Altered Phenotype of beta-Cells and Other Pancreatic Cell Lineages in Patients With Diffuse Congenital Hyperinsulinism in Infancy Caused by Mutations in the ATP-Sensitive K-Channel

Diffuse congenital hyperinsulinism in infancy (CHI-D) arises from mutations inactivating the K-ATP channel; however, the phenotype is difficult to explain from electrophysiology alone. Here we studied wider abnormalities in the beta-cell and other pancreatic lineages. Islets were disorganized in CHI-D compared with controls. PAX4 and ARX expression was decreased. A tendency toward increased NKX2.2 expression was consistent with its detection in two-thirds of CHI-D delta-cell nuclei, similar to the fetal pancreas, and implied immature delta-cell function. CHI-D delta-cells also comprised 10% of cells displaying nucleomegaly. In CHI-D, increased proliferation was most elevated in duct (5- to 11-fold) and acinar (7- to 47-fold) lineages. Increased beta-cell proliferation observed in some cases was offset by an increase in apoptosis; this is in keeping with no difference in INSULIN expression or surface area stained for insulin between CHI-D and control pancreas. However, nuclear localization of CDK6 and P27 was markedly enhanced in CHI-D beta-cells compared with cytoplasmic localization in control cells. These combined data support normal beta-cell mass in CHI-D, but with G(1)/S molecules positioned in favor of cell cycle progression. New molecular abnormalities in delta-cells and marked proliferative increases in other pancreatic lineages indicate CHI-D is not solely a beta-cell disorder.