Hyperinsulinism (HI) in newborns is a severe condition defined by the excessive and unregulated production of insulin, the hormone responsible for lowering blood sugar levels. This overproduction causes dangerously low blood sugar, known as hypoglycemia, which is particularly threatening to the developing brain. HI is the most frequent cause of persistent hypoglycemia in infants and young children, requiring immediate medical intervention. Although rare, occurring in approximately 1 in 30,000 to 50,000 live births, the condition demands urgent attention due to the high risk of permanent neurological damage if not promptly managed.
Understanding How Hyperinsulinism Affects Newborns
Insulin is produced by beta cells in the pancreas and normally promotes the uptake of glucose from the bloodstream into cells for energy or storage. When blood glucose levels drop, the pancreas typically reduces insulin secretion to prevent hypoglycemia. In hyperinsulinism, this feedback mechanism fails, and insulin continues to be secreted inappropriately, even when blood sugar is low.
The high levels of insulin force glucose into muscle and fat tissues, effectively starving the brain of its primary fuel source. High insulin also inhibits the body’s natural compensatory mechanisms, such as glycogenolysis and gluconeogenesis, which generate new glucose during fasting. Furthermore, insulin suppresses the production of ketones and free fatty acids, which the brain can use as alternative energy sources. This lack of both primary (glucose) and secondary (ketone) fuels leaves the rapidly developing brain vulnerable to injury, making hyperinsulinism a medical emergency.
Recognizing Symptoms and Identifying Underlying Causes
Newborns experiencing hypoglycemia often exhibit non-specific symptoms, making early detection challenging. Common signs include lethargy, jitteriness or tremors, poor feeding, and excessive sleepiness. In severe episodes, infants may experience apnea, hypothermia, or seizures, indicating the brain is deprived of energy. Because these symptoms overlap with other neonatal issues, persistent hypoglycemia requiring a high rate of continuous glucose infusion is the strongest clinical indicator of hyperinsulinism.
The causes of HI are divided into transient and persistent forms. Transient hyperinsulinism is temporary and acquired, often associated with perinatal stress factors. Risk factors include maternal diabetes, intrauterine growth restriction, or birth asphyxia, and the condition usually resolves within days or weeks after birth.
Persistent hyperinsulinism, also known as congenital hyperinsulinism, is usually caused by genetic mutations that permanently dysregulate insulin secretion. The most common genetic causes involve mutations in the ABCC8 and KCNJ11 genes, which encode components of the potassium channel in pancreatic beta cells. A fault in this channel prevents it from closing, leading to continuous, unregulated insulin release regardless of blood sugar levels.
Genetic hyperinsulinism is classified into two main histological types based on the extent of affected pancreatic tissue. This classification significantly influences long-term treatment strategies.
Diffuse Hyperinsulinism
In diffuse hyperinsulinism, the insulin-producing beta cells are abnormally hyperactive throughout the entire pancreas.
Focal Hyperinsulinism
Focal hyperinsulinism involves a small, localized area of abnormal cells within an otherwise healthy pancreas.
Confirmation of Diagnosis and Acute Stabilization
Diagnosis relies on collecting a “critical sample” of blood when the infant is actively hypoglycemic. This sample is analyzed for glucose, insulin, C-peptide, ketones, and free fatty acid levels. High insulin and C-peptide levels alongside suppressed ketones and free fatty acids strongly indicate hyperinsulinism, as the high insulin prevents the body from breaking down fat for alternative fuel.
Maintaining a normal blood glucose level often requires a high rate of glucose infusion, typically exceeding 8 mg/kg/min, suggesting excessive insulin action. Following biochemical confirmation, genetic testing identifies the underlying mutation to determine if the condition is transient or persistent. For persistent HI, specialized imaging, such as an 18F-DOPA PET scan, differentiates between focal and diffuse forms. This imaging pinpoints the location of abnormal cells in focal disease, which is necessary for surgical planning.
Acute stabilization involves rapidly raising blood glucose levels to prevent brain injury. This is achieved by administering a bolus of intravenous dextrose, followed by a continuous, high-concentration dextrose infusion. If IV access is delayed, glucagon can be given to temporarily stimulate the release of stored glucose from the liver. The immediate goal is to maintain blood glucose above 70 mg/dL until definitive treatment can be initiated.
Long-Term Medical Management and Developmental Outcomes
Long-term management focuses on consistent blood glucose control to protect the brain from further hypoglycemic episodes. First-line treatment is Diazoxide, a drug that opens potassium channels in pancreatic beta cells, suppressing insulin secretion. If the patient is unresponsive to Diazoxide—common with severe potassium channel mutations—Octreotide, a somatostatin analog that directly inhibits insulin release, may be used as a second-line medication.
For patients with confirmed focal hyperinsulinism, surgery is a potential curative option. A surgeon can perform a partial pancreatectomy to remove only the localized area of abnormal tissue identified by imaging. This targeted approach often resolves the condition completely, offering the best chance for full recovery with minimal complications.
If the disease is diffuse or unresponsive to medical therapy, a near-total pancreatectomy may be necessary to control life-threatening hypoglycemia. While effective, removing a large portion of the pancreas carries a high risk of developing insulin-dependent diabetes and pancreatic exocrine insufficiency later in life. The risk of permanent neurological damage or developmental delay remains a major concern. Even with aggressive treatment, neurodevelopmental issues have been reported, requiring continuous monitoring of blood glucose levels throughout childhood.