Scholarlink

Aims/hypothesis <p>The bromodomain and extra-terminal (BET) protein family acts as ‘epigenetic readers’ to identify the acetylation marks on histones that convert the acetylated lysine residues into observable phenotypes. BET proteins have gained attention due to their ability to modulate the transcription of pathology-related genes involved in cancer and autoimmune diseases, including type 1 diabetes mellitus. However, targeting BET proteins may have secondary effects on other host cells. We aimed to elucidate possible secondary effects of BET inhibition on pancreatic beta cell function.</p> Methods <p>We studied the effect of the small-molecule BET inhibitor I-BET151 on pancreatic beta cells in vitro, ex vivo and in vivo. GTTs, ITTs and glucose-stimulated insulin secretion assays were performed in healthy mice and a mouse model of diabetes following daily i.p. injections of I-BET151 for 2 weeks. Transcriptomic analysis was carried out on primary mouse islets, which were subjected to ex vivo I-BET151 treatment. Changes in expression were further validated in primary human islets.</p> Results <p>Administration of I-BET151 modestly but significantly increased glucose excursions and reduced insulin responses in both healthy mice and diabetic mice. We found that I-BET151 exposure significantly reduced the expression of <i>Hnf4α</i> (also known as <i>Hnf4a</i>; MODY1), <i>Gck</i> (MODY2), <i>Hnf1α</i> (also known as <i>Hnf1a</i>; MODY3), <i>Glut2</i> and other genes essential for beta cell function in rat INS-1E insulinoma cells and in mouse primary islets and human islets. Global gene expression analysis in cells treated with I-BET151 showed a downregulation of the phosphoinositide-3-kinase (PI3K)–Akt pathway. Downregulation of forkhead box protein O1, a downstream transcriptional factor of the PI3K–Akt pathway, partially rescued I-BET151-driven downregulation of <i>Gck</i> and insulin secretion. Likewise, islets from I-BET151-treated mice showed a modest reduction in glucose-stimulated insulin secretion.</p> Conclusions/interpretation <p>The results presented here suggest that BET inhibition therapy should be used with caution due to possible bimodal effects at high concentrations at the detriment of pancreatic beta cell function.</p> Graphical Abstract <p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

I-BET151 modulates glucokinase gene expression and beta cell function in part through changes in FOXO1 expression

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年9月26日

查看全文
  • Qing Wei Calvin Ho,
  • James A. Miller,
  • Divya Gunaseelan,
  • Rosi Chelliah,
  • Hemapriya Jayaranga Babu,
  • Xin Yan Chew,
  • Surabhi Devaraj,
  • Vanessa Shiyun Tay,
  • Dewei Kong,
  • Xiaoling Wang,
  • Daphne Yuanling Tan,
  • Guy A. Rutter,
  • Bernett Lee,
  • Adrian Kee Keong Teo,
  • Yusuf Ali

摘要

Aims/hypothesis

The bromodomain and extra-terminal (BET) protein family acts as ‘epigenetic readers’ to identify the acetylation marks on histones that convert the acetylated lysine residues into observable phenotypes. BET proteins have gained attention due to their ability to modulate the transcription of pathology-related genes involved in cancer and autoimmune diseases, including type 1 diabetes mellitus. However, targeting BET proteins may have secondary effects on other host cells. We aimed to elucidate possible secondary effects of BET inhibition on pancreatic beta cell function.

Methods

We studied the effect of the small-molecule BET inhibitor I-BET151 on pancreatic beta cells in vitro, ex vivo and in vivo. GTTs, ITTs and glucose-stimulated insulin secretion assays were performed in healthy mice and a mouse model of diabetes following daily i.p. injections of I-BET151 for 2 weeks. Transcriptomic analysis was carried out on primary mouse islets, which were subjected to ex vivo I-BET151 treatment. Changes in expression were further validated in primary human islets.

Results

Administration of I-BET151 modestly but significantly increased glucose excursions and reduced insulin responses in both healthy mice and diabetic mice. We found that I-BET151 exposure significantly reduced the expression of Hnf4α (also known as Hnf4a; MODY1), Gck (MODY2), Hnf1α (also known as Hnf1a; MODY3), Glut2 and other genes essential for beta cell function in rat INS-1E insulinoma cells and in mouse primary islets and human islets. Global gene expression analysis in cells treated with I-BET151 showed a downregulation of the phosphoinositide-3-kinase (PI3K)–Akt pathway. Downregulation of forkhead box protein O1, a downstream transcriptional factor of the PI3K–Akt pathway, partially rescued I-BET151-driven downregulation of Gck and insulin secretion. Likewise, islets from I-BET151-treated mice showed a modest reduction in glucose-stimulated insulin secretion.

Conclusions/interpretation

The results presented here suggest that BET inhibition therapy should be used with caution due to possible bimodal effects at high concentrations at the detriment of pancreatic beta cell function.

Graphical Abstract