BSPED2013 Oral Communications Oral Communications 3 (6 abstracts)
Successful treatment of four patients with severe hyperinsulinaemic hypoglycaemia with a novel therapy using mTOR inhibitor
Senthil Senniappan 1 , Sanda Alexandrescu 3 , Nina Tatevian 3 , Pratik Shah 1 , Ved Arya 1 , Sarah Flanagan 2 , Sian Ellard 2 , Dyanne Rampling 1 , Michael Ashworth 1 , Robert Brown 3 & Khalid Hussain 1
1Great Ormond Street Hospital, London, UK; 2University of Exeter Medical School, Exeter, UK; 3University of Texas Medical School, Houston, Texas, USA.
Introduction: Hyperinsulinaemic hypoglycaemia (HH) is the most common cause of severe and persistent hypoglycaemia in neonates. The treatment of diazoxide unresponsive HH involves pancreatectomy. Mammalian target of rapamycin (mTOR) is a protein kinase that regulates cellular proliferation. We aimed to evaluate the efficacy of mTOR inhibitor Sirolimus and assess mTOR expression in the pancreas of infants with severe HH.
Methods: Four infants with severe, persistent HH were recruited. Treatment with maximal doses of diazoxide and octreotide (35 μg/kg per day) was unsuccessful in all infants who required high concentrations of intravenous dextrose and intravenous glucagon to maintain normoglycaemia. We commenced treatment with Sirolimus and the dose was gradually increased based on serum concentration. Morphoproteomic analysis was performed on the tissue from two patients with diffuse HH to understand the role of mTOR in the pathogenesis of HH.
Results: Genetic testing suggested diffuse disease in three infants due to homozygous or maternally inherited heterozygous ABCC8 mutations, but no mutation was identified in the fourth case. Following treatment with Sirolimus, all patients showed good glycaemic response over the following weeks. Intravenous dextrose fluids and glucagon were discontinued and oral feeds were established. Hematoxylin–eosin and insulin-staining showed β-cell hyperplasia in the exocrine pancreas. Overexpression of (p)-mTOR on the plasmalemmal compartment consistent with mTORC1 was noted in acinar elements.
Conclusion: We report, for the first time, the successful use of mTOR inhibitor Sirolimus in four infants with a severe form of diffuse HH. Our preliminary data suggest that mTOR inhibitors are a novel therapeutic option, individually or as adjuvant, for the severe forms of HH thereby averting the need for surgery and its associated complications. Morphoproteomic and histopathologic findings favour acinar-islet transdifferentiation as a key process and suggests a role for a constitutively activated and overexpressed mTORC1 pathway in the pathogenesis.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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