Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.740319
Title: Islet pathobiology in congenital hyperinsulinism in infancy
Author: Han, Bing
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2017
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Abstract:
Congenital Hyperinsulinism of Infancy (CHI) is a potentially lethal condition caused by excessive, unregulated insulin release from pancreatic β-cells. It is a complex clinical condition and the current understanding of this disease is still not completed. In this thesis, we investigated the disease islet pathobiology from 4 main perspectives; Using nucleomegaly as a novel diagnostic marker; Identifying the mosaic of immature delta-cells in atypical CHI (CHI-A); Assessing the insulin secretory profile at the ultrastructural level; Investigating endocrine cell turnover and the driving force/mechanism behind it. By quantifying the enlarged nuclei in the endocrine pancreas of patients with CHI, we discovered that the increased incidence of nucleomegaly is pathognomic for diffuse CHI (CHI-D). This finding potentially set a novel diagnostic hallmark for intraoperative diagnoses. A characteristic of CHI-A is a combination of active and quiescent islets. The maintained expression of NKX2.2 in somatostatin positive cells suggests an immature delta-cells phenotype in quiescent islets and this is potentially contributing to the pathobiology of CHI-A. By examining the insulin secretory profile at the ultrastructural level, as well as investigating the crucial exocytosis-related genes from both RNA and protein levels, our data suggested a greater secretory capacity in β-cells from focal CHI lesion compared to CHI-D. Despite seeing a maintained potential for proliferative (Ki67) in CHI samples, there was no significant increase in apoptosis rates (cleaved caspase-3) and whole cell mass compared to control samples. Alterations in the cellular localisation of cell cycle regulators are a plausible explanation for these abnormal disease dynamics. These data expanded our knowledge on understanding CHI, and provided us new clues for the phenotypical alterations and pathobiological mechanisms in patients with this disease. Meanwhile, they also provided new insights in the future management of CHI.
Supervisor: Dunne, Mark ; Cosgrove, Karen Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.740319  DOI: Not available
Keywords: Islet Pathobiology ; Congenital Hyperinsulinism
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