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Glucocorticoids and glucolipotoxicity alter the DNA methylome and function of human EndoC-βH1 cells

Dos Santos, Cristiane ; Karagiannopoulos, Alexandros LU orcid ; Rafacho, Alex ; Perfilyev, Alexander LU orcid ; Eliasson, Lena LU orcid ; Ling, Charlotte LU orcid and Bacos, Karl LU orcid (2022) In Life Sciences 307.
Abstract

AIMS: Synthetic glucocorticoids, including dexamethasone (DEX), are clinically prescribed due to their immunoregulatory properties. In excess they can perturb glucose homeostasis, with individuals predisposed to glucose intolerance more sensitive to these negative effects. While DEX is known to negatively impact β-cell function, it is unclear how. Hence, our aim was to investigate the effect of DEX on β-cell function, both alone and in combination with a diabetogenic milieu in the form of elevated glucose and palmitate.

MAIN METHODS: Human pancreatic EndoC-βH1 cells were cultured in the presence of high glucose and palmitate (glucolipotoxicity) and/or a pharmacological concentration of DEX, before functional and molecular... (More)

AIMS: Synthetic glucocorticoids, including dexamethasone (DEX), are clinically prescribed due to their immunoregulatory properties. In excess they can perturb glucose homeostasis, with individuals predisposed to glucose intolerance more sensitive to these negative effects. While DEX is known to negatively impact β-cell function, it is unclear how. Hence, our aim was to investigate the effect of DEX on β-cell function, both alone and in combination with a diabetogenic milieu in the form of elevated glucose and palmitate.

MAIN METHODS: Human pancreatic EndoC-βH1 cells were cultured in the presence of high glucose and palmitate (glucolipotoxicity) and/or a pharmacological concentration of DEX, before functional and molecular analyses.

KEY FINDINGS: Either treatment alone resulted in reduced insulin content and secretion, while the combination of DEX and glucolipotoxicity promoted a strong synergistic effect. These effects were associated with reduced insulin biosynthesis, likely due to downregulation of PDX1, MAFA, and the proinsulin converting enzymes, as well as reduced ATP response upon glucose stimulation. Genome-wide DNA methylation analysis found changes on PDE4D, MBNL1 and TMEM178B, all implicated in β-cell function, after all three treatments. DEX alone caused very strong demethylation of the glucocorticoid-regulated gene ZBTB16, also known to influence the β-cell, while the combined treatment caused altered methylation of many known β-cell regulators and diabetes candidate genes.

SIGNIFICANCE: DEX treatment and glucolipotoxic conditions separately alter the β-cell epigenome and function. The combination of both treatments exacerbates these changes, showing that caution is needed when prescribing potent glucocorticoids in patients with dysregulated metabolism.

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author
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publishing date
type
Contribution to journal
publication status
published
subject
in
Life Sciences
volume
307
article number
120854
publisher
Elsevier
external identifiers
  • pmid:35917939
  • scopus:85135824696
ISSN
1879-0631
DOI
10.1016/j.lfs.2022.120854
language
English
LU publication?
yes
additional info
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
id
d0ef2b24-08ab-4559-bad3-18237f729e0f
date added to LUP
2022-08-24 10:50:13
date last changed
2024-06-10 19:59:02
@article{d0ef2b24-08ab-4559-bad3-18237f729e0f,
  abstract     = {{<p>AIMS: Synthetic glucocorticoids, including dexamethasone (DEX), are clinically prescribed due to their immunoregulatory properties. In excess they can perturb glucose homeostasis, with individuals predisposed to glucose intolerance more sensitive to these negative effects. While DEX is known to negatively impact β-cell function, it is unclear how. Hence, our aim was to investigate the effect of DEX on β-cell function, both alone and in combination with a diabetogenic milieu in the form of elevated glucose and palmitate.</p><p>MAIN METHODS: Human pancreatic EndoC-βH1 cells were cultured in the presence of high glucose and palmitate (glucolipotoxicity) and/or a pharmacological concentration of DEX, before functional and molecular analyses.</p><p>KEY FINDINGS: Either treatment alone resulted in reduced insulin content and secretion, while the combination of DEX and glucolipotoxicity promoted a strong synergistic effect. These effects were associated with reduced insulin biosynthesis, likely due to downregulation of PDX1, MAFA, and the proinsulin converting enzymes, as well as reduced ATP response upon glucose stimulation. Genome-wide DNA methylation analysis found changes on PDE4D, MBNL1 and TMEM178B, all implicated in β-cell function, after all three treatments. DEX alone caused very strong demethylation of the glucocorticoid-regulated gene ZBTB16, also known to influence the β-cell, while the combined treatment caused altered methylation of many known β-cell regulators and diabetes candidate genes.</p><p>SIGNIFICANCE: DEX treatment and glucolipotoxic conditions separately alter the β-cell epigenome and function. The combination of both treatments exacerbates these changes, showing that caution is needed when prescribing potent glucocorticoids in patients with dysregulated metabolism.</p>}},
  author       = {{Dos Santos, Cristiane and Karagiannopoulos, Alexandros and Rafacho, Alex and Perfilyev, Alexander and Eliasson, Lena and Ling, Charlotte and Bacos, Karl}},
  issn         = {{1879-0631}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Life Sciences}},
  title        = {{Glucocorticoids and glucolipotoxicity alter the DNA methylome and function of human EndoC-βH1 cells}},
  url          = {{http://dx.doi.org/10.1016/j.lfs.2022.120854}},
  doi          = {{10.1016/j.lfs.2022.120854}},
  volume       = {{307}},
  year         = {{2022}},
}