Diazoxide-resistant diffuse hyperinsulinism

Diazoxide-resistant diffuse hyperinsulinism is a severe form of congenital hyperinsulinism (CHI) in which excessive insulin secretion occurs from all beta cells throughout the pancreas and does not respond to diazoxide, the first-line medical therapy for hyperinsulinism. This condition is most commonly caused by biallelic (homozygous or compound heterozygous) loss-of-function mutations in the ABCC8 gene (encoding the SUR1 subunit) or the KCNJ11 gene (encoding the Kir6.2 subunit) of the pancreatic beta-cell ATP-sensitive potassium (KATP) channel. These mutations render the KATP channels non-functional, leading to constitutive insulin secretion regardless of blood glucose levels. The condition primarily affects the endocrine pancreas but has systemic consequences due to persistent and severe hypoglycemia. Affected infants typically present in the neonatal period with severe, recurrent hypoglycemia that can cause seizures, brain damage, and neurodevelopmental impairment if not promptly and adequately treated. Key clinical features include macrosomia at birth, high glucose requirements to maintain normoglycemia, and inappropriately elevated insulin levels during episodes of hypoglycemia. Because the diffuse form involves the entire pancreas, it cannot be cured by limited surgical resection as can the focal form of hyperinsulinism. Management of diazoxide-resistant diffuse hyperinsulinism is challenging. Since diazoxide is ineffective, second-line therapies such as octreotide (a somatostatin analog) and continuous glucagon infusion may be attempted, though these often provide only partial control. In medically unresponsive cases, near-total pancreatectomy (removing approximately 95-98% of the pancreas) may be required, though this carries a significant risk of subsequent diabetes mellitus and exocrine pancreatic insufficiency. Newer therapies, including long-acting somatostatin analogs and mTOR inhibitors such as sirolimus, are being explored. Genetic testing and 18F-DOPA PET scanning are critical to distinguish diffuse from focal disease, as focal disease may be curable with limited surgery. Early diagnosis and aggressive management are essential to minimize the risk of irreversible neurological damage.

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