Acute Complications of Diabetes Mellitus PDF

Acute Complications of Diabetes Mellitus ILOs At the end of this session, the student will be able to: ▪ Define diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS). ▪ Understand the pathogenesis of DKA and HHS. ▪ Identify the clinical and laborat...

Acute Complications of Diabetes Mellitus ILOs At the end of this session, the student will be able to: ▪ Define diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS). ▪ Understand the pathogenesis of DKA and HHS. ▪ Identify the clinical and laboratory diagnostic criteria of DKA and HHS. ▪ Discuss the lines of treatment of DKA and HHS. ▪ Define hypoglycemia, and its etiological factors. ▪ Recognize the clinical and laboratory criteria of hypoglycemia. ▪ Discuss the management of hypoglycemia. Diabetic Coma Diabetic coma requires differentiation: (1) Hypoglycemic coma from excessive insulin or oral hypoglycemic agents. (2) Hyperglycemic coma with either severe insulin deficiency (DKA) or mild to moderate insulin deficiency (hyperglycemic hyperosmolar state). (3) Lactic acidosis, particularly when patients with diabetes have severe infections. Diabetic Ketoacidosis (DKA): Essentials of Diagnosis Hyperglycemia > than 250 mg/dL. Metabolic acidosis with blood pH < 7.3; serum bicarbonate < 15 mEq/L. Serum positive for ketones. Clinical Findings Diabetic ketoacidosis (DKA) is a disorder primarily in patients with type 1 diabetes but can occur in patients with type 2 diabetes who have severe illness, such as sepsis or trauma. DKA may be the initial manifestation of type 1 diabetes or may result from increased insulin requirements in type 1 diabetes patients during the course of infection, myocardial infarction, or surgery. It is a life-threatening medical emergency. Annual incidence: 5-8 episodes of DKA per 1000 diabetic persons. Poor compliance, either for psychological reasons or because of inadequate education, is one of the most common causes of recurrent DKA. The appearance of DKA is usually preceded by a day or more of polyuria and polydipsia associated with marked fatigue, nausea, and vomiting. If untreated, mental stupor ensues that can progress to coma. Drowsiness is common, but frank coma only occurs in about 10% of patients.  On physical examination, evidence of dehydration, with rapid deep breathing and a "fruity" breath odour of acetone strongly suggests the diagnosis. Hypotension with tachycardia indicates profound fluid and electrolyte depletion, and mild hypothermia is usually present. Abdominal pain/tenderness may be present in the absence of abdominal disease. Conversely, cholecystitis or pancreatitis may occur with minimal symptoms and signs. Laboratory Findings Typically, the patient has a plasma glucose > 250 mg/dl , positive serum ketones, hyperkalemia, and mild hyponatremia. Acidosis may be severe (pH 6.9 to 7.2 and bicarbonate 5-15 mEq/L); PCO2 is low related to compensatory hyperventilation. Fluid depletion is marked. In euglycemic ketoacidosis, the patient can have severe acidosis and fluid depletion but the plasma glucose less than 250 mg/day. This condition is seen in patients in whom diabetic ketoacidosis develops while receiving treatment with SGLT2 inhibitors. Ketoacidosis with lower glucose levels also occurs in pregnancy and may reflect the expanded plasma volume and the increased glomerular filtration rate. Hyperkalemia occurs despite total body potassium depletion because of shift of potassium from the intracellular to extracellular spaces due to metabolic acidosis. Serum sodium is generally reduced due to polyuria and vomiting and because severe hyperglycemia shifts intracellular water into extracellular compartment. For every 100 mg/dl of plasma glucose, serum sodium decreases by 1.6 mEq/L. The decrease in serum sodium may be greater when patients have more severe hyperglycemia and a correction factor may be used. A convenient method of estimating effective serum osmolality is as follows (normal values are 280-300 mOsm/kg): 2 [measured Na" ] + Glucose (mg/dL)/18. Coma occurs when the effective serum osmolality exceeds 330 mOsm/Kg. Ketoacidemia represents the effect of insulin lack. Insulin lack associated with elevated levels of growth hormone, catecholamines, and glucagon contributes to increases in lipolysis from adipose tissue and in hepatic ketogenesis. One of the ketones in diabetic ketoacidosis is acetoacetic acid which, along with its byproduct acetone, is measured by nitroprusside reagents. The more prevalent beta hydroxybutyric acid has no ketone group and is therefore not detected by conventional nitroprusside tests.  Bedside diagnostic reagents are then unreliable, suggesting no ketonemia in cases where beta-hydroxybutyric acid is a major factor in producing the acidosis. Combined glucose and ketone meters that measure blood beta-hydroxybutyrate concentration on capillary blood are available. Many laboratories can also measure blood beta-hydroxybutyrate measurement. Nonspecific elevations of serum amylase and lipase occurs in about 16-25% of cases of DKA, and an imaging study may be necessary if the diagnosis of acute pancreatitis is suspected. Leukocytosis as high as 25,000/mcl may occur with or without associated infection. The presence of an elevated or even a normal temperature can suggest the presence of an infection since patients with DKA are generally hypothermic if uninfected. Treatment Patients with mild DKA are alert and have pH levels between 7.25 and 7.30; those with moderate ketoacidosis are either alert or a little drowsy and have pH levels between 7.0 and 7.24; and those with severe ketoacidosis are stuporosed and have a pH less than 7.0. Patients with mild ketoacidosis can be treated in the emergency department, but those with moderate or severe ketoacidosis require admission to the ICU. Therapeutic goals are to restore plasma volume and tissue perfusion, reduce blood glucose and osmolality toward normal, correct acidosis, replenish electrolyte losses, and identify and treat precipitating factors. Gastric intubation is recommended in the comatosed patient to prevent vomiting and aspiration. An indwelling urinary catheter may also be necessary. In patients with pre-existing heart or kidney failure or those in severe cardiovascular collapse, a central venous pressure catheter should be inserted to evaluate the degree of hypovolemia and to monitor subsequent fluid administration. A comprehensive flow sheet that includes vital signs, serial laboratory data, and therapeutic interventions (eg, fluids, insulin) should be meticulously maintaine. Plasma glucose should be recorded hourly and electrolytes and pH at least every 2- 3 hours during the initial treatment period. Bedside glucose meters should be used to titrate the insulin therapy.  The patient should not receive sedatives or opioids in order to avoid masking signs and symptoms of impeding cerebral edema. A. Fluid Replacement: In most patients, the fluid deficit is 4-5 L. Initially, 0.9% saline solution is the solution of choice to help re-expand the contracted vascular volume and should be started in the emergency department as soon as the diagnosis is established. The saline should be infused rapidly to provide 1 L/h over the first 1-2 hours. After the first 2 L of fluid have been given, the intravenous infusion should be at the rate of 300-400 mL/h. Use 0.9% ("normal") saline unless the serum sodium is greater than 150 mEq/L, when 0.45% ("half normal") saline solution should be used. The volume status should be carefully monitored clinically. Excessive fluid replacement (more than 5 L in 8 hours) may contribute to acute respiratory distress syndrome or cerebral edema. When blood glucose falls to approximately 250 mg/dl, the fluids should be changed to a 5% glucose-containing solution to maintain serum glucose in the range of 250-300 mg/dl. This will prevent the development of hypoglycemia and will also reduce the likelihood of cerebral edema, which could result from too rapid decline of blood glucose. B. Insulin Replacement: Immediately after initiation of fluid replacement, regular insulin can be given intravenously in a loading dose of 0.1 unit/kg as a bolus. Then, intravenous doses of insulin of 0.1 unit/kg/h are continuously infused; this is sufficient to replace the insulin deficit in most patients. Replacement of insulin deficiency helps correct the acidosis by reducing the flux of fatty acids to the liver, reducing ketone production by the liver. Insulin treatment reduces the hyperosmolality by reducing the hyperglycemia. It accomplishes this by increasing removal of glucose through peripheral utilization as well as by decreasing production of glucose by the liver, by direct inhibition of gluconeogenesis and glycogenolysis. The insulin dose should be adjusted to lower the glucose concentration by about 50-70 mg/dL/h. C. Potassium:  Total body potassium loss from polyuria and vomiting may be high. However, because of shifts of potassium from cells into the extracellular space as a consequence of acidosis, serum potassium is usually normal to slightly elevated. As the acidosis is corrected, potassium flows back into the cells, and hypokalemia can develop if potassium replacement is not instituted. Potassium chloride in doses of 10-30 mEq/h should be infused. Replacement should be postponed if serum potassiumis above 5 mEq/L. If serum potassium is less than 3.5 mEq/L, insulin therapy should be delayed until the potassium level is corrected. D. Sodium Bicarbonate: The use of sodium bicarbonate in the management of DKA has been questioned because of the following potentially harmful consequences: (1) development of hypokalemia from rapid shift of potassium into cells if the acidosis is overcorrected. (2) tissue anoxia from reduced dissociation of oxygen from hemoglobin when acidosis is rapidly reversed (leftward shift of the oxygen dissociation curve); and (3) cerebral acidosis resulting from lowering of cerebrospinal fluid pH. Therefore, it is recommended that bicarbonate be administered in DKA only with severe acidosis (arterial blood pH is 7.0 or less), with careful monitoring. One or two ampules of sodium bicarbonate (one ampule=44 mEq/50 mL) should be added to 1 L of 0.45% saline with 20 mEq KCl and infused over 2 hours. It can be repeated until the arterial pH reaches 7.1, but it should not be given if the pH is 7.1 or greater since additional bicarbonate would increase the risk of rebound metabolic alkalosis. Alkalosis shifts potassium from serum into cells, which could precipitate a fatal cardiac arrhythmia. E. Treatment of Associated Infection: Antibiotics are prescribed as indicated. Cholecystitis and pyelonephritis may be particularly severe in these patients. F. Transition to Subcutaneous Insulin Regimen:  Once DKA is controlled and the patient is awake and able to eat, subcutaneous insulin therapy can be initiated. The amount of insulin required in the previous 8 hours can be helpful in estimating the initial insulin doses. Half the total daily dose can be given as a long-acting basal insulin and the other half as short-acting insulin premeals. The patient should receive subcutaneous basal insulin and rapid-acting insulin analog with the first meal and the insulin infusion discontinued an hour later. The overlap of the subcutaneous insulin action and insulin infusion is necessary to prevent relapse of the DKA. Patients with type 2 diabetes and DKA due to severe illness may initially require insulin therapy but can often transition back to oral agents during outpatient follow-up. Hyperglycemic Hyperosmolar State (HHS) ESSENTIALS OF DIAGNOSIS: Hyperglycemia > 600 mg/dL. Serum osmolality > 310 mOsm/kg. No acidosis; blood pH > 7.3 , Serum bicarbonate> 15 mEq/L. Normal anion gap (< 14 mEq/L).  The second most common form of hyperglycemic coma. Characterized by severe hyperglycemia in the absence of significant ketosis, with hyperosmolality and dehydration. Most patients are typically middle-aged to elderly type 2 diabetic patients. Underlying chronic kidney disease or heart failure is common, and the presence of either worsens the prognosis. A precipitating event such as infection, myocardial infarction, stroke, or recent surgery is often present. Certain medications such as phenytoin, diazoxide, corticosteroids, and diuretics have been implicated in its pathogenesis. Pathogenesis A partial or relative insulin deficiency may initiate the syndrome by reducing glucose utilization of muscle, fat, and liver increasing hepatic glucose output, with massive glycosuria, and water loss. If a patient is unable to maintain adequate fluid intake because of an associated acute or chronic illness, marked dehydration results. As the plasma volume contracts, kidney function becomes impaired, limiting the urinary glucose losses and exacerbating the hyperglycemia. Severe hyperosmolality develops that causes mental confusion and coma. Ketosis is virtually absent in spite of insulin insufficiency, as some insulin remains that is sufficient to prevent ketogenesis. Clinical Findings Symptoms and Signs: Onset may be insidious over a period of days or weeks, with weakness, polyuria, and polydipsia. Lack of features of DKA (vomiting, rapid deep breathing) may retard the diagnosis and delay therapy until dehydration becomes more profound. Reduced intake of fluid is a common feature, due to either inappropriate lack of thirst, nausea, or inaccessibility of fluids to elderly, bedridden patients. A history of ingestion of large quantities of glucose containing fluids, such as soft drinks or orange juice, can occasionally be obtained.  Lethargy and confusion develop as serum osmolality exceeds 310 mOsm/kg. Convulsions and coma can occur if osmolality exceeds 330 mOsm/kg. Physical examination confirms the presence of profound dehydration in a lethargic or comatosed patient without Kaussmaul respirations. Laboratory Findings: Severe hyperglycemia is present, with blood glucose values ranging from 800 mg/dL to 2400 mg/dL. As dehydration progresses, serum sodium can exceed 140 mEq/L, producing serum osmolality readings of 330- 440 mOsm/kg. Ketosis and acidosis are usually absent or mild. Prerenal azotemia is the rule, with high serum urea being typical. Treatment A. Fluid Replacement: Fluid replacement is of paramount importance. Fluid deficit may be as much as 6-10 L. If hypovolemia is present as evidenced by hypotension and oliguria, fluid therapy should be initiated with 0.9% saline. In all other cases, 0.45% saline appears to be preferable as the initial replacement solution because body fluids are markedly hyperosmolar. As much as 4-6 L of fluid may be required in the first 8-10 hours. Careful monitoring of the patient is required for proper sodium and water replacement. An important end point of fluid therapy is to restore urinary output to 50 mL/h or more. Once blood glucose reaches 250 mg/dL, fluid replacement should include 5% dextrose. The rate of dextrose infusion should be adjusted to maintain glycemic levels of 250-300 mg/dl in order to reduce the risk of cerebral edema. B. Insulin: Less insulin may be required to reduce the hyperglycemia in non-ketotic patients as compared to those with DKA. In fact, fluid replacement alone can reduce hyperglycemia considerably by correcting the hypovolemia, which then increases both glomerular filtration and renal excretion of glucose. Start the insulin infusion rate at 0.05 unit/kg/h (bolus is not needed) and titrate to lower blood glucose levels by 50-70 mg/dl per hour. Once the patient has stabilized and the blood glucose falls to around 250 mg/dl, insulin can be given subcutaneously. C. Potassium: With the absence of acidosis, there may be no initial hyperkalemia unless associated end-stage chronic kidney disease is present. This results in less severe total potassium depletion than in DKA, and less potassium replacement is therefore needed. However, because initial serum potassium is usually not elevated and because it declines rapidly as a result of insulin's effect on driving potassium intracellularly, it is recommended that potassium replacement be initiated early. Potassium chloride (10 mEq/L) can be added to the initial bottle of fluids administered if the patient's serum potassium is not elevated. Prognosis Complications & Prognosis: The severe dehydration and low output state may predispose the patient to complications such as myocardial infarction, stroke, pulmonary embolism, and mesenteric vein thrombosis. Fluid replacement remains the primary approach to prevent these complications. Low-dose heparin prophylaxis is reasonable. The overall mortality rate of hyperglycemic hyperosmolar state coma is more than 10 times that of DKA. This is because of its higher incidence in older patients, who may have associated major illnesses and whose dehydration is often excessive because of delays in recognition and treatment. After the patient is stabilized, the appropriate form of long-term management of the diabetes must be determined.  Insulin treatment should be continued for a few weeks but patients usually recover sufficient endogenous insulin to make a trial of oral agents. Education of the patient and caregivers should be instituted. They should be taught how to recognize situations (nausea and vomiting, infection) that predispose to recurrence of HHS. Hypoglycemia: Drug-induced Hypoglycemia The most common complication of insulin. The signs and symptoms of hypoglycemia may be divided into those resulting from stimulation of the autonomic nervous system and those from neuroglycopenia. When the blood glucose falls to around 54 mg/dL, the patient starts to experience both sympathetic (tachycardia, palpitations, sweating, tremulousness) and parasympathetic (nausea, hunger) nervous system symptoms. If these autonomic symptoms are ignored and the glucose levels fall further (to around 50 mg/dl, then neuroglycopenic symptoms appear, including irritability, confusion, blurred vision, tiredness, headache, and difficulty speaking. A further decline in glucose can lead to loss of consciousness or even a seizure. With repeated episodes of hypoglycemia, there is adaptation, and autonomic symptoms do not occur until the blood glucose levels are much lower and so the first symptoms are often due to neuroglycopenia. This condition is referred to as “hypoglycemic unawareness.” It has been shown that hypoglycemic unawareness can be reversed by keeping glucose levels high for a period of several weeks. Except for sweating, most of the sympathetic symptoms of hypoglycemia are blunted in patients receiving beta-blocking agents. Though not absolutely contraindicated, these medications must be used with caution in patients with diabetes who require insulin, and selective blocking agents are preferred. Hypoglycemia can occur in a patient taking sulfonylureas, repaglinide, and nateglinide, particularly if the patient is elderly, has kidney or liver disease. It occurs more frequently with the use of long-acting sulfonylureas than with shorter-acting agents.  Otherwise, hypoglycemia in insulin-treated patients occurs as a consequence of three factors: behavioural issues, impaired counterregulatory systems, and complications of diabetes. Behavioural issues include injecting too much insulin for the amount of carbohydrates ingested. Drinking alcohol in excess, especially on an empty stomach, can also cause hypoglycemia. In patients with type 1 diabetes, hypoglycemia can occur during or even several hours after exercise, and so glucose levels need to be monitored. Some patients do not like their glucose levels to be high, and they treat every high glucose level aggressively. These individuals who "stack" their insulin- that is, give another dose of insulin before the first injection has had its full action-can develop hypoglycemia. Counterregulatory issues resulting in hypoglycemia include impaired glucagon response, sympatho-adrenal responses, and cortisol deficiency. Patients with diabetes of greater than 5 years in duration lose their glucagon response to hypoglycemia. As a result, they are at a significant disadvantage in protecting themselves against falling glucose levels. Unfortunately, aging, autonomic neuropathy, or hypoglycemic unawareness due to repeated low glucose levels further blunts the sympatho-adrenal responses. Occasionally, Addison disease develops in persons with type I diabetes mellitus; when this happens, insulin requirements fall significantly, and unless insulin dose is reduced, recurrent hypoglycemia will develop. Complications of diabetes that increase the risk for hypoglycemia include autonomic neuropathy, gastroparesis, and end-stage chronic kidney disease. The sympathetic nervous system is an important system alerting the individual that the glucose level is falling by causing symptoms of tachycardia, palpitations, sweating, and tremulousness. Failure of the sympatho-adrenal responses increases the risk of hypoglycemia. In addition, in patients with gastroparesis, if insulin is given before a meal, the peak of insulin action may occur before the food is absorbed causing the glucose levels to fall. Finally, in end-stage chronic kidney disease, hypoglycemia can occur presumably because of decreased insulin clearance as well as loss of renal contribution to gluconeogenesis in the postabsorptive state. To prevent and treat insulin-induced hypoglycemia, the diabetic patient should carry glucose tablets or juice at all times. For most episodes, ingestion of 15 grams of carbo- hydrate is sufficient to reverse the hypoglycemia.  The patient should be instructed to check the blood glucose in 15 minutes and treat again if the glucose level is still low. A parenteral (1 mg) or nasal inhalation (3 mg) glucagon emergency kit should be provided to every patient with diabetes who is receiving insulin therapy. Family or friends should be instructed how to inject it subcutaneously or intramuscularly into the buttock, arm, or thigh in the event that the patient is unconscious. The medication can occasionally cause vomiting, and the unconscious patient should be turned on his or her side to protect the airway. Glucagon mobilizes glycogen from the liver, raising the blood glucose. After the patient recovers consciousness, additional oral carbohydrate should be given. People with diabetes receiving hypoglycemic medication therapy should also wear an identification Medic Alert bracelet or necklace or carry a card in his or her wallet. Medical personnel treating severe hypoglycemia can give 50 ml of 50% glucose solution by rapid intravenous infusion. If intravenous access is not available, 1 mg of glucagon can be injected intramuscularly or 3 mg given by nasal spray. Hypoglycemia in Non-diabetic Subjects 2 principal types: fasting and postprandial. Symptoms begin at plasma glucose levels in the range of 70 mg/dL and impairment of brain function at approximately 50 mg/dL. Fasting hypoglycemia is often subacute or chronic and usually presents with neuroglycopenia as its principal manifestation. Postprandial hypoglycemia is relatively acute and is often presenting with symptoms of neurogenic autonomic discharge (sweating, palpitations, anxiety, tremors).  Fasting hypoglycemia may occur in certain endocrine disorders, such as hypopituitarism, Addison disease, or myxedema; in liver malfunction, such as acute alcoholism or liver failure; and in end-stage kidney disease. These conditions are usually obvious, with hypoglycemia being only a secondary feature. When fasting hypoglycemia is a primary manifestation developing in adults without apparent endocrine disorders, the principal diagnostic possibilities include: (1) hyperinsulinism, due to either pancreatic B cell tumors, iatrogenic or surreptitious administration of insulin. (2) hypoglycemia due to extra-pancreatic tumors. Postprandial (reactive) hypoglycemia: may occur after gastrointestinal surgery and is particularly associated with the dumping syndrome after gastrectomy and Roux- en-Y gastric bypass surgery. Alcohol-related hypoglycemia is due to hepatic glycogen depletion combined with alcohol-mediated inhibition of gluconeogenesis.  It is most common in malnourished individuals with excessive alcohol intake but can occur in anyone who is unable to ingest food after an acute alcoholic episode followed by gastritis and vomiting. Immunopathologic hypoglycemia is an extremely rare condition in which anti- insulin antibodies or antibodies to insulin receptors develop spontaneously. Pancreatic B Cell Tumors Hypogycemia due to pancreatic B cell tumours : Fasting hypoglycemia in an otherwise healthy, well-nourished adult is rare and is most commonly due to an adenoma of the islets of Langerhans. 90% of such tumours are single and benign, but multiple adenomas can occur as well as malignant tumours. Adenomas may be familial, and multiple adenomas have been found in conjunction with tumours of the parathyroids and pituitary (MEN type 1). Over 99% of insulinomas are located within the pancreas and less than 1% in ectopic pancreatic tissue. Clinical Findings: Should be considered in healthy-appearing persons who have fasting hypoglycemia associated with CNS dysfunction such as confusion or abnormal behaviour. A delay in diagnosis can result in unnecessary treatment for psychomotor epilepsy or psychiatric disorders and may cause irreversible brain damage. In long-standing cases, obesity can result as a consequence of overeating to relieve symptoms. Whipple triad is characteristic of hypoglycemia regardless of the cause. It consists of (1) a history of hypoglycemic symptoms, (2) an associated low plasma glucose level (40-50 mg/dl), and (3) relief of symptoms upon ingesting fast acting carbohydrates in approximately 15 minutes. The hypoglycemic symptoms in insulinoma often develop in the early morning or after missing a meal. Occasionally, they occur after exercise. Patients typically complain of neuroglycopenic symptoms such as blurred vision or diplopia, headache, feelings of detachment, slurred speech, and weakness. Personality and mental changes vary from anxiety to psychotic behaviour, convulsions and coma. Hypoglycemic unawareness is very common and adrenergic symptoms of palpitations and sweating may be blunted. With availability of home glucometers, patients sometimes present with documented fingerstick blood glucose levels in 40s and 50s. Access to sulfonylureas or insulin should be explored-does a family member have diabetes? Medication-dispensing errors should be excluded-has the patient's prescription medication changed in shape or color? Patients with insulinoma or factitious hypoglycemia usually have a normal physical examination. Laboratory Findings: B cell adenomas do not reduce secretion of insulin in the presence of hypoglycemia.  The diagnostic test is to demonstrate inappropriately elevated serum insulin, proinsulin, and C-peptide levels, at time of hypoglycemia. The diagnostic criteria for insulinoma after a 72-hour fast: Other causes of hyperinsulinemic hypoglycemia include factitious administration of insulin or sulfonylureas. Factitious use of insulin will result in suppression of endogenous insulin secretion and low C-peptide levels. In patients who have injected insulin, the insulin/C- peptide ratio will be greater than 1. An elevated circulating proinsulin level in the presence of fasting hypoglycemia is characteristic B cell adenomas and does not occur in factitious hyperinsulinism. Thus, high C-peptide levels are characteristic of insulinomas. The patient should be brought by a family member to the office after an overnight fast and observed in the office. Activity such as walking should be encouraged and fingerstick blood glucose measured repeatedly during observation. If symptoms occur or fingerstick blood glucose is below 50 mg/dL, then samples for plasma glucose, insulin, C-peptide, proinsulin, sulfonylurea screen, serum ketones, and antibodies to insulin should be sent.  If outpatient observation does not result in hypoglycemia and if the clinical suspicion remains high, then the patient should undergo an inpatient supervised 72- hour fast. In 30% of patients with insulinoma, the blood glucose levels often drop below 45 mg/dL after an overnight fast, but some patients require up to 72 hours to develop symptomatic hypoglycemia. However, the term "72-hour fast" is actually a misnomer in most cases since the fast should be immediately terminated as soon as symptoms appear, and laboratory confirmation of hypoglycemia is available. The demonstration of a non-suppressed insulin level in the presence of hypoglycemia suggests the diagnosis of insulinoma. If hypoglycemia does not develop after fasting for up to 72 hours, insulinoma must be considered an unlikely diagnosis. Preoperative Localization of B Cell Tumours: Most tumours are in the pancreas, and ectopic cases are rare. Because of the small size of these tumours (averaging 1.5 cm in diameter), imaging studies do not necessarily identify all of them. A pancreatic dual phase helical CT scan can identify 82-94% of the lesions. MRI scans with gadolinium can be helpful in detecting a tumour in 85% of cases. If still unable to detect: CT/PET Scan. If not localized yet: Endoscopic Ultrasound with or without taking a fine needle biopsy. Treatment: The treatment of choice for insulin-secreting tumours is surgical resection. While waiting for surgery, patients should be given oral diazoxide. In patients with a single benign pancreatic B cell adenoma, 90-95% have a successful cure at the first surgical attempt when intraoperative ultrasound is used by a skilled surgeon. Diazoxide should be administered on the day of the surgery because it reduces the risk of hypoglycemia during surgery. Laparoscopy using ultrasound and enucleation has been successful with a single tumour of the body or tail of the pancreas, but open surgery remains necessary for tumours in the head of pancreas.  Non-Islet Cell Tumors Non-Islet cell tumour hypoglycemia : These rare causes of hypoglycemia include mesenchymal tumours such as retroperitoneal sarcomas, hepatocellular carcinomas, and adrenocortical carcinomas. The tumours are frequently large and readily visualized on CT scans or MRI. In many cases the hypoglycemia is due to the release of an incompletely processed insulin-like growth factor 2 (IGF-2) by the tumour. The diagnosis is supported by laboratory documentation of serum insulin levels below 5 microunit/ml, with plasma glucose levels of 45 mg/dL or lower. Ectopic insulin production has been described in bronchial carcinoma, ovarian carcinoma, and small cell carcinoma of the cervix. Hypoglycemia due to IgF-1 released from a metastatic large cell carcinoma of the lung has also been reported. GLP-1-secreting tumours (ovarian and pNETs) can also cause hypoglycemia by stimulating insulin release from normal pancreatic islets. The prognosis for these tumours is generally poor, and surgical removal should be attempted when feasible. Dietary management of the hypoglycemia is the mainstay of medical treatment, since diazoxide is usually ineffective. Postprandial Hypoglycemia Hypoglycemia Following Gastric Surgery: Hypoglycemia sometimes develops in patients who have undergone gastric surgery (e.g. gastrectomy, gastrojejunostomy, Nissan fundoplication, and Roux-en-Y), especially when they consume foods containing high levels of simple carbohydrates. This late dumping syndrome occurs 1-3 hours after a meal, a result of rapid delivery of carbohydrates in the proximal small bowel and rapid absorption of glucose. The hyperinsulinemic response to high carbohydrate load causes hypoglycemia.  Excessive release of gastrointestinal hormones such as GLP-1 plays a role in this hyperinsulinemic response. The symptoms include light-headedness, sweating, confusion and even loss of consciousness after eating a high carbohydrate meal. To document hypoglycemia, the patient should consume a meal that leads to symptoms during everyday life. An oral glucose tolerance test is not recommended because many normal persons have false-positive test results. Treatment for secondary dumping includes dietary modification, but this may be difficult to sustain. Patients can try more frequent meals with smaller portions of less rapidly digested carbohydrates. Alpha-glucosidase therapy may be a useful adjunct to a low carbohydrate diet. Octreotide 50 mcg administered subcutaneously two or three times a day 30 minutes prior to each meal has been reported to improve symptoms. Treatment with a GLP-1 receptor agonist, may prevent post gastric bypass hypoglycemia. Functional Alimentary Hypoglycemia: Patients have symptoms suggestive of increased sympathetic activity, including anxiety, weakness, tremor, sweating or palpitations after meals. Physical examination and laboratory tests are normal. It is not recommended that patients with symptoms suggestive of increased sympathetic activity undergo either a prolonged oral glucose tolerance test or a mixed meal test. Instead, the patients should be given home blood glucose monitors (with memories) and instructed to monitor fingerstick glucose levels at the time of symptoms. Only patients who have symptoms when their fingerstick blood glucose is low (less than 50 mg/dL) and who have resolution of symptoms when the glucose is raised by eating rapidly released carbohydrate need additional evaluation. Patients who do not have evidence for low glucose levels at time of symptoms are generally reassured by their findings. Counselling and support should be the mainstays in therapy, with dietary manipulation only an adjunct. Occult Diabetes: This condition is characterized by a delay in early insulin release from pancreatic B cells, resulting in initial exaggeration of hyperglycemia during a glucose tolerance test. In response to this hyperglycemia, an exaggerated insulin release produces a late hypoglycemia 4-5 hours after ingestion of glucose. These patients are often obese and frequently have a family history of diabetes. Patients with this type of postprandial hypoglycemia often respond to reduced intake of refined sugars with multiple, small meals high in dietary fiber. In the obese, treatment is directed at weight reduction to achieve ideal weight. These patients should be considered to have prediabetes or early diabetes (type 1 or 2) and advised to have periodic medical evaluations. Autoimmune Hypoglycemia: Patients with autoimmune hypoglycemia have early postprandial hyperglycemia followed by hypoglycemia 3-4 hours later. The hypoglycemia is attributed to a dissociation of insulin antibody-immune complexes, releasing free insulin. The disorder is associated with methimazole (Graves’ disease), sulfhydryl- containing medications (captopril, penicillamine) as well as other drugs such as hydralazine, isoniazid, and procainamide. It has been also reported in patients with autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus, and polymyositis as well as in plasma cell myeloma where antibodies cross-react with insulin. High titres of insulin autoantibodies, usually IgG class, can be detected. Insulin, proinsulin, and C-peptide levels may be elevated. In most cases, hypoglycemia is transient and may resolve spontaneously within 3-6 months, particularly when the offending medications are stopped. The most consistent treatment: Small, frequent, low-carbohydrate meals.  Prednisone (30-60 mg orally daily) has been used to lower the titer of insulin antibodies. Factitious Hypoglycemia Factitious hypoglycemia may be difficult to document. A suspicion of self-induced hypoglycemia is supported when the patient is associated with the health professions or has access to diabetic medications taken by a diabetic member of the family. The triad of hypoglycemia, high immunoreactive insulin, and suppressed plasma C-peptide immunoreactivity is pathognomonic of exogenous insulin administration. Insulin and C-peptide are secreted in a 1:1 molar ratio. A large fraction of the endogenous insulin is cleared by the liver, whereas C- peptide, which is cleared by the kidney, has a lower metabolic clearance rate. For this reason, the molar ratio of insulin and C-peptide in a hypoglycemic patient should be less than 1.0 in cases of insulinoma and is greater than 1.0 in cases of exogenous insulin administration. When sulfonylureas, repaglinide, and nateglinide are suspected as a cause of factitious hypoglycemia, a plasma level of these medications to detect their presence may be required to distinguish laboratory findings from those of insulinoma. Hypoglycemia due to insulin receptor antibodies Hypoglycemia due to insulin receptor autoantibodies is an extremely rare syndrome; most cases have occurred in women often with a history of autoimmune disease. Almost all of these patients have also had episodes of insulin resistant diabetes and acanthosis nigricans. Their hypoglycemia may be either fasting or postprandial and is often severe and is attributed to an agonistic action of the antibody on the insulin receptor. Balance between the antagonistic and agonistic effects of the antibodies determines whether insulin- resistant diabetes or hypoglycemia occurs. Hypoglycemia was found to respond to corticosteroid therapy but not to plasmapheresis or immunosuppression.