Hyperinsulinemic hypoglycemia (HH) is a condition characterized by abnormally low blood glucose levels caused by the body producing and releasing too much insulin. This disorder involves the inappropriate secretion of insulin from pancreatic beta cells, occurring even when blood sugar concentrations are already low. Hyperinsulinism is the most frequent cause of persistent and severe hypoglycemia in infants and children, though it can also affect adults. Because the brain relies on glucose for fuel, untreated or recurrent episodes of low blood sugar can lead to seizures and permanent neurological damage, requiring prompt and specialized care.
Understanding the Core Mechanism
The body normally maintains blood glucose within a narrow, stable range through a precise feedback loop involving the pancreatic beta cells. When glucose enters the beta cell, it is metabolized, leading to an increase in the ratio of adenosine triphosphate (ATP) to adenosine diphosphate (ADP). This ATP/ADP ratio controls the activity of the ATP-sensitive potassium (\(\text{K}_{\text{ATP}}\)) channels on the cell surface. Under normal conditions, high glucose and the resulting high ATP/ADP ratio close these \(\text{K}_{\text{ATP}}\) channels, triggering a cascade that results in insulin release.
In hyperinsulinemic hypoglycemia, this regulation is perturbed, causing the beta cells to secrete insulin regardless of the low blood glucose level. The central malfunction is the failure of the \(\text{K}_{\text{ATP}}\) channels to close properly, or other defects in the insulin secretion pathway, leading to a continuous and unregulated insulin flow. This excessive insulin acts rapidly to clear the remaining glucose from the bloodstream by promoting its uptake into muscle, liver, and fat tissues. The high insulin concentration also suppresses the body’s natural counter-regulatory response, preventing the production of alternative fuels like ketones and free fatty acids.
Distinguishing Causes and Types
The origins of hyperinsulinemic hypoglycemia are diverse, ranging from genetic defects to temporary conditions in newborns. The most common and often most severe form is Congenital Hyperinsulinism (CHI), caused by genetic mutations that disrupt the insulin secretion pathway in the beta cells. Mutations in the ABCC8 and KCNJ11 genes, which encode the subunits of the \(\text{K}_{\text{ATP}}\) channel, are the most frequent cause of severe CHI. Other genetic forms involve mutations in genes regulating various metabolic steps involved in insulin release.
CHI is classified histologically into two main types: focal and diffuse. The diffuse form involves all beta cells across the entire pancreas, typically resulting from autosomal recessive mutations in \(\text{K}_{\text{ATP}}\) channel genes. The focal form is a localized lesion in one part of the pancreas, usually caused by a paternally inherited \(\text{K}_{\text{ATP}}\) channel mutation combined with a loss of heterozygosity in the affected pancreatic cells.
Hyperinsulinism can also be acquired or transient, especially in the newborn period following certain stressors. Transient neonatal hyperinsulinism often resolves within the first few months of life. Risk factors include:
- Maternal diabetes
- Perinatal asphyxia
- Intrauterine growth restriction
- Syndromic conditions, such as Beckwith-Wiedemann Syndrome or Kabuki Syndrome
High glucose exposure in utero from maternal diabetes can cause the fetal pancreas to develop an overgrowth of insulin-producing beta cells, leading to severe hypoglycemia after birth when the glucose supply is withdrawn.
Recognizing the Signs and Diagnosis
The symptoms of hyperinsulinemic hypoglycemia vary depending on the patient’s age, but they primarily stem from the brain being starved of glucose, a state known as neuroglycopenia. In infants, the signs can be subtle and include poor feeding, lethargy, jitteriness, muscle hypotonia, and, in severe cases, seizures. Persistent hypoglycemia carries a significant risk of irreversible brain injury, underscoring the need for rapid detection and management.
Diagnosis relies on a specialized medical workup, beginning with the collection of a “critical sample” of blood obtained at the exact moment the patient is hypoglycemic (plasma glucose level below 50 mg/dL). This sample must be analyzed simultaneously for glucose, insulin, C-peptide, and metabolic fuels like free fatty acids and beta-hydroxybutyrate. A finding of detectable or inappropriately high insulin and C-peptide concentrations, along with suppressed levels of free fatty acids and ketones, confirms the diagnosis of hyperinsulinism.
The severity of the condition is often reflected by the high glucose infusion rate required to maintain normal blood sugar. A supervised fasting test may also be conducted in a controlled environment to confirm the insulin dysregulation and determine the patient’s fasting tolerance. Once the biochemical diagnosis is established, genetic testing is performed to identify the specific gene mutation, which is crucial for guiding the appropriate long-term treatment strategy.
Management and Treatment Approaches
The immediate priority in managing HH is acute stabilization to prevent neurological damage by restoring blood glucose levels. This is achieved by administering intravenous dextrose, often at high infusion rates, to counteract the excessive insulin activity. Glucagon, a hormone that stimulates the liver to release glucose, may also be given as an emergency measure to temporarily raise blood sugar.
Long-term management focuses on medical therapy to control the inappropriate insulin secretion. The first-line pharmacological treatment is Diazoxide, which works by opening the \(\text{K}_{\text{ATP}}\) channels in the beta cells, thereby inhibiting the release of insulin. Patients with milder forms of CHI or specific genetic mutations often respond well to Diazoxide. Management includes frequent feedings and specialized diets, sometimes including uncooked cornstarch for slow glucose release.
For patients whose hypoglycemia is unresponsive to Diazoxide, a somatostatin analog like Octreotide is the next medical option. Octreotide works by binding to receptors on the beta cells, which helps to suppress insulin secretion. If medical therapy fails to maintain safe blood glucose levels, particularly in severe, diazoxide-unresponsive cases of CHI, surgical intervention becomes necessary.
The surgical approach is a pancreatectomy, involving the partial or near-total removal of the pancreas. For the focal form of CHI, surgery is curative as the surgeon can precisely remove only the small, hyperactive lesion identified through specialized imaging. In the diffuse form, the disease involves the entire pancreas, often necessitating a near-total pancreatectomy, which carries a risk of recurrent hypoglycemia and the long-term complication of developing insulin-dependent diabetes.