Insulin and Glucose Alter Death-Associated Protein Kinase 3 (DAPK3) DNA Methylation in Human Skeletal Muscle

Abstract

DNA methylation is altered by environmental factors. We hypothesized that DNA methylation is altered in skeletal muscle in response to either insulin or glucose exposure. We performed a genome-wide DNA methylation analysis in muscle from healthy men before and after insulin exposure. DNA methylation of selected genes was determined in muscle from healthy men and men with type 2 diabetes before and after a glucose tolerance test. Insulin altered DNA methylation in the 3' untranslated region of the calcium pump <i>ATP2A3</i> gene. Insulin increased DNA methylation in the gene body of <i>DAPK3</i>, a gene involved in cell proliferation, apoptosis, and autophagy. <i>DAPK3</i> methylation was reduced in patients with type 2 diabetes. Carbohydrate ingestion reduced <i>DAPK3</i> DNA methylation in healthy men and men with type 2 diabetes, suggesting glucose may play a role. Supporting this, <i>DAPK3</i> DNA methylation was inversely correlated with the 2-h glucose concentration. Whereas glucose incorporation to glycogen was unaltered by small interfering RNA against <i>DAPK3</i>, palmitate oxidation was increased. In conclusion, insulin and glucose exposure acutely alter the DNA methylation profile of skeletal muscle, indicating that DNA methylation constitutes a rapidly adaptive epigenetic mark. Furthermore, insulin and glucose modulate <i>DAPK3</i> DNA methylation in a reciprocal manner, suggesting a feedback loop in the control of the epigenome.