GATA6 Controls Insulin Biosynthesis and Secretion in Adult β-Cells.

Abstract

GATA4 and GATA6 play essential, but redundant, roles in pancreas formation in mice, and <i>GATA6</i> mutations cause pancreatic agenesis in humans. <i>GATA6</i> 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 <i>Gata6</i> is specifically inactivated in the pancreas. These mice develop glucose intolerance. Islets deficient in GATA6 activity display decreased insulin content and impaired insulin secretion. <i>Gata6</i>-deficient β-cells exhibit ultrastructural abnormalities, including increased immature insulin granules, swollen mitochondria, and disorganized endoplasmic reticulum. We also demonstrate that <i>Pdx1</i> 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.