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Infants with congenital hyperinsulinism often require pancreatectomy. Recessive mutations of the ATP-dependent plasma membrane potassium channel (K(ATP)) genes, SUR1 and K(ir)6.2, cause diffuse hyperinsulinism. K(ATP) channel mutations can also cause focal disease through loss of heterozygosity for maternal 11p, resulting in expression of a paternal mutation. This study evaluated whether focal vs. diffuse hyperinsulinism could be diagnosed by acute insulin response (AIR) tests and whether arterial calcium stimulation/venous sampling (ASVS) could localize focal lesions. Fifty infants with diazoxide-unresponsive hyperinsulinism were studied. Focal lesions occurred in 70% of the cases. Positive AIR calcium occurred in 17 of 30 focal and 10 of 13 diffuse cases (P < 0.04). Positive AIR tolbutamide occurred in 27 of 30 focal vs. seven of 13 diffuse cases (P < 0.02); K(ATP) channel mutations were identified in four of the latter. ASVS localized the lesion in 24 of 33 focal cases (73%) but correctly diagnosed diffuse disease in only four of 13 cases. These results indicate that preoperative AIR tests do not distinguish focal vs. diffuse disease because some K(ATP) channel mutations retain responsiveness to tolbutamide. The ASVS test can be used to localize focal lesions in infants. The combination of ASVS, careful intraoperative histologic analysis, and surgical expertise succeeded in correcting hypoglycemia in 86% of the infants with focal hyperinsulinism.

Recessive mutations of sulfonylurea receptor 1 (SUR1) and potassium inward rectifier 6.2 (Kir6.2), the two adjacent genes on chromosome 11p that comprise the ␤-cell plasma membrane ATP-sensitive K ؉ (K ATP ) channels, are responsible for the most common form of congenital hyperinsulinism in children. The present study was undertaken to identify the genetic defect in a family with dominantly inherited hyperinsulinism affecting five individuals in three generations. Clinical tests were carried out in three of the patients using acute insulin responses (AIRs) to intravenous stimuli to localize the site of defect in insulin regulation. The affected individuals showed abnormal positive calcium AIR, normal negative leucine AIR, subnormal positive glucose AIR, and impaired tolbutamide AIR. This AIR pattern suggested a K ATP channel defect because it resembled that seen in children with recessive hyperinsulinism due to two common SUR1 mutations, g3992-9a and delPhe1388. Genetic linkage to the K ATP locus was established using intragenic polymorphisms. Mutation analysis identified a novel trinucleotide deletion in SUR1 exon 34 that results in the loss of serine 1387. Studies of delSer1387 in COSm6 cells confirmed that the expressed mutant protein assembles with Kir6.2 and trafficks to the plasma membrane, but it had no 86 Rb efflux ion transport activity. These results indicate that hyperinsulinism in this family is caused by a SUR1 mutation that is expressed dominantly rather than recessively. Diabetes 52: [2403][2404][2405][2406][2407][2408][2409][2410] 2003 C ongenital hyperinsulinism in children is a disorder of persistent hypoglycemia that is caused by genetic mutations in the pathways regulating insulin secretion by pancreatic islets (1). The most common of these disorders is associated with recessive mutations of the two adjacent genes on chromosome 11p that comprise the ␤-cell ATP-sensitive K ϩ (K ATP ) channel: the high-affinity sulfonylurea receptor 1 (SUR1 or ABCC8) and its regulated ion pore, potassium inward rectifier 6.2 (Kir6.2 or KCNJ11) (2-5). Mutations in these channel genes can also cause sporadic focal hyperinsulinism through a two-hit mechanism involving loss of heterozygosity for the maternal 11p, leading to expression of a paternally transmitted K ATP mutation (6,7). In addition, Huopio et al. (8) recently reported a family with a dominantly expressed mutation of SUR1. Children with either the focal or diffuse forms of disease associated with K ATP channel mutations often present with severe hypoglycemia at birth. Because the channel is impaired, they often do not respond to medical therapy with the channel agonist diazoxide and thus frequently require near-total pancreatectomy.In 1998, we reported three families with congenital hyperinsulinism in whom the disease was transmitted in a dominant, rather than recessive, manner (9). We subsequently identified the genetic defects in two of these families as being dominantly expressed mutations of glutamate dehydrogenase (GDH; GLUD1 on 10q) (10) and ...

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