Diazoxide-sensitive diffuse hyperinsulinism

Diazoxide-sensitive diffuse hyperinsulinism is a form of congenital hyperinsulinism (CHI) characterized by inappropriate and excessive secretion of insulin from pancreatic beta cells throughout the entire pancreas (diffuse pattern), which responds favorably to treatment with diazoxide. Congenital hyperinsulinism is the most common cause of persistent hypoglycemia in neonates and infants. In this form, the unregulated insulin secretion leads to recurrent episodes of severe hypoglycemia (low blood sugar), which can cause seizures, brain damage, and neurodevelopmental impairment if not promptly recognized and treated. Symptoms typically include lethargy, poor feeding, jitteriness, and in severe cases, loss of consciousness or seizures due to dangerously low blood glucose levels. The diffuse form means that all beta cells across the pancreas are affected, as opposed to focal forms where only a localized region of the pancreas is involved. The designation "diazoxide-sensitive" indicates that patients respond to diazoxide, a potassium channel (KATP channel) opener that suppresses insulin secretion. This responsiveness distinguishes it from diazoxide-unresponsive forms, which often involve inactivating mutations in the KATP channel genes (ABCC8 or KCNJ11) and may require more aggressive interventions including near-total pancreatectomy. Diazoxide-sensitive diffuse hyperinsulinism may be caused by mutations in several genes, including those encoding glutamate dehydrogenase (GLUD1), glucokinase (GCK), hepatocyte nuclear factors (HNF4A, HNF1A), short-chain 3-hydroxyacyl-CoA dehydrogenase (HADH), or uncoupling protein 2 (UCP2), among others. Management centers on maintaining normal blood glucose levels to prevent neurological damage. Diazoxide is the first-line medical therapy and is effective in this subtype, often allowing patients to avoid surgery. Additional supportive measures may include frequent feeding, glucose infusions during acute episodes, and in some cases adjunctive medications such as octreotide. Long-term follow-up is important to monitor for resolution of hypoglycemia (which may occur with age in some genetic subtypes), neurodevelopmental outcomes, and potential side effects of diazoxide therapy such as fluid retention and hypertrichosis.

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