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Glucolipotoxicity alters insulin secretion via epigenetic changes in human islets

Hall, Elin LU ; Jönsson, Josefine LU orcid ; Ofori, Jones K. LU ; Volkov, Petr LU ; Perfilyev, Alexander LU orcid ; Nitert, Marloes Dekker LU ; Eliasson, Lena LU orcid ; Ling, Charlotte LU orcid and Bacos, Karl LU orcid (2019) In Diabetes 68(10). p.1965-1974
Abstract

Type 2 diabetes (T2D) is characterized by insufficient insulin secretion and elevated glucose levels, often in combination with high levels of circulating fatty acids. Long-term exposure to high levels of glucose or fatty acids impair insulin secretion in pancreatic islets, which could partly be due to epigenetic alterations. We studied the effects of high concentrations of glucose and palmitate combined for 48 h (glucolipotoxicity) on the transcriptome, the epigenome, and cell function in human islets. Glucolipotoxicity impaired insulin secretion, increased apoptosis, and significantly (false discovery rate <5%) altered the expression of 1,855 genes, including 35 genes previously implicated in T2D by genomewide association studies... (More)

Type 2 diabetes (T2D) is characterized by insufficient insulin secretion and elevated glucose levels, often in combination with high levels of circulating fatty acids. Long-term exposure to high levels of glucose or fatty acids impair insulin secretion in pancreatic islets, which could partly be due to epigenetic alterations. We studied the effects of high concentrations of glucose and palmitate combined for 48 h (glucolipotoxicity) on the transcriptome, the epigenome, and cell function in human islets. Glucolipotoxicity impaired insulin secretion, increased apoptosis, and significantly (false discovery rate <5%) altered the expression of 1,855 genes, including 35 genes previously implicated in T2D by genomewide association studies (e.g., TCF7L2 and CDKN2B). Additionally, metabolic pathways were enriched for downregulated genes. Of the differentially expressed genes, 1,469 also exhibited altered DNA methylation (e.g., CDK1, FICD, TPX2, and TYMS). A luciferase assay showed that increased methylation of CDK1 directly reduces its transcription in pancreatic β-cells, supporting the idea that DNA methylation underlies altered expression after glucolipotoxicity. Follow-up experiments in clonal β-cells showed that knockdown of FICD and TPX2 alters insulin secretion. Together, our novel data demonstrate that glucolipotoxicity changes the epigenome in human islets, thereby altering gene expression and possibly exacerbating the secretory defect in T2D.

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Diabetes
volume
68
issue
10
pages
1965 - 1974
publisher
American Diabetes Association Inc.
external identifiers
  • scopus:85072546848
  • pmid:31420409
ISSN
0012-1797
DOI
10.2337/db18-0900
project
Do dietary factors impact the epigenome and thereby metabolism in humans?
language
English
LU publication?
yes
id
e3c30d9f-d6a9-4d36-9274-788b29e27447
date added to LUP
2020-01-16 12:05:44
date last changed
2024-06-26 09:45:24
@article{e3c30d9f-d6a9-4d36-9274-788b29e27447,
  abstract     = {{<p>Type 2 diabetes (T2D) is characterized by insufficient insulin secretion and elevated glucose levels, often in combination with high levels of circulating fatty acids. Long-term exposure to high levels of glucose or fatty acids impair insulin secretion in pancreatic islets, which could partly be due to epigenetic alterations. We studied the effects of high concentrations of glucose and palmitate combined for 48 h (glucolipotoxicity) on the transcriptome, the epigenome, and cell function in human islets. Glucolipotoxicity impaired insulin secretion, increased apoptosis, and significantly (false discovery rate &lt;5%) altered the expression of 1,855 genes, including 35 genes previously implicated in T2D by genomewide association studies (e.g., TCF7L2 and CDKN2B). Additionally, metabolic pathways were enriched for downregulated genes. Of the differentially expressed genes, 1,469 also exhibited altered DNA methylation (e.g., CDK1, FICD, TPX2, and TYMS). A luciferase assay showed that increased methylation of CDK1 directly reduces its transcription in pancreatic β-cells, supporting the idea that DNA methylation underlies altered expression after glucolipotoxicity. Follow-up experiments in clonal β-cells showed that knockdown of FICD and TPX2 alters insulin secretion. Together, our novel data demonstrate that glucolipotoxicity changes the epigenome in human islets, thereby altering gene expression and possibly exacerbating the secretory defect in T2D.</p>}},
  author       = {{Hall, Elin and Jönsson, Josefine and Ofori, Jones K. and Volkov, Petr and Perfilyev, Alexander and Nitert, Marloes Dekker and Eliasson, Lena and Ling, Charlotte and Bacos, Karl}},
  issn         = {{0012-1797}},
  language     = {{eng}},
  number       = {{10}},
  pages        = {{1965--1974}},
  publisher    = {{American Diabetes Association Inc.}},
  series       = {{Diabetes}},
  title        = {{Glucolipotoxicity alters insulin secretion via epigenetic changes in human islets}},
  url          = {{http://dx.doi.org/10.2337/db18-0900}},
  doi          = {{10.2337/db18-0900}},
  volume       = {{68}},
  year         = {{2019}},
}