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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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References

  1. Lubchenco LO and Bard H (1971) Incidence of hypoglycemia in newborn infants by birth weight and gestational age. Pediatrics 47: 831–838

    CAS  PubMed  Google Scholar 

  2. McQuarrie I (1954) Idiopathic spontaneously occurring hypoglycemia in infants; clinical significance of problem and treatment. AMA Am J Dis Child 87: 399–428

    CAS  PubMed  Google Scholar 

  3. Bruining GJ (1990) Recent advances in hyperinsulinism and the pathogenesis of diabetes mellitus. Curr Opin Pediatr 2: 758–765

    Article  Google Scholar 

  4. Otonkoski T et al. (1999) A point mutation inactivating the sulfonylurea receptor causes the severe form of persistent hyperinsulinemic hypoglycemia of infancy in Finland. Diabetes 48: 408–415

    Article  CAS  Google Scholar 

  5. Thomas PM et al. (1995) Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science 268: 426–429

    Article  CAS  Google Scholar 

  6. Thomas PM et al. (1996) Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy. Hum Mol Genet 11: 1809–1812

    Article  Google Scholar 

  7. Glaser B et al. (1998) Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med 338: 226–230

    Article  CAS  Google Scholar 

  8. Stanley CA et al. (1998) Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med 338: 1352–1357

    Article  CAS  Google Scholar 

  9. Clayton PT et al. (2001) Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of β-oxidation in insulin secretion. J Clin Invest 108: 457–465

    Article  CAS  Google Scholar 

  10. Dunne MJ et al. (2004) Hyperinsulinism in infancy: from basic science to clinical disease. Physiol Rev 84: 239–275

    Article  CAS  Google Scholar 

  11. Fournet JC and Junien C (2003) The genetics of neonatal hyperinsulinism. Horm Res 59 (Suppl 1): 30–34

    CAS  PubMed  Google Scholar 

  12. Huopio H et al. (2000) Dominantly inherited hyperinsulinism caused by a mutation in the sulfonylurea receptor type 1. Diabetes 106: 897–906

    CAS  Google Scholar 

  13. Thornton PS et al. (2003) Clinical and molecular characterization of a dominant form of congenital hyperinsulinism caused by a mutation in the high-affinity sulfonylurea receptor. Diabetes 52: 2403–2410

    Article  CAS  Google Scholar 

  14. Magge SN et al. (2004) Familial leucine-sensitive hypoglycemia of infancy due to a dominant mutation of the β-cell sulfonylurea receptor. J Clin Endocrinol Metab 89: 4450–4456

    Article  CAS  Google Scholar 

  15. Lin YW et al. (2006) A novel KCNJ11 mutation associated with congenital hyperinsulinism reduces the intrinsic open probability of β-cell ATP-sensitive potassium channels. J Biol Chem 281: 3006–3012

    Article  CAS  Google Scholar 

  16. Gloyn AL et al. (2004) Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med 350: 1838–1849

    Article  CAS  Google Scholar 

  17. Verkarre V et al. (1998) Paternal mutation of the sulfonylurea receptor (SUR1) gene and maternal loss of 11p15 imprinted genes lead to persistent hyperinsulinism in focal adenomatous hyperplasia. J Clin Invest 102: 1286–1291

    Article  CAS  Google Scholar 

  18. Sempoux C et al. (2003) The focal form of persistent hyperinsulinemic hypoglycemia of infancy: morphological and molecular studies show structural and functional differences with insulinoma. Diabetes 52: 784–794

    Article  CAS  Google Scholar 

  19. Fournet JC et al. (2001) Unbalanced expression of 11p15 imprinted genes in focal forms of congenital hyperinsulinism: association with a reduction to homozygosity of a mutation in ABCC8 or KCNJ11. Am J Pathol 158: 2177–2184

    Article  CAS  Google Scholar 

  20. Suchi M et al. (2003) Histopathology of congenital hyperinsulinism: retrospective study with genotype correlations. Pediatr Dev Pathol 6: 322–333

    Article  Google Scholar 

  21. Yakovac WC et al. (1971) β Cell nesidioblastosis in idiopathic hypoglycemia of infancy. J Pediatr 79: 226–231

    Article  CAS  Google Scholar 

  22. Rahier J et al. (2000) Persistent hyperinsulinaemic hypoglycaemia of infancy: a heterogeneous syndrome unrelated to nesidioblastosis. Arch Dis Child Fetal Neonatal Ed 82: F108–F112

    Article  CAS  Google Scholar 

  23. Stanley CA (2004) Hyperinsulinism/hyperammonemia syndrome: insights into the regulatory role of glutamate dehydrogenase in ammonia metabolism. Mol Genet Metab 81 (Suppl 1): S45–S51

    Article  CAS  Google Scholar 

  24. Kelly A et al. (2002) Glutaminolysis and insulin secretion: from bedside to bench and back. Diabetes 51 (Suppl 3): S421–S426

    Article  CAS  Google Scholar 

  25. Hsu BY et al. (2001) Protein-sensitive and fasting hypoglycemia in children with the hyperinsulinism/hyperammonemia syndrome. J Pediatr 138: 383–389

    Article  CAS  Google Scholar 

  26. Raizen DM et al. (2005) Central nervous system hyperexcitability associated with glutamate dehydrogenase gain of function mutations. J Pediatr 146: 388–394

    Article  CAS  Google Scholar 

  27. Matschinsky FM (2002) Regulation of pancreatic β-cell glucokinase: from basics to therapeutics. Diabetes 51 (Suppl 3): S394–S404

    Article  CAS  Google Scholar 

  28. de Lonlay P et al. (2005) Dominantly inherited hyperinsulinaemic hypoglycaemia. J Inherit Metab Dis 28: 267–276

    Article  CAS  Google Scholar 

  29. Christesen HB et al. (2002) The second activating glucokinase mutation (A456V): implications for glucose homeostasis and diabetes therapy. Diabetes 51: 1240–1246

    Article  CAS  Google Scholar 

  30. Gloyn AL et al. (2003) Insights into the biochemical and genetic basis of glucokinase activation from naturally occurring hypoglycemia mutations. Diabetes 52: 2433–2440

    Article  CAS  Google Scholar 

  31. Cuesta-Munoz AL et al. (2004) Severe persistent hyperinsulinemic hypoglycemia due to a de novo glucokinase mutation. Diabetes 53: 2164–2168

    Article  CAS  Google Scholar 

  32. Molven A et al. (2004) Familial hyperinsulinemic hypoglycemia caused by a defect in the SCHAD enzyme of mitochondrial fatty acid oxidation. Diabetes 53: 221–227

    Article  CAS  Google Scholar 

  33. Hussain K et al. (2005) Hyperinsulinism of infancy associated with a novel splice site mutation in the SCHAD gene. J Pediatr 146: 706–708

    Article  CAS  Google Scholar 

  34. Eaton S et al. (2003) Short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency associated with hyperinsulinism: a novel glucose-fatty acid cycle? Biochem Soc Trans 31: 1137–1139

    Article  CAS  Google Scholar 

  35. Collins JE and Leonard JV (1984) Hyperinsulinism in asphyxiated and small-for-dates infants with hypoglycemia. Lancet 2 (8398): 311–313

    Article  Google Scholar 

  36. Hoe FM et al. (2006) Clinical features and insulin regulation in infants with syndrome of prolonged neonatal hyperinsulinism. J Pediatr 148: 207–212

    Article  CAS  Google Scholar 

  37. Li M et al. (1998) Molecular genetics of Wiedemann-Beckwith syndrome. Am J Med Genet 79: 253–259

    Article  CAS  Google Scholar 

  38. Munns CF and Batch JA (2001) Hyperinsulinism and Beckwith-Wiedemann syndrome. Arch Dis Child Fetal Neonatal Ed 84: F67–F69

    Article  CAS  Google Scholar 

  39. Hussain K et al. (2005) Hyperinsulinemic hypoglycemia in Beckwith-Wiedemann syndrome due to defects in the function of pancreatic β-cell adenosine triphosphate-sensitive potassium channels. J Clin Endocrinol Metab 90: 4376–4382

    Article  CAS  Google Scholar 

  40. DeBaun MR et al. (2000) Hypoglycemia in Beckwith-Wiedemann syndrome. Semin Perinatol 24: 164–171

    Article  CAS  Google Scholar 

  41. Marquardt T et al. (2003) Congenital disorders of glycosylation: review of their molecular bases, clinical presentations and specific therapies. Eur J Pediatr 162: 359–379

    CAS  PubMed  Google Scholar 

  42. Böhles H et al. (2001) Hyperinsulinaemic hypoglycaemia-leading symptom in a patient with congenital disorder of glycosylation Ia (phosphomannomutase deficiency). J Inherit Metab Dis 24: 858–862

    Article  Google Scholar 

  43. de Lonlay P et al. (1999) Hyperinsulinemic hypoglycemia as a presenting sign in phosphomannose isomerase deficiency: a new manifestation of carbohydrate-deficient glycoprotein syndrome treatable with mannose. J Pediatr 135: 379–383

    Article  CAS  Google Scholar 

  44. Babovic-Vuksanovic D et al. (1999) Severe hypoglycemia as a presenting symptom of carbohydrate-deficient glycoprotein syndrome. J Pediatr 135: 775–781

    Article  CAS  Google Scholar 

  45. Sun L et al. (2005) Congenital disorder of glycosylation Id presenting with hyperinsulinemic hypoglycemia and islet cell hyperplasia. J Clin Endocrinol Metab 90: 4371–4375

    Article  CAS  Google Scholar 

  46. Ferry RJ Jr et al. (2000) Calcium-stimulated insulin secretion in diffuse and focal forms of congenital hyperinsulinism. J Pediatr 137: 239–246

    Article  CAS  Google Scholar 

  47. Grimberg A et al. (2001) Dysregulation of insulin secretion in children with congenital hyperinsulinism due to sulfonylurea receptor mutations. Diabetes 50: 322–328

    Article  CAS  Google Scholar 

  48. Kelly A et al. (2001) Acute insulin responses to leucine in children with the hyperinsulinism/hyperammonemia syndrome. J Clin Endocrinol Metab 86: 3724–3728

    Article  CAS  Google Scholar 

  49. Stanley CA et al. (2004) Preoperative evaluation of infants with focal or diffuse congenital hyperinsulinism by intravenous acute insulin response tests and selective pancreatic arterial calcium stimulation. J Clin Endocrinol Metab 89: 288–296

    Article  CAS  Google Scholar 

  50. Giurgea I et al. (2004) Acute insulin responses to calcium and tolbutamide do not differentiate focal from diffuse congenital hyperinsulinism. J Clin Endocrinol Metab 89: 925–929

    Article  CAS  Google Scholar 

  51. Dubois J et al. (1995) Hyperinsulinism in children: diagnostic value of pancreatic venous sampling correlated with clinical, pathological and surgical outcome in 25 cases. Pediatr Radiol 25: 512–516

    Article  CAS  Google Scholar 

  52. Ribeiro MJ et al. (2005) Characterization of hyperinsulinism in infancy assessed with PET and 18F-fluoro-l-DOPA. J Nucl Med 46: 560–566

    PubMed  Google Scholar 

  53. Otonkoski T et al. (2006) Noninvasive diagnosis of focal hyperinsulinism of infancy with [18F]-DOPA positron emission tomography. Diabetes 55: 13–18

    Article  CAS  Google Scholar 

  54. Hardy O et al. Diagnosis and localization of focal hyperinsulinism by 18F-fluorodopa PET scan. J Pediatr, in press

  55. Ericson LE et al. (1977) Accumulation of dopamine in mouse pancreatic β-cells following injection of L-DOPA. Localization to secretory granules and inhibition of insulin secretion. Diabetologia 13: 117–124

    Article  CAS  Google Scholar 

  56. Borelli MI et al. (1997) Presence of DOPA decarboxylase and its localization in adult rat pancreatic islet cells. Diabetes Metab 23: 161–163

    CAS  PubMed  Google Scholar 

  57. de Lonlay P et al. (2006) Congenital hyperinsulinism: pancreatic [18F]fluoro-l-dihydroxyphenylalanine (DOPA) positron emission tomography and immunohistochemistry study of DOPA decarboxylase and insulin secretion. J Clin Endocrinol Metab 91: 933–940

    Article  CAS  Google Scholar 

  58. Dayton PG et al. (1975) Metabolism and disposition of diazoxide. A mini-review. Drug Metab Dispos 3: 226–229

    CAS  PubMed  Google Scholar 

  59. Müller D et al. (2004) Should nifedipine be used to counter low blood sugar levels in children with persistent hyperinsulinaemic hypoglycaemia? Arch Dis Child 89: 83–85

    Article  Google Scholar 

  60. Glaser B et al. (1993) Persistent hyperinsulinemic hypoglycemia of infancy: long term treatment without pancreatectomy. J Pediatr 123: 644–650

    Article  CAS  Google Scholar 

  61. Suchi M et al. (2004) Congenital hyperinsulinism: intraoperative biopsy interpretation can direct the extent of pancreatectomy. Am J Surg Pathol 28: 1326–1335

    Article  Google Scholar 

  62. De Vroede M et al. (2004) Laparoscopic diagnosis and cure of hyperinsulinism in two cases of focal adenomatous hyperplasia in infancy. Pediatrics 114: e520–e522

    Article  Google Scholar 

  63. Leibowitz G et al. (1995) Hyperinsulinemic hypoglycemia of infancy (nesidioblastosis) in clinical remission: high incidence of diabetes mellitus and persistent β-cell dysfunction at long term follow up. J Clin Endocrinol Metab 80: 386–392

    CAS  PubMed  Google Scholar 

  64. Meissner T et al. (2003) Long-term follow-up of 114 patients with congenital hyperinsulinism. Eur J Endocrinol 149: 43–51

    Article  CAS  Google Scholar 

  65. Menni F et al. (2001) Neurologic outcomes of 90 neonates and infants with persistent hyperinsulinemic hypoglycemia. Pediatrics 107: 476–479

    Article  CAS  Google Scholar 

  66. Steinkrauss L et al. (2005) Effects of hypoglycemia on developmental outcome in children with congenital hyperinsulinism. J Pediatr Nurs 20: 109–118

    Article  Google Scholar 

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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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