Glucocorticoids and glucolipotoxicity alter the DNA methylome and function of human EndoC-beta H1 cells

Author(s)

dos Santos, Cristiane ; Karagiannopoulos, Alexandros ; Rafacho, Alex ; Perfilyev, Alexander ; Eliasson, Lena ; Ling, Charlotte ; Bacos, Karl

• Document type: Journal article
• Source: Life Sciences; v. 307, p. 10-pg., 2022-08-09.

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 beta-cell function, it is unclear how. Hence, our aim was to investigate the effect of DEX on beta-cell function, both alone and in combination with a diabetogenic milieu in the form of elevated glucose and palmitate. Main methods: Human pancreatic EndoC-beta H1 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 beta-cell function, after all three treatments. DEX alone caused very strong demethylation of the glucocorticoid-regulated gene ZBTB16, also known to influence the beta-cell, while the combined treatment caused altered methylation of many known beta-cell regulators and diabetes candidate genes. Significance: DEX treatment and glucolipotoxic conditions separately alter the beta-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. (AU)

• FAPESP's process: 19/10543-8 - Investigation on epigenetic mechanisms involved in islet dysfunction by prenatal glucocorticoid treatment
• Grantee: Cristiane dos Santos
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate