ESPE2015 Free Communications Beta cell disorders (6 abstracts)
Failure to Terminate Cell Proliferation Contributes to the Pathobiology of Congenital Hyperinsulinism in Infancy
Bing Han a , Zainab Mohammad a, , Lindsey Rigby b , Ross Craigie b , Mars Skae b , Raja Padidela b , Edmund Cheesman b , Karen Cosgrove a , Indi Banerjee b & Mark Dunne a
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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