New Concepts in Diabetes and Its Treatment - part 5 pdf

It has been reportedthat almost all diabetic patients show a deficient glucagon secretory response to hypoglycemia, perhaps as a result of the long-term hyperglycemia glucosetoxicity or

Potassium administration is often required This cation may be normal

in serum even if the total body content is decreased When the plasma level

is low, 30–40 mmol/h of potassium should be infused, and a lower dose(20 mmol/h) should also be given when serum potassium is normal, becausewith the beginning of therapy a further fall in serum potassium occurs as aresult of the effect of insulin (which causes a shift of potassium into the cells)and fluid replacement (that dilutes serum potassium) ECG represents a usefultool to assess intracellular potassium concentration, showing flat or inverted

T waves when intracellular potassium is low and peaked T waves when tracellular potassium is high

in-Bicarbonate administration is only required in patients with severe acidosis(pH=7) Bicarbonate should be given at a slow rate (about 44 mEq during 1

or 2 h) and discontinued when the pH rises to 7.1 In DKA, glycerate (2,3-DPG) is low in red cells, which decreases oxygen delivery This

2,3-diphospho-is counterbalanced by acidos2,3-diphospho-is, which favors oxygen delivery A rapid tion of acidosis with bicarbonate may leave the effect of the 2,3-DPG unop-posed, causing impaired oxygen release which, in presence of volume depletionand reduced tissue perfusion may favor the development of tissue hypoxiaand lactic acidosis

correc-In presence of infections, antibiotic therapy should be employed Whenthe patient is comatose, insert a nasogastric tube, use a urinary catheter (if

no urine passes within 3 h) and heparinize in case of hyperosmolar comadevelopment or in presence of thrombosis risk factors

After the recovery from a diabetic ketoacidotic episode, it is useful toaccurately review the causes to reduce the risk of recurrence

Hyperosmolar Nonketotic Syndrome

Hyperosmolar nonketotic syndrome (HNKS) is an acute complicationobserved most often in type 2 diabetic patients and is characterized by symp-toms and signs due to volume depletion (caused by excessive hyperglycemiaand consequent hyperosmolality and osmotic diuresis), with varying degree

of clouding of sensorium, ranging from absence of mental impairment (about10%) to frank coma (about 10%) HNKS is a serious complication, whichentails a mortality rate as high as?40%

Pneumonia (favored by sensory clouding which facilitates aspiration oforopharyngeal secretions) may develop in HNKS patients, as well as otherinfections The dehydration elevates plasma viscosity and may favor throm-bosis Disseminated intravascular coagulation (DIC) may also occur, withbleeding manifestations

Laboratory findings include a marked hyperglycemia (usually higher thanthat occurring in DKA, reaching a level of?800 mg/dl or 44 mmol/l) whichcauses increase in serum osmolality (which may be as high as?350 mosm/l),whereas sodium is normal or slightly changed Urea nitrogen and creatinineare elevated, together with inorganic acids (phosphates and sulfates) because

of prerenal azotemia consequent to volume depletion In contrast to DKA,

in HNKS the metabolic acidosis is absent or mild, and bicarbonates are slightlychanged When present, acidosis is due to retention of inorganic acids (seeabove), i.e a small amount of ketone bodies as well as a certain amount oflactate (due to tissue hypoperfusion consequent to volume depletion).The extreme hyperglycemia with the ensuing hyperosmolality may befavored by the abundant hyperglycemic diuresis in patients who are unable tocompensate the large fluid loss with urine by adequate water drinking, as itoften occurs in old patients, who have an attenuated sensation of thirst andwho often live alone or in nursing homes However, it should be kept inmind that HNKS may be precipitated by several factors, including infections,cerebrovascular events, hypertonic peritoneal dialysis, parenteral nutrition oradministration of the osmotic agent mannitol or diuretics as well as corticoste-roids and phenytoin

The lack of acidosis in HNKS may be the result of several factors.(1) HNKS develops in type 2 diabetic patients, who possess a varying degree

of residual endogenous insulin secretion Since lipolysis is more sensitive toinsulin than the glucose homeostatic mechanisms, it is possible that the residualinsulin secretion, while unable to stimulate glucose utilizaton and to represshepatic glucose production, is able to refrain lipolysis, thus limiting the FFA

afflux to liver and therefore the ketogenic process (2) The endogenously creted insulin reaches, through the portal vein, the liver, which is insulinized

se-to a sufficient degree to prevent activation of ketogenesis (i.e to allow glucose

to be utilized in sufficient amount to produce enough malonyl-CoA, whichinhibits the ketogenic process at the level of CPT-1 (3) There may be glucagonresistance, which prevents glucagon to exert its ketogenic effects (see underDKA) (4) There may be an enhanced activity of the Cori cycle, with increased

afflux of lactate to the liver, where it may be in part metabolized to CoA, thus refraining ketogenesis

malonyl-HNKS treatment is primarily directed to restore blood volume and correcthyperosmolality This may require the supply of intravenous fluid in the totalamount up to 8–10 liters Therapy may be started by intravenous infusion ofsaline at the rate of 1.5 liters/h for the first 2 h, followed by infusion of 0.5liter/h of half-normal saline (0.45%) adjusted according to the clinical andlaboratory response Insulin should also be given This may be done according

to the small dose regimen described under DKA, although some patients may

require larger doses Potassium should be supplied (see under DKA) withspecial attention because, in the absence of acidosis, the intracellular K+transfer induced by insulin administration is more pronounced Attentionshould also be paid to the possible development of infections or thrombosis

or DIC to start timely the appropriate therapy

preg-F Belfiore, Institute of Internal Medicine, University of Catania, Ospedale Garibaldi,

I–95123 Catania (Italy)

Tel +39 095 330981, Fax +39 095 310899, E-Mail francesco.belfiore@iol.it

In infants, during the first 48 h of life, hypoglycemia may occur, withglycemic values =30 mg% or 1.7 mmol/l, with a frequency of about 10% oflive births A brief hypoglycemic episode can cause moderate alterations ofthe brain whereas prolonged hypoglycemia can cause profound dysfunctions,tissue damage and also death of the brain This depends on the fact that thedeposit of glycogen in brain is negligible (the reserve of energy lasts 2–3 min)and that glucose is not synthesized by the central nervous system (CNS) Thus,glucose (together with oxygen) is an obligate primary energy substrate for thebrain tissue and is entirely derived from the circulation The brain tissueutilizes 120 g/day of glucose and about 90% of total energy needed for cerebralfunctions derives from glucose oxidation The brain cannot utilize alternativesubstrates (as circulating FFA) as energy fuel thus being very sensitive tohypoglycemia In some particular situations, at least some parts of the brainmight utilize ketoacids.

Hypoglycemia is a very uncommon event, apart from persons with diabetestreated with insulin or hypoglycemic drugs The diagnosis of hypoglycemia isbased upon Whipple’s triad, i.e hypoglycemia, symptoms of hypoglycemia, andcorrection of the symptoms with the normalization of blood glucose

Glucose Counterregulation

Insulin regulates glycemia through modulation of hepatic glucose tion in the postabsorptive state and glucose utilization in the postprandialstate, and it is the only hormone able to physiologically reduce glycemiclevel In catabolic states (fasting), insulin concentration falls and the levels ofcounterregulatory hormones rise; in fact, hypoglycemia is capable of inducingthe release of counterregulatory hormones, including glucagon, catechola-mines (epinephrine and norepinephrine – released both from adrenal medullaand the sympathetic neurons), cortisol and GH The glucagon secretory re-sponse to hypoglycemia is largely CNS-independent whereas catecholamine,cortisol and GH responses are prevailingly CNS-dependent Glucagon actswithin minutes and is the primary hormone of glucose maintenance (by stimu-lating hepatic glucose production through increase in glycogenolysis and glu-coneogenesis) Catecholamines also act swiftly, stimulating glucose productionand limiting glucose utilization in humans through bothb2- anda2-adrenergicmechanisms Cortisol and GH, on the contrary, act within several hourswith a delayed glucoregulatory action (antagonizing insulin action, mobilizingsubstrate and activating hepatic gluconeogenesis through the induction of therelative gluconeogenic enzymes) All these hormones have a synergic action

produc-on the inductiproduc-on of hyperglycemia and produc-on the preventiproduc-on and correctiproduc-on ofhypoglycemia Glucagon plays the most important counterregulatory actionwhereas catecholamines play a minor role, that becomes important when there

is glucagon deficiency, as it often happens early during the course of diabetesmellitus Catecholamines are the warning system in hypoglycemia through thesymptoms and signs of adrenergic overactivity Cortisol and GH play no role

in short-term hypoglycemia but have a substantial role in the recovery fromlong-term hypoglycemia The relevance of other hormones or neurotransmit-ters in preventing and correcting hypoglycemia has been debated but it is notdefinitely established In type 1 diabetic patients, counterregulation is oftenaltered and, in some patients it may be very deficient It has been reportedthat almost all diabetic patients show a deficient glucagon secretory response

to hypoglycemia, perhaps as a result of the long-term hyperglycemia (glucosetoxicity) or the loss of the regulating effect of insulin on glucagon secretion

In the presence of a defective glucagon secretion, type 1 diabetic patients duringhypoglycemic episodes became dependent upon catecholamines to correct lowglycemic level, i.e epinephrine response compensates for deficient glucagonresponse Some diabetic patients with long-standing disease have also a defi-cient catecholamine response to hypoglycemia and this combined disorderimpairs glucose counterregulation and represents a high risk of iatrogenichypoglycemia in these subjects GH and cortisol responses to hypoglycemia

Table 1 Causes of hypoglycemia

A Fasting hypoglycemia B Postprandial or reactive hypoglycemia

1 Reduced glucose production Alimentary hypoglycemia (gastrectomy, Liver or renal insu fficiency gastrojejunostomy, pyloroplasty Deficiency of counterregulatory hormones or vagotomy)

Childhood ketotic hypoglycemia Hyperthyroidism

(substrate or enzyme deficiency) Obesity with hyperinsulinism

Drugs (alcohol, salicylates, b-blockers) Early stage of type 2 diabetes, prediabetes

or IGT

2 Increased glucose utilization

Idiopathic reactive hypoglycemia b-Cell tumor or insulinoma

Idiopathic postprandial syndrome or Functional hypersecretion of b-cells

pseudohypoglycemia Autoantibodies to insulin

Inherited disorders of carbohydrate Autoantibodies to insulin receptors

metabolism in children Sepsis

Intake of leucine in leucine-sensitive Insulin or insulin-releasing drugs

children (sulfonylureas, pentamidine, quinine)

Newborn hypoglycemia (first hours of life,

if mother is diabetic)

Extrapancreatic non- b-cell tumors

Childhood nonketotic hypoglycemia

(deficit of carnitine or of enzymes of

FFA utilization

Exhaustive exercise

3 Factitious or artifactual

Factitious hypoglycemia (surreptitious

insulin or sulfonylurea administration)

Artifactual hypoglycemia (in hemolytic

anemia or in leukemia or in hyperlipemia)

in type 1 diabetes are usually not reduced, but deficiency of their secretionmay occur

Classification of Hypoglycemia (see table 1)

Postabsorptive or Fasting Hypoglycemia

Fasting hypoglycemia may result from impaired hepatic glucose tion (involving glycogenolysis or gluconeogenesis) or enhanced peripheralglucose utilization It can be induced by several causes, listed below

produc-Reduced Glucose Production This occurs in the following instances:

(1) Chronic failure of critical organs such as liver diseases (hepatitis,cirrhosis or hepatoma, severe heart failure with hepatic congestion) which

impair hepatic glucose production, or conditions of inadequate substrate storeand supply (chronic renal failure, malnutrition, starvation or cachexia, ano-rexia nervosa, late pregnancy).

(2) Deficiency of counterregulatory hormones (glucagon and epinephrine,cortisol and GH) that impairs gluconeogenesis, as occurs in hypopituitarism,

in adrenal insufficiency and rarely in glucagon deficiency

(3) Ketotic hypoglycemia of infancy and childhood, linked to substratedeficiency or due to defects in one or more of the gluconeogenic or glyco-genolytic enzymes, sometimes associated to lactic acidosis

(4) Drugs such as alcohol (which inhibits hepatic gluconeogenesis) cially when associated to fasting, salicylates (a common cause of hypoglycemia

espe-in espe-infants) which would espe-increase peripheral glucose utilization and reducehepatic gluconeogenesis,b-blockers (which reduce the glycogenolytic response

(2) Sepsis (cytokines associated to endotoxinemia increase insulin lease)

re-(3) Insulin or drugs that stimulate insulin release, such as sulfonylureacompounds in diabetic patients, pentamidine (which exerts a toxic effect withb-cell cytolysis), and quinine (which induces massive insulin release, althoughthis effect is not well demonstrated)

(4) Hypoglycemia of infants born from diabetic mothers, occurring duringthe first hours of life (provoked by fetal hyperinsulinemia linked to hyperplasia

of b-cells induced by maternal hyperglycemia and hyperglucagonemia).(5) Non-b-cell or extrapancreatic large tumors of mesenchymal (50%) orepithelial origin (5–10%) or hepatomas (25%) or other carcinomas (5–10%)

or some malignant hematologic diseases (5–10%), in which hypoglycemia isinduced by production of insulin-like growth factors such as IGF-2, thatinteracts with insulin receptors (and may suppress endogenous insulin secre-tion), or by overutilization of glucose (by the tumoral tissue)

(6) Nonketotic hypoglycemia due to systemic carnitine deficiency or zymatic defects which limit the utilization of FFA or ketones (which entailsenhanced glucose oxidation for energetic purposes).

en-(7) Prolonged and exhaustive exercise, especially in untrained persons(increased glucose utilization)

Factitious or Artifactual Hypoglycemia Two conditions should be

dis-tinguished:

(1) Factitious hypoglycemia from deliberate and surreptitious insulin orsulfonylurea assumption (especially in medical people or family members ofdiabetic patients with psychiatric disturbances)

(2) Artifactual hypoglycemia as it may occur in hemolytic anemia or inleukemia and leukemic reactions (due to overutilization of glucose in the testtube by young erythrocytes or leukemic leukocytes) or in the presence ofmarked hyperlipemia (which may cause a 15% – or more – underestimation

of glucose concentration)

Postprandial or Reactive Hypoglycemia

This form of hypoglycemia occurs within 6 h after a meal, and includesseveral forms, listed below:

(1) Alimentary hypoglycemia (or alimentary hyperinsulinism) caused bygastrectomy, gastrojejunostomy, pyloroplasty or vagotomy, involving about5–10% of operated patients and developing 30–120 min after ingestion ofcarbohydrate-containing meals (due to rapid gastric emptying and glucoseabsorption which stimulate excessive insulin release, and perhaps also to hyper-secretion of enterohormones such as enteroglucagon, secretin, GIP, etc.); itmay perhaps also occur in patients with hyperthyroidism, or in obesity withhyperinsulinism

(2) Early stage of type 2 diabetes or prediabetes or IGT (deficient phase insulin release leads to higher glucose elevation with subsequent excessivestimulation of insulin secretion) However, it should be mentioned that therelationship between the early stage of type 2 diabetes or prediabetes or IGTand postprandial hypoglycemia is not well established

early-(3) Idiopathic reactive hypoglycemia or true hypoglycemia (with loweredglucose levels), a rare syndrome characterized by adrenergic symptoms withoutsymptoms of severe neuroglycopenia, probably linked to an increased insulinresponse or a higher affinity of insulin receptors or to a subtle dysfunction ofgastrointestinal tract

(4) Idiopathic postprandial syndrome or pseudohypoglycemia (with anear-normal glycemic value), characterized by adrenergic symptoms andlight symptoms of neuroglycopenia, which develop regularly and repetitivelyduring the patient’s life (causes are unknown and might include enhanced

Table 2 Clinical signs and symptoms of hypoglycemia

Sympathetic/parasympathetic activation Neuroglycopenia

A Clinical signs and symptoms of adrenergic Clinical signs and symptoms of

systolic hypertension Paresthesias and motor dysfunction

B Clinical signs and symptoms of Cognitive impairment, mental confusion

Semi-coma, coma and even death

epinephrine release in some subjects, with stress or anxiety contributing inmany subjects)

(5) Inherited disorders of carbohydrate metabolism in children (hereditaryfructose intolerance from deficiency of fructose-1-P aldolase or galactosemiafrom deficiency of galactose-1-P uridyltransferase)

(6) Intake of leucine in leucine-sensitive children (due to increased insulinsecretion)

Clinical Signs and Symptoms of Hypoglycemia (see table 2)

The clinical manifestations of hypoglycemia are generally nonspecific andvarying, not only from patient to patient but also in the same subject from episode

to episode Their development can depend not only on the glycemic value butalso on the rate of the fall in blood glucose Manifestations can be distinguishedinto adrenergic (due to sympathetic activation) and neuroglycopenic (due toneuronal alterations secondary to glucose deprivation) When glucose dropsrapidly, adrenergic symptoms are most evident while when glucose drops gradu-ally neuroglycopenic symptoms may dominate the clinical picture During a hy-poglycemic episode, the response of counterregulatory hormones begins beforethe symptomatic glucose threshold is reached

Neuropenic symptoms may not occur even in the presence of glucoselevel as low as 25–30 mg/dl (1.4–1.7 mmol/l) due to the ability of normalpersons to increase brain blood flow and therefore glucose delivery Thisadaptation may be prevented in patients with cerebral atherosclerosis andinelastic vessels, in whom neuropenic symptoms may appear at relatively highglucose levels.

It should be pointed out that severe hypoglycemic reactions may occureven in the presence of near-normal or even high glycemic values (pseudohypo-glycemia), especially in diabetic patients; on the other hand, there may be noclinical hypoglycemic reactions with very low concentrations of plasma glucose(25–30 mg% or 1.4–1.7 mmol/l) The most important factors probably are therate of fall in glycemia and the fact that the glucose plasma level may notstrictly reflect the glucose concentration in brain tissue A glycemic range(55–70 mg% or 3.00–3.88 mmol/l) seems to exist in which dysfunction fromneuroglycopenia and activation of counterregulatory hormones occur butsymptoms are not yet manifest; therefore, the value of 3.88 mmol/l may be acut-off value of hypoglycemia, useful and safe to consider in the treatment ofdiabetes mellitus

Adrenergic Symptoms and Signs

These are due to catecholamine hypersecretion that develops in response

to a blood glucose level=53 mg% or 2.95 mmol/l, and include pallor, anxiety,tremor, palpitations, tachycardia (occasionally with crises of systolic hyperten-sion) and acute sensation of hunger It is noteworthy that symptoms and signsinduced by parasympathetic response can also occur during hypoglycemia,producing nausea, eructation, cold sweating, mitigation of expected tachy-cardia or true bradycardia, and mild hypotension

Neuroglycopenic Symptoms and Signs

These are due to dysfunction of CNS that develops in response to cemia =45 mg% or 2.50 mmol/l, and include headache, dizziness, fatigue,irritability or apathy, lethargy, frequent yawning, cognitive impairment, mentalconfusion, inebriation, personality changes and psychotic behavior, disturbedvision and diplopia, perioral numbness, paresthesias, motor dysfunction, con-vulsions, occasionally transient hemiparesis or focal neurologic deficits (espe-cially in elderly diabetic patients), semi-coma, complete loss of consciousnessuntil hypoglycemic coma and even death The different neurologic manifesta-tions have been correlated with specific sites of the brain involved in differentdegrees of hypoglycemia Clinical hypoglycemic symptoms and signs some-times suggest true mental disorders, accounting for the frequent reportedmistake or delay in diagnosis

hypogly-In children, adrenergic manifestations are near-absent and copenic symptoms can predominate with seizures simulating true crises ofepilepsy A failure to develop several adrenergic symptoms before the develop-ment of neuroglycopenic symptoms (hypoglycemia unawareness) is observed

neurogly-in 50% of patients with long-standneurogly-ing diabetes (due to the reduced response ofsympathetic system to hypoglycemia, secondary to the autonomic neuropathy).However, glucose threshold may also be lowered by hypoglycemia itself whichmay cause subsequent hypoglycemia unawareness, as it may be observed inpatients with insulinoma

Hypoglycemia Induced by Insulin or Sulfonylurea Treatment

The commonest form of hypoglycemia is that induced by insulin or fonylureas as well as by ethanol It accounts for about 60% of patients hospital-ized for hypoglycemia, while renal disease accounts for 15%, liver diseases for15% and malnutrition for 10% In diabetic patients, hypoglycemic episodescan be isolated or recurrent, and are due to a mismatch of insulin or sulfonylu-rea therapy to meal pattern or physical activity In long-standing diabetes, adefective counterregulation with deficiency of glucagon and epinephrine maycontribute; these subjects are at 25-fold increased risk for severe iatrogenichypoglycemic crises during intensive insulin treatment

sul-In type 1 diabetics, mild to moderate symptomatic hypoglycemic crisesoccur in about 90% of patients (frequently during the night) In insulin-treateddiabetics, severe hypoglycemia or hypoglycemic coma was reported in 9–10%

of cases in 1 year during conventional insulin therapy, and higher figures mostprobably apply for patients treated with intensive insulin regimen

The most serious hypoglycemic episodes in diabetic patients can happenwith the sulfonylurea compounds They may occur at any time after ingestion

of the drug (from 30–60 min to many hours later) and are characterized bydiminished or absent autonomic signs, prolonged or relapsing hypoglycemiaand by a response to glucose which is not as prompt as in insulin-inducedhypoglycemic episodes

Predisposing factors may hasten the onset or increase the intensity of thehypoglycemic effects of insulin or sulfonylureas (table 3) It is important toavoid hypoglycemia in a diabetic mother in the early period of gestationbecause maternal hypoglycemia can cause malformations, for a detrimental

effect on growth and differentiation of the fetus

Hypoglycemia can have unfavorable long- or short-term effects on vascularcomplications of diabetes In fact, it increases systolic and diastolic pressures,glomerular filtration rate, viscosity and platelet aggregation Repeated episodes

Table 3 Predisposing factors in drug-induced diabetic hypoglycemia

Undernutrition or omission of food or Administration of a b-blocker

Renal or hepatic dysfunction Lowered glycemic threshold for

Erroneous high insulin or sulfonylurea doses (with compromised recognition of Increased absorption of insulin from the site developing hypoglycemia)

of injection

of hypoglycemia can result in neuropsychologic deficits, especially in youngerpatients (EEG changes and cognitive impairment) and, if severe, hypoglycemiacan be fatal Related to hypoglycemia is the Somogyi phenomenon, which is

a posthypoglycemic hyperglycemia that most often follows a nocturnal fall inblood glucose level (p50 mg/dl) and is due to the response of counterregu-latory hormones and the subsequent increase in glycemia It can be contrasted

by reducing the evening doses of drugs The Somogyi phenomenon should bedistinguished from the morning hyperglycemia which may be seen in insulin-treated patients, named ‘dawn phenomenon’, linked to the increase in GHsecretion normally associated with sleep

Diagnosis

Hypoglycemia in a diabetic patient taking insulin or sulfonylurea drugs

is not a diagnostic problem, especially considering that clinical symptoms aremost characteristic Instant glycemic determination (which can be obtainedalso with a self-blood glucose monitoring device) confirms or excludes thediagnosis of hypoglycemia In hypoglycemic children, seizures are commonand may simulate epilepsy (on the other hand, hypoglycemia may favor ortrigger an epileptic focus) An EEG performed successively may help in thediagnosis

Diagnostic problems exist in nondiabetic subjects with symptoms of poglycemia because of the several possible causes (factitious or reactive hy-poglycemia, insulinoma, extrapancreatic tumors, etc.) In the presence of apatient with suspicion of hypoglycemia, it is crucial to demonstrate the hypogly-cemia with a specific determination of blood glucose in specimens obtainedduring the hypoglycemic event Very useful in the diagnosis of hypoglycemia

hy-is also the assessment of levels of plasma insulin, C-peptide, counterregulatory

Table 4 Diagnostic tests for hypoglycemia

Simultaneous determination of glycemia Tolbutamide test

and insulinemia during hypoglycemic Glucagon test

Supervised fasting (the gold standard test) Proinsulin determination

C-peptide suppression test Leucine test

Sulfonylurea assay in plasma or urine Search for antibodies to insulin

hormones, drugs or alcohol It is important to have an accurate history ofthe patient to distinguish between fasting or postprandial hypoglycemia and torelate hypoglycemic episodes and symptoms and signs The clinical evaluationshould refer to weight loss (extrapancreatic tumor or endocrine deficits) orweight gain (insulinoma or reactive hypoglycemia), presence of autoantibodiesagainst insulin receptors (acanthosis nigricans), hepatomegaly (galactosemia

or glycogenosis), and presence of tumoral abdominal masses (of mesenchymal

or epithelial origin) localized by CT or abdominal sonography If an insulinoma

is suspected, the tumor should be localized before surgery with sonography (also used intraoperatively), celiac angiography or CT evaluation.Several diagnostic tests can be very helpful (table 4), and are outlinedbelow:

ultra-(1) Simultaneous determination of glycemia and insulinemia during thehypoglycemic episode and at fasting on 3 consecutive days

(2) Supervised fast, which consists of simultaneous determinations every4–6 h of glycemia, insulinemia and C-peptide during fasting periods of 24,

48 and 72 h In insulinoma, glycemia falls while C-peptide and insulinemiaremain near-unmodified Quantitation of plasma cortisol, FFA, glucagon andtotal ketones can sometimes be useful In normal male individuals, meanglucose at 72 h is 3.4–3.9 mmol/l (or 62–71 mg%) and in normal female in-dividuals is 2.7–2.9 mmol/l (or 48–52 mg%) while mean insulin is 6 and

4lU/mL, respectively A diagnosis of hypoglycemia is probable with values

of glycemia=2.5 mmol/l (or 45 mg%) and presence of symptoms which arerapidly relieved by administration of glucose In the presence of hyperinsuline-mia and increase of C-peptide an insulinoma should be suspected, while inthe presence of hyperinsulinemia with a low level of C-peptide the possibility

of factitious hypoglycemia induced by exogenous insulin (with suppression ofC-peptide secretion) should be considered On the other hand, in factitioushypoglycemia induced by sulfonylureas, both plasma insulin and C-peptidelevels are increased