Hypoglycemia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2], Seyedmahdi Pahlavani, M.D. [3]

Hypoglycemia is a pathologic state induced by a lower than normal level of glucose in the blood. It happens usually when blood glucose level is less than 60 or 70 mg/dL, different values (typically below 40, 50, 60, or 70 mg/dL) have been defined as low. Patients with type 1 diabetes may suffer an average of two episodes of symptomatic hypoglycemia per week, thousands of such episodes over a lifetime of diabetes, and one episode of severe symptoms per year. Causes of hypoglycemia depend on age; neonatal causes are transient neonatal hypoglycemia, prematurity, intrauterine growth retardation, perinatal asphyxia, sepsis, congenital hypopituitarism, congenital hyperinsulinism, infant of a diabetic mother, Beckwith-Wiedemann syndrome and inborn errors of carbohydrate metabolism. Adult hypoglycemia caused mainly by insulin or insulin secretagogue drugs, alcohol, hepatic failure, renal failure, cardiac failure, sepsis, non-islet cell pancreatic tumors, insulinoma, and reactive hypoglycemia. The pathophysiology of hypoglycemia depends on the failure of physiological defense mechanisms and hormones, such as insulin, glucagon, and epinephrine to correct hypoglycemia. Most of these defense mechanisms are hormones that control glycogenolysis and gluconeogenesis. No single value alone serves to define the hypoglycemia. Accordingly, diagnostic criteria (Whipple’s triad) is needed to diagnose hypoglycemia. Complications in adults include increased risk of dementia, cardiovascular complications and maybe death. Prognosis is generally good with prompt treatment. However, 4-10% of deaths of patients with type 1 diabetes are due to hypoglycemia. Screening of hypoglycemia should be obtained in infants who are at risk for hypoglycemia. Surveillance should be continued every three to six hours for the first 48 hours of life. Medical treatment of hypoglycemia depends on the severity of symptoms and etiology. If asymptomatic, repeating the measurement in short time and avoiding critical tasks. Twenty grams of glucose is usually sufficient to raise the blood glucose in a severe hypoglycemic and symptomatic patients. Glucose should be administered subcutaneously or intramuscularly or 25% of dextrose serum should be given intravenously. In case of postprandial hypoglycemia, the patient should have frequent small meals or snacks and foods should be high in fiber, avoiding foods high in sugar. Surgery is the treatment of choice for insulinoma.

Hypoglycemia is a Greek word that means under-sweet blood. In 1922, hypoglycemia was first discovered by James Collip when he was working on purifying insulin. He injected insulin into a rabbit and realized a reduction in blood glucose levels. Collip injected a large dose of insulin to the rabbit, that lead to coma and death of the rabbit.

Hypoglycemia can be classified based on severity into 5 categories, include severe hypoglycemia, symptomatic hypoglycemia, asymptomatic hypoglycemia, probable symptomatic hypoglycemia, and pseudo hypoglycemia. It is also can be classified based on severity into mild, moderate and severe.

The pathophysiology of hypoglycemia depends on the failure of physiological defense mechanisms and hormones such as insulin, glucagon, and epinephrine to correct hypoglycemia. Most of these defense mechanisms are hormones that control glycogenolysis and gluconeogenesis. Insulinoma is a rare benign pancreatic neuroendocrine tumor that arises from β islet cells. It is mediated by a mutation in mTOR/P70S6K signaling pathway. Non-islet-cell tumors(NICTH) are large tumors of mesenchymal or epithelial cell types originate from the pancreas. NICTH appears to be increased glucose utilization and inhibition of glucose release from the liver. This happens as a result of tumor production of incompletely processed IGF-2. On gross pathology insulinomas have a gray to red-brown appearance, encapsulated and are usually small and solitary tumors. Although there is a case report of a large (9cm), pedunculated and weighing more than 100 g. On microscopic histopathological analysis, patterns like trabecular, gyriform, lobular and solid structures, particularly with amyloid in a fibrovascular stroma, are characteristic findings of insulinoma. It is also evaluated for the mitotic index and immunohistochemistry staining by Chromogranin A, synaptophysin, and Ki-67 index.

Causes of hypoglycemia depend on age; neonatal causes are transient neonatal hypoglycemia, prematurity, intrauterine growth retardation, perinatal asphyxia, sepsis, congenital hypopituitarism, beta sympathomimetic drugs, congenital hyperinsulinism, infant of a diabetic mother, Beckwith-Wiedemann syndrome and inborn errors of carbohydrate metabolism. Causes of adult hypoglycemia are: insulin or insulin secretagogue drugs, alcohol, hepatic failure, renal failure, cardiac failure, sepsis, non-islet cell pancreatic tumors, insulinoma, reactive hypoglycemia, post gastric bypass hypoglycemia, and autoimmunee hypoglycemia. 

Hypoglycemia should be differentiated from other causes of autonomic hyperactivity symptoms. Neonatal hypoglycemia should be differentiated from other causes of neurological symptoms in neonates such as sepsis, metabolic diseases: urea cycle disorders, and branched-chain organic acidemias, hyponatremia and neonatal asphyxia. In adults, hypoglycemia should be differentiated from other diseases that may cause autonomic hyperactivity symptoms, such as hyperthyroidism, anxiety, arrhythmia, and pheochromocytoma.

Patients with type 1 diabetes may suffer an average of two episodes of symptomatic hypoglycemia per week, thousands of such episodes over a lifetime of diabetes, and one episode of severe symptoms per year. Hypoglycemia is less frequent in type 2 diabetes than it is in type1. Event rate for severe hypoglycemia range from 40 to 100 percent of those in type 1 diabetes. There is no racial or gender predilection of hypoglycemia.

Risk factors of hypoglycemia include diabetic patients with excessive insulin doses especially after missed meals or after exercise. Nocturnal fasting and alcohol intake are less common risk factors in diabetic patients.

Screening of hypoglycemia should be obtained in infants who are at risk for hypoglycemia. Surveillance should be continued every three to six hours for the first 48 hours of life. Treatment should be started immediately after primary blood test and we should not wait for the confirmatory laboratory results due to high risk of the neurological outcome.

If left untreated, patients with hypoglycemia may progress to develop anxiety, nervousness, tremor, palpitations, and sweating. Common complications of hypoglycemia include psychomotor retardation, epilepsy and prematurity in neonates. Complications in adults include increased risk of dementia, cardiovascular complications and may be death. Prognosis is generally good. Four to ten percent of death in patients with type 1 diabetes are due to hypoglycemia.

Diagnostic criteria of hypoglycemia include symptoms of hypoglycemia, a low plasma glucose concentration correlated with symptoms, and correction of glucose level relieves symptoms. These criteria called Whipple’s triad. Neonatal hypoglycemia can be diagnosed by measuring multiple metabolic panels include plasma insulin, plasma C-peptide, beta-hydroxybutyrate, blood pH, bicarbonate, lactate, free fatty acids, acylcarnitine profile, plasma free and total carnitine levels.

Hypoglycemic symptoms and manifestations can be divided into those produced by the counterregulatory hormones: adrenergic symptoms include anxiety, nervousness, tremor, palpitations, sweating, coldness. Glucagon induced manifestations include hunger, nausea, vomiting. Neuroglycopenic Manifestations are irritability, weakness, apathy, lethargy, confusion, and amnesia.

Main signs of hypoglycemia are tachycardia and ventricular arrhythmia. Neurological manifestations include altered mental status, hypotonia, focal or general motor deficit and jerks. Neonatal hypoglycemia signs include large for gestational age, hepatomegaly in Beckwith-Wiedemann syndrome and glycogen storage diseases. Ambiguous genitalia, hypertension, hyponatremia, and hyperkalemia are found in congenital adrenal insufficiency.

Laboratory investigations of hypoglycemia depend on many tests: plasma glucose is usually <55-70 mg/dL, insulin, c-peptide, proinsulin, sulfonylurea screen, beta-hydroxybutyrate, and 24-hour fasting glucose level are another tests that are required to establish the etiology.

On EKG, hypoglycemia is characterized by sinus tachycardia and supraventricular tachycardia.

There are no x-ray findings in hypoglycemia.

CT scan can be used for diagnosing insulinoma and islet-cell hypertrophy. Currently, with the advances in technology. The sensitivity has risen to 80% and 94.4% for helical CT scan with dual-phase multidetector CT scan. Insulinoma is hypervascular and CT shows greater enhancement than rest of the pancreatic parenchyma. It can appear hypovascular and hypodense lesions after the administration of contrast.

MRI is helpful in the diagnosis of insulinoma in the case of failed CT. MRI has better sensitivity than CT scan. Insulinoma shows low intensity on T1 weighted and high intensity on T2 weighted signals, having better visualization on T1 and T2 weighted images with fat suppression. Large tumors (≥ 2 cm) exhibit typically homogenous pattern and ring enhancement. A similar pattern is seen in metastatic lesion as of primary tumor.

Transabdominal ultrasound has low sensitivity varying between 0-66% in detecting insulinoma. The sensitivity increases with the use of more invasive endoscopic ultrasound (93%) and intraoperative ultrasound (86%).We see hypoechoic lesions and hypervascular mass on the ultrasound.

There are no other imaging findings associated with hypoglycemia.

Other tests include: injection of calcium gluconate into splanchnic arteries and venous sampling searching for insulin.

Medical treatment of hypoglycemia depends on the severity of symptoms and the cause. If asymptomatic, repeating the measurement in short time and avoiding critical tasks. Twenty grams of glucose is usually sufficient to raise the blood glucose in a severe hypoglycemic and symptomatic patients. Glucose should be administered subcutaneously or intramuscularly or 25% of dextrose serum should be given intravenously. In case of postprandial hypoglycemia. The patient should have frequent small meals or snacks and foods should be high in fiber, avoiding foods high in sugar. Surgery is the best treatment for insulinoma.

Surgical removal of the insulinoma is the treatment of choice and resection of metastatic liver disease.

The main stay in primary prevention is patient education about symptoms, blood glucose level control, and hypoglycemia treatment. Reactive hypoglycemia prevention depends on changing eating habits to smaller meals and avoiding excessive sugar intake.

Secondary Prevention is the same as primary prevention.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2]

Hypoglycemia is a Greek word that means under-sweet blood. In 1922, hypoglycemia was first discovered by James Collip when he was working on purifying insulin. He injected insulin into a rabbit and realized a reduction in blood glucose levels. Collip injected of a large doses of insulin to the rabbit, that lead to coma and death of rabbit.

• In 1869, Paul Langerhans was the first who discovered a collection of cells within the pancreas. He called it islets of Langerhans.^[1]
• In 1901, Eugene Opie was the first who discovered that destruction of islet cells results in diabetes mellitus.
• In 1921, Frederick Banting and Charles Best, orthopedic surgeons were the first who discovered insulin in the pancreatic extracts of dogs. With help of James B. Collip and J.J.R. Macleod, they developed insulin for human treatment. Nobel Prize was awarded to Banting and Macleod for this discovery.
• In 1922, hypoglycemia was first discovered by James Collip when he was working on purifying insulin. He injected insulin into a rabbit and realized the reduction in blood glucose levels. Collip discovered that injection of a large dose of insulin, the rabbit got into a coma and died.
• Hypoglycemia is a Greek word means under-sweet blood.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2]

Hypoglycemia can be classified based on its severity into 5 categories, including severe hypoglycemia, symptomatic hypoglycemia, asymptomatic hypoglycemia, probable symptomatic hypoglycemia, and pseudo hypoglycemia. It also maybe classified based on severity into mild, moderate and severe subtypes.

Classification of hypoglycemia in diabetics according to the American Diabetes Association‘s (ADA) and the Endocrine Society Workgroup on Hypoglycemia is:^[1][2][3][4]

• Severe event in which patient loses consciousness or becomes very dizzy. Patients usually require the assistance of another person to actively administer carbohydrate or glucagon.
• Resolution of neuroglycopenic symptoms after administration of glucose

• The symptoms of hypoglycemia are seen with plasma glucose concentration ≤70 mg/dL.

• Measured plasma glucose concentration of ≤70 mg/dl without typical symptoms of hypoglycemia.

• When hypoglycemic symptoms do not correlate with low plasma glucose level (but likely due to plasma glucose concentration (70 mg/dL-3.9 mmol/liter).

• Patients with poor glycemic control can experience symptoms of hypoglycemia at plasma glucose levels >70 mg/dL.

• It is characterized by adrenergic and mild neurological symptoms that can be prevented by oral glucose intake.

• It is characterized by the presence of neurological symptoms that can prevent the patient from taking oral glucose and most of the patients need help from an observer.

• It is characterized by the presence of severe neurological symptoms and most of the patients need glucagon and intravenous dextrose.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2] Amandeep Singh M.D.[3]

The pathophysiology of hypoglycemia depends on the failure of physiological defense mechanisms and hormones such as insulin, glucagon, and epinephrine to correct hypoglycemia. Most of these defense mechanisms are hormones that control glycogenolysis and gluconeogenesis. Insulinoma is a rare benign pancreatic neuroendocrine tumor that arises from β islet cells. It is mediated by a mutation in mTOR/P70S6K signaling pathway. Non-islet-cell tumors (NICTH) are large tumors of mesenchymal or epithelial cell types originate from the pancreas. Hypoglycemia due to NICTH appears to be related to increased glucose utilization and inhibition of glucose release from the liver. This happens as a result of tumor production of incompletely processed IGF-2. On gross pathology insulinomas have a gray to red-brown appearance, encapsulated and are usually small and solitary tumors. On microscopic histopathological analysis, patterns like trabecular, gyriform, lobular and solid structures, particularly with amyloid in a fibrovascular stroma, are characteristic findings of insulinoma. It is also evaluated for the mitotic index and immunohistochemistry staining by Chromogranin A, synaptophysin, and Ki-67 index.

1. Insulin binds to its receptor which involves many protein activation cascades.^[1]
2. Binding of insulin to the α-subunit results in changes which activate tyrosine kinase domains on each β-subunit.
3. The tyrosine kinase activity causes phosphorylation of intracellular enzymes.
4. The phosphorylation of MAP-Kinase leads to induction of gene expression.
5. Phosphorylation of PI-3K isolates the GLUT-4 Vesicle and sends the vesicles back to the cell membrane.
6. The GLUT-4 vesicles fuse with the cellular membrane allowing glucose to be transported into the cell.

Insulin is involved in many aspects of metabolism including:^[2]

• Insulin decreases blood glucose concentration by inducing uptake of the glucose by peripheral cells. This function is as a result of increased GLUT4 transporter insertion in the cell membrane of muscles and fat tissues which allows glucose to enter the cells.
• Increase of DNA replication and protein synthesis via control of amino acids uptake.
• Induction of glycogen synthesis when glucose levels are high.
• Increase of cellular potassium uptake.
• Decreased gluconeogenesis and glycogenolysis; decreased production of glucose from noncarbohydrate substrates, primarily in the liver (the vast majority of endogenous insulin arriving into the liver never leaves the liver).
• Increase of lipid synthesis: insulin forces fat cells to use blood glucose, which is converted into triglycerides; a decrease of insulin causes the reverse.
• Decrease in lipolysis: insulin forces reduction in conversion of fat cell lipid stores into blood fatty acids and glycerol; a decrease of insulin causes the reverse.
• Decrease in proteolysis: insulin decreases the breakdown of protein.
• Decrease of renal sodium excretion.

The pathophysiology of hypoglycemia mainly relies on the failure of physiological defense mechanisms and hormones such as insulin, glucagon and epinephrine to correct hypoglycemia. Most of these hormones control glycogenolysis and gluconeogenesis, including:

• Insulin

The most important and the first mechanism to counter-regulate hypoglycemia is the ability to suppress insulin release. This happens early when blood glucose level is between 80–85 mmHg. This can not occur in patients with absolute beta-cell failure, type 1 diabetes mellitus, and long-standing type 2 diabetes.^[3] High insulin levels inhibit hepatic glycogenolysis causing more hypoglycemia.

• Glucagon

Hypoglycemia stimulates secretion of glucagon. This happens when blood glucose level falls between 65–70 mmHg. Failure to secrete glucagon may be the result of beta-cell failure and high insulin level that inhibits glucagon secretion.^[4]

• Epinephrine

Epinephrine response to hypoglycemia becomes suppressed in many patients.^[5] This happens when blood glucose level falls between 65–70mmHg. A suppressed epinephrine response causes defective glucose counter-regulation and hypoglycemia unawareness occurs.^[6] This may be due to shifting the glycemic threshold for the sympathoadrenal response to a lower plasma glucose concentration. The brain is the first organ to be affected by decreased blood glucose level. Impairment of judgment and Seizures may occur resulting in coma.

• Insulinoma is a rare benign pancreatic neuroendocrine tumor that arises from β islet cells.^[1][7]
• It usually occurs sporadically but 10% are found to be associated with MEN 1 syndrome.^[2]
• It is thought that insulinoma is mediated by a mutation in mTOR/P70S6K signaling pathway. An oral mTOR inhibitor (Everolimus) may make better glycemic control in people having an insulinoma.^[4]
• Mitochondria plays a key role in glucose and insulin coupling to assure insulin secretion after glucose stimulation in pancreatic β cells. Coupling is impaired due to abnormal mitochondrial function in β cells causes the death of the cell.^[6]
• YY1 regulates this mitochondrial function.^[7] T372R mutation increases the transcription of YY1. The understanding of role and functions of YY1 in β cells in near future might prove to be therapeutic potentials.^[8]
• The progression to hypoglycemia is actually because of decreased glucose synthesis rather than increased use due to the direct effect of insulin on the liver.^[9]
• The neuroglycopenic symptoms appear eventually due to decreased blood glucose. Hypoglycemia stimulates catecholamine release which produces adrenergic symptoms.^[10]

• Non-islet-cell tumors are large tumors of mesenchymal or epithelial cell types originate from the pancreas.
• NICTH appears to be increased glucose utilization and inhibition of glucose release from the liver.
• This happens as a result of tumor production of incompletely processed IGF-2.^[8]
• Incompletely processed IGF-2 also suppresses glucagon and growth hormone release.^[9]
• The net result is continued glucose utilization by skeletal muscle and inhibition of glucose release, glycogenolysis, and gluconeogenesis in the liver.^[9]

• Currently, 58 genomic regions are found to be associated with type 1 diabetes mellitus (DM).
• The major susceptibility gene for type1 DM is located on HLA region of chromosome 6. It accounts for 40-50% of the genetic risk for type1 DM. This region encodes for class II major histocompatibility complex (MHC) molecules. Class II major histocompatibility complex (MHC) molecules play an important role in presenting antigen to helper T cells and initiating an immune response.
• Other major susceptibility genes which were associated with Type1 DM include polymorphisms in the promoter region of the insulin gene, the CTLA-4 gene, interleukin 2 receptor, CTLA4, and PTPN22.
• Presence of certain genes confers protection against the development of the disease. Haplotypes DQA1*0102, DQB1*0602 are extremely rare in individuals with type1 DM (<1%) and appears to provide protection from type1 DM.

• Deregulation of imprinted gene expression in the chromosome 11p15.5 region can result in the BWS phenotype.
• The critical BWS genes in that region include insulin-like growth factor 2 (IGF2), H19, cyclin-dependent kinase inhibitor 1C (CDKN1C), potassium channel voltage-gated KQT-like subfamily member 1 (KCNQ1), and KCNQ1-overlapping transcript 1 (KCNQ1OT1, or long QT intronic transcript 1).

One of the causes of hypoglycemia is insulinoma. The gross pathology of insulinoma is described below:

• On gross pathology, insulinomas have a grey to red-brown appearance, encapsulated and are usually small and solitary tumors.
• Insulinoma is firm, homogeneous, pedunculated and rarely weighing more than 100g.^[13]

• Almost all insulinomas arises from pancreas, extrapancreatic ones causing hypoglycemia are rare.^[14]
• Tumors may have a cystic component.
• Lipid-rich insulinomas mimic adrenal cortical neoplasia.
• Features of malignancy: Large size, invasion to fibro-adipose tissue, invasion to adjacent organs, and invasion to large vessels.^[15]

• On microscopic histopathological analysis, patterns like trabecular, gyriform, lobular and solid structures, particularly with amyloid in a fibrovascular stroma, are characteristic findings of insulinoma.^[16]
• It is also evaluated for the mitotic index (mitosis per 10 high-power fields) and immunohistochemistry staining by Chromogranin A, synaptophysin, and Ki-67 index.^[17]
• The structure of tumor cells observed under electron microscopy as group A characterized by abundant well-granulated typical B cells with the trabecular arrangement and group B as scarce well-granulated typical B cells and a medullary arrangement.

• 
  Histopathology of a pancreatic endocrine tumor (insulinoma). Source:https://librepathology.org/wiki/Neuroendocrine_tumour_of_the_pancreas^[18]
• 
  Histopathology of a pancreatic endocrine tumor (insulinoma). Chromogranin A immunostain. Source:https://librepathology.org/wiki/Neuroendocrine_tumour_of_the_pancreas^[18]
• 
  Histopathology of a pancreatic endocrine tumor (insulinoma). Insulin immunostain. Source:https://librepathology.org/wiki/Neuroendocrine_tumour_of_the_pancreas^[18]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Carlos A Lopez, M.D. [2] Mohammed Abdelwahed M.D[3]

Causes of hypoglycemia depend on age; neonatal causes are transient neonatal hypoglycemia, Prematurity, intrauterine growth retardation, perinatal asphyxia, sepsis, congenital hypopituitarism, beta sympathomimetic drugs, congenital hyperinsulinism, infant of a diabetic mother, Beckwith-Wiedemann syndrome and inborn errors of carbohydrate metabolism. Causes of adult hypoglycemia are: insulin or insulin secretagogue drugs, alcohol, hepatic failure, renal failure, cardiac failure, sepsis, non-islet cell pancreatic tumors, insulinoma, reactive hypoglycemia, post gastric bypass hypoglycemia, and autoimmunee hypoglycemia.

• Transient neonatal hypoglycemia:
  • Blood glucose level in healthy newborns falls due to loss of the mothers’ glucose supply that passes the placenta.^[1] Plasma glucose level is corrected by glycogenolysis and gluconeogenesis.^[2]

• Prematurity
• Intrauterine growth retardation
• perinatal asphyxia
• Maternal hyperglycemia due to diabetes or iatrogenic glucose administration
• Sepsis
• Congenital hypopituitarism:
  • Cortisol and growth hormone regulate glucose level
• Maternal use of beta-sympathomimetics
  • Interrupts glycogenolysis by blocking epinephrine’s effect.^[3]
• Hypothermic infants who have increased rates of glucose utilization and decreased glucose availability.
• Severe hepatic dysfunction
  • Leads to impairment of both glycogenolysis and gluconeogenesis.
• Congenital hyperinsulinism:^[4]
  • Infant of a diabetic mother is most commonly affected by hypoglycemia due to hyperinsulinism. Prolonged intrapartum hyperglycemia in fetus leads to hypertrophied and hyperfunctioning beta cells causing hyperinsulinism. It is transient and resolves two days after birth.
  • Beckwith-Wiedemann syndrome
  • Persistent hyperinsulinemic hypoglycemia of infancy: it is a mutation in genes encoding enzymes that control intracellular metabolic pathways of the pancreatic beta cell.
  • Excess exogenous insulin given to newborns with hyperglycemia may result in hypoglycemia.^[5]
  • Neonatal conditions associated with excessive insulin secretion include alloimmune hemolytic disease of the newborn, heart failure and sepsis.^[6]
  • Polycythemia may lead to greater glucose utilization by the increased mass of red blood cells.
  • Nesidioblastosis
• Inborn errors of metabolism:^[7]
  • Disorders of gluconeogenesis: fructose-1,6-bisphosphatase deficiency, pyruvate carboxylase deficiency.
  • Disorders of carbohydrate metabolism: hereditary fructose intolerance, galactosemia.
  • Disorders of fatty acid metabolism: medium or long-chain acyl-CoA dehydrogenase deficiency).^[8]

• Drugs are the most common cause of hypoglycemia in adults.^[9] The most important causes of hypoglycemia in adults include:
  • Insulin or insulin secretagogues such as sulfonylurea and glyburide are the most common drugs that may cause hypoglycemia due to longer duration of action^[10]. They suppress hepatic glucose production and stimulate glucose utilization which may result in hypoglycemia.
  • Quinolones
  • Pentamidine
  • Quinine
  • Beta blockers
  • Angiotensin-converting enzyme inhibitors
  • IGF-1
    • Especially in older patients with underlying renal or hepatic dysfunction^[11]
  • Alcohol
    • Due to hepatic glycogen depletion in fasting patients
    • Alcohol can induce hypoglycemia alone or associated with other hypoglycemic drugs
• Critical illnesses:
  • Hepatic failure
  • Renal failure
  • Cardiac failure
  • Sepsis
    • It occurs due to impaired liver gluconeogenesis
    • Sepsis induced cytokines secretion cause suppression of gluconeogenesis^[12]
• Hormone deficiency: cortisol in acquired adrenal insufficiency or acquired hypopituitarism^[13]
• Non islet cell tumor: hypoglycemia usually occurs as a result of tumor production of IGF-2
• Insulinoma
• Reactive hypoglycemia or postprandial
  • A hypoglycemia that occurs as a reaction to food ingestion within 4 hours after meals due to functional hyperinsulinism^[14]
• Post gastric bypass hypoglycemia
  • Rapid jejunal emptying with exaggerated insulin response
• Insulin autoimmune hypoglycemia
  • Occurs in patients who have antibodies directed to endogenous insulin or to the insulin receptor^[15]
• Accidental, surreptitious, or malicious hypoglycemia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2]

Hypoglycemia should be differentiated from other causes of autonomic hyperactivity symptoms. Neonatal hypoglycemia should be differentiated from other causes of neurological symptoms in neonates such as sepsis, metabolic diseases: urea cycle disorders, and branched-chain organic acidemias, hyponatremia and neonatal asphyxia. In adults, hypoglycemia should be differentiated from other diseases that may cause autonomic hyperactivity symptoms, such as hyperthyroidism, anxiety, arrhythmia, and pheochromocytoma.

*(NIPHS) non-insulinoma pancreatogenous hypoglycemia syndrome

• Differentials for Hypoglycemia on the basis of Laboratory findings:^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2]

Patients with type 1 diabetes may suffer an average of two episodes of symptomatic hypoglycemia per week, thousands of such episodes over a lifetime of diabetes, and one episode of severe symptoms per year. Hypoglycemia is less frequent in type 2 diabetes than it is in type1. Event rate for severe hypoglycemia range from 40 to 100 percent of those in type 1 diabetes. There is no racial or gender predilection of hypoglycemia.

• Worldwide, the incidence of severe hypoglycemia event was 4800 per 100.000 patient per year and of moderate events was 13100 per 100.000 patient per year.^[1][2]
• Rates of hypoglycemia were increased in children < 6 years of age.

• Patients with type 1 diabetes may have increased frequency of symptomatic hypoglycemia which may include one severe episode per year.
• Hypoglycemia is less frequent in type 2 diabetes than it is in type1.^[3]
• Event rate (the proportion of patients with diabetes mellitus in whom the event is observed) for severe hypoglycemia in insulin-treated type 2 diabetes is approximately 30% of that in type 1.^[4]
• Event rate for severe hypoglycemia ranges from 40 to 100 percent of patients with type 1 diabetes.^[5]
• Frequency of hypoglycemia in patients with type 2 diabetes is the same as type 1 diabetes, as insulin deficiency occurs at the end in DM type 2 and require aggressive treatment with insulin.^[6]
• Hypoglycemia is uncommon in individuals who do not have drug-treated diabetes mellitus.^[7]

• Hypoglycemia commonly affects patients with type 2 diabetes. So, the risk of severe hypoglycemia is low in the first few years (7%) and that risk increases to 25% later in the course of diabetes according to the UK Hypoglycemia Study.^[8]

• There is no gender predilection of hypoglycemia.

• There is no racial predilection of hypoglycemia.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2]

Risk factors of hypoglycemia include diabetic patients with excessive insulin doses especially after missed meals or after exercise. Nocturnal fasting and alcohol intake are less common risk factors in diabetic patients.

Risk factors of hypoglycemia include:^[1][2]

• Excessive amounts of Insulin or insulin secretagogues drugs, inappropriate timing or type of administration
• Decreased glucose intake (missed meals and overnight)
• Increased glucose need during exercise
• Decreased endogenous glucose production after alcohol intake
• Sensitivity to insulin is increased due to:
  • Weight loss
  • Improved glycemic control
  • Physiologically in the middle of the night
• Renal failure may cause decreased Insulin clearance

There are three defense mechanisms against hypoglycemia:^[3][4]

• Decrease in insulin levels
• Increase in glucagon production
• Increase in epinephrine levels

Failure of any of these defense mechanisms increase the chance of hypoglycemia. This occurs rapidly in type 1 diabetes and more gradually in type 2 diabetes mainly due to:^[5]

• Absolute endogenous insulin deficiency in type1 DM
• A history of severe hypoglycemia, hypoglycemia unawareness, or both
• Aggressive glycemic therapy (lower HbA1C levels, lower glycemic goals)

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2]

Screening of hypoglycemia should be obtained in infants who are at risk for hypoglycemia. Surveillance should be continued every three to six hours for the first 48 hours of life. Treatment should be started immediately after a primary blood test.

Screening of hypoglycemia should be obtained in infants who are at risk for hypoglycemia:

• First feed should occur within one hour after birth even before the screening.
• Surveillance should be continued every three to six hours for the first 24 to 48 hours of life.^[1]
• Neonates with low blood glucose concentrations should be continually monitored until concentrations can be maintained with regular feedings in a normal range of >50 mg/dL.
• Hypoglycemia disorder should be considered if an infant is unable to maintain glucose concentrations >60 mg/dL after 48 hours of age.

• Plasma glucose concentration in an infant with a low glucose value determined by a finger stick glucose measure should be confirmed by laboratory measurement. Glucose concentration measured in whole blood is 15% lower than that in plasma.^[2][3]
• Treatment should be started immediately after primary blood test and we should not wait for the confirmatory laboratory results due to high risk of the neurological outcome.
• Continuous glucose monitoring using a sensor that measures interstitial glucose concentration was reported to be reliable.^[4]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2]

If left untreated, patients with hypoglycemia may progress to develop anxiety, nervousness, tremor, palpitations, and sweating. Common complications of hypoglycemia include psychomotor retardation, epilepsy and prematurity in neonates. Complications in adults include increased risk of dementia, cardiovascular complications and may be death. Prognosis is generally good. Four to ten percent of death in patients with type 1 diabetes are due to hypoglycemia.

• The symptoms of hypoglycemia are usually developed in the second decade of life, and start with symptoms such as anxiety, nervousness, tremor, palpitations, and sweating.
• Without treatment, patient may develop symptoms of adrenergic manifestations such as confusion, amnesia, dizziness, delirium, double vision, slurred speech, generalized or focal seizures which may eventually lead to death.
• Lower values of plasma glucose may cause the following manifestations:
  • Values ≤55 mg/dL causes cognitive impairment and EEG (Electroencephalogram) changes.
  • Values <40 mg/dL causes drowsiness and change in behavior.
  • Values <30 mg/dL can cause seizures, permanent neurological deficits and even death.^[1]

• Psychomotor retardation
• Epilepsy^[2]
• Prematurity

• It depends on:
  • Duration of the attacks
  • Age of the patients
• Older patients show more complications than younger patients.^[3]
• Increased risk of dementia^[4]
• Episodes of dizziness increase the risk of falls and fractures.
• Severe hypoglycemia may increase the risk of cardiovascular complications in type 2 diabetes patients.^[5]

• Prognosis of hypoglycemia is generally good with treatment. Without treatment, hypoglycemia may be fatal.
• Four to ten percents of deaths of patients with type 1 diabetes are due to hypoglycemia.^[6]