Glucolipotoxicity alters insulin secretion via epigenetic changes in human islets

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Hall, ElinLund University,Lunds universitet,Skåne University Hospital (author)

Glucolipotoxicity alters insulin secretion via epigenetic changes in human islets

Article/chapterEnglish2019

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2019-08-16
American Diabetes Association,2019

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LIBRIS-ID:oai:lup.lub.lu.se:e3c30d9f-d6a9-4d36-9274-788b29e27447
https://lup.lub.lu.se/record/e3c30d9f-d6a9-4d36-9274-788b29e27447URI
https://doi.org/10.2337/db18-0900DOI

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Language:English
Summary in:English

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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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Jönsson, JosefineLund University,Lunds universitet,Diabetes - epigenetik,Forskargrupper vid Lunds universitet,Diabetes - Epigenetics,Lund University Research Groups,Skåne University Hospital(Swepub:lu)jo7760jo (author)
Ofori, Jones K.Lund University,Lunds universitet,Diabetes - öcellsexocytos,Forskargrupper vid Lunds universitet,Diabetes - Islet Cell Exocytosis,Lund University Research Groups,Skåne University Hospital(Swepub:lu)med-joi (author)
Volkov, PetrLund University,Lunds universitet,Skåne University Hospital(Swepub:lu)med-pvo (author)
Perfilyev, AlexanderLund University,Lunds universitet,Diabetes - epigenetik,Forskargrupper vid Lunds universitet,Diabetes - Epigenetics,Lund University Research Groups,Skåne University Hospital(Swepub:lu)med-apy (author)
Nitert, Marloes DekkerLund University,Lunds universitet,Institutionen för experimentell medicinsk vetenskap,Medicinska fakulteten,Department of Experimental Medical Science,Faculty of Medicine,Skåne University Hospital(Swepub:lu)medk-mad (author)
Eliasson, LenaLund University,Lunds universitet,Diabetes - öcellsexocytos,Forskargrupper vid Lunds universitet,Diabetes - Islet Cell Exocytosis,Lund University Research Groups,Skåne University Hospital(Swepub:lu)mphy-lel (author)
Ling, CharlotteLund University,Lunds universitet,Diabetes - epigenetik,Forskargrupper vid Lunds universitet,Diabetes - Epigenetics,Lund University Research Groups,Skåne University Hospital(Swepub:lu)endo-cl0 (author)
Bacos, KarlLund University,Lunds universitet,Diabetes - epigenetik,Forskargrupper vid Lunds universitet,Diabetes - Epigenetics,Lund University Research Groups,Skåne University Hospital(Swepub:lu)medk-kb0 (author)
Lunds universitetSkåne University Hospital (creator_code:org_t)

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In:Diabetes: American Diabetes Association68:10, s. 1965-19740012-17971939-327X

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