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• Re: Treatment of the hyperinsulinaemic hypoglycaemia unresponsive to diazoxide and octreotide: sirolimus should be considered
  Arunabha Ghosh
  Published on: 20 April 2016
• Treatment of the hyperinsulinaemic hypoglycaemia unresponsive to diazoxide and octreotide: sirolimus should be considered
  Federico Marchetti
  Published on: 18 January 2016

• Published on: 20 April 2016

  Re: Treatment of the hyperinsulinaemic hypoglycaemia unresponsive to diazoxide and octreotide: sirolimus should be considered

  • Arunabha Ghosh
  • Other Contributors:
    • Indraneel Banerjee and Andrew Morris

  We agree that sirolimus may help children with Congenital Hyperinsulinism who do not respond to diazoxide or octreotide. Sirolimus is, however, unlicensed, with little long term experience, and the mechanism by which it reduces hypoglycaemia remains speculative. As sirolimus is an immunosuppressant, its use in young infants has to be carefully monitored in specialist centres under strict protocols. We are, therefore, re...

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  We agree that sirolimus may help children with Congenital Hyperinsulinism who do not respond to diazoxide or octreotide. Sirolimus is, however, unlicensed, with little long term experience, and the mechanism by which it reduces hypoglycaemia remains speculative. As sirolimus is an immunosuppressant, its use in young infants has to be carefully monitored in specialist centres under strict protocols. We are, therefore, reluctant to advocate the routine use of sirolimus in Congenital Hyperinsulinism until more evidence has accumulated.

  Arunabha Ghosh Indraneel Banerjee Andrew Morris

  Conflict of Interest:

  None declared

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  Conflict of Interest:
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• Published on: 18 January 2016

  Treatment of the hyperinsulinaemic hypoglycaemia unresponsive to diazoxide and octreotide: sirolimus should be considered

  • Federico Marchetti, Director
  • Other Contributors:
    • Vanna Graziani

  Dear Editor

  In their excellent review on the hypoglycaemia in childhood the authors suggest that for the management of the hyperinsulinaemic hypoglycaemia (HH) diazoxide is the first-line therapy (1). Patients who do not respond to diazoxide may respond to the octreotide but the efficacy of this is often limited by tachyphylaxis. Mutations in ABCC8 and KCNJ11 are associated with severe HH that is unresponsive to...

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  Dear Editor

  In their excellent review on the hypoglycaemia in childhood the authors suggest that for the management of the hyperinsulinaemic hypoglycaemia (HH) diazoxide is the first-line therapy (1). Patients who do not respond to diazoxide may respond to the octreotide but the efficacy of this is often limited by tachyphylaxis. Mutations in ABCC8 and KCNJ11 are associated with severe HH that is unresponsive to medical treatment with diazoxide and octreotide. The treatment option for patients with medically unresponsive forms of diffuse HH is a subtotal pancreatectomy, but some patients who have undergone surgery continue to have recurrent hypoglycemia, whereas diabetes mellitus and exocrine pancreatic insufficiency develop in others (1).

  The authors of the review make no mention of the possible use of the mammalian target of rapamycin (mTOR) inhibitor sirolimus recently reported to be effective and safe for the severe, diffuse form of HH that had been unresponsive to maximal doses of diazoxide and octreotide (2-5). No major adverse reactions were observed during the 1-year follow-up period in the first 4 cases described (2). This finding is reinforced by the latest cases report of others infant (3,4) and older children (5).

  The suggested method of action of sirolimus includes the reduction of beta-cell proliferation, inhibition of insulin production, and induced peripheral insulin resistance (4). The sirolimus-sensitive mTORC1 pathway is present in the exocrine pancreas and the relatively sirolimus-resistant IGF1R/mTORC2/Akt pathway is overexpressed in the beta-cells, thereby suggesting that sirolimus is effective in treating diffuse HH by reducing the transdifferentiation of exocrine elements to insulin-producing cells (5).

  Even if further studies are needed, primarily to identify long-term sequelae and side effects, sirolimus appears to be a promising therapeutic option to treat children with severe HH unresponsive to diazoxide and octreotide.

  Federico Marchetti, Vanna Graziani

  Department of Paediatrics, S. Maria delle Croci Hospital, Ravenna, Italy. 48121 Ravenna, Italy e-mail: fedemarche@tin.it

  References

  1. Ghosh A, Banerjee I, Morris AAM. Recognition, assessment and management of hypoglycaemia in childhood Arch Dis Child Published Online First: 30 December 2015 doi:10.1136/archdischild-2015-308337

  2. Senniappan S, Brown RE, Hussain K. Sirolimus in severe hyperinsulinemic hypoglycemia. N Engl J Med 2014;370(25):2448-9.

  3. Abraham MB, Shetty VB, Price G, et al. Efficacy and safety of sirolimus in a neonate with persistent hypoglycaemia following near-total pancreatectomy for hyperinsulinaemic hypoglycaemia. J Pediatr Endocrinol Metab 2015;28(11-12):1391-8

  4. Meder U, Bokodi G, Balogh L, et al. Severe hyperinsulinemic hypoglycemia in a neonate: response to sirolimus therapy. Pediatrics. 2015;136(5):e1369-72

  5. Minute M, Patti G, Tornese G, Faleschini E, Zuiani C, Ventura A. Sirolimus therapy in congenital hyperinsulinism: a successful experience beyond infancy. Pediatrics. 2015;136(5):e1373-6

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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