Abstract
Objectives: To quantify islet cell nucleomegaly in controls and tissues obtained from patients with congenital hyperinsulinism in infancy (CHI) and to examine the association of nucleomegaly with proliferation.Methods: High-content analysis of histologic sections and serial block-face scanning electron microscopy were used to quantify nucleomegaly.Results: Enlarged islet cell nuclear areas were 4.3-fold larger than unaffected nuclei, and the mean nuclear volume increased to approximately threefold. Nucleomegaly was a normal feature of pediatric islets and detected in the normal regions of the pancreas from patients with focal CHI. The incidence of nucleomegaly was highest in diffuse CHI (CHI-D), with more than 45% of islets containing two or more affected cells. While in CHI-D nucleomegaly was negatively correlated with cell proliferation, in all other cases, there was a positive correlation.Conclusions: Increased incidence of nucleomegaly is pathognomonic for CHI-D, but these cells are nonproliferative, suggesting a novel role in the pathobiology of this condition.
Highlights
congenital hyperinsulinism in infancy (CHI) is broadly characterized by the inappropriate release of insulin from pancreatic b cells for the level of glycemia and is associated with hypoglycemia-induced brain injury and adverse long-term neurologic outcomes in more than one-third of cases.[1,2,3]
The most common origins of drug-unresponsive disease are due to inactivating mutations in either the ABCC8 or KCNJ11 genes
To quantify the nuclear volume of islet cells, we digitally reconstructed the nuclei of cells from transmission electron microscopy (TEM) images of the tissue block following 100-nm serial sectioning
Summary
To quantify islet cell nucleomegaly in controls and tissues obtained from patients with congenital hyperinsulinism in infancy (CHI) and to examine the association of nucleomegaly with proliferation
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