Background: Congenital Hyperinsulinism in Infancy (CHI) is characterised by inappropriate insulin release from islet β-cells. 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 the inappropriate expression of foetal-like transcription factors and enhanced cell proliferation. We hypothesised that islet cell differentiation and neogenesis would also be enhanced in disease.
Method: Pancreatic tissue was obtained from 26 patients with CHI following surgery. Eight-five per cent of patients carried ABCC8 gene defects and 15% carried mutations in KCNJ11. Twelve patients had diffuse-CHI (age: 213 months) and 14 patients had focal disease (age: 110 months). Tissue samples were fixed and processed for use in immunohistochemical analysis. Quantification of both single insulin-expressing cells within ductal epithelia (a marker of differentiation) and islet cell clusters associated with ducts (neogenesis) was carried out 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 (19.4±4 cells/cm2 n=12 vs. 4.9±2.9 cells/cm2 n=8) and islet neogenesis (15.2±3.8 events/cm2 n=12 vs. 0.9±0.3 events/cm2 n=8) were enhanced in diffuse CHI tissue in comparison to age-matched controls. To investigate whether these findings were related to gene defects in ACCB8/KNCJ11 or as a direct consequence of hyperinsulinism, we also analysed focal CHI tissue. In both lesions (somatic less of maternal imprinting, n=11) and non-focal domains (unaffected by ACCB8/KNCJ11 defects, n=14), no differences were found in the incidence of either cell differentiation (5.6±1.6 vs. 5.8±1.3 cells/cm2) or neogenesis (1.05±0.86 vs. 1.4±0.6 events/cm2). Furthermore, these values were not significantly different to control data.
Conclusion: Diffuse CHI is associated with a 17-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 are likely to be responsible for inappropriate increases in new islet cell formation in CHI.
23 - 25 Nov 2016
British Society for Paediatric Endocrinology and Diabetes