Primary hyperinsulinism is a rare but important cause of hypoglycemia in infants and children. It is the most common cause of neonatal hypoglycemia that persists beyond the first few hours of life. 
The clinical presentation varies with the age of the child. Early diagnosis and treatment are essential to prevent seizures and neurologic sequelae. Persistent hypoglycemia and inappropriately high concentrations of circulating insulin are diagnostic findings. The concentrations of free fatty acids (FFAs) and ketones (ie, beta-hydroxybutyrate, acetoacetate) are low. Several genetic causes of persistent hyperinsulinism have been identified. [2, 3, 4, 5, 6, 7, 8, 9, 10] See the image below.
The differential diagnosis of hypoglycemia is extensive, and determining the underlying cause is often difficult. An understanding of glucose homeostasis can help narrow the differential diagnosis. In the fasting state, glucose is provided through glycogenolysis in the liver. After a few hours of fasting, insulin levels fall, and increased lipolysis creates free fatty acids and glycerol. Fatty acids do not cross the blood-brain barrier and, therefore, are not used by the brain. However, fatty acids are used by the heart and muscle. Increased free fatty acids result in production of ketones, and the brain is able to metabolize ketones as an alternative source of fuel.
Disorders that result from defective glycogenolysis in the liver lead to hypoglycemia within a few hours of fasting. This hypoglycemia occurs in the setting of low insulin levels.
Disorders of fat metabolism result in the unavailability of free fatty acids and ketones as alternative fuels. Hypoglycemia occurs after several hours of fasting. Circulating insulin levels also are low.
Growth hormone deficiency and hypocortisolemia also can cause hypoglycemia associated with low insulin levels, possibly by unopposed insulin action and decreased ketogenesis.
Hypoglycemia associated with elevated insulin levels makes certain disorders unlikely, such as defects in gluconeogenesis, free fatty acid synthesis, and ketogenesis; growth hormone deficiency; and cortisol deficiency. Conversely, hypoglycemia associated with ketonuria makes hyperinsulinism less likely. Ketonuria does not rule out hyperinsulinemia.
Glucose and several amino acids stimulate insulin secretion under physiologic conditions, and the sequence of events leading to insulin secretion is well delineated. The rate of insulin secretion is dependent on the ratio of ATP to ADP within the beta cell. The rate of glucose entry into the beta cell is facilitated by a glucose transporter, and the entry rate exceeds the oxidation rate of glucose. Glucokinase is the rate-limiting step of glycolysis (ATP production), not glucose transport.
The first step in glycolysis (ie, conversion of glucose to glucose-6-phosphate [G-6-P] by glucokinase) is the rate-limiting step in glucose metabolism. Thus, glucokinase regulates the rate of glucose oxidation and subsequent insulin secretion. An increase in the intracellular ATP/ADP ratio activates ATP-sensitive potassium-dependent channels (KATPs) in the cell membrane. KATP consists of 2 subunits, the sulfonylurea receptor (SUR1) and the potassium inward rectifier channel (Kir6.2). Activation leads to closure of the potassium channel and depolarization of the cell membrane. Opening of a voltage-gated calcium channel allows influx of calcium and results in insulin secretion.
Transient hyperinsulinism usually results from environmental factors such as maternal diabetes and birth asphyxia. However, children with persistent hyperinsulinism may have a genetic defect that results in inappropriate secretion of insulin.
Hyperinsulinemia is estimated to occur in 1 in 50,000 live births.
Autosomal recessive forms of hyperinsulinemic hypoglycemia are more common in inbred populations of Saudi Arabia and among Ashkenazi Jews.
Glucose is the primary substrate used by the CNS. Free fatty acids do not cross the blood-brain barrier; however, the brain can metabolize ketones. Unrecognized or poorly controlled hypoglycemia may lead to persistent severe neurologic damage. Patients with hyperinsulinism are at high risk of developing seizures, mental retardation, and permanent brain damage.
Transient hyperinsulinism is relatively common in neonates. An infant of a diabetic mother, an infant who is small or large for gestational age, or any infant who has experienced severe stress may have high insulin concentrations. In contrast, congenital hyperinsulinism is rare.
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