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, because with the beginning of therapy a further fall in serum potassium occurs as a result of the effect of insulin (which causes a shift of potassium into the cells) and fluid replacement (that dilutes serum potassium). ECG represents a useful tool to assess intracellular potassium concentration, showing flat or inverted T waves when intracellular potassium is low and peaked T waves when in- tracellular potassium is high. Bicarbonate administration isonly required inpatients 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, 2,3-diphospho- glycerate (2,3-DPG) is low in red cells, which decreases oxygen delivery. This is counterbalanced by acidosis, which favors oxygen delivery. A rapid correc- 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 depletion and reduced tissue perfusion may favor the development of tissue hypoxia and lactic acidosis. In presence of infections, antibiotic therapy should be employed. When the patient is comatose, insert a nasogastric tube, use a urinary catheter (if no urine passes within 3 h) and heparinize in case of hyperosmolar coma development or in presence of thrombosis risk factors. After the recovery from a diabetic ketoacidotic episode, it is useful to accurately review the causes to reduce the risk of recurrence. Hyperosmolar Nonketotic Syndrome Hyperosmolar nonketotic syndrome (HNKS) is an acute complication observed most often in type 2 diabetic patients and is characterized by symp- toms and signs due to volume depletion (caused by excessive hyperglycemia and consequent hyperosmolality and osmotic diuresis), with varying degree of clouding of sensorium, ranging from absence of mental impairment (about 10%) to frank coma (about 10%). HNKS is a serious complication, which entails a mortality rate as high as ?40%. Pneumonia (favored by sensory clouding which facilitates aspiration of oropharyngeal secretions) may develop in HNKS patients, as well as other infections. The dehydration elevates plasma viscosity and may favor throm- bosis. Disseminated intravascular coagulation (DIC) may also occur, with bleeding manifestations. 108Belfiore/Iannello Laboratory findings include a marked hyperglycemia (usually higher than that occurring in DKA, reaching a level of ?800 mg/dl or 44 mmol/l) which causes increase in serum osmolality (which may be as high as ?350 mosm/l), whereas sodium is normal or slightly changed. Urea nitrogen and creatinine are 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 slightly changed. When present, acidosis is due to retention of inorganic acids (see above), i.e. a small amount of ketone bodies as well as a certain amount of lactate (due to tissue hypoperfusion consequent to volume depletion). The extreme hyperglycemia with the ensuing hyperosmolality may be favored by the abundant hyperglycemic diuresis in patients who are unable to compensate the large fluid loss with urine by adequate water drinking, as it often occurs in old patients, who have an attenuated sensation of thirst and who often live alone or in nursing homes. However, it should be kept in mind that HNKS may be precipitated by several factors, including infections, cerebrovascular events, hypertonic peritoneal dialysis, parenteral nutrition or administration 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 to insulin than the glucose homeostatic mechanisms, itis possible that the residual insulin secretion, while unable to stimulate glucose utilizaton and to repress hepatic glucose production, is able to refrain lipolysis, thus limiting the FFA afflux to liver and therefore the ketogenic process. (2) The endogenously se- creted insulin reaches, through the portal vein, the liver, which is insulinized 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, which inhibits the ketogenic process at the level of CPT-1. (3) There may be glucagon resistance, which prevents glucagon to exert its ketogenic effects (see under DKA). (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 malonyl- CoA, thus refraining ketogenesis. HNKS treatment is primarily directed to restore blood volume and correct hyperosmolality. This may require the supply of intravenous fluid in the total amount up to 8–10 liters. Therapy may be started by intravenous infusion of saline at the rate of 1.5 liters/h for the first 2 h, followed by infusion of 0.5 liter/h of half-normal saline (0.45%) adjusted according to the clinical and laboratory response. Insulin should also be given. This may be done according to the small dose regimen described under DKA, although some patients may 109Clinical Emergencies in Diabetes require larger doses. Potassium should be supplied (see under DKA) with special attention because, in the absence of acidosis, the intracellular K + transfer induced by insulin administration is more pronounced. Attention should also be paid to the possible development of infections or thrombosis or DIC to start timely the appropriate therapy. Suggested Reading Foster DW, McGarry JD: The metabolic derangements and treatment of diabetic ketoacidosis. N Engl J Med 1983;309:159–169. Genuth SM: Diabetic ketoacidosis and hyperglycemic hyperosmolar coma. Curr Ther Endocrinol Metab 1997;6:438–447. Gonzalez-Campoy JM, Robertson RP: Diabetic ketoacidosis and hyperosmolar nonketotic state: Gaining control over extreme hyperglycemic complications. Postgrad Med 1996;99:143–152. Silink M: Practical management of diabetic ketoacidosis in childhood and adolescence. Acta Paediatr 1998;425(suppl):63–66. Siperstein MD: Diabetic ketoacidosis and hyperosmolar coma. Endocrinol Metab Clin North Am 1992; 21:415–432. Umpierrez GE, Khajavi M, Kitabchi AE: Review: Diabetic ketoacidosis and hyperglycemic hyperosmolar nonketotic syndrome. Am J Med Sci 1996;311:225–233. Whiteman VE, Homko CJ, Reece EA: Management of hypoglycemia and diabetic ketoacidosis in preg- nancy. Obstet Gynecol Clin North Am 1996;23:87–107. 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 110Belfiore/Iannello Chapter VIII Belfiore F, Mogensen CE (eds): New Concepts in Diabetes and Its Treatment. Basel, Karger, 2000, pp 111–124 Clinical Emergencies in Diabetes. 2: Hypoglycemia F. Belfiore, S. Iannello Institute of Internal Medicine, University of Catania, Ospedale Garibaldi, Catania, Italy Definition The term hypoglycemia refers to a biochemical conditionresulting from an abnormally low plasma glucose level, less than the lower value of the normal range(50–45 mg% or 2.8–2.5 mmol/l). Thus, the term hypoglycemiaseemsinap- propriate to define a variety of clinical manifestations associated with abnor- mally low blood glucose and consisting of signs and symptoms of adrenergic activation and neuroglycopenia, responsive to glucose administration. In infants, during the first 48 h of life, hypoglycemia may occur, with glycemic values =30 mg% or 1.7 mmol/l, with a frequency of about 10% of live births. A brief hypoglycemic episode can cause moderate alterations of the brain whereas prolonged hypoglycemia can cause profound dysfunctions, tissue damage and also death of the brain. This depends on the fact that the deposit 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 the brain tissue and is entirely derived from the circulation. The brain tissue utilizes 120 g/day of glucose and about 90% of total energy needed for cerebral functions derives from glucose oxidation. The brain cannot utilize alternative substrates (as circulating FFA) as energy fuel thus being very sensitive to hypoglycemia. In some particular situations, at least some parts of the brain might utilize ketoacids. Hypoglycemia is avery uncommon event, apart from persons withdiabetes treated with insulin or hypoglycemic drugs. The diagnosis of hypoglycemia is based upon Whipple’s triad,i.e. hypoglycemia, symptomsof hypoglycemia, and correction of the symptoms with the normalization of blood glucose. 111 Glucose Counterregulation Insulin regulates glycemia through modulation of hepatic glucose produc- tion in the postabsorptive state and glucose utilization in the postprandial state, and it is the only hormone able to physiologically reduce glycemic level. In catabolic states (fasting), insulin concentration falls and the levels of counterregulatory hormones rise; in fact, hypoglycemia is capable of inducing the release of counterregulatory hormones, including glucagon, catechola- mines (epinephrine and norepinephrine – released both from adrenal medulla and 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 acts within 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 production and limiting glucose utilization in humans through both  2 - and  2 -adrenergic mechanisms. Cortisol and GH, on the contrary, act within several hours with a delayed glucoregulatory action (antagonizing insulin action, mobilizing substrate and activating hepatic gluconeogenesis through the induction of the relative gluconeogenic enzymes). All these hormones have a synergic action on the induction of hyperglycemia and on the prevention and correction of hypoglycemia. Glucagon plays the most important counterregulatory action whereas catecholamines play a minor role, that becomes important when there is glucagon deficiency, as it often happens early during the course of diabetes mellitus. Catecholamines are the warning system in hypoglycemia through the symptoms and signs of adrenergic overactivity. Cortisol and GH play no role in short-term hypoglycemia but have a substantial role in the recovery from long-term hypoglycemia. The relevance of other hormones or neurotransmit- ters in preventing and correcting hypoglycemia has been debated but it is not definitely established. In type 1 diabetic patients, counterregulation is often altered and, in some patients it may be very deficient. It has been reported that almost all diabetic patients show a deficient glucagon secretory response to hypoglycemia, perhaps as a result of the long-term hyperglycemia (glucose toxicity) or the loss of the regulating effect of insulin on glucagon secretion. In the presence of adefective glucagon secretion, type1 diabetic patients during hypoglycemic episodes became dependent upon catecholamines to correct low glycemic level, i.e. epinephrine response compensates for deficient glucagon response. Some diabetic patients with long-standing disease have also a defi- cient catecholamine response to hypoglycemia and this combined disorder impairs glucose counterregulation and represents a high risk of iatrogenic hypoglycemia in these subjects. GH and cortisol responses to hypoglycemia 112Belfiore/Iannello Table 1. Causes of hypoglycemia A. Fasting hypoglycemia B. Postprandial or reactive hypoglycemia 1. Reduced glucose production Alimentary hypoglycemia (gastrectomy, Liver or renal insufficiency gastrojejunostomy, pyloroplasty Deficiencyofcounterregulatoryhormones or vagotomy) Childhood ketotic hypoglycemia Hyperthyroidism (substrate or enzyme deficiency) Obesity with hyperinsulinism Drugs (alcohol, salicylates, -blockers) Early stage of type 2 diabetes, prediabetes or IGT 2. Increased glucose utilization Idiopathic reactive hypoglycemia -Cell tumor or insulinoma Idiopathic postprandial syndrome or Functional hypersecretion of -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--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 secretion may occur. Classification of Hypoglycemia (see table 1) Postabsorptive or Fasting Hypoglycemia Fasting hypoglycemia may result from impaired hepatic glucose produc- tion (involving glycogenolysis or gluconeogenesis) or enhanced peripheral glucose utilization. It can be induced by several causes, listed below. 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 113Clinical Emergencies in Diabetes impair hepatic glucose production, or conditions of inadequate substrate store and supply (chronic renal failure, malnutrition, starvation or cachexia, ano- rexia nervosa, late pregnancy). (2) Deficiency ofcounterregulatory hormones (glucagon andepinephrine, 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 substrate deficiency 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) espe- cially when associated to fasting, salicylates (a common cause of hypoglycemia in infants) which would increase peripheral glucose utilization and reduce hepatic gluconeogenesis, -blockers (which reduce the glycogenolytic response to epinephrine). Increased Glucose Utilization. Several causes may lead to increased glucose utilization: (1) Endogenous hyperinsulinism (that causes glucose overutilization) produced by: (a) -cell tumor or insulinoma (a rare, most often small and single, benign tumor occurring in 1/250,000 adult individuals) or islet cell hyperplasia (nesidioblastosis), a rare syndrome in adult subjects; (b) func- tional hypersecretion of -cells; (c) autoimmune hypoglycemia (autoantibod- ies against insulin, with inappropriate release of antibody-bound insulin in the circulation), common in Japan; (d) rare instances of acanthosis nigricans (insulin receptor autoantibodies, which most often cause insulin resistant diabetes, can in some patients act as insulin-like factors); (e) ectopic insulin secretion. (2) Sepsis (cytokines associated to endotoxinemia increase insulin re- lease). (3) Insulin or drugs that stimulate insulin release, such as sulfonylurea compounds in diabetic patients, pentamidine (which exerts a toxic effect with -cell cytolysis), and quinine (which induces massive insulin release, although this effect is not well demonstrated). (4) Hypoglycemia of infants born from diabetic mothers, occurring during the first hours of life (provoked by fetal hyperinsulinemia linked to hyperplasia of -cells induced by maternal hyperglycemia and hyperglucagonemia). (5) Non--cell or extrapancreatic large tumors of mesenchymal (50%) or epithelial origin (5–10%) or hepatomas (25%) or other carcinomas (5–10%) or some malignant hematologic diseases (5–10%), in which hypoglycemia is induced by production of insulin-like growth factors such as IGF-2, that interacts with insulin receptors (and may suppress endogenous insulin secre- tion), or by overutilization of glucose (by the tumoral tissue). 114Belfiore/Iannello (6) Nonketotic hypoglycemia due to systemic carnitine deficiency or en- zymatic defects which limit the utilization of FFA or ketones (which entails enhanced glucose oxidation for energetic purposes). (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 or sulfonylurea assumption (especially in medical people or family members of diabetic patients with psychiatric disturbances). (2) Artifactual hypoglycemia as it may occur in hemolytic anemia or in leukemia and leukemic reactions (due to overutilization of glucose in the test tube by young erythrocytes or leukemic leukocytes) or in the presence of marked 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 includes several forms, listed below: (1) Alimentary hypoglycemia (or alimentary hyperinsulinism) caused by gastrectomy, gastrojejunostomy, pyloroplasty or vagotomy, involving about 5–10% of operated patients and developing 30–120 min after ingestion of carbohydrate-containing meals (due to rapid gastric emptying and glucose absorption which stimulate excessive insulin release, and perhaps also to hyper- secretion of enterohormones such as enteroglucagon, secretin, GIP, etc.); it may perhaps also occur in patients with hyperthyroidism, or in obesity with hyperinsulinism. (2) Early stage of type 2 diabetes or prediabetes or IGT (deficient early- phase insulinrelease leadsto higherglucose elevation with subsequent excessive stimulation of insulin secretion). However, it should be mentioned that the relationship between the early stage of type 2 diabetes or prediabetes or IGT and postprandial hypoglycemia is not well established. (3) Idiopathic reactive hypoglycemia or true hypoglycemia (with lowered glucose levels), a rare syndrome characterized by adrenergic symptoms without symptoms of severe neuroglycopenia, probably linked to an increased insulin response or a higher affinity of insulin receptors or to a subtle dysfunction of gastrointestinal tract. (4) Idiopathic postprandial syndrome or pseudohypoglycemia (with a near-normal glycemic value), characterized by adrenergic symptoms and light symptoms of neuroglycopenia, which develop regularly and repetitively during the patient’s life (causes are unknown and might include enhanced 115Clinical Emergencies in Diabetes Table 2. Clinical signs and symptoms of hypoglycemia Sympathetic/parasympathetic activation Neuroglycopenia A. Clinical signs and symptoms of adrenergic Clinical signs and symptoms of activation neuroglycopenia Pallor, tremor, palpitations and anxiety Headache, dizziness, fatigue, irritability or Acute sensation of hunger apathy and lethargy Occasionally hypothermia, vomiting, Frequent yawning and perioral numbness fever, moderate tachycardia, crises of Disturbed vision and diplopia systolic hypertension Paresthesias and motor dysfunction B. Clinical signs and symptoms of Cognitive impairment, mental confusion and inebriation parasympathetic activation Personality changes, psychotic behavior Nausea and eructation Occasionally transient hemiparesis or Cold sweating focal neurologic deficits Mitigation of expected tachycardia or true Convulsions (in children simulating true bradycardia crises of epilepsy) Mild hypotension Semi-coma, coma and even death epinephrine release in some subjects, with stress or anxiety contributing in many subjects). (5) Inherited disorders ofcarbohydrate metabolism in children (hereditary fructose intolerance from deficiency of fructose-1-P aldolase or galactosemia from deficiency of galactose-1-P uridyltransferase). (6) Intake of leucine in leucine-sensitive children (due to increased insulin secretion). Clinical Signs and Symptoms of Hypoglycemia (see table 2) The clinical manifestations of hypoglycemia are generally nonspecific and varying,notonlyfrompatienttopatientbutalsointhesamesubjectfromepisode to episode. Their development can depend not only on the glycemic value but also on the rate of the fall in blood glucose. Manifestations can be distinguished into adrenergic (due to sympathetic activation) and neuroglycopenic (due to neuronal alterations secondary to glucose deprivation). When glucose drops rapidly, adrenergicsymptoms are most evident whilewhenglucose drops gradu- ally neuroglycopenic symptoms may dominate the clinical picture. During a hy- poglycemic episode, the response of counterregulatory hormones begins before the symptomatic glucose threshold is reached. 116Belfiore/Iannello Neuropenic symptoms may not occur even in the presence of glucose level as low as 25–30 mg/dl (1.4–1.7 mmol/l) due to the ability of normal persons to increase brain blood flow and therefore glucose delivery. This adaptation may be prevented in patients with cerebral atherosclerosis and inelastic vessels, in whom neuropenic symptoms may appear at relatively high glucose levels. It should be pointed out that severe hypoglycemic reactions may occur even in the presence of near-normal or even high glycemic values (pseudohypo- glycemia), especially in diabetic patients; on the other hand, there may be no clinical 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 the rate of fall in glycemia and the fact that the glucose plasma level may not strictly 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 from neuroglycopenia and activation of counterregulatory hormones occur but symptoms are not yet manifest; therefore, the value of 3.88 mmol/l may be a cut-off value of hypoglycemia, useful and safe to consider in the treatment of diabetes 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 signs induced 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 hypogly- cemia =45 mg% or 2.50 mmol/l, and include headache, dizziness, fatigue, irritability or apathy, lethargy, frequent yawning, cognitive impairment, mental confusion, inebriation, personality changes and psychotic behavior, disturbed vision 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 consciousness until hypoglycemic coma and even death. The different neurologic manifesta- tions have been correlated with specific sites of the brain involved in different degrees of hypoglycemia. Clinical hypoglycemic symptoms and signs some- times suggest true mental disorders, accounting for the frequent reported mistake or delay in diagnosis. 117Clinical Emergencies in Diabetes [...]... and to use a rapid-acting insulin analogue before the main evening meal Hypoglycemia in Insulinoma and Extrapancreatic Tumors In insulinoma patients, surgery is the elective treatment, while medical treatment is indicated only in the presurgical phase (diazoxide in doses of 300–1,200 mg/day, per os, and octreotide in doses of 100–600 g/day, subcutaneously) Treatment of nonpancreatic insulin-producing... subjects; this proinsulin excess is lacking in factitious hypoglycemia) (11) Leucine test (intravenous L-leucine infusion, 200 mg in 30 min, or an oral load of 0. 15 g/kg, with serial samples obtained for 1 or 2 h, respectively), that evokes an excessive insulin response in children susceptible to leucine and in about 70% of patients with insulinoma (12) Search for antibodies to insulin (if present in persons... an insulin peak P130 U/ml), useful in glycogenosis (in this disease, however, enzyme determinations in liver and muscle biopsy are the best diagnostic test) (9) Vigorous exercise in fasted state will provoke hypoglycemia in insulinoma patients (this is not a well-standardized test) (10) Proinsulin determination (? 25% of total insulinemia in about 85% of patients with insulinoma, compared to 10– 15% ... epinephrine, norepinephrine, GH and glucagon), useful in cases of counterregulatory hormone deficiencies (7) Intravenous tolbutamide infusion (1 g over 3 min), positive in about 80% of the cases with insulin-secretory tumors (induces a severe hypoglycemia, with average value of glycemic levels at 120, 150 and 180 min O 55 mg/dl in lean and O62 mg/dl in obese subjects) (8) Glucagon test (1 mg intravenous... hand, in factitious hypoglycemia induced by sulfonylureas, both plasma insulin and C-peptide levels are increased Belfiore/Iannello 120 (3) C-peptide suppression test, based on the fact that suppression of the release of endogenous insulin and C-peptide during insulin infusion (0.1 25 U/kg over 1 h or over 3 h) is impaired in about 90% of patients with insulinoma (4) Assay of sulfonylurea compounds in. .. useful in the diagnosis of hypoglycemia is also the assessment of levels of plasma insulin, C-peptide, counterregulatory Clinical Emergencies in Diabetes 119 Table 4 Diagnostic tests for hypoglycemia Simultaneous determination of glycemia and insulinemia during hypoglycemic episodes Supervised fasting (the gold standard test) C-peptide suppression test Sulfonylurea assay in plasma or urine 5h-OGTT Insulin... test Vigorous exercise during fasting Proinsulin determination Leucine test Search for antibodies to insulin Search for autoantibodies against insulin or insulin receptors hormones, drugs or alcohol It is important to have an accurate history of the patient to distinguish between fasting or postprandial hypoglycemia and to relate hypoglycemic episodes and symptoms and signs The clinical evaluation should... fasting periods of 24, 48 and 72 h In insulinoma, glycemia falls while C-peptide and insulinemia remain near-unmodified Quantitation of plasma cortisol, FFA, glucagon and total ketones can sometimes be useful In normal male individuals, mean glucose at 72 h is 3.4–3.9 mmol/l (or 62–71 mg%) and in normal female individuals is 2.7–2.9 mmol/l (or 48 52 mg%) while mean insulin is 6 and 4 U/mL, respectively... values of glycemia =2 .5 mmol/l (or 45 mg%) and presence of symptoms which are rapidly relieved by administration of glucose In the presence of hyperinsulinemia and increase of C-peptide an insulinoma should be suspected, while in the presence of hyperinsulinemia with a low level of C-peptide the possibility of factitious hypoglycemia induced by exogenous insulin (with suppression of C-peptide secretion)... antibodies to insulin (if present in persons not receiving insulin therapy can indicate a surreptitious insulin use) or for autoantibodies against insulin or insulin receptors (useful to diagnose acanthosis nigricans and early stage of insulin-resistant diabetes) Treatment Hypoglycemia in Diabetic Patients The treatment of hypoglycemia depends upon the cause and the severity of the hypoglycemic episode Diagnosis . hypoglycemia in insu- linoma patients (this is not a well-standardized test). (10) Proinsulin determination (? 25% of total insulinemia in about 85% of patients with insulinoma, compared to 10– 15% of. both in normal persons and in subjects with pseudohypo- glycemia). (6) Insulin tolerance test (0.1 U/kg intravenous insulin and determina- tions of ACTH, cortisol, epinephrine, norepinephrine,. 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