title: 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 pumpATP2A3gene. Insulin increased DNA methylation in the gene body ofDAPK3, a gene involved in cell proliferation, apoptosis, and autophagy.DAPK3methylation was reduced in patients with type 2 diabetes. Carbohydrate ingestion reducedDAPK3DNA methylation in healthy men and men with type 2 diabetes, suggesting glucose may play a role. Supporting this,DAPK3DNA methylation was inversely correlated with the 2-h glucose concentration. Whereas glucose incorporation to glycogen was unaltered by small interfering RNA againstDAPK3, 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 modulateDAPK3DNA methylation in a reciprocal manner, suggesting a feedback loop in the control of the epigenome.
authors.affiliation: Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Mudry
authors.affiliation: Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: David G
authors.initials: DG
authors.lastname: Lassiter
authors.affiliation: Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Carolina
authors.initials: C
authors.lastname: Nylén
authors.affiliation: Integrative Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sonia
authors.initials: S
authors.lastname: García-Calzón
authors.affiliation: Division of Surgery, Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Näslund
authors.affiliation: Integrative Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Krook
authors.affiliation: Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden juleen.zierath@ki.se.|Integrative Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.|Section of Integrative Physiology, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Juleen R
authors.initials: JR
authors.lastname: Zierath
mesh_terms: D001706:Biopsy; D001786:Blood Glucose / Q000378:metabolism; D016022:Case-Control Studies; D019175:DNA Methylation; D064550:Death-Associated Protein Kinases / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D006003:Glycogen / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D012333:RNA, Messenger; D006003:Glycogen; C579101:DAPK3 protein, human; D064550:Death-Associated Protein Kinases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506949:ATP2A3 protein, human; D005947:Glucose