期刊
DIABETES
卷 68, 期 10, 页码 1965-1974出版社
AMER DIABETES ASSOC
DOI: 10.2337/db18-0900
关键词
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资金
- Vetenskapsradet (the Swedish Research Council) [349-2006-237, 2009-1039]
- European Research Council Consolidator grant [725840]
- Swedish Foundation for Strategic Research [IRC15-0067]
- Region Skane
- Knut och Alice Wallenbergs Stiftelse
- Novo Nordisk Foundation
- Ragnar Soderbergs Stiftelse
- Diabetesfonden
- Direktor Albert Pahlsson Stiftelse
- Tore Nilsson Foundation
- Fredrik och Ingrid Thurings Stiftelse
- Nilsson-Ehle Foundation
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 genome-wide 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 beta-cells, supporting the idea that DNA methylation underlies altered expression after glucolipotoxicity. Follow-up experiments in clonal beta-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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