Diazoxide-resistant hyperinsulinism

Diazoxide-resistant hyperinsulinism is a severe form of congenital hyperinsulinism (CHI) in which excessive insulin secretion from pancreatic beta cells cannot be adequately controlled by diazoxide, the first-line medical therapy for hyperinsulinism. Congenital hyperinsulinism is the most common cause of persistent hypoglycemia (low blood sugar) in neonates and infants. In diazoxide-resistant cases, the underlying genetic defect most frequently involves loss-of-function mutations in the ABCC8 or KCNJ11 genes, which encode the two subunits (SUR1 and Kir6.2) of the ATP-sensitive potassium (KATP) channel in pancreatic beta cells. Because diazoxide works by opening these KATP channels, mutations that render the channels non-functional result in a lack of therapeutic response. The condition primarily affects the endocrine system, specifically the pancreas, but the resulting severe and recurrent hypoglycemia can have devastating effects on the developing brain, leading to seizures, intellectual disability, and permanent neurological damage if not promptly and effectively managed. Key symptoms include persistent neonatal or infantile hypoglycemia, macrosomia (large birth weight), lethargy, poor feeding, seizures, and inappropriately elevated insulin levels during episodes of low blood sugar. Management of diazoxide-resistant hyperinsulinism is challenging and often requires alternative medical therapies such as octreotide (a somatostatin analog) or glucagon infusions to stabilize blood glucose levels. Continuous glucose feeding via nasogastric tube or gastrostomy may be necessary. In many cases, particularly those with diffuse disease affecting the entire pancreas, near-total pancreatectomy (surgical removal of most of the pancreas) is required, though this carries a significant risk of subsequent diabetes mellitus and exocrine pancreatic insufficiency. In focal forms of the disease, where only a localized region of the pancreas is affected, limited surgical resection guided by 18F-DOPA PET/CT imaging can be curative. Genetic testing and accurate differentiation between focal and diffuse disease are critical for guiding treatment decisions.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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