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Hyperinsulinemic hypoglycemia in infancy: Current concepts in diagnosis and management

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Abstract

Purpose

Molecular basis of various forms of hyperinsulinemic hypoglycemia, involving defects in key genes regulating insulin secretion, are being increasingly reported. However, the management of medically unresponsive hyperinsulinism still remains a challenge as current facilities for genetic diagnosis and appropriate imaging are limited only to very few centers in the world. We aim to provide an overview of spectrum of clinical presentation, diagnosis and management of hyperinsulinism.

Methods

We searched the Cochrane library, MEDLINE and EMBASE databases, and reference lists of identified studies.

Conclusions

Analysis of blood samples, collected at the time of hypoglycemic episodes, for intermediary metabolites and hormones is critical for diagnosis and treatment. Increased awareness among clinicians about infants “at-risk” of hypoglycemia, and recent advances in genetic diagnosis have made remarkable contribution to the diagnosis and management of hyperinsulinism. Newer drugs like lanreotide (long acting somatostatin analogue) and sirolimus (mammalian target of rapamycin (mTOR) inhibitor) appears promising as patients with diffuse disease can be treated successfully without subtotal pancreatectomy, minimizing the long-term sequelae of diabetes and pancreatic insufficiency. Newer insights in understanding the molecular and histological basis and improvements in imaging and surgical techniques will modify the approach to patients with congenital hyperinsulinism.

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References

  1. Arya VB, Senniappan S, Guemes M, Hussain K. Neonatal hypoglycemia. Indian J Pediatr. 2014; 81:58–65.

    Article  PubMed  Google Scholar 

  2. Straussman S, Levitsky LL. Neonatal hypoglycemia. Curr Opin Endocrinol Diabetes Obes. 2010;17:20–4.

    PubMed  CAS  Google Scholar 

  3. Menni F, de Lonlay P, Sevin C, Touati G, Peigne C, Barbier V, et al. Neurologic outcomes of 90 neonates and infants with persistent hyperinsulinemic hypoglycemia. Pediatrics. 2001;107:476–9.

    Article  PubMed  CAS  Google Scholar 

  4. Hussain K, Blankenstein O, De Lonlay P, Christesen HT. Hyperinsulinaemic hypoglycaemia: biochemical basis and the importance of maintaining normoglycaemia during management. Arch Dis Child. 2007;92:568–70.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Hawdon J. Glucose homeostasis in the healthy fetus and neonate. In: Rennie JM, editor. Metabolic and Endocrine Disorders. Textbook of Neonatology. London: Elsevier, Churchill Livingstone. 2005;851–52.

    Google Scholar 

  6. Henquin JC. Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes. 2000;49:1751–60.

    Article  PubMed  CAS  Google Scholar 

  7. Yorifuji T. Congenital hyperinsulinism: Current status and future prospectives. Ann Pediatr Endocrinol Metab. 2014;19:57–68.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Inagaki N, Gonoi T, Clement JP, Namba N, Inazawa J, Gonzalez G, et al. Reconstitution of IKATP: An inward rectifier subunit plus the sulfonylurea receptor. Science. 1995;270:1166–70.

    Article  PubMed  CAS  Google Scholar 

  9. Zhang T, Li C. Mechanisms of amino acid-stimulated insulin secretion in congenital hyperinsulinism. Acta Biochim Biophys Sin (Shanghai). 2013;45:36–43.

    Article  Google Scholar 

  10. World Health Organization. Hypoglycaemia of the Newborn. Review of the Literature. Geneva: WHO, 1997;WHO/CHD/97.1.

    Google Scholar 

  11. Thornton PS, Stanley CA, De Leon D, Harris D, Haymond MW, Hussain K, et al. Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children. J Pediatr. 2015; 167:238–45.

    Article  PubMed  Google Scholar 

  12. Tin W. Defining neonatal hypoglycaemia: a continuing debate. Semin Fetal Neonatal Med. 2014;19:27–32.

    Article  PubMed  Google Scholar 

  13. Adamkin DH, Committee on Fetus and Newborn. Postnatal glucose homeostasis in late-preterm and term infants. Pediatrics. 2011;127:575–79.

    Article  PubMed  Google Scholar 

  14. Kapoor RR, Flanagan SE, James C, Shield J, Ellard S, Hussain K. Hyperinsulinaemic hypoglycaemia. Arch Dis Child. 2009;94:450–7.

    Article  PubMed  CAS  Google Scholar 

  15. Vanhaltren K, Malhotra A. Characteristics of infants at risk of hypoglycaemia secondary to being ‘infant of a diabetic mother’. J Pediatr Endocrinol Metab. 2013;26:861–5.

    PubMed  CAS  Google Scholar 

  16. Chong JH, Chandran S, Agarwal P, Rajadurai VS. Delayed presentation of prolonged hyperinsulinaemic hypoglycaemia in a preterm small-for-gestational age neonate. BMJ Case Rep. 2013. Doi:10.1136/bcr-2013-200920.

    Google Scholar 

  17. Bellanne-Chantelot C, Saint-Martin C, Ribeiro MJ, Vaury C, Verkarre V, Arnoux JB, et al. ABCC8 and KCNJ11 molecular spectrum of 109 patients with diazoxideunresponsive congenital hyperinsulinism. J Med Genet. 2010;47:752–59.

    Article  PubMed  CAS  Google Scholar 

  18. James C, Kapoor RR, Ismail D, Hussain K. The genetic basis of congenital hyperinsulinism. J Med Genet. 2009;46:289–99.

    Article  PubMed  CAS  Google Scholar 

  19. Mohammed Z, Hussain K. The genetics of hyperinsulinemic hypoglycemia. NeoReviews. 2013;14: 179–88.

    Article  Google Scholar 

  20. Verkarre V, Fournet JC, de Lonlay P, Gross-Morand MS, Devillers M, Rahier J, et al. 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. 1998;102:1286–91.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Flanagan SE, Clauin S, Bellanne-Chantelot C, de Lonlay P, Harries LW, Gloyn AL, et al. Update of mutations in the genes encoding the pancreatic b-cell K (ATP) channel subunits Kir6.2 (KCNJ11) and sulfonylurea receptor 1 (ABCC8) in diabetes mellitus and hyperinsulinism. Hum Mutat. 2009;30:170–80.

    Article  PubMed  CAS  Google Scholar 

  22. Stanley CA, Lieu YK, Hsu BY, Burlina AB, Greenberg CR, Hopwood NJ, et al. Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med. 1998;338:1352–7.

    Article  PubMed  CAS  Google Scholar 

  23. MacMullen C, Fang J, Hsu BY, Kelly A, de Lonlay-Debeney P, Saudubray JM, et al. Hyperinsulinism/hyperammonemia syndrome in children with regulatory mutations in the inhibitory guanosine triphosphate-binding domain of glutamate dehydrogenase. J Clin Endocrinol Metab. 2001;86:1782–7.

    PubMed  CAS  Google Scholar 

  24. Hussain K, Clayton PT, Krywawych S, Chatziandreou I, Mills P, Ginbey DW, et al. Hyperinsulinism of infancy associated with a novel splice site mutation in the SCHAD gene. J Pediatr. 2005;146:706–8.

    Article  PubMed  CAS  Google Scholar 

  25. Chandran S, Yap F, Hussain K. Molecular mechanisms of protein induced hyperinsulinaemic hypoglycaemia. World J Diabetes. 2014;5:666–77.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Cuesta-Muñoz A, Huopio H, Otonkoski T, Gomez-Zumaquero JM, Näntö-Salonen K, Rahier J, et al. Severe persistent hyperinsulinemic hypoglycemia due to a de novo glucokinase mutation. Diabetes. 2004;53:2164–8.

    Article  PubMed  Google Scholar 

  27. Gonzalez Barroso MM, Giurgea I, Bouillaud F, Anedda A, Bellanne Chantelot C, Hubert L, et al. Mutations in UCP2 in congenital hyperinsulinism reveal a role for regulation of insulin secretion. PLoS One. 2008;3:e3850.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Gupta RK, Vatamaniuk MZ, Lee CS, Flaschen RC, Fulmer JT, Matschinsky FM, et al. The MODY1 gene HNF 4alpha regulates selected genes involved in insulin secretion. J Clin Invest. 2005;115:100615.

    Google Scholar 

  29. Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, et al. Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med. 2007;4:e118.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Otonkoski T, Kaminen N, Ustinov J, Lapatto R, Meissner T, Mayatepek E, et al. Physical exercise-induced hyperinsulinemic hypoglycemia is an autosomal-dominant trait characterized by abnormal pyruvate induced insulin release. Diabetes. 2003;52:199–204.

    Article  PubMed  CAS  Google Scholar 

  31. Munns CF, Batch JA. Hyperinsulinism and Beckwith-Wiedemann syndrome. Arch Dis Child Fetal Neonatal Ed. 2001;84:F67–9.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. Sun L, Eklund EA, Chung WK, Wang C, Cohen J, Freeze HH. Congenital disorder of glycosylation id presenting with hyperinsulinemic hypoglycemia and islet cell hyperplasia. J Clin Endocrinol Metab. 2005;90:4371–5.

    Article  PubMed  CAS  Google Scholar 

  33. Baumann U, Preece MA, Green A, Kelly DA, McKiernan PJ. Hyperinsulinism in tyrosinaemia type I. J Inherit Metab Dis. 2005;28:131–35.

    Article  PubMed  CAS  Google Scholar 

  34. Kapoor RR, Flanagan SE, Arya VB, Shield JP, Ellard S, Hussain K. Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism. Eur J Endocrino. 2013;168:557–64.

    Article  CAS  Google Scholar 

  35. Vannucci RC, Vannucci SJ. Hypoglycemic brain injury. Semin Neonatol. 2001;6:147–55.

    Article  PubMed  CAS  Google Scholar 

  36. Chandran S, Rajadurai VS, Alim AH, Hussain K. Current perspectives on neonatal hypoglycemia, its management, and cerebral injury risk. Research and Reports in Neonatology. 2015;5:17–30.

    Google Scholar 

  37. Mazor-Aronovitch K, Gillis D, Lobel D, Hirsch HJ, Pinhas-Hamiel O, Modan-Moses D, et al. Long-term neurodevelopmental outcome in conservatively treated congenital hyperinsulinism. Eur J Endocrinol. 2007;157:491–7.

    Article  PubMed  CAS  Google Scholar 

  38. Wang L, Fan G, Ji X, Sun B, Guo Q. MRI findings of brain damage due to neonatal hypoglycemia. Zhonghua Fang She Xue Za Zhi. 2009,43:42–5.

    CAS  Google Scholar 

  39. Deshpande S, Ward Platt M. The investigation and management of neo-natal hypoglycaemia. Semin Fetal Neonatal Med. 2005;10:351–61.

    Article  PubMed  Google Scholar 

  40. Senniappan S, Arya VB, Hussain K. The molecular mechanisms, diagnosis and management of congenital hyperinsulinism. Indian J Endocr Metab. 2013;17:19–30.

    Article  CAS  Google Scholar 

  41. Harris DL, Battin MR, Weston PJ, Harding JE. Continuous glucose monitoring in newborn babies at risk of hypoglycemia. J Pediatr. 2010;157:198–202.

    Article  PubMed  Google Scholar 

  42. Saif M, Kapoor A, Kochar IP, Jindal R. Continuous glucose monitoring system for congenital hyperinsulinemia. Indian Pediatr. 2013;50:421–2.

    Article  PubMed  Google Scholar 

  43. Hussain K. Investigations for neonatal hypoglycaemia. Clin Biochem. 2011;44:465–6.

    Article  PubMed  Google Scholar 

  44. Hussain K, Blankenstein O, De Lonlay P, Christesen HT. Hyperinsulinaemic hypoglycaemia: biochemical basis and the impor-tance of maintaining normoglycaemia during management. Arch Dis Child. 2007;92:568–70.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Aynsley-Green A, Hussain K, Hall J, Saudubray JM, Nihoul-Fékété C, De Lonlay-Debeney P, et al. Practical management of hyperinsulinism in infancy. Arch Dis Child Fetal Neonatal Ed. 2000;82:F98–107.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  46. Tas E, Mahmood B, Garibaldi L, Sperling M. Liver injury may increase the risk of diazoxide toxicity: a case report. Eur j Pediatr. 2015;174:403–6.

    Article  PubMed  Google Scholar 

  47. Hussain K. Diagnosis and management of hyperinsulinaemic hypoglycaemia of infancy. Horm Res. 2008;69:2–13.

    Article  PubMed  CAS  Google Scholar 

  48. Kim-Hanh Le Quan Sang, Jean-Baptiste Arnoux, Asmaa Mamoune, Saint-Martin C, Bellanné-Chantelot C, Valayannopoulos C, et al. Successful treatment of congenital hyperinsulinism with long-acting release octreotide. Eur J Endocrino. 2012;166:333–9.

    Article  Google Scholar 

  49. Modan-Moses D, Koren I, Mazor-Aronovitch K, Pinhas-Hamiel O, Landau H. Treatment of congenital hyperinsulinism with Lanreotide acetate (Somatuline Autogel). J Clin Endocrinol Metab. 2011; 96:2312–7.

    Article  PubMed  CAS  Google Scholar 

  50. Moens K, Berger V, Ahn JM, Van Schravendijk C, Hruby VJ, Pipeleers D, et al. Assessment of the role of interstitial glucagon in the acute glucose secretory responsiveness of in situ pancreatic beta-cells. Diabetes. 2002;51:669–75.

    Article  PubMed  CAS  Google Scholar 

  51. Senniappan S, Alexandrescu S, Tatevian N, Shah P, Arya V, Flanagan S, et al. Sirolimus therapy in infants with severe hyperinsulinemic hypoglycemia. N Engl J Med. 2014;370:1131–7.

    Article  PubMed  CAS  Google Scholar 

  52. Hussain K, Aynsley-Green A. Hyperinsulinaemic hypoglycaemia in preterm neonates. Arch Dis Child Fetal Neonatal Ed. 2004;89:F65–7.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  53. Mohnike K, Blankenstein O, Christesen HT, de Lonlay J, Hussain K, Koopmans KP, et al. Proposal for a standardized protocol for 18-F DOPA-PET (PET/CT) in congenital hyperinsulinism. Horm Res. 2006;66:40–2.

    Article  PubMed  CAS  Google Scholar 

  54. Bax KN, van der Zee DC. The laparoscopic approach towards hyperinsulinism in children. Sem Ped Surg. 2007;16:245–51.

    Article  Google Scholar 

  55. Leibowitz G, Glaser B, Higazi AA, Salameh M, Cerasi E, Landau H. Hyperinsulinemic hypoglycemia of infancy (nesidioblastosis) in clinical remission: High incidence of diabetes mellitus and persistent beta-cell dysfunction at long-term follow-up. J Clin Endocrinol Metab. 1995;80:386–92.

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. From Department of Neonatology, KK Women’s and Children’s Hospital, Singapore, Singapore

    Shrenik Vora, Suresh Chandran & Victor Samuel Rajadurai

  2. Genetics and Epigenetics in Health and Disease Genetics and Genomic Medicine Programme, UCL Institute of Child Health, Great Ormond Street Hospital for Children, 30 Guilford Street, London, UK

    Khalid Hussain

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  1. Shrenik Vora
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  2. Suresh Chandran
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  3. Victor Samuel Rajadurai
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  4. Khalid Hussain
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Correspondence to Shrenik Vora.

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Vora, S., Chandran, S., Rajadurai, V.S. et al. Hyperinsulinemic hypoglycemia in infancy: Current concepts in diagnosis and management. Indian Pediatr 52, 1051–1059 (2015). https://doi.org/10.1007/s13312-015-0772-1

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