ESPE Abstracts (2015) 84 FC9.3

Beta cell disorders

Failure to Terminate Cell Proliferation Contributes to the Pathobiology of Congenital Hyperinsulinism in Infancy

Bing Hana, Zainab Mohammada,b, Lindsey Rigbyb, Ross Craigieb, Mars Skaeb, Raja Padidelab, Edmund Cheesmanb, Karen Cosgrovea, Indi Banerjeeb & Mark Dunnea


aUniversity of Manchester, Manchester, UK; bRoyal Manchester Children’s Hospital, Manchester, UK

Background: Diffuse congenital hyperinsulinism in infancy (CHI-D) mainly arises from mutations in KATP channel genes. In addition, there are also several reports of increased cell proliferation in CHI-D. We hypothesised that the higher rates of proliferation in CHI-D are as a consequence of failure to terminate proliferation in the neonatal period.

Objective and hypotheses: To test this we examined the proliferative index (PI) of CHI-D tissue and compared with focal CHI (CHI-F), which is associated with loss of cell cycle repression in β-cells within the focal domain.

Methods: PI was assessed by Ki67 or phosphohistone-H3 immunohistochemistry using samples of whole pancreas from patients positive for mutations in ABCC8 with CHI-D (n=10) or CHI-F (n=6) and foetal/neonatal (n=12), juvenile and adult control tissues (n=5). Analysis of digitized images was used to calculate the average PI (mean±S.E.M.) from 45 000 cells/tissue section.

Results: In controls there was an inverse correlation between the PI and age. At 10 weeks post-conception more than 27% of the total cells were Ki67+. At term the PI was ~7%, which declined sharply to 2.6±0.1% (n=3) at 8 weeks and 0.5% from 6 to 10 months. From 8 years until adulthood, PI was 0.1±0.03% (n=5). In CHI tissue – including non-lesion domains of CHI-F, there was a similar inverse correlation with age, but the rates of decline were markedly decreased. Thus, up to 8 weeks following birth 8±0.4% (n=5) of cells were Ki67+; 4±0.4% (n=3) up to 7 months and 3% up to 10 months of age. Importantly, there was little overall difference in the PI between CHI-F (non-lesion) and CHI-D; 4±0.4 vs 5±1 respectively.

Conclusion: We suggest that enhanced rates of proliferation in CHI arise from failure to terminate proliferation by a mechanism that is not directly attributable to the genetic cause of disease.

Funding: National Institute for Health Research.

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