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

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

Author information

1
Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Universidad Pablo de Olavide, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas (CSIC), Seville, Spain.
2
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.
3
Universidad Miguel Hernández, Elche, Spain.
4
Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
5
Institute for Cancer Research, Medical University of Vienna, Vienna, Austria.
6
Unidad de Gestión de Endocrinología y Nutrición, Instituto de Biomedicina de Sevilla (IBiS), Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Hospital Universitario Virgen del Rocío, Seville, Spain.
7
Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Universidad Pablo de Olavide, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas (CSIC), Seville, Spain anabel.rojas@cabimer.es.

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.

PMID:
29263149
DOI:
10.2337/db17-0364
[Indexed for MEDLINE]
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