Background: Congenital Hyperinsulinism in Infancy (CHI) is characterised by inappropriate insulin release. We currently attribute hypoglycaemia to β-cell dysfunction because of defects in the ion channel genes ABCC8 or KCNJ11. However, the CHI pancreas is also associated with inappropriate expression of foetal-like transcription factors and enhanced cell proliferation.
Hypothesis: As the CHI pancreas bears similarities to the foetal pancreas, we hypothesised that stem cell differentiation and neogenesis are enhanced in CHI.
Method: Tissue was obtained from 25 CHI patients positive for ABCC8 or KCNJ11 gene defects following surgery. Twelve patients had diffuse-CHI (age at surgery 213 months) and 13 patients had focal disease (110 months). Tissue samples were fixed and processed for immunohistochemical analysis. Quantification of both single insulin-expressing cells within ductal epithelia (differentiation) and islet cell clusters associated with ducts (neogenesis) was performed and normalised to the area of the tissue section. Control data was obtained from age-match pancreata (n=8, 112 months).
Results: Both islet cell differentiation (13.6±3.4 cells/μm2 n=12 vs 4.5±2.9 cells/μm2 n=8) and islet neogenesis (10.2±2.3 events/μm2 n=12 vs 1.4±0.6 events/μm2 n=8) were enhanced in diffuse-CHI tissue in comparison to controls. To investigate whether these findings were related to ACCB8/KNCJ11 defects or as a direct consequence of hyperinsulinism, we also analysed focal-CHI tissue. No differences were found in the incidence of either cell differentiation (3.9±2 vs 5.4±1.6 cells/μm2) or neogenesis (1.9±1.5 vs 1.0±0.4 events/μm2) in lesion (n=6) and non-lesion domains (n=12).
Conclusion: Diffuse CHI is associated with a 7-fold increase in islet cell neogenesis and a 4-fold increase in the incidence of islet cell differentiation from duct progenitors. As neither is enhanced in focal-CHI, this suggests that ABBC8/KCNJ11 defects in progenitor cells and not paracrine effects of insulin hypersecretion are likely to be responsible for inappropriately increased new islet cell formation in diffuse CHI.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology