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Islet Pathobiology in Congenital Hyperinsulinism in Infancy

Han, Bing

[Thesis]. Manchester, UK: The University of Manchester; 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 δ-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 δ-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.

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3-D reconstruction model for Figure 3.2 can be found as a supplementary material at American Journal of Clinical Pathology online. Published paper information: Han B, Newbould M, Batra G, Cheesman E, Craigie RJ, Mohamed Z, et al. Enhanced Islet Cell Nucleomegaly Defines Diffuse Congenital Hyperinsulinism in Infancy but Not Other Forms of the Disease. Am J Clin Pathol. 2016;145(6):757–68. DOI: 10.1093/AJCP/AQW075.