Sustained expression of the transcription factor GLIS3 is required for normal beta cell function in adults
Open Access
- 29 November 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in EMBO Molecular Medicine
- Vol. 5 (1), 92-104
- https://doi.org/10.1002/emmm.201201398
Abstract
Genome‐wide association studies identified GLIS3 as a susceptibility locus for type 1 and type 2 diabetes. Global Glis3 deficiency in mice leads to congenital diabetes and neonatal lethality. In this study, we explore the role of Glis3 in adulthood using Glis3+/− and conditional knockout animals. We challenged Glis3+/− mice with high fat diet for 20 weeks and found that they developed diabetes because of impaired beta cell mass expansion. GLIS3 controls beta cell proliferation in response to high‐fat feeding at least partly by regulating Ccnd2 transcription. To determine if sustained Glis3 expression is essential to normal beta cell function, we generated Glis3fl/fl/Pdx1CreERT+ animal by intercrossing Glis3fl/fl mice with Pdx1CreERT+ mice and used tamoxifen (TAM) to induce Glis3 deletion in adults. Adult Glis3fl/fl/Pdx1CreERT+ mice are euglycaemic. TAM‐mediated beta cell‐specific inactivation of Glis3 in adult mice downregulates insulin expression, leading to hyperglycaemia and subsequently enhanced beta cell apoptosis. We conclude that normal Glis3 expression is required for pancreatic beta cell function and mass maintenance during adulthood, which impairment leads to diabetes in adults.This publication has 39 references indexed in Scilit:
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