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Journal of Pediatric Endocrinology and Metabolism

Editor-in-Chief: Kiess, Wieland

Ed. by Bereket, Abdullah / Cohen, Pinhas / Darendeliler, Feyza / Dattani, Mehul / Gustafsson, Jan / Luo, Feihong / Mericq, Veronica / Roth, Christian / Toppari, Jorma

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Volume 28, Issue 5-6 (May 2015)

Issues

Sirolimus therapy in a patient with severe hyperinsulinaemic hypoglycaemia due to a compound heterozygous ABCC8 gene mutation

Pratik Shah
  • Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, London, UK
  • Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, UK
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Ved Bhushan Arya
  • Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, London, UK
  • Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, UK
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Sarah E. Flanagan / Kate Morgan
  • Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, London, UK
  • Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, UK
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Sian Ellard / Senthil Senniappan
  • Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, London, UK
  • Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, UK
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Khalid Hussain
  • Corresponding author
  • Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, London, UK
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2014-12-17 | DOI: https://doi.org/10.1515/jpem-2014-0371

Abstract

Introduction: Hyperinsulinaemic hypoglycaemia (HH) is the most common cause of severe and persistent hypoglycaemia in neonates. The treatment of severe diazoxide unresponsive HH involves near total pancreatectomy. Mammalian target of rapamycin (mTOR) is a protein kinase that regulates cellular proliferation. mTOR inhibitors are used in cancer patients and recently found to be effective in the treatment of insulinoma and HH patients.

Case: A 36 weeks large for gestational age neonate presented with severe hypoglycaemia on day 1 of life. The hypoglycaemia screen confirmed HH and genetic testing revealed compound heterozygous ABCC8 mutation, confirming diffuse disease. He was unresponsive to the maximal dose of diazoxide (15 mg/kg/day), hence needed treatment with higher concentration of intravenous glucose (25 mg/kg/min), intravenous glucagon and subcutaneous octreotide (30 μg/kg/day) infusions to maintain normoglycaemia. Sirolimus, a mTOR inhibitor, was commenced at 9 weeks of age following which he showed a marked improvement in his glycaemic control. After 4 weeks of sirolimus therapy, he was discharged home on subcutaneous octreotide injection (20 μg/kg/day) and oral sirolimus, thereby avoiding the need for a near total pancreatectomy.

Conclusion: We report the first case of compound heterozygous ABCC8 mutation causing severe diffuse HH that responded to therapy with a mTOR inhibitor.

Keywords: hyperinsulinaemic hypoglycaemia; mTOR; sirolimus

References

  • 1.

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

  • 2.

    Senniappan S, Shanti B, James C, Hussain K. Hyperinsulinaemic hypoglycaemia: genetic mechanisms, diagnosis and management. J Inherit Metab Dis 2012;35:589–601.CrossrefWeb of SciencePubMedGoogle Scholar

  • 3.

    Arnoux JB, Verkarre V, Saint-Martin C, Montravers F, Brassier A, et al. Congenital hyperinsulinism: current trends in diagnosis and therapy. Orphanet J Rare Dis 2011;6:63.PubMedCrossrefWeb of ScienceGoogle Scholar

  • 4.

    Rahier J, Guiot Y, Sempoux C. Morphologic analysis of focal and diffuse forms of congenital hyperinsulinism. Semin Pediatr Surg 2011;20:3–12.CrossrefWeb of SciencePubMedGoogle Scholar

  • 5.

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

  • 6.

    Rahier J, Guiot Y, Sempoux C. Persistent hyperinsulinaemic hypoglycaemia of infancy: a heterogeneous syndrome unrelated to nesidioblastosis. Arch Dis Child Fetal Neonatal Ed 2000;82:F108–12.Google Scholar

  • 7.

    Pierro A, Nah SA. Surgical management of congenital hyperinsulinism of infancy. Semin Pediatr Surg 2011;20:50–3.CrossrefPubMedGoogle Scholar

  • 8.

    Beltrand J, Caquard M, Arnoux JB, Laborde K, Velho G, et al. Glucose metabolism in 105 children and adolescents after pancreatectomy for congenital hyperinsulinism. Diabetes Care 2012;35:198–203.PubMedWeb of ScienceGoogle Scholar

  • 9.

    Alexandrescu S, Tatevian N, Olutoye O, Brown RE. Persistent hyperinsulinemic hypoglycemia of infancy: constitutive activation of the mTOR pathway with associated exocrine-islet transdif ferentiation and therapeutic implications. Int J Clin Exp Pathol 2010;3:691–705.Google Scholar

  • 10.

    Kwon G, Marshall CA, Pappan KL, Remedi MS, McDaniel ML. Signaling elements involved in the metabolic regulation of mTOR by nutrients, incretins, and growth factors in islets. Diabetes 2004;53 (Suppl 3):S225–32.Google Scholar

  • 11.

    Kulke MH, Bergsland EK, Yao JC. Glycemic control in patients with insulinoma treated with everolimus. N Engl J Med 2009;360:195–7.Web of ScienceGoogle Scholar

  • 12.

    Bourcier ME, Sherrod A, DiGuardo M, Vinik AI. Successful control of intractable hypoglycemia using rapamycin in an 86-year-old man with a pancreatic insulin-secreting islet cell tumor and metastases. J Clin Endocrinol Metab 2009;94;3157–62.Web of ScienceCrossrefGoogle Scholar

  • 13.

    Mohamed Z, Arya VB, Hussain K. Hyperinsulinaemic hypoglycaemia: genetic mechanisms, diagnosis and management. J Clin Res Pediatr Endocrinol 2012;4:169–81.CrossrefPubMedGoogle Scholar

  • 14.

    Pratt EB, Yan FF, Gay JW, Stanley CA, Shyng SL. Sulfonylurea receptor 1 mutations that cause opposite insulin secretion defects with chemical chaperone exposure. Journal of Biological Chemistry. 2009;284:7951–9.Web of ScienceGoogle Scholar

  • 15.

    Le Bacquer O, Queniat G, Gmyr V, Kerr-Conte J, Lefebvre B, et al. mTORC1 and mTORC2 regulate insulin secretion through Akt in INS-1 cells. J Endocrinol 2013;216:21–9.Google Scholar

  • 16.

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

  • 17.

    Leibiger IB, Leibiger B, Moede T, Berggren PO. Exocytosis of insulin promotes insulin gene transcription via the insulin receptor/PI-3 kinase/p70 s6 kinase and CaM kinase pathways. Mol Cell 1998;1:933–8.Google Scholar

  • 18.

    Barlow AD, Xie J, Moore CE, Campbell SC, Shaw JA, et al. Rapamycin toxicity in MIN6 cells and rat and human islets is mediated by the inhibition of mTOR complex 2 (mTORC2). Diabetologia 2012;55:1355–65.Web of ScienceGoogle Scholar

  • 19.

    Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 2006;22:159–68.CrossrefGoogle Scholar

  • 20.

    Aspinwall CA, Lakey JR, Kennedy RT. Insulin-stimulated insulin secretion in single pancreatic beta cells. J Biol Chem 1999;274:6360–5.Google Scholar

  • 21.

    Yang SB, Lee HY, Young DM, Tien AC, Rowson-Baldwin A, et al. Rapamycin induces glucose intolerance in mice by reducing islet mass, insulin content, and insulin sensitivity. J Mol Med (Berl) 2012;90:575–85.Web of ScienceCrossrefPubMedGoogle Scholar

  • 22.

    Sankhala K, Mita A, Kelly K, Mahalingam D, Giles F, et al. The emerging safety profile of mTOR inhibitors, a novel class of anticancer agents. Target Oncol 2009;4:135–42.Web of ScienceCrossrefPubMedGoogle Scholar

  • 23.

    Thomas NJ, Brooke AM, Besser GM. Long-term maintenance of normoglycaemia using everolimus in a patient with disseminated insulinoma and severe hypoglycaemia. Clin Endocrinol (Oxf) 2013;78:799–800.Web of ScienceCrossrefGoogle Scholar

About the article

Corresponding author: Khalid Hussain, Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, London, UK, Phone: +44-(0)20-7-905-2128, Fax: +44-(0)20-7-404-6191, E-mail:

aESPE membership: Khalid Hussain


Received: 2014-08-31

Accepted: 2014-10-22

Published Online: 2014-12-17

Published in Print: 2015-05-01


Citation Information: Journal of Pediatric Endocrinology and Metabolism, ISSN (Online) 2191-0251, ISSN (Print) 0334-018X, DOI: https://doi.org/10.1515/jpem-2014-0371.

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