title: Diabetes propels the risk for cardiovascular disease: sweet monocytes becoming aggressive?
abstract: Diabetes strongly predisposes to cardiovascular disease (CVD), the leading cause of mortality in these patients, as well as in the entire population. Hyperglycemia is an important cardiovascular risk factor as shown by the observation that even transient periods of hyperglycemia, despite return to normoglycemia during follow-up, increase the risk for CVD, a phenomenon termed 'hyperglycemic memory'. The molecular mechanisms underlying this phenomenon remain largely unknown. As inflammation plays an important role in the pathogenesis of atherosclerosis, we propose that long-term functional reprogramming of monocytes and macrophages, induced by hyperglycemia, plays an important role in the phenomenon of hyperglycemic memory leading to cardiovascular complications in patients with diabetes. In this review, we discuss recent insights showing that innate immune cells possess the capacity to reprogram their function through epigenetically mediated rewiring of gene transcription, a process termed 'trained immunity'. The long-term reprogramming of monocytes can be induced by microbial as well as metabolic products, and involves a shift in cellular metabolism from oxidative phosphorylation to aerobic glycolysis. We hypothesize that hyperglycemia in diabetes patients induces long-term activation of monocytes and macrophages through similar mechanisms, thereby contributing to plaque development and subsequent macrovascular complications.
authors.affiliation: Department of Internal Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Radboudumc, (463), P. O. Box 9101, 6500 HB, Nijmegen, The Netherlands. janna.vandiepen@radboudumc.nl.
authors.forename: Janna A
authors.identifier: 0000-0001-9091-1075
authors.initials: JA
authors.lastname: van Diepen
authors.affiliation: Department of Internal Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Radboudumc, (463), P. O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Thiem
authors.affiliation: Department of Internal Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Radboudumc, (463), P. O. Box 9101, 6500 HB, Nijmegen, The Netherlands.|Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, 6703 HA, Wageningen, The Netherlands.
authors.forename: Rinke
authors.initials: R
authors.lastname: Stienstra
authors.affiliation: Department of Internal Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Radboudumc, (463), P. O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Niels P
authors.initials: NP
authors.lastname: Riksen
authors.affiliation: Department of Internal Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Radboudumc, (463), P. O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Cees J
authors.initials: CJ
authors.lastname: Tack
authors.affiliation: Department of Internal Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Radboudumc, (463), P. O. Box 9101, 6500 HB, Nijmegen, The Netherlands.|Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Center, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000209:etiology* / Q000276:immunology; D003920:Diabetes Mellitus / Q000276:immunology / Q000473:pathology*; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000276:immunology; D007109:Immunity; D009000:Monocytes / Q000473:pathology*; D012307:Risk Factors
keywords: Atherosclerosis; Diabetes; Epigenetics; Hyperglycemia; Inflammation; Metabolism; Trained immunity