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Insulinoma.net

www.insulinoma.net - www.gep-net.com
Prof. Dr. A.A.R. Starke – Dr. Christiane Saddig
Heinrich-Heine-Universität Düsseldorf – Medizinische Klinik
Hypoglycemia
Definition:
Independent of perceptable simultaneous symptoms, hypoglycemia is defined as a
blood glucose measurement in capillary blood below 40 mg/dl (2.22 mmol/l).

Blood glucose readings between 40 and 50 mg/dl (2.22-2.78 mmol/l ) represent
hypoglycemia, if adrenergic and/or neurological symptoms are simultaneously
observed.

Comment: for patients without Diabetes mellitus
The blood glucose measurement has to be performed by means of valid
enzymatical - photometrical or electrochemical - methods. Glucose-Analyzers used in
"Glucose-Meters" based upon dry chemistry strips have been developed for diabetic They are unreliable in the hypoglycemic range ( <50 mg/dl) and only useful for
rough estimations to be checked by laboratory chemistry.
Blood glucose levels above (>) 60 mg/dl ( >3.33 mmol/l) have to be considered
as normal levels, even when symptoms or complaints compatible with hypoglycemia are simultaneously observed. Such levels definitely rule out the diagnosis of hypoglycemia as a cause of the symptoms.
Low-normal blood glucose levels between 50 and 60 mg/dl (2.77-3.33 mmol/l) represent a
range of uncertainty, which may occasionally be reached in completely healthy persons as well as
regularly during fasting periods for more than 24 hrs.
If blood glucose in this range levels do occur in the overnight fasted patient, before main meals or 3- 5 hrs. after main meals, a physician considered to be familiar with hypoglycemia should beconsulted.
Symptoms
Symptoms compatible with hypoglycemia occur:
1. through activation of the sympathetic nervous system and result in uncomfortable
adrenergic symptoms posing no danger for the patient
2. through cerebral shortage of glucose supply and may result in serious and debiliating
neurological (neuroglycopenic) symptoms.
general symptoms
nausea, dizziness, collapse, weight gain
sweating, tremor, palpitations, tachycardia, agitation, nervosity,
adrenergic symptoms
impairment of consciousness, mental concentration,
neuroglycopenic
vision, speech, memory, blurred vision, fatigue,
symptoms
seizures, paralyses, ataxia, loss of consciousness,
aggressive behaviour
Typical clinical situations in patients suspected of hypoglycemia
history of suspicious
blood glucose unknown
symptoms
history of suspicious
blood glucose "low"
symptoms
history of suspicious
blood glucose normal
symptoms
no history of symptoms
blood glucose by chance: "low"
history of typical
proof of hypoglycemia and relief of symptoms by
symptoms
carbohydrate intake: "Whipple`s triad"
www.insulinoma.net www.gep-net.com (Prof. Dr.Achim Starke Dr. Christiane Saddig)
clinically healthy patient:
Diagnosis of an insulinoma in adult patients with confirmed orfsuspicious symptoms related to
hypoglycemia has to be of prime concern in the differential diagnosis of hypoglycemia.
Despite significant disabling signs due to adrenergic and / or neuroglycopenic symptoms the
patients clinically appear to be healthy and do not present with pathological findings during
physical inspection and investigation.
True postpandial hypoglycemia is rare and very often the diagnosis is assumed despite
lack of objective data. A different entity is the adrenergic postprandial syndrome (APS),
often misclassified as reactive hypoglycemia.
Postprandial hypoglycemia should not be confused with the "early dumping syndrome"
presenting with uncomfortable autonomic symptoms, which may occur shortly after intake
of rapidly absorbed concentrated sugars and accelerated gastric emptying.
www.insulinoma.net www.gep-net.com (Prof. Dr.Achim Starke Dr. Christiane Saddig)
Disease / Cause
1. mostly benign insulin-secreting tumors of the pancreas
2. malignant insulinoma (10-15%)
Insulinoma
3. insulinoma in familial multiple endocrine neoplasia type I (MEN I /
menin gene) - pancreatic, parathyroid, and pituitary endocrine tumors
4. rare: microadenomatosis, beta-cell-hyperplasia
("nesidioblastosis" in adults ?)
alimentary postprandial
a: prototype: resection of stomach (Billroth) or
hypoglycemia
b: rapid gastric emptying after carbohydrate-rich nutrients
"reactive or functional"
mechanism: GLP-1 (glucagon-like-peptide 1) ? hypoglycemia
c: insulin resistance: (i.e.early type-II diabetes with postprandial
hyperglycemia, >180 mg/dl) after carbohydrates (30--90 min) and late
elevated insulin response / rightward shift of insulin secretion curve
d: increased insulin sensitivity / glucagon ?
together with liver disease (cirrhosis) and malnutrition
Medical drugs +
factitious hypoglycaemia
Insulin or anti-diabetic drugs (beta-cytotropic agents, i.e. sulfonylureas) extreme physical activity
extreme athletics: marathon, triathlon, ski-longrun mesenchymal non-islet-cell
e.g. fibrosarcoma; elevated "big" IGF II levels (insulin like growth factor II) AIS / IAIS : autoimmune insulin syndrome assoc. with autoimmune
disease
insulin autoimmune
1. anti-insulin autoantibodies (in Japan / Graves' disease, lupus
syndrome
erythematosus, rheumatoid arthritis, insulin injections) AIS / IAIS
2.insulin receptor autoantibodies (Lupus erythematosus, scleroderma,
primary biliary liver cirrhosis, ITP - purpura, Hashimoto's thyroiditis)
PHHI: familial persistent
hyperinsulinemic

diffuse nesidioblastosis / gene mutations (SUR1, Kir6.2 locus) hypoglycemia of "infancy"
clinically ill patient
The underlying disease and impaired condition of the patient do not cause problems in the
differential diagnosis.

Hypoxia and metabolic acidosis (lactic acidosis) lead to inhibition and attenuation of hepatic
gluconeogenesis.
. Efficient gluconeogenesis is essentially required for a constant blood glucose level
(glucose homoeostasis). In addition, gluconeogenesis in normal kidneys contributes to glucose
homoeostasis.
www.insulinoma.net www.gep-net.com (Prof. Dr.Achim Starke Dr. Christiane Saddig)
Disease / Cause: Internal
Medicine
severe liver failure
renal insufficiency (uremia)
metabolic acidosis, retarded insulin elimination severe cardial insufficiency
hypoxia with alteration of hepatic glucose metabolism , (cardiomyopathy)
acidosis, hypoxia, liver failure, renal failure shock, multiple organ failure
acidosis, hypoxia, liver failure, renal failure pituitary insufficiency / adrenal insufficiency / endocrine crises
hypothyroidism: lack of ACTH, GH (growth hormone),cortisol, thyroxin medical drugs in diseases of liver /
anorexia, kachexia; (malignant tumor disease, extreme malnutrition
leucemia, lymphoma, myeloma (plasmocytoma): bone marrow and lymph node diseases
glycogen storage disease, fructose intolerance, inborn errors of metabolism
Starke A, Saddig C. Hypoglykämien im Erwachsenenalter. In: Diabetes mellitus. Urban & Fischer,
München Jena, 2. Aufl. 2000, S. 775-782
Service FJ. Hypoglycemic disorders. New Engl J Med 332, 1995, 1144-1152
www.insulinoma.net www.gep-net.com (Prof. Dr.Achim Starke Dr. Christiane Saddig)
postprandial Hypoglycemia
In the presence of vegetative adrenergic symptoms postprandial hypoglycemia should only be
considered if biochemical hypoglycemia does occur within 2-4 hours after intake of a standardized
testmeal (rich in carbohydrates)
during laboratory test conditions, e.g. as compared to a testmeal rich
in proteins
.
Postprandial hypoglycemia typically may occur after a carbohydrate rich meal, thus also classified as
"alimentary hypoglycemia". This is in contrast to fasting hypoglycemia or spontaneous hypoglycemia in
insulinoma.
! Eventually patients with insulinoma may experience hypoglycemia within 3-6 hours after an oral
glucose load (depending upon the insulin secretion pattern of the tumor). The hypoglycemia cannot be
efficiently counterregulated, fasting needs to be withdrawn.
Patients with postprandial hypoglycemia are able to counterregulate hypoglycemia adaequately
and thus return to the normal range of blood glucose levels .

postprandial hypoglycemia and “ d i a b e t e s “ ?
! Very often we have to face the erroneus notion, postprandial or meal-associated hypoglycemia
being mistaken as "an early sign" of diabetes mellitus ???
It is true that real hypoglycemia after a meal may occur early in the developement of type II
diabetes. However,
these are caused by untimely delayed and therefore increased insulin secretion
when elevated hyperglycemic blood glucose levels have been detected early-postprandially (so
called right-shift of the insulin secretion curve)
Typically co-existence of hyperglycemia and hypoglycemia is found but not hypoglycemia alone.
The HbA1c may be normal, too.
postprandial hypoglycemia and
pancreatogenous Non-Insulinoma Hypoglycemia
! postprandial hypoglycemia together with clearly neuroglycopenic symptoms may be a
challenging
issue if caused by pancreatogenous hyperinsulinemic Non-Insulinoma Hypoglycemia
( = islet cell hypertrophy). According to J.Service (Mayo Clinic Rochester MN) this is probably the correct
terminus for rare islet cell hyperplasia or nesidioblastosis in adults.
www.insulinoma.net www.gep-net.com (Prof. Dr.Achim Starke Dr. Christiane Saddig)
The oral glucose tolerance test (OGTT) does not allow the diagnosis of postprandial hypogylcemia,
since the "meal" is not physiological and the availibility of glucose in the gastrointestinal tract of short
duration. Glucose tolerance testing is suitable for screening purposes.
The term "reactive" or "functional" hypoglycemia is outdated and should not be used.
Postprandial hypoglycemia is to be differentiated from the Adrenergic Postprandial Syndrome - APS
(Normoglycemia)
Despite normal concentrations of blood glucose patients face unspecific symptoms (sweating,
tremor, palpitations, anxiety, nausea) caused through autonomic adrenergic counterregulation.
The adrenergic tone elicits the symptoms and simultaneously avoids hypoglycemia through
biochemical mechanisms
(action of epinephrine / adrenaline; see "Gluco-Homeostasis".
APS represents a reactive or functional dysregulation of the autonomic nervous system and
should not be classified as "hypoglycemia". Terms like "pseudohypoglycemia" or even "non-
hypoglycemia"
should be avoided, since they do not address the virtual presence of discomfort
reported by these patients.
The biochemically defined cutoff for hypoglycemia as tolerated in the brain is 2.8 mmol/l (50
mg/dl)
. A counterregulatory response (epinephrine/adrenaline and glucagon) is triggered at higher
blood glucose levels in the range of > 60 mg/dl (cutoff 3.1-3.3 mmol/l). Glucagon does not cause
symptoms, but epinephrine does.
Dumping - Syndrome
The early dumping-syndrome does occur within 30 minutes in 10-15% of patients after resective
gastric surgery. These are orthostatic hemodynamic symptoms induced secondary to a rise in
intestinal osmotic pressure due to a rapid emptying of the osmotically active gastric content.
Symptoms are characterized as adrenergic symptoms, in addition patients experience nausea,
intestinal rumors, fullness, falling blood pressure with tachycardia/bradycardia.
Causes are: catecholamines, serotonin, vasoactive kinines; intraluminal pressure. Eventually and
depending upon the carbohydrate content transient hyperglycemia may even be seen.
The late dumping-syndrome is identical with true postprandial hypoglycemia in patients after
gastric surgery caused by an imbalance of postprandial hyperinsulinemia and availability of
carbohydrates.

It may occur in patients with dysfunction of intestinal motility without prior gastric surgery. Increase
of the intestinal passage and contractions are mediated by the secretion of intestinal hormones /
peptides (cholecystokinine - CCK, gastrin, motilin, neurotensin (?), substance P).
www.insulinoma.net www.gep-net.com (Prof. Dr.Achim Starke Dr. Christiane Saddig)
Causes of postprandial hypoglycemia:
Increased insulin secretion (triggered through increased glucagon-like peptide 1 - secretion
("early responder")
Rapid gastric emptying (after gastric surgery):
a. stimulation of insulin secretion
b. stimulation of GLP-1-secretion, GIP
Renal glucosuria
Increased insulin sensitivity (increased non-oxidative glucose metabolism)
Decreased insulin sensitivity ("insulin resistance") with initially decreased insulin
response, thereafter right-shifted increased insulin response ("late responder").
? Decreased glucagon secretion / glucagon resistance (hyposensitivity of glucagon receptors)
Literature postprandial hypoglycemia:
Hogan MJ, Service FJ, Sharbrough FW, Gerich JE. Oral glucose tolerance test compared with a mixed mealin the diagnosis of reactive hypoglycemia. Mayo Clin Proc 58:1983, 491-496 Gastineau CF. Is reactive hypoglycemia a clinical entity? Mayo Clin Proc 58:1983, 545-549 Lefebvre PJ, Andreani D, Marks V, Creutzfeldt W. Statement on postprandial or reactive hypoglycemia.
Diabetes Care 11: 1988, 439 Brun JF, Fedou C, Mercier J. Postprandial reactive hypoglycemia. Diabetes & Metabolism 26:2000, 337-351 www.insulinoma.net www.gep-net.com (Prof. Dr.Achim Starke Dr. Christiane Saddig)
Drugs - Pharmaceuticals
Medical drugs and pharmaceuticals potentially causing hypoglycemia:
Hypoglycemia has been described in context with several pharmaceuticals of quite
different origin.
Often these were single and quite rare observations or reports without known
mechanisms of action. They should, however, always be considered as one reason of causing
hypoglycemia.
A cause of hypoglycemia may be drug-induced toxic liver and kidney lesions. Hypoglycemia maybecome evident due to prescription of drugs despite preexisting liver or kidney failure. Quite often this is the case during simple pain relieving therapy with salicylates or antibiotic therapy withsulfonamides containing sulfamethoxazol.
The stimulatory action of several drugs (including salicylates and antiarrhythmics) is still unknown, although stimulatory actions on insulin secretion have been observed.
Never should the hypoglycemia provoking action of alcohol be underestimated. In patients under
influence of alcohol presenting with unclear impaired consciousness a determination of the bloodglucose is always mandatory ! Therapy with acetyl salicylic acid in the range of grams may clinically be relevant due to its
widespread use, predominantly when overdosed in children.
We do not comment here upon the use of blood glucose lowering drugs designed for the
treatment of diabetes (including insulin) - the oral antidiabetic agents, predominantly the
sulfonylureas, if taken by non-diabetic patients.
www.insulinoma.net www.gep-net.com (Prof. Dr.Achim Starke Dr. Christiane Saddig)
Starke/Saddig 2001
Drug name
Drug class
www.insulinoma.net
(Generic)
Salicylic acid
Acetylsalicylic
ANALGETICS
derivatives
acid (Aspirin®)
in children; inhibition ofcerebral glucose metabolism Pyrazolone-
Phenazone,
Derivatives
Propyphenazone
Phenacetine,
p-Aminophenol-
Paracetamol
Derivatives
(Acetaminophen)
Diclofenac,
Indomethacine
Disopyramide,
Chinidine,
ANTIARRHYTHMICS
Flecainide,
Propafenone
ANTIMALARIAL
Chloroquine,
Derivatives
Mefloquine
ANTIBIOTICS
Sulfonamides
Sulfamethoxazol
Tetracyclines
Pentamidine
unselective ß-
Betablocker
Propanolol
blockers
Psychopharm. drugs
Butyrophenones
Haloperidol
Fluoxetine,
Clomipramine
MAO-Inhibitors
Antithyroid
Methimazole
Thiamazole
other drugs
ACE - Inhibitors
Enalapril
Antiarrhythmic
Procainamide
Antihypertensive
Dihydralazine
Antihistaminics
Toxic Substances
Insectizides
Source:Starke A, Saddig C. Hypoglykämien im Erwachsenenalter. In: Diabetes mellitus. Urban & Fischer, München Jena, 2.
Aufl. 2000, S. 775-782Service FJ. Hypoglycemic disorders. New Engl J Med 332, 1995, 1144-1152Virally ML, Guillausseau PJ. Hypoglycemia in adults. Diabetes & Metabolism 25, 1999, 477-490 www.insulinoma.net www.gep-net.com (Prof. Dr.Achim Starke Dr. Christiane Saddig)
PHYSIOLOGY
Glucohomeostasis
Mathematics of Glucohomeostasis
During normal conditions the basal glucose requirement amounts to 2 mg/kg/min. This
results in 10 gramms per hour for a normal weight adult of 75 kg. The brain requires around
5-6 g/h, day or night, during rest or "work". About 4 g/h are used by the muscles, fat tissue, the
organs (liver, heart) and the red blood cells, mostly requiring insulin for glucose uptake. The
liver thus has to produce 10 g/h, mostly achieved by glucagon.
A blood volume of 70 ml / kg results in 5.25 L of blood in an adult of 75 kg body weight.
At an arterial blood glucose concentration of 50 mg / dl we just find 2.75 gramm of free
circulating glucose.
A cerebral blood flow of 15 % of the total circulation (CMV) will result in 900 ml / minute
(60 ml/100 g/minute) resp. 54 liters / hour for a normal brain mass of 1500 g. This means
a total calculated glucose content of 27 gramms (= 0.45 g/minute).
At least 20 % ( = 5.4 g ) thereof are extracted by the brain, which will result in a decrease
of the arterial blood glucose concentration from 50 mg / dl to a venous concentration
of 40 mg / dl
(difference: 10 mg / dl = 90 mg / 900 ml per minute = 5.4 g / 54 l per hour).
This simple calculation demonstrates the essential and critical requirement of a minimal
arterial blood glucose concentration of 50 mg/d
l in order to guarantee the demands of the
brain for proper functionality. These are not met at 40 mg/dl and thus would cause
neurological symptoms. Normal brain blood flow and cardiac output are essential. Attenuation
of cardiac function (insufficiency, cardiomyopathy) and attenuation of cerebral blood flow
(stroke, sclerosis) demonstrate the fragile equilibrium in case of prevailing hypoglycemia.
"Stress-Hyperglycemia" during the postaggressive metabolic state essentially means the
physiological adaptation to jeopardized cerebral blood flow in order to meet the fuel needs by
the brain. This is achieved by a biochemical centralisation of the glucose metabolism
analogous to the hemodynamic centralisation of the circulation during shock (cardiogenous,
hemorrhagic, hypovolemic). Metabolic centralisation physiologically resembles a glucagon-
mediated "endogenous infusion of glucose".

www.insulinoma.net www.gep-net.com (Prof. Dr.Achim Starke Dr. Christiane Saddig)
Literature Glucohomeostasis
Unger RH: The milieu interieur and the islets of Langerhans. Diabetologia 20 (1981) 1-11 Unger RH, Orci L: Glucagon and the A-cell. Physiology and pathophysiology. N Engl J Med 304 (1981)1518-1524 Unger RH: Insulin-glucagon relationships in the defense against hypoglycemia. Diabetes 32 (1983) 575-583 Unger RH: Glucagon physiology and pathophysiology in the light of new advances. Diabetologia 28 (1985)574-578 Starke AAR, Imamura T, Unger RH: Relationsship of glucagon suppression by insulin and somatostatin tothe ambient glucose concentration. J Clin Invest 79 (1987) 20-24 Physiology of Glucoregulation
Basal glucoregulation
Glucoregulation during physical activity
Glucoregulation during famine
Alimentary postprandial glucoregulation
Glucoregulation during postaggression ("fight or flight")
(surgery, trauma, shock)
Glucose - Counterregulation
HIERARCHY of Hypoglycemia - Counterregulation
Attenuation of Insulin-Sensitvity
("physiological Insulin-Resistence")
Suppression of Insulin-Secretion
Stimulation of Glucagon-Sensitivity
Stimulation of Glucagon - Secretion
Stimulation of the autonomic adrenergic nervous system
Potentiation of counterregulation
(Cortisol, Growth hormone, Endorphins)
www.insulinoma.net www.gep-net.com (Prof. Dr.Achim Starke Dr. Christiane Saddig)

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