ISLET ORGANISATION AND PROLIFERATION IN CONGENITAL HYPERINSULINISM

Abstract

Pancreatic Islet cell development and maintenance is a complex process, which remains poorly understood. This project explores normal islet cellular morphology and proliferation rate through the comparison of pancreatic tissue obtained from age matched control subjects and patients with a rare disease of the endocrine pancreas, congenital Hyperinsulinism (CHI). Congenital hyperinsulinism of infancy (CHI) mainly arises from loss-of-function mutations in the KATP channel genes KCNJ11 or ABCC8 which code for the K channel subunits. As a consequence, dysregulated insulin release causes profound hypoglycaemia in neonates that could lead to brain injury and have an impact on neurodevelopment. Three main forms; Focal (F-CHI), Atypical (A-CHI) and Diffuse (D-CHI) disease are recognised. This is a histological comparative study to type the differences in proliferative index, apoptotic index and changes in islet cell composition of alpha -cell and β-cells in CHI disease, particularly of the F-CHI lesion and non-lesion pancreatic tissues to age-matched control pancreata and Insulinoma tissues.All CHI tissue was found to have a higher Ki67 index than Insulinoma and age related control tissue. Interestingly, F-CHI retained enhanced cellular proliferation both inside and outside the F-CHI lesion with a more gradual age related decline. In addition, alpha-cell mass was found to be decreased inside the lesion compared to non-lesion tissue and controls. Expression of cell cycle regulator CDK6 was more pronounced in CHI tissue islets in comparison to controls. Apoptotic rate in the CHI disease in comparison to controls was relatively low across all samples. In contrast, Insulinoma tissue retained higher apoptotic rates. The increased proliferation in F-CHI cannot be solely attributed to maternal 11p15 deletion as this is confined to the lesion. The proliferation is likely to be altered as a result of the CHI disease disrupting important cell cycle regulators, autocrine and paracrine signals that may be influencing the cell cycle.

Date of Award	1 Aug 2017
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Mark Dunne (Supervisor), Karen Cosgrove (Supervisor) & Indraneel Banerjee (Supervisor)