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

Nature Clinical Practice Endocrinology & Metabolism volume 3, pages 57–68 (2007)Cite this article

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 (KATP channels). KATP hyperinsulinism is the most common and severe form of congenital hyperinsulinism. Infants suffering from KATP 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 KATP 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.

Key Points

  • Hyperinsulinism is the most common cause of persistent hypoglycemia in infants and children

  • To date, mutations in five genes are known to encode proteins that cause congenital hyperinsulinism: sulfonylurea receptor 1 and Kir6.2 (the two components of the ATP-dependent potassium channel), glutamate dehydrogenase, glucokinase, and short chain 3-hydroxyacyl-CoA dehydrogenase

  • ATP-dependent potassium channel hyperinsulinism is the most common and severe form of hyperinsulinism and can present as diffuse or focal disease; this disease can be cured by surgical resection

  • A multidisciplinary approach is important in the management of infants with congenital hyperinsulinism; the goal of therapy is to avoid neurodevelopmental complications by preventing and treating hypoglycemia

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Figure 1: Glucose-stimulated insulin secretion in pancreatic β-cells.
Figure 2: Histological forms of congenital hyperinsulinism.
Figure 3: Mechanisms of hyperinsulinism and hyperammonemia in GDH hyperinsulinism.
Figure 4: Current management paradigm for congenital hyperinsulinism.

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Acknowledgements

The authors receive grant support from NIH grants K12-DK-063682-02 (DDDL) and 2RO1DK5628-06 and 2RO1 DK53012-07 (CAS).

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Authors and Affiliations

  1. the Division of Endocrinology, DD De León is an Assistant Professor of Pediatrics, and CA Stanley is a Professor of Pediatrics, at the University of Pennsylvania, Philadelphia, PA, USA DD De León is an Attending Physician in, and CA Stanley Chief of, The Children's Hospital of Philadelphia.,

    Diva D De León & Charles A Stanley

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Correspondence to Charles A Stanley.

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De León, D., Stanley, C. Mechanisms of Disease: advances in diagnosis and treatment of hyperinsulinism in neonates. Nat Rev Endocrinol 3, 57–68 (2007). https://doi.org/10.1038/ncpendmet0368

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