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

Abstract

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 studied wider abnormalities in the β-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 δ-cell nuclei, similar to the fetal pancreas, and implied immature δ-cell function. CHI-D δ-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 β-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 β-cells compared with 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.

• Authors: Rachel J Salisbury, Bing Han, Rachel E Jennings, Andrew A Berry, Adam Stevens, Zainab Mohamed, Sarah A Sugden, Ronald De Krijger, Sarah E Cross, Paul P V Johnson, Melanie Newbould, Karen E Cosgrove, Karen Piper Hanley, Indraneel Banerjee, Mark J Dunne, Neil A Hanley
• Journal: Diabetes (Diabetes) Vol. 64 Issue 9 Pg. 3182-8 (Sep 2015) ISSN: 1939-327X [Electronic] United States
• PMID: 25931474 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Chemical References

• ABCC8 protein, human
• ARX protein, human
• CDKN1B protein, human
• Homeobox Protein Nkx-2.2
• Homeodomain Proteins
• Insulin
• Kir6.2 channel
• NKX2-2 protein, human
• Nuclear Proteins
• PAX4 protein, human
• Paired Box Transcription Factors
• Potassium Channels, Inwardly Rectifying
• Sulfonylurea Receptors
• Transcription Factors
• Zebrafish Proteins
• nkx2.2b protein, zebrafish
• Cyclin-Dependent Kinase Inhibitor p27
• CDK6 protein, human
• Cyclin-Dependent Kinase 6

Topics

• Case-Control Studies
• Cell Lineage
• Cell Proliferation
• Child
• Child, Preschool
• Congenital Hyperinsulinism (genetics, metabolism)
• Cyclin-Dependent Kinase 6 (metabolism)
• Cyclin-Dependent Kinase Inhibitor p27 (metabolism)
• Fetus (cytology)
• Glucagon-Secreting Cells (cytology, metabolism)
• Homeobox Protein Nkx-2.2
• Homeodomain Proteins (metabolism)
• Humans
• Infant
• Infant, Newborn
• Insulin (metabolism)
• Insulin-Secreting Cells (cytology, metabolism)
• Mutation
• Nuclear Proteins
• Paired Box Transcription Factors (metabolism)
• Potassium Channels, Inwardly Rectifying (genetics)
• Somatostatin-Secreting Cells (cytology, metabolism)
• Sulfonylurea Receptors (genetics)
• Transcription Factors (metabolism)
• Zebrafish Proteins