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Glucolipotoxicity Alters Insulin Secretion via Epigenetic Changes in Human Islets
Elin Hall1, Josefine Jönsson1, Jones K Ofori2
1Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, Malmö, Sweden.
Diabetes
|August 18, 2019
Summary
High glucose and fatty acids (glucolipotoxicity) impair insulin secretion in type 2 diabetes (T2D) by altering the epigenome and gene expression in human pancreatic islets.
Area of Science:
- Endocrinology
- Epigenetics
- Molecular Biology
Background:
- Type 2 diabetes (T2D) involves impaired insulin secretion and high glucose/fatty acid levels.
- Chronic exposure to high glucose or fatty acids can damage pancreatic islets and affect insulin secretion.
- Epigenetic alterations are suspected contributors to glucolipotoxicity-induced pancreatic islet dysfunction.
Purpose of the Study:
- To investigate the effects of combined high glucose and palmitate (glucolipotoxicity) on human islets.
- To analyze changes in transcriptome, epigenome, and cell function under glucolipotoxic conditions.
- To explore the role of DNA methylation in altered gene expression and insulin secretion defects in T2D.
Main Methods:
- Human islets were exposed to high glucose and palmitate for 48 hours.
- Transcriptome analysis (gene expression profiling) was performed.
- DNA methylation patterns were analyzed, and luciferase assays were used to confirm methylation effects on gene transcription.
- Gene knockdown experiments were conducted in clonal beta-cells.
Main Results:
- Glucolipotoxicity impaired insulin secretion and increased apoptosis in human islets.
- 1,855 genes showed significantly altered expression, including 35 T2D-associated genes.
- 1,469 differentially expressed genes also exhibited altered DNA methylation.
- Increased methylation of CDK1 reduced its transcription, and knockdown of FICD and TPX2 affected insulin secretion.
Conclusions:
- Glucolipotoxicity induces significant epigenetic changes in human pancreatic islets.
- Altered DNA methylation contributes to changes in gene expression following glucolipotoxicity.
- These epigenetic modifications may exacerbate the insulin secretory defects observed in type 2 diabetes.
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