title: Blood-based biomarkers of age-associated epigenetic changes in human islets associate with insulin secretion and diabetes.
abstract: Aging associates with impaired pancreatic islet function and increased type 2 diabetes (T2D) risk. Here we examine whether age-related epigenetic changes affect human islet function and if blood-based epigenetic biomarkers reflect these changes and associate with future T2D. We analyse DNA methylation genome-wide in islets from 87 non-diabetic donors, aged 26-74 years. Aging associates with increased DNA methylation of 241 sites. These sites cover loci previously associated with T2D, for example, KLF14. Blood-based epigenetic biomarkers reflect age-related methylation changes in 83 genes identified in human islets (for example, KLF14, FHL2, ZNF518B and FAM123C) and some associate with insulin secretion and T2D. DNA methylation correlates with islet expression of multiple genes, including FHL2, ZNF518B, GNPNAT1 and HLTF. Silencing these genes in β-cells alter insulin secretion. Together, we demonstrate that blood-based epigenetic biomarkers reflect age-related DNA methylation changes in human islets, and associate with insulin secretion in vivo and T2D.
authors.affiliation: Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, CRC 91:12, Jan Waldenströms gata 35, 20502 Malmö, Sweden.
authors.forename: Karl
authors.initials: K
authors.lastname: Bacos
authors.affiliation: Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, Tagensvej 20, 2200 Copenhagen, Denmark.|Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark.
authors.forename: Linn
authors.initials: L
authors.lastname: Gillberg
authors.affiliation: Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, CRC 91:12, Jan Waldenströms gata 35, 20502 Malmö, Sweden.
authors.forename: Petr
authors.initials: P
authors.lastname: Volkov
authors.affiliation: Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, Tagensvej 20, 2200 Copenhagen, Denmark.
authors.forename: Anders H
authors.initials: AH
authors.lastname: Olsson
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Universitetsparken 1, 2100 Copenhagen, Denmark.
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Universitetsparken 1, 2100 Copenhagen, Denmark.
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Universitetsparken 1, 2100 Copenhagen, Denmark.
authors.forename: Anette Prior
authors.initials: AP
authors.lastname: Gjesing
authors.affiliation: Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark.
authors.forename: Hans
authors.initials: H
authors.lastname: Eiberg
authors.affiliation: Department of Endocrinology, Abdominal Centre, Helsinki University Hospital; Folkhalsan Research Center; Research Program for Diabetes and Obesity, Hartmaninkatu 8, Helsinki 00014, Finland.|Finnish Institute for Molecular Medicine, University of Helsinki, Hartmaninkatu 8, 00014 Helsinki, Finland.
authors.forename: Tiinamaija
authors.initials: T
authors.lastname: Tuomi
authors.affiliation: Diabetes and Endocrinology, Department of Clinical Sciences, Lund University Diabetes Centre, Jan Waldenströms gata 35, 20502 Malmö, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Almgren
authors.affiliation: Finnish Institute for Molecular Medicine, University of Helsinki, Hartmaninkatu 8, 00014 Helsinki, Finland.|Diabetes and Endocrinology, Department of Clinical Sciences, Lund University Diabetes Centre, Jan Waldenströms gata 35, 20502 Malmö, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.affiliation: Islet cell exocytosis, Department of Clinical Sciences, Lund University Diabetes Centre, Jan Waldenströms gata 35, 20502 Malmö, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Eliasson
authors.affiliation: Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, Tagensvej 20, 2200 Copenhagen, Denmark.|Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark.
authors.forename: Allan
authors.initials: A
authors.lastname: Vaag
authors.affiliation: Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, CRC 91:12, Jan Waldenströms gata 35, 20502 Malmö, Sweden.
authors.forename: Tasnim
authors.initials: T
authors.lastname: Dayeh
authors.affiliation: Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, CRC 91:12, Jan Waldenströms gata 35, 20502 Malmö, Sweden.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Ling
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D015415:Biomarkers / Q000097:blood; D019175:DNA Methylation; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism*; D057890:Epigenomics; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000502:physiology*; D008875:Middle Aged
chemical_list: D015415:Biomarkers; D007328:Insulin