Mechanisms of Disease: advances in diagnosis and treatment of hyperinsulinism in neonates

Abstract

Hyperinsulinism is the single most common mechanism of hypoglycemia in neonates. Dysregulated insulin secretion is responsible for the transient and prolonged forms of neonatal hypoglycemia, and congenital genetic disorders of insulin regulation represent the most common of the permanent disorders of hypoglycemia. Mutations in at least five genes have been associated with congenital hyperinsulinism: they encode glucokinase, glutamate dehydrogenase, the mitochondrial enzyme short-chain 3-hydroxyacyl-CoA dehydrogenase, and the two components (sulfonylurea receptor 1 and potassium inward rectifying channel, subfamily J, member 11) of the ATP-sensitive potassium channels (K(ATP) channels). K(ATP) hyperinsulinism is the most common and severe form of congenital hyperinsulinism. Infants suffering from K(ATP) hyperinsulinism present shortly after birth with severe and persistent hypoglycemia, and the majority are unresponsive to medical therapy, thus requiring pancreatectomy. In up to 40-60% of the children with K(ATP) hyperinsulinism, the defect is limited to a focal lesion in the pancreas. In these children, local resection results in cure with avoidance of the complications inherent to a near-total pancreatectomy. Hyperinsulinism can also be part of other disorders such as Beckwith-Wiedemann syndrome and congenital disorders of glycosylation. The diagnosis and management of children with congenital hyperinsulinism requires a multidisciplinary approach to achieve the goal of therapy: prevention of permanent brain damage due to recurrent hypoglycemia.

Mechanism of Hyperinsulinism in Short-chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency Involves Activation of Glutamate Dehydrogenase

“…Congenital hyperinsulinism is the most common cause of persistent hypoglycemia in infants and children (1). Six genetic loci have been associated with the disorder.…”

Alternating hypoglycemia and hyperglycemia in a toddler with a homozygous p.R1419H ABCC8 mutation: an unusual clinical picture

“…However, the relatively mild phenotypes of the patient and her father contrasted with this "classical" clinical picture of homozygous recessive ABCC8 mutations, which are typically very severe and present early in life (7,17,18). Therefore, we tested the effects of this mutation in a reconstituted system, using Rb + efflux assays of CosM6 cells transfected with Kir6.2/ KCNJ11 and WT or SUR1[R1419H] to measure functional K ATP channel expression (Figure 3).…”

“…The most common outcome of recessively inherited ABCC8 gene mutations is to prevent expression of functional channels, leading to severe HI that presents early in life and is unresponsive to diazoxide. Most patients require subtotal pancreatectomy (7,8). In some cases, as reported for a splice site mutation of ABCC8, there can be variability in the age and severity of presentation in homozygous individuals (9,10).…”

A Neonatal Case of Congenital Hyperinsulinism Due to Homozygous KCNJ11 Gene Mutation

“…'nın (11) KH tanılı 300 olguluk serisinde, olguların %45,3'ünde spesifik bir genetik mutasyonun varlığı belirlenmiş ve bunların önemli bir kısmının SUR1 genindeki ABCC8 mutasyonu olduğu bildirilmiştir. KH ikinci sıklıkta GDH enzimi ile ilişkili GLUD1 genindeki aktive edici mutasyona bağlı oluşur ve hiperinsülinizm-hiperamonyemi sendromu şeklinde kliniğe yansır (12) . Olgumuzun amonyak düzeyinin normal olması nedeniyle bu genetik defekt dışlanmıştır.…”