Pathophysiology of Diffuse ATP-Sensitive Potassium Channel Hyperinsulinism

The most severe form of congenital hyperinsulinism (HI) is caused by inactivating mutations in the genes encoding the ATP-sensitive potassium (KATP) channels. In KATPHI, loss of functional channels results in inappropriate insulin responses to glucose. Thus, there is a failure to suppress insulin secretion when glucose levels fall, but there is also a blunting of glucose-stimulated insulin release. There are three distinct subtypes of diffuse KATPHI: (1) recessive (biallelic) diazoxide-unresponsive; (2) dominant (monoallelic) diazoxide-unresponsive; and (3) dominant (monoallelic) diazoxide-responsive. Mutations that prevent production of the channels or impair the trafficking of mature channels to the plasma membrane act recessively and result in severe hypoglycemia presenting shortly after birth. These children do not respond to medical therapy with diazoxide. The dominant defects allow the expression of channels on the plasma membrane as hetero-octamers comprised of both mutant and wild-type subunits; in those with sufficient partial function, the hypoglycemia may present later and respond to diazoxide. Our understanding of the natural history of KATPHI is incomplete, but progression to diabetes in children treated with surgical pancreatectomy is not uncommon. Whether the diabetes is a consequence of the treatment (pancreatectomy) or of dysregulated islet function itself is not fully known. Further exploration of genotype-phenotype correlations may facilitate appropriate management decisions and prediction of outcomes for affected children.