TY - JOUR
T1 - mTOR inhibitors for the treatment of severe congenital hyperinsulinism
T2 - perspectives on limited therapeutic success
AU - Szymanowski, Marie
AU - Salomon Estebanez, Maria
AU - Padidela, Raja
AU - Han, Bing
AU - Mosinska, Karolina
AU - Stevens, Adam
AU - Damaj, Lena
AU - Pihan-Le Bars, Florence
AU - Lascouts, Emilie
AU - Reynaud, Rachel
AU - Ferreira, Catherine
AU - Bansept, Claire
AU - de Lonlay, Pascale
AU - Saint-Martin, Cécile
AU - Dunne, Mark
AU - Banerjee, Indi
AU - Arnoux, Jean-Baptiste
PY - 2016
Y1 - 2016
N2 - CONTEXT: Congenital hyperinsulinism (CHI) is the commonest cause of persistent hypoglycemia in neonates and infants. In medically unresponsive CHI, subtotal pancreatectomy is performed to achieve euglycaemia with consequent diabetes in later life. Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor has been reported to obviate the need for pancreatectomy, but experience is limited.OBJECTIVE: We have investigated the efficacy and adverse effect profile of mTOR inhibitors in the treatment of severe CHI.DESIGN, SETTING, AND PATIENTS: An observational review of ten severe CHI patients treated with mTOR inhibitors, in France and the United-Kingdom, with the intention of achieving glycaemic control without pancreatectomy. Safety information was recorded.MAIN OUTCOME MEASURE(S): We examined if mTOR inhibitors achieved glycemic control, fasting tolerance and weaning of supportive medical therapy.RESULTS: mTOR inhibition achieved euglycaemia, fasting tolerance and reduced medical therapy in only 3 (30%) patients. Triglyceride levels were elevated in 5 (50%) patients. One child required blood transfusion for anemia, four had stomatitis, two had sepsis, one developed varicella zoster, and two patients developed gut dysmotility in association with exocrine pancreatic insufficiency. In silico analysis of transcriptome arrays from CHI patients revealed no significant association between mTOR signaling and disease. Pancreatic tissue from two patients who did not respond to sirolimus showed no reduction in cell proliferation, further suggesting that mTOR signaling did not downregulate proliferation in the CHI pancreas.CONCLUSION: mTOR inhibitor treatment is associated with very limited success and must be used with caution in children with severe CHI.
AB - CONTEXT: Congenital hyperinsulinism (CHI) is the commonest cause of persistent hypoglycemia in neonates and infants. In medically unresponsive CHI, subtotal pancreatectomy is performed to achieve euglycaemia with consequent diabetes in later life. Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor has been reported to obviate the need for pancreatectomy, but experience is limited.OBJECTIVE: We have investigated the efficacy and adverse effect profile of mTOR inhibitors in the treatment of severe CHI.DESIGN, SETTING, AND PATIENTS: An observational review of ten severe CHI patients treated with mTOR inhibitors, in France and the United-Kingdom, with the intention of achieving glycaemic control without pancreatectomy. Safety information was recorded.MAIN OUTCOME MEASURE(S): We examined if mTOR inhibitors achieved glycemic control, fasting tolerance and weaning of supportive medical therapy.RESULTS: mTOR inhibition achieved euglycaemia, fasting tolerance and reduced medical therapy in only 3 (30%) patients. Triglyceride levels were elevated in 5 (50%) patients. One child required blood transfusion for anemia, four had stomatitis, two had sepsis, one developed varicella zoster, and two patients developed gut dysmotility in association with exocrine pancreatic insufficiency. In silico analysis of transcriptome arrays from CHI patients revealed no significant association between mTOR signaling and disease. Pancreatic tissue from two patients who did not respond to sirolimus showed no reduction in cell proliferation, further suggesting that mTOR signaling did not downregulate proliferation in the CHI pancreas.CONCLUSION: mTOR inhibitor treatment is associated with very limited success and must be used with caution in children with severe CHI.
U2 - 10.1210/jc.2016-2711
DO - 10.1210/jc.2016-2711
M3 - Article
C2 - 27691052
SN - 0021-972X
JO - The Journal of Clinical Endocrinology and Metabolism
JF - The Journal of Clinical Endocrinology and Metabolism
ER -
