Sirolimus therapy in infants with severe hyperinsulinemic hypoglycemia.

Hyperinsulinemic hypoglycemia is the most common cause of severe, persistent neonatal hypoglycemia. The treatment of hyperinsulinemic hypoglycemia that is unresponsive to diazoxide is subtotal pancreatectomy. We examined the effectiveness of the mammalian target of rapamycin (mTOR) inhibitor sirolimus in four infants with severe hyperinsulinemic hypoglycemia that had been unresponsive to maximal doses of diazoxide (20 mg per kilogram of body weight per day) and octreotide (35 μg per kilogram per day). All the patients had a clear glycemic response to sirolimus, although one patient required a small dose of octreotide to maintain normoglycemia. There were no major adverse events during 1 year of follow-up.

[1]  G. Besser,et al.  Long‐term maintenance of normoglycaemia using everolimus in a patient with disseminated insulinoma and severe hypoglycaemia , 2013, Clinical endocrinology.

[2]  A. Green,et al.  Next-generation sequencing reveals deep intronic cryptic ABCC8 and HADH splicing founder mutations causing hyperinsulinism by pseudoexon activation. , 2013, American journal of human genetics.

[3]  K. Hussain,et al.  Hyperinsulinaemic Hypoglycaemia: Genetic Mechanisms, Diagnosis and Management , 2012, Journal of clinical research in pediatric endocrinology.

[4]  C. Stanley,et al.  Novel presentations of congenital hyperinsulinism due to mutations in the MODY genes: HNF1A and HNF4A. , 2012, The Journal of clinical endocrinology and metabolism.

[5]  S. Ellard,et al.  Partial ABCC8 gene deletion mutations causing diazoxide‐unresponsive hyperinsulinaemic hypoglycaemia , 2012, Pediatric diabetes.

[6]  F. Brunelle,et al.  Glucose Metabolism in 105 Children and Adolescents After Pancreatectomy for Congenital Hyperinsulinism , 2012, Diabetes Care.

[7]  E. D. de Vries,et al.  Everolimus induces rapid plasma glucose normalization in insulinoma patients by effects on tumor as well as normal tissues. , 2011, The oncologist.

[8]  N. Verhoeven,et al.  Metabolic Profiles in Children During Fasting , 2011, Pediatrics.

[9]  Robert E. Brown,et al.  Persistent hyperinsulinemic hypoglycemia of infancy: constitutive activation of the mTOR pathway with associated exocrine-islet transdifferentiation and therapeutic implications. , 2010, International journal of clinical and experimental pathology.

[10]  Y. Deshaies,et al.  Chronic Rapamycin Treatment Causes Glucose Intolerance and Hyperlipidemia by Upregulating Hepatic Gluconeogenesis and Impairing Lipid Deposition in Adipose Tissue , 2010, Diabetes.

[11]  E. Baudin,et al.  Daily Oral Everolimus Activity in Patients with Metastatic Pancreatic Neuroendocrine Tumors after Failure of Cytotoxic Chemotherapy: A Phase II Trial , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  A. Vinik,et al.  Successful control of intractable hypoglycemia using rapamycin in an 86-year-old man with a pancreatic insulin-secreting islet cell tumor and metastases. , 2009, The Journal of clinical endocrinology and metabolism.

[13]  F. Giles,et al.  The emerging safety profile of mTOR inhibitors, a novel class of anticancer agents , 2009, Targeted Oncology.

[14]  Christophe Magnan,et al.  mTOR Inhibition by Rapamycin Prevents β-Cell Adaptation to Hyperglycemia and Exacerbates the Metabolic State in Type 2 Diabetes , 2008, Diabetes.

[15]  N. Hay,et al.  The two TORCs and Akt. , 2007, Developmental cell.

[16]  G. Korbutt,et al.  The impact of the mTOR inhibitor sirolimus on the proliferation and function of pancreatic islets and ductal cells , 2006, Diabetologia.

[17]  S. di Paolo,et al.  Chronic inhibition of mammalian target of rapamycin signaling downregulates insulin receptor substrates 1 and 2 and AKT activation: A crossroad between cancer and diabetes? , 2006, Journal of the American Society of Nephrology : JASN.

[18]  D. Sabatini,et al.  Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. , 2006, Molecular cell.

[19]  M. Mcdaniel,et al.  Signaling elements involved in the metabolic regulation of mTOR by nutrients, incretins, and growth factors in islets. , 2004, Diabetes.

[20]  Michael G. Roper,et al.  Roles of Insulin Receptor Substrate-1, Phosphatidylinositol 3-Kinase, and Release of Intracellular Ca2+ Stores in Insulin-stimulated Insulin Secretion in β-Cells* , 2000, The Journal of Biological Chemistry.

[21]  C. Sempoux,et al.  Persistent hyperinsulinaemic hypoglycaemia of infancy: a heterogeneous syndrome unrelated to nesidioblastosis , 2000, Archives of disease in childhood. Fetal and neonatal edition.

[22]  Robert T. Kennedy,et al.  Insulin-stimulated Insulin Secretion in Single Pancreatic Beta Cells* , 1999, The Journal of Biological Chemistry.

[23]  P. Berggren,et al.  Exocytosis of insulin promotes insulin gene transcription via the insulin receptor/PI-3 kinase/p70 s6 kinase and CaM kinase pathways. , 1998, Molecular cell.

[24]  A. Rosenberg,et al.  Glycemic Control in Patients with Insulinoma Treated with Everolimus , 2009 .

[25]  C. Stanley,et al.  Molecular and immunohistochemical analyses of the focal form of congenital hyperinsulinism , 2006, Modern Pathology.