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Diazoxide-Responsive Forms of Congenital Hyperinsulinism

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Congenital Hyperinsulinism

Part of the book series: Contemporary Endocrinology ((COE))

Abstract

Diazoxide responsiveness is typically the starting point for distinguishing congenital hyperinsulinism phenotypes since those who do not respond will often require surgery. Operationally, diazoxide responsiveness is defined as being able to appropriately develop a hyperketonemic response to fasting (beta-hydroxybutyrate >2 mmol/L) prior to developing hypoglycemia (<2.8–3.3 mmol/L, <50–60 mg/dL), in addition to preventing any food-induced hypoglycemia. Of note, only 35% of diazoxide-responsive patients have an identifiable mutation in one of the currently known hyperinsulinism genes. Perinatal stress-induced hyperinsulinism is a transient but often prolonged form of hyperinsulinism associated with risk factors such as birth asphyxia and intrauterine growth restriction. Screening for hypoglycemia is crucial when these risk factors are present, as is starting diuretic treatment before diazoxide to avoid fluid overload and pulmonary hypertension. Genetic forms of diazoxide-responsive hyperinsulinism include a distinctive form caused by dominant activating mutations in glutamate dehydrogenase (GDH). Leucine-induced and fasting hypoglycemia, mild hyperammonemia, and neurologic abnormalities, most commonly atypical absence epilepsy, are key features. Recessive inactivating mutations in short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), an inhibitor of GDH and a fatty acid oxidation enzyme, also cause leucine-sensitive hypoglycemia, but without hyperammonemia. Heterozygous mutations in the transcription factors, hepatocyte nuclear factors 4A and 1A, cause hyperinsulinism and evolve into young adult-onset diabetes (HNF4A-MODY and HNF1A-MODY, respectively). Finally, mutations in the mitochondrial transport protein, uncoupling protein 2 (UCP2), and the plasma membrane protein, monocarboxylate transporter 1 (MCT1), cause rare forms of hyperinsulinism with the unique features of post-glucose load and exercise-induced hypoglycemia, respectively.

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Authors and Affiliations

  1. Department of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Manchester, UK

    Daphne Yau

  2. Division of Endocrinology and Diabetes, Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Charles A. Stanley

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  1. Division of Endocrinology and Diabetes, Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Diva D. De León-Crutchlow

  2. Division of Endocrinology and Diabetes, Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Charles A. Stanley

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Yau, D., Stanley, C.A. (2019). Diazoxide-Responsive Forms of Congenital Hyperinsulinism. In: De León-Crutchlow, D., Stanley, C. (eds) Congenital Hyperinsulinism. Contemporary Endocrinology. Humana Press, Cham. https://doi.org/10.1007/978-3-030-02961-6_2

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