Glucocorticoids reduce Slc2a2 (GLUT2) gene expression through HNF1 in pancreatic β-cells

in Journal of Molecular Endocrinology
Authors:
Yuka Ono Laboratory of Molecular Medical Bioscience, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan

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Kohsuke Kataoka Laboratory of Molecular Medical Bioscience, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan

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https://orcid.org/0000-0001-5685-3908

Correspondence should be addressed to K. Kataoka: kkataoka@yokohama-cu.ac.jp
DOI:
https://doi.org/10.1530/JME-24-0077
Volume/Issue:
Volume 74: Issue 2
Article Type:
Research Article
Article ID:
e240077
Online Publication Date:
10 Jan 2025
Copyright:
© the author(s) 2025
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Glucose transporter type 2 (GLUT2), encoded by the Slc2a2 gene, is essential for glucose-stimulated insulin secretion (GSIS) in pancreatic islet β-cells, and low expression of GLUT2 is associated with β-cell dysfunction during the progression of type 2 diabetes in humans and animal models. Glucocorticoids are stress hormones that regulate inflammation and metabolism through the glucocorticoid receptor (GR), a member of the nuclear receptor superfamily, and synthetic glucocorticoids are widely used for the treatment of inflammatory disorders. Prolonged exposure to glucocorticoids induces β-cell dysfunction and diabetes, but the effects of Slc2a2 gene repression in β-cells, if any, and the mechanisms involved remain unclear. In the present study, we measured the expression of GSIS-related genes in the MIN6 β-cell line and found that Slc2a2 mRNA expression was selectively reduced by dexamethasone (DEX), a synthetic glucocorticoid. Using bioinformatics and reporter assays, we identified two β-cell enhancers of the Slc2a2 gene, one within the first intron and another located approximately 40 kb downstream of the transcription start site. The latter enhancer (designated as E3c) was responsible for the DEX-induced repression of the Slc2a2 gene. Of the previously identified β-cell-enriched transcription factors (NEUROD1, MAFA, HNF1α and HNF1β) that activate the E3c enhancer, the transcriptional activity of HNF1α and HNF1β, responsible for maturity-onset diabetes of the young types 3 and 5, respectively, was repressed by DEX and GR. This functional link between HNF1α/HNF1β and GR should help elucidate the mechanism of glucocorticoid-induced β-cell dysfunction and diabetes.

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Online ISSN:
1479-6813
Print ISSN:
0952-5041
Copyright:
© the author(s) 2025
Article ID:
e240077
Article Type:
Research Article
Received Date:
25 Jul 2024
Rev-recd:
06 Nov 2024
Accepted Date:
17 Dec 2024
Print Publication Date:
01 Feb 2025
Online Publication Date:
10 Jan 2025
Keywords:
pancreatic β-cell; gene regulation; glucocorticoid; glucose transporter 2; HNF1

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