Altered phenotype of β-cells and other pancreatic cell lineages in patients with diffuse congenital hyperinsulinism in infancy due to mutations in the ATP-sensitive K-channel.

Diffuse congenital hyperinsulinism in infancy (CHI-D) arises from mutations inactivating the KATP channel, however, the phenotype is difficult to explain from electrophysiology alone. Here we have studied wider abnormalities in the β-cell and other pancreatic lineages. Islets were disorganized in CHI-D compared to control. PAX4 and ARX expression was decreased. A tendency to increased NKX2.2 expression was consistent with its detection in two-thirds of CHI-D δ-cell nuclei, similar to the fetal pancreas and implying immature δ-cell function. CHI-D δ-cells also comprised 10% of cells displaying nucleomegaly. Increased proliferation in CHI-D was most elevated in duct (5-11 fold) and acinar (7-47 fold) lineages. Increased β-cell proliferation observed in some cases was offset by an increase in apoptosis; 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 β-cells compared to cytoplasmic localization in control cells. These combined data support normal β-cell mass in CHI-D, but with G1/S molecules positioned in favor of cell cycle progression. New molecular abnormalities in δ-cells and marked proliferative increases in other pancreatic lineages indicate CHI-D is not solely a β-cell disorder.