Congenital hyperinsulinism (CHI) is the commonest cause of recurrent and persistent hypoglycaemia in infants. Histologically there are two distinct types: focal and diffuse. The medical therapy for diffuse CHI involves diazoxide, glucagon and octreotide. The patients who are unresponsive to medical therapy require a near total pancreatectomy. However, this often fails to provide the best outcome as some patients continue to have recurrent hypoglycaemia whilst others develop diabetes mellitus in the long term. This study aimed to understand the gene expression pattern in the pancreatic tissues of the patients with diffuse CHI so as to identify novel mechanism(s) and therapeutic options. Gene expression microarray using RNA extracted from fresh frozen pancreatic tissue samples (obtained from children who underwent pancreatectomy) revealed significant overexpression of mammalian target of rapamycin (mTOR) and insulin-like growth factors in the diffuse CHI patients in comparison with normal controls. Immunostaining suggested an activation of mTOR pathway (which regulates cellular proliferation) in diffuse CHI and transdifferentiation of exocrine pancreatic elements into insulin producing cells, contributing to β-cell hyperplasia. Further clinical study on the role of the mTOR inhibitor sirolimus in patients with medically unresponsive diffuse CHI (who would have required pancreatectomy otherwise) revealed a good glycaemic response to sirolimus and the infants were able to come off intravenous fluids, glucagon and octreotide infusions, thereby preventing the need for a major surgery. Subsequent follow up to 12 months revealed that the patients were normoglycaemic on sirolimus therapy without any major side effects. Hence treatment with mTOR inhibitors offers an alternative therapeutic option for the patients with severe forms of diffuse CHI. Further studies involving larger group of patients to assess the long term safety and efficacy of mTOR inhibitors in the management of diffuse CHI are needed.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:626703 |
| Date | January 2014 |
| Creators | Karuppanan Senniappan, S. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1421065/ |
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