Glucocorticoids and glucolipotoxicity alter the DNA methylome and function of human EndoC-βH1 cells
Cristiane Dos Santos1, Alexandros Karagiannopoulos2, Alex Rafacho3
1Laboratory of endocrine pancreas and metabolism - LAPEM, Department of Structural and Functional Biology, Institute of Biology, Campinas State University - UNICAMP, 13083-862 Campinas, Brazil; Epigenetics and Diabetes Unit, Department of Clinical Sciences Malmö, Lund University Diabetes Center, Lund University, Clinical Research Centre, Scania University Hospital, Malmö, Sweden.
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.
Insights
Dexamethasone (DEX) and high glucose/palmitate impair pancreatic beta-cell function and insulin secretion. Combining these treatments synergistically worsens beta-cell dysfunction and alters DNA methylation patterns.
Area of Science:
- Endocrinology
- Molecular Biology
- Epigenetics
Background:
- Synthetic glucocorticoids like dexamethasone (DEX) are used for their immune-regulatory effects.
- Excessive glucocorticoid use can disrupt glucose homeostasis, particularly in individuals with glucose intolerance.
- DEX is known to impair pancreatic beta-cell function, but the underlying mechanisms remain unclear.
Purpose of the Study:
- To investigate the impact of DEX on pancreatic beta-cell function.
- To examine the combined effects of DEX and a diabetogenic environment (high glucose and palmitate) on beta-cell function.
- To explore the molecular mechanisms, including epigenetic changes, underlying DEX-induced beta-cell dysfunction.
Main Methods:
- Human pancreatic EndoC-βH1 cells were utilized for in vitro studies.
- Cells were exposed to high glucose and palmitate (glucolipotoxicity) and/or dexamethasone (DEX).
- Functional assays (insulin content, secretion, ATP response) and molecular analyses (gene expression, DNA methylation) were performed.
Main Results:
- Both DEX and glucolipotoxicity individually reduced insulin content and secretion.
- The combination of DEX and glucolipotoxicity exhibited a synergistic negative effect on beta-cell function.
- These impairments were linked to reduced insulin biosynthesis (downregulation of PDX1, MAFA) and impaired glucose-stimulated ATP production.
- Genome-wide DNA methylation analysis revealed significant alterations in genes associated with beta-cell function and diabetes, with DEX uniquely demethylating ZBTB16.
Conclusions:
- DEX and glucolipotoxicity independently alter the pancreatic beta-cell epigenome and function.
- The combined exposure exacerbates these detrimental effects, highlighting a synergistic impact.
- Caution is advised when prescribing potent glucocorticoids to patients with metabolic dysregulation due to potential severe beta-cell impairment.
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