwin RS. Hypoglycemia in IDDM. Diabetes, 1989, 38, 1193- gie de l’Hôtel-Dieu, 1983. Flammarion Médecine-Sciences, Paris, 54 Luyckx AS, Lefèbvre PJ. Plasma insulin in reactive hypoglycemia.
29 Lefèbvre PJ. Hypoglycemia: post-prandial or reactive. Current Diabetes, 1971, 20, 435-442.
therapy in Endocrinology and Metabolism, 1988, 3, 339-341.
55 Rosen SG, Clutter WE, Berk MA, Shah SD, Cryer PE. Epinephrine 30 Lefèbvre PJ. Hypoglycemia or non-hypoglycemia. Acta Clinica Bel- supports the postabsorbtive plasma glucose concentration and pre- gica, 1997, 52, 241-244.
vents hypoglycemia when glucagon secretion is deficient in man. J 31 Deary IJ, Hepburn DA, MacLeod KM, Frier BM. Partitioning the Clin Invest, 1984, 72, 405-411.
symptoms of hypoglycemia using multi-sample confirmatory factor 56 Cohen N, Rossetti L, Shlimovich P, Halbertam M, Hu M, Shamoon analysis. Diabetologia, 1993, 36, 771-777.
H. Counterregulation of hypoglycemia, skeletal muscle glycogen 32 Lev-Ran A, Anderson RW. The diagnosis of postprandial hypoglyce- metabolism during three hours of physiological hyperinsulinemia in mia. Diabetes, 1981, 30, 996-999.
humans. Diabetes, 1995, 44, 423-430.
57 Abilgaard N, Orskov L, Petersen JA, Alberti KG, Schmitz O, Moller 33 Permutt MA. Postprandial hypoglycemia. Diabetes, 1976, 25, 719- N. Forearm substrate exchange during hyperinsulinaemic hypogly- caemia in normal man. Diabet Med, 1995, 12, 218-223.
34 Fariss BL. Prevalence of post-glucose-load glycosuria and hypogly- 58 Capaldo BR, Napoli R, Guida R, et al. Forearm muscle resistance cemia in a group of healthy young men. Diabetes, 1974, 23, 89-91.
during hypoglycemia: role of adrenergic mechanisms and hypogly- 35 Merimee TJ. Spontaneous hypoglycemia in man. Adv Intern Med, cemia per se. Am J Physiol, 1998, 268, E248-E254.
59 Shamoon H, Fiedman S, Canton C, Zaharovicz L, Hu M, Rossetti L.
36 Lefèbvre PJ, Luyckx AS. The breakfast tolerance test: a return to Increased epinephrine and skeletal muscle responses to hypoglyce- physiology. Diabetes Metab, 1976, 2, 15-19.
mia in non-insulin dependent diabetes mellitus. J Clin Invest, 1994, 37 Hadji-Georgoupouios A, Schmidt MI, Margolis S, Kowarski AA.
Elevated hypoglycemic index, and late hyperinsulinism in symptom- 60 Orskov L, Bak JF, Abilgard N, et al. Inhibition of muscle glycogen atic postprandial hypoglycemia. J Clin Endocrinol Metab, 1980, 50, synthase activity and non-oxidative glucose disposal during hypogly- cemia in normal man. Diabetologia, 1996, 39, 226-234.
38 Palardy J, Havrankova J, Lepage R, Matte R, Bélanger R, D’Amour 61 Deibert DC, DeFronzo RA. Epinephrine-induced insulin resistance in P, Ste Marie LG. Blood glucose measurements during symptomatic man. J Clin Invest, 1980, 65, 717-721.
episodes in patients with suspected postprandial hypoglyceniia. N 62 Raz I, Katz A, Spencer MK. Epinephrine inhibits insulin-mediated Engl J Med, 1989, 321, 1421-1425.
glycogenolysis but enhances glycolysis in human skeletal muscle.
39 Kansal PC, Buss RW, Pino JA, Bosheil BR. Glucose tolerance test Am J Physiol, 1991, 260, E430-E435.
vs. meal test in reactive hypoglycemia. Diabetes, 1977, 26, 403-407.
63 Shepard PR, Kahn BB. Glucose transporters and insulin action.
Implications for insulin resistance and diabetes mellitus. N Engl J 40 Kansal PC, Buss, RW, Pino JA, Bosheil BR. Glucose tolerance test Med, 1999, 341, 248-257.
vs. meal test in reactive hypoglycemia. Diabetes, 1977, 26, 403-407.
64 Cline GW, Petersen KF, Krssak M, Shen J, Hundal RS, Trajanoski Z, 41 Hofeldt F, Charles A, Eichner H, Shackelford, A, and O’Barr P.
Inzucchi S, Dresner A, Rothman DL, Shulman GI. Impaired glucose Absence of hypoglycemia after a test meal in patients with idiopathic transport as a cause of decreased insulin-stimulated muscle glycogen reactive hypoglycemia. Diabetes, 1978, 27, 201-208.
synthesis in type 2 diabetes. N Engl J Med, 1999, 341, 240-246.
42 Owens DR, Wragg KG, Bitiggs PL, Luzio S, Kingber G, Davies C.
65 Zisman A, Peroni OD, Abel ED, Michael MD, Mauvais Jarvis F, Comparison of the metabolic response to a glucose tolérance test and Lowell BB, Wojtaszewski JF, Hirshman MF, Virkamaki A, Goodyear a standardized test meal and the response to serial test meals in LJ, Kahn CR, Kahn BB. Targeted disruption of the glucose trans- normal healthy subjects. Diabetes Care, 1979, 2, 409-413.
porter 4 selectively in muscle causes insulin resistance and glucose 43 Buss RW, Kawsal PC, Roddam RF. Mixed meal tolerance test and intolerance. Nat Med, 2000, 8, 924-928.
reactive hypoglycemia. Horm Metab Res, 1982, 14, 281-283.
66 Koivisto UM, Martinez-Valdez H, Bilan PJ, Burdett E, Ramlal T, 44 Hogan MJ, Service FJ, Sharbrough FW, Gerich JE. Oral glucose Klip A. Differential regulation of the GLUT-1 and GLUT-4 glucose tolerance test compared with a mixed meal in the hypoglycemia. A transport systems by glucose and insulin in L6 muscle cells in caveat on simulation. Mayo Clinic Proc, 1983, 58, 491-496.
culture. J Biol Chem, 1998, 266, 2615-2621.
45 Brun JF, Fédou C, Bouix O, Raynaud E, Orsetti A. Evaluation of a 67 Mathoo JMA, Shi ZQ, Vranic M. Opposite effects of acute hypogly- standardized hyperglucidic breakfast test in postprandial reactive cemia and acute hyperglycemia on glucose transport and glucose hypoglycaemia. Diabetologia, 1995, 38, 494-501.
transporters in perfused rat skeletal muscle. Diabetes, 1999, 48,1281-1288.
46 Orsetti A, Brun JF, Fedou C, Rodier M, Bouhaddioui L, Richard JFL.
68 Chiasson JL, Shikama H, Chu DT, Exton JH. Inhibitory effects of Etude de la glycoregulation à l’aide d’un petit dejeuner standardisé epinephrine on insulin-stimulated glucose uptake by rat skeletal chez 21 obèses. Diabetes Metab, 1989, 14, 169 (abstract).
muscle. J Clin Invest, 1981, 68, 706-713.
47 Service JF. Hypoglycemic disorders. N Engl J Med, 1995, 332, 69 Conn JW. The spontaneous hypoglycemias. Importance of etiology in determining treatment. JAMA, 1940, 115, 1669.
48 Wasada T, Katsumori K, Saeki A, Kuroki H, Arii H, Saito S, Omori 70 Owada K, Wasada T, Miyazono Y, Yoshino H, Hasumi S, Kuroki H, Y. Lack of C-peptide suppression by exogenous hyperinsulinemia in Yano K, Maruyama A, Kawai K, Omori Y. Highly increased insulin subjects with symptoms suggesting reactive hypoglycemia. Endocr J, secretion in a patient with postprandial hypoglycemia: role of glucagon-like peptide-1 (7-36) amide. Endocr J, 1995, 42, 147-151.
49 Del Sindaco P, Casucci G, Pampanelli S, Polonsky K, Fanelli C, 71 Davis MR, Mellman M, Shamoon H. Physiologic hyperinsulinemia Torlone E, Santeusanio F, Brunetti P, Bolli GB. Late post-prandial enhances counterregulatory hormone response to hypoglycemia in hypoglycaemia as the sole presenting feature of secreting pancreatic IDDM. J Clin Endocrinol Metab, 1993, 76, 1383-1385.
beta-cell adenoma in a subtotally gastrectomized patient. Eur J En- 72 Lefèbvre P. Stratégie d’exploration des hypoglycémies de l’adulte.
docrinol, 1997, 136, 96-99.
Ann Endocrinol (Paris), 1993, 54, 409-412.
50 Kurlan R. Postprandial (reactive) hypoglycemia and restless leg 73 Scheen AJ, Lefebvre PJ. Hypoglycémie réactive. Encycl Méd Chir syndrome: related neurologic disorders? Mov Disord, 1998, 13, 619- (Elsevier, Paris), encyclopédie pratique de Médecine, 1998, 6-0600, 51 Berlin I, Grimaldi A, Landault C, Cesselin F, Puech AJ. Suspected 74 Miholic J, Orskov C, Holst JJ, Kotzerke J, Meyer HJ. Emptying of postprandial hypoglycemia is associated with beta-adrenergic hyper- the gastric substitute, glucagon-like peptide-1 (GLP-1), and reactive sensitivity and emotional distress. J Clin Endocrinol Metab, 1994, hypoglycemia after total gastrectomy. Dig Dis Sci, 1991, 36, 1361- 75 Toft Nielsen M, Madsbad S, Holst JJ. Exaggerated secretion of 98 Raynaud E, Perez Martin A, Brun JF, Fedou C, Mercier J. Insulin glucagon-like peptide-1 (GLP-1) could cause reactive hypoglycae- sensitivity measured with the minimal model is higher in moderately mia. Diabetologia, 1998, 41, 1180-1186.
overweight women with predominantly lower body fat. Horm Metab 76 Hofeldt FD, Lufkin EG, Hagler L, Block MB, Dippé SE, Davis JW, Res, 1999, 31, 415-417.
Levin SR, Forsham PH, Herman RH. Are abnormalities in insulin 99 Freedman DS, Rimm AA. The relation of body fat distribution, as secretion responsible for reactive hypoglycemia. Diabetes, 1974, 23, assessed by sex girth measurements, to diabetes mellitus in women.
Am J Public Health, 1989, 79, 715-720.
77 Luyckx A, Lefèbvre P. Glycosurie rénale et insulinémie. Ann Endocr 100 Terry RB, Stefanick ML, Haskell WL, Wood PD. Contributions of (Paris), 1967, 28, 141-145.
regional adipose tissue depots to plasma lipoprotein concentrations in 78 Rosselin GE, Dérot M. Plasma insulin levels in renal diabetes. Acta overweight men and women: possible protective effects of tight fat.
Diabet Lat, 1968, 5 (Suppl. 1), 341-358.
Metabolism, 1991, 40, 733-740.
79 Tamburrano G, Leonetti F, Sbraccia P, Giaccari A, Locuratolo N, 101 Valdes CT, Elkind-Hirsch KE. Intravenous glucose tolerance test - Lala A. Increased insulin sensitivity in patients with idiopathic reac- derived insulin sensitivity changes during the menstrual cycle. J Clin tive hypoglycemia. J Clin Endocrinol Metab, 1989, 69, 885-890.
Endocrinol Metab, 1991, 72, 642-646.
80 Leonetti F, Foniciello M, Iozzo P, Riggio O, Merli M, Giovannetti P, 102 Escalante Pulido JM, Alpizar Salazar M. Changes in insulin sensitiv- Sbraccia P, Giaccari A, Tamburrano G. Increased nonoxidative glu- ity, secretion and glucose effectiveness during menstrual cycle. Arch cose metabolism in idiopathic reactive hypoglycemia. Metabolism, Med Res, 1999, 30, 19-22.
103 Merimee TJ, Tyson JE. Stabilization of plasma glucose during fast- 81 Brun JF, Bouix O, Monnier JF, Blachon C, Jourdan N, Baccara MT, ing. N Engl J Med, 1974, 291, 1275-1277.
Fédou C, Orsetti A. Increased insulin sensitivity and basal insulin 104 Merimee TJ, Tyson JE. Hypoglycemia in man. Pathologic and physi- effectiveness in postprandial reactive hypoglycaemia. Acta Diabeto- ologic variants. Diabetes, 1977, 26, 161-165.
logica, 1996, 33, 1-6.
105 Chen M, Bergman RN, Porte D Jr. Insulin resistance and b-cell 82 Villanueva-Penacarrillo ML, Alcantara AI, Clemente F, Delgado E, dysfunction in aging: the importance of dietary carbohydrate. J Clin Valverde I. Potent glycogenic effect of GLP-1 (7-36) amide in rat Endocrinol Metab, 1988, 67, 951-957.
skeletal muscle. Diabetologia, 1994, 37, 1163-1166.
106 Marsoobian V, Grosvenor M, Jacob M, Ipp E. Very-low-energy diets 83 Bergman RN. Toward physiological understanding of glucose toler- alter the counterregulatory response to falling plasma glucose con- ance. Minimal model approach. Diabetes, 1986, 38, 1512-1527.
centrations. Am J Clin Nutr, 1995, 61, 373-378.
84 Kahn SE, Prigeon RL, McCulloch DK, Boyko EJ, Bergman RN, Schwartz MW, Neifing JL, Ward K Beard JC, Palmer JP, Porte DJ, Jr.
107 Lochner A, Wulff J, Madison LL. Ethanol-induced hypoglycaemia. I.
Quantification of the relationship between insulin sensitivity an The acute-effects of ethanol on hepatic glucose output and peripheral b-cell function in human subjects. Diabetes, 1993, 42, 1163-1672.
glucose utilisation in fasted dogs. Metabolism, 1967, 16, 1-18.
85 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, 108 Lefèbvre PJ, Jandrain B, Scheen AJ. Hypoglycémie post-prandiale et Turner RC. Homeostasis model assessment, insulin resistance and prise d’alcool. In: Journées Annuelles de Diabétologie de l’Hôtel- beta-cell function from fasting plasma glucose and insulin concentra- Dieu, 1992. Flammarion Médecine-Sciences, Paris, 217-228.
tions in man. Diabetologia, 1985, 28, 412-419.
109 O’Keefe SJD, Marks V. Lunchtime gin and tonic: a cause of reactive 86 Raynaud E, Pérez-Martin A, Brun JF, Aissa Benhaddad A, Mercier J.
hypoglycaemia. Lancet, 1977, i, 1286-1288.
Revised concept for the estimation of insulin sensitivity from a single 110 Baker SG, Joffe BI, Shires R, Viljoen M, Lamprey JM, Seftel HC.
sample. Diabetes Care, 1999, 22, 1003-1004.
Alcohol-potentiated reactive hypoglycaemia depends on the nature of 87 Brun JF, Raynaud E, Mercier J. HOMA and related simplified evalu- the carbohydrate ingested at the same time. Alcohol and Alcoholism, ations of insulin sensitivity from fasting insulin and glucose: no need for log transformation but beware of limits of validity! Diabetes 111 Jandrain BJ, Gérard J, Verdin E, Lefèbvre PJ. Effect of acarbose on Care, 2000, 23, 1037-1038.
the hormonal and metabolic response to the simultaneous ingestion 88 Pontiroli AE, Alberetto M, Capra F, Pozza G. The glucose clamp of sucrose and ethanol. In: Andreani (D.), Marks (V.), Lefèbvre (P.J.).
technique for the study of patients with hypoglycemia: insulin resis- Hypoglycemia. Raven Press, New York, 1987, 237-244.
tance as a feature of insulinoma. J Endocrinol Invest, 1990, 13, 112 Metz R, Berger S, Mako M. Potentiation of the plasma insulin response to glucose by prior administration of alcohol. An apparent 89 Mirouze J, Orsetti A, Monnier L, Bringer J, Pham TC. Les hypogly- islet-priming effect. Diabetes, 1969, 18, 517-522.
cémies tardives du diabète chimique: anomalies du Glucagon pan- 113 Friedenberg R, Metz R, Mako M, Surmackzynska B. Differential créatique, effets de la pectine. Diabetes Metab, 1979, 5, 279-285.
plasma insulin response to glucose and glucagon stimulation follow- 90 Leonetti F, Morviducci L, Giaccari A, Sbraccia P, Caiola S, Zorretta ing ethanol priming. Diabetes, 1971, 20, 397-403.
D, Lostia O, Tamburrano G. Idiopathic reactive hypoglycemia: a role 114 Kuhl C, Andersen O. Glucose and tolbutamide-mediated insulin for glucagon? J Endocrinol Invest, 1992, 15, 273-278.
response after preinfusion with ethanol. Diabetes, 1974, 23, 821-826.
91 Ahmadpour S, Kabadi UM. Pancreatic alpha-cell function in idio- 115 Nikkila EA, Taskinen MR. Ethanol-induced alterations of glucose pathic reactive hypoglycemia. Metabolism, 1997, 46, 639-643.
tolerance, postglucose hypoglycaemia, and insulin secretion in nor- 92 Pears J, Jung RT, Browning MC, Taylor R, Burchell A. Reactive mal, obese, and diabetic subjects. Diabetes, 1975, 24, 933-943.
hypoglycaemia in association with disordered islet function and ab- 116 Dornhorst A, Ouyang A. Effect of alcohol on glucose tolérance.
normal hepatic glucose-6-phosphatase activity: response to diazox- Lancet, 1971, 2, 957-959.
ide. Diabet Med, 1991, 8, 268-271.
117 McMonagle J, Felig P. Effects of ethanol ingestion on glucose 93 Sasaki M, Mogi T, Wada Y, Hirosawa I, Koizumi A. An endemic tolérance and insulin secretion in normal and diabetic subjects. Me- condition of biochemical hypoglycemia among male volunteers. Ind tabolism, 1975, 24, 625-632.
Health, 1996, 34, 323-333.
118 Lacavalier L, Bolli G, Cryer P, Gerich J. Contributions of gluconeo- 94 Letiexhe MR, Scheen AJ, Gérard PL, Desaive C, Lefèbvre PJ.
genesis and glycogenolysis during glucose counterregulation in nor- Insulin secretion, clearance and action before and after gastroplasty mal humans. Am J Physiol, 1989, 256 (Endocrinol Metab 19), E844- in severely obese subjects. Int J Obes Relat Metab Disord, 1994, 18, 119 Yki-Jàrvinen H, Nikkilä EA. Ethanol decreases glucose utilisation in 95 Goodpaster BH, Kelley DE, Wing RR, Meier A, Thaete FL. Effects healthy man. J Clin Endocrinol Metab, 1985, 61, 941-945.
of weight loss on regional fat distribution and insulin sensitivity inobesity. Diabetes, 1999, 48, 839-847.
120 Yki-Jàrvinen H, Koivisto VA, Ylikhari R, Taskinen MR. Acute ef- 96 Brun JF, Bringer J, Raynaud E Renard E, Orsetti A. Interrelation de fects of ethanol and acetate on glucose kinetics in normal subjects.
la masse grasse viscérale et du muscle dans le diabète de type II: Am J Physiol, 1988, 254 (Endocrinol Metab 17), E175-E180.
Implications Pratiques. Diabetes Metab, 1997, 23, 16-34.
121 Kolaszynski JW, Ylikahri R, Härkonen M, Koivisto VA. The acute 97 Tremblay A, Doucet E, Imbeault P. Physical activity and weight effect of ethanol on counterregulatory response and recovery from maintenance. Int J Obes Relat Metab Disord, 1999, 23 (Suppl 3), insulin-induced hypoglycaemia. J Clin Endocrinol Metab, 1988, 67, 122 Kerr D, MacDonald IA, Heller SR, Tattersall RB. Alcohol causes 136 Speth PAJ, Jansen JBMJ, Lamers CBHW. Acarbose and pectin in the hypoglycaemic unawareness in healthy volunteers and patients with dumping syndrome. In Proceedings Ist International Symposium on type 1 (insulin-dependent) diabetes. Diabetologia, 1990, 33, 216- Acarbose. Effects on carbohydrate and fat metabolism (W.
Creutzfeldt, Ed.). International Congress Series 594, Excerpta 123 Flanagan D, Wood P, Sherwin R, Debrah K, Kerr D. Gin and tonic Medica, Amsterdam, 1982, pp. 524-526.
and reactive hypoglycemia: what is important-the gin, the tonic, orboth? J Clin Endocrinol Metab, 1998, 83, 796-800.
137 Taylor RH, Jenkins DJA, Barker HM. Low-dose acarbose and the dumping syndrome. lit Proceedings Ist International Symposium on 124 Marks V, Wright J. Alcohol-provoked hypoglycaemia. In: Andreani Acarbose. Effects on carbohydrate and fat metabolism (W.
D, Lefèbvre PJ, Marks V eds. Current views on hypoglycaemia and Creutzfeldt, Ed.). International Congress Series 594, Excerpta glucagon. Academic Press, London, 1980, 283-295.
Medica, Amsterdam, 1982, pp. 527-529.
125 Fabrykant M, Pacella BL. The association of spontaneous hypogly- cemia with hypocalcemia and electro-cerebral dysfunction. Proc Am 138 Jandrain B, Gérard J, Verdin E, Lefèbvre PJ. Effect of acarbose on Diab Assoc, 1947, 7, 233-236.
the hormonal and metabolic response to the simultaneous ingestion 126 Cathelineau G, Vexiau P, Guitard M. Effect of calcium infusion on of sucrose and ethanol. In: Creutzfeldt (W.). Acarbose for the treat- plasma glucose in reactive hypoglycemia. Horm Metab Res, 1981, ment of diabetes mellitus. Springer, Berlin, 1988, 66.
139 Giuliano D, Luyckx A, Lefèbvre PJ. Comparative effects of met- 127 Vexiau P, Cathelineau G, Luyckx AS, Lefèbvre PJ. L’amélioration de formin and indanorex in the treatment of reactive hypoglycemia. Int la tolérance au glucose et la correction des hypoglycémies réaction- J Clin Pharmacol, 1979, 17, 76-81.
nelles induites par la perfusion intraveineuse de calcium ne peuvents’expliquer par des modifications de la glucagonémie. Diabetes and Metabolism, 1986, 12, 177-185.
Keller D, Santigo J, Kipnis DM, Petmutt MA. Cholinergic studies inreactive hypoglycemia. Diabetes, 1974, 23, 341.
128 Ozgen AG, Hamulu F, Bayraktar F, Cetínkalp S, Yilmaz C, Túzún M, Kabalak T. Long-term treatment with acarbose for the treatment of 141 Stambaugh JE, Tucker DC. Effect of diphenylhydantoin on glucose reactive hypoglycemia. Eat Weight Disord, 1998, 3, 136-140.
tolerance in patients with hypoglycemia. Diabetes, 1974, 23, 679- 129 Lefèbvre PJ, Standl E, eds. New aspects in diabetes. Treatment strategies with alpha-glucosidase inhibitors. Berlin, New York, deGryter, 1992.
142 Mirouze J, Collard F, Thuan CD. Functional hypoglycemia: a trial of 130 Gérard J, Luyckx AS, Lefèbvre PJ. Acarbose in reactive hypoglyce- treatment with phenytoin. Effects on blood sugar and blood insulin mia, a double blind study. Internat J Clin Pharmacol Therap Toxicol, curves. Therapie, 1976, 31, 605-613.
131 Richard JL, Rodier M, Monnier L, Orsetti A, Mirouze J. Effect of McCarty MF. Chromium and other insulin sensitizers may enhance acarbose on glucose and insulin response to sucrose load in reactive glucagon secretion: implications for hypoglycemia and weight con- hypoglycemia. Diabetes Metab, 1988, 14, 114-118.
trol. Med Hypotheses, 1996, 46, 77-80.
132 Schrezenmeir J, Kasper H. Therapeutic effect of acarbose in reactive 144 Goode PN, Farndon JR, Anderson J, Johnston ID, Morte JA. Diaz- hypoglycemia. In Proceedings Ist International Symposium on Acar- oxide in the management of patients with insulinoma. World J Surg, bose. Effects on carbohydrate and fat metabolism (W. Creutzfeldt, Ed.). International Congress Series 594, Excerpta Medica, Amster-dam, 1982, pp. 530-535.
145 Wales JK. Diazoxide treatment of reactive hypoglycaemia. Diabet 133 Lefebvre PJ, Scheen AJ. The use of acarbose in the prevention and treatment of hypoglycaemia. Eur J Clin Invest, 1994, 24, 40-44.
134 Renard E, Parer Richard C, Richard JL, Jureidini S, Orsetti A, 146 Mirouze J, Pham TC, Selam JL, Bringer J, Chenon D. Post- Mirouze J. Effect of Miglitol (Bay m1099), a new alpha-glucosidase hyperglycaemic hypoglycaemia: effects of somatostatin. Nouv Presse inhibitor, on glucose, insulin, C-peptide and GIP responses to an oral Med, 1981, 10, 2947-2949.
sucrose load in patients with post-prandial hypoglycaemic symp-toms. Diabetes Metab, 1991, 17, 3355-3362.
147 Lehnert H, Beyer J, Weber P, Krause U, Schrezenmeir J. Treatment 135 Buchanan KD, McLoughlin JC, Alam MJ. Acarbose in the dumping of severe reactive hypoglycemia with a somatostatin analogue (SMS syndrome. In Proceedings Ist International Symposium on Acarbose.
201-995). Arch Intern Med, 1990, 150, 2401-2402.
Effects on carbohydrate and fat metabolism (W. Creutzfeldt, Ed.).
International Congress Series 594. Excerpta Medica, Amsterdam, 148 Ford CV. Somatization and fashionable diagnoses: illness as a way of life. Scand J Work Environ Health, 1997, 23, 7-16.
Pesq. Vet. Bras. 24(2):57-60, abr./jun. 2004Antimicrobial resistance and R-plasmid in Salmonella sppNorma S. Lázaro2*, Anita Tibana3, Dália P. Rodrigues4, Eliane M.F. Reis4, Bianca R. .- Lázaro N.S., Tibana A., Rodrigues D.P., Reis E.M.F., Quintaes B.R. & Hofer E. 2004. Antimicrobial resistance and R-plasmid in Salmonella spp from swine and abattoirenvironments. Pesquisa Veterinár