GATA6 controls Insulin biosynthesis and secretion in Adult ß cell

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 functionL.V. was supported by a contract from Spanish Ministry of Economy and Competitiveness (RYC-2013-14533). E.R.-S. was supported by a “Juan de la Cierva” postdoctoral fellowship from Spanish Ministry of Economy and Competitiveness (IJCI-2014-19251). This work was supported by grants from ISCIII cofunded by Fondos FEDER (PI14/01015, RD/0019/0028, and RD16/0011/0034 to B.S. and PI14/ 0804 to A.R.) and “Ramón y Cajal” program from the Spanish Ministry of Economy and Competitiveness (PI14/0804, RYC-2013-14533 to A.R.). P.M. was supported by a Juan de la Cierva fellowship from Spanish Ministry of Science and Innovation and by a Stand-Alone Grant from the Austrian Science Fund (FWF P27361-B23). Work by I.Q. was supported by the Spanish Ministry of Economy and Competitiveness (BFU2016-77125-R). Work by D.A.C. was supported by the Nicolás Monardes program of Andalusian Ministry of Health (C-0015-2014) and the Andalusian Ministry of Science and Innovation (CTS-7478).Peer reviewe