Dysregulation of insulin secretion in children with congenital hyperinsulinism due to sulfonylurea receptor mutations

Mutations in the high-affinity sulfonylurea receptor (SUR)-1 cause one of t he severe recessively inherited diffuse forms of congenital hyperinsulinism or, when associated with loss of heterozygosity, focal adenomatosis. me hy pothesized that SUR1 mutations mould render the beta -cell insensitive to s ulfonylureas and to glucose. Stimulated insulin responses mere compared amo ng eight patients with diffuse hyperinsulinism (two mutations), six carrier parents, and ten normal adults. In the patients with diffuse hyperinsulini sm, the acute insulin response to intravenous tolbutamide was absent and di d not overlap with the responses seen in either adult group. There mas posi tive, albeit significantly blunted, acute insulin response to intravenous d extrose in the patients with diffuse hyperinsulinism. Graded infusions of g lucose, to raise and then lower plasma glucose concentrations over 4 h, cau sed similar rises in blood glucose but lower peak insulin levels in the hyp erinsulinemic patients. Loss of acute insulin response to tolbutamide can i dentify children with diffuse SUR1 defects. The greater response to glucose than to tolbutamide indicates that ATP-sensitive potassium (K-ATP) channel -independent pathways are involved in glucose-mediated insulin release in p atients with diffuse SUR1 defects. The diminished glucose responsiveness su ggests that SUR1 mutations and lack of K-ATP channel activity may contribut e to the late development of diabetes in patients with hyperinsulinism inde pendently of subtotal pancreatectomy.