Background: Congenital hyperinsulinism in infancy (CHI) is associated with inappropriate insulin release from β-cells. This is causally linked to defects in the ion channel genes ABCC8 and KCNJ11 regulating insulin, but little is known about the metabolic support for sustained insulin exocytosis.
Objective and hypotheses: We hypothesised that inappropriate insulin release in CHI would require sustained ATP generation by enhanced mitochondrial activity. To test this we have quantified total mitochondrial volumes in individual islet β-cells and in glucagon-secreting α-cells from in CHI tissue and compared these with control samples.
Method: Pancreatic tissue was obtained from five patients with CHI following surgery. All patients were positive for ABCC8 gene defects. Tissue samples were fixed and embedded for use in serial block face-scanning electron microscopy. This was used to generate ultrastructural images of islet cells from serial sections of tissue 100 nm thick. From these images islet cells were digitally reconstructed in 3 dimensions for analysis of mitochondrial volume. Mitochondrial density was calculated by expressing mitochondrial volume as a proportion of total cytoplasmic volume for an individual cell.
Results: The profiles of mitochondria in β-cells demonstrated higher order organisation and complexity of structures and networks in contrast to those in α-cells. In α-cells the mitochondrial volume was approximately 2% of the cytoplasmic volume, with no difference between CHI and controls; 2.7±0.3% (n=3) vs. 3±0.4 (n=3), respectively. However, in contrast in β-cells there was a 2.5-fold increase in the mitochondrial density in CHI tissue compared to controls; 7.3±0.3% (n=6) and 3±0.2% (n=3), suggesting increased mitochondrial activity sustaining insulin hypersecretion.
Conclusion: In CHI β-cells we found greater mitochondrial density implying that mitochondrial expansion associates with the pathobiology of islet β-cells providing energy capacity to sustain uncontrolled insulin release.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology