GATA6 Controls Insulin Biosynthesis and Secretion in Adult β-Cells

Diabetes. 2018 Mar;67(3):448-460. doi: 10.2337/db17-0364. Epub 2017 Dec 20.

Abstract

GATA4 and GATA6 play essential, but redundant, roles in pancreas formation in mice, and GATA6 mutations cause pancreatic agenesis in humans. GATA6 mutations have also recently been linked to adult-onset diabetes, with subclinical or no exocrine insufficiency, suggesting an important role for GATA6 in human β-cell physiology. To investigate the role of GATA6 in the adult endocrine pancreas, we generated mice in which Gata6 is specifically inactivated in the pancreas. These mice develop glucose intolerance. Islets deficient in GATA6 activity display decreased insulin content and impaired insulin secretion. Gata6-deficient β-cells exhibit ultrastructural abnormalities, including increased immature insulin granules, swollen mitochondria, and disorganized endoplasmic reticulum. We also demonstrate that Pdx1 expression in adult β-cells depends on GATA sites in transgenic reporter mice and that loss of GATA6 greatly affects β-cell-specific gene expression. These findings demonstrate the essential role of GATA6 in β-cell function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / analysis
  • Endoplasmic Reticulum Stress*
  • Female
  • GATA6 Transcription Factor / genetics
  • GATA6 Transcription Factor / metabolism*
  • Gene Expression Regulation, Developmental
  • Genes, Reporter
  • Glucose Intolerance / blood
  • Glucose Intolerance / metabolism
  • Glucose Intolerance / pathology
  • Glucose Intolerance / physiopathology
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Insulin / biosynthesis*
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology
  • Insulin-Secreting Cells / ultrastructure
  • Male
  • Mice, Knockout
  • Mice, Transgenic
  • Microscopy, Electron, Transmission
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Mitochondria / ultrastructure
  • Mutation
  • Organelle Biogenesis
  • Secretory Vesicles / metabolism*
  • Secretory Vesicles / pathology
  • Secretory Vesicles / ultrastructure
  • Tissue Culture Techniques
  • Trans-Activators / genetics
  • Trans-Activators / metabolism

Substances

  • Blood Glucose
  • GATA6 Transcription Factor
  • Gata6 protein, mouse
  • Homeodomain Proteins
  • Insulin
  • Trans-Activators
  • pancreatic and duodenal homeobox 1 protein