title: Proinflammatory Effects of Hypoglycemia in Humans With or Without Diabetes.
abstract: Severe hypoglycemic events have been associated with increased cardiovascular mortality in patients with diabetes, which may be explained by hypoglycemia-induced inflammation. We used ex vivo stimulations of peripheral blood mononuclear cells (PBMCs) and monocytes obtained during hyperinsulinemic-euglycemic (5.0 mmol/L)-hypoglycemic (2.6 mmol/L) clamps in 11 healthy participants, 10 patients with type 1 diabetes and normal awareness of hypoglycemia (NAH), and 10 patients with type 1 diabetes and impaired awareness (IAH) to test whether the composition and inflammatory function of immune cells adapt to a more proinflammatory state after hypoglycemia. Hypoglycemia increased leukocyte numbers in healthy control participants and patients with NAH but not in patients with IAH. Leukocytosis strongly correlated with the adrenaline response to hypoglycemia. Ex vivo, PBMCs and monocytes displayed a more robust cytokine response to microbial stimulation after hypoglycemia compared with euglycemia, although it was less pronounced in patients with IAH. Of note, hypoglycemia increased the expression of markers of demargination and inflammation in PBMCs. We conclude that hypoglycemia promotes mobilization of specific leukocyte subsets from the marginal pool and induces proinflammatory functional changes in immune cells. Inflammatory responses were less pronounced in IAH, indicating that counterregulatory hormone responses are key modulators of hypoglycemia-induced proinflammatory effects. Hypoglycemia-induced proinflammatory changes may promote a sustained inflammatory state.
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands jacqueline.ratter@radboudumc.nl.|Division of Human Nutrition, Wageningen University, Wageningen, the Netherlands.
authors.forename: Jacqueline M
authors.identifier: 0000-0002-3807-9442
authors.initials: JM
authors.lastname: Ratter
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Hanne M M
authors.initials: HM
authors.lastname: Rooijackers
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Cees J
authors.initials: CJ
authors.lastname: Tack
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Anneke G M
authors.initials: AG
authors.lastname: Hijmans
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Bastiaan E
authors.initials: BE
authors.lastname: de Galan
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.|Division of Human Nutrition, Wageningen University, Wageningen, the Netherlands.
authors.forename: Rinke
authors.initials: R
authors.lastname: Stienstra
mesh_terms: D000328:Adult; D001364:Awareness; D016022:Case-Control Studies; D018932:Chemokine CCL2 / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000187:drug effects / Q000276:immunology; D003922:Diabetes Mellitus, Type 1; D004837:Epinephrine / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D006801:Humans; D007003:Hypoglycemia / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000187:drug effects / Q000276:immunology; D019344:Lactic Acid / Q000378:metabolism; D007964:Leukocytosis / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000276:immunology; D055815:Young Adult
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D016207:Cytokines; C508585:IL1B protein, human; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D012333:RNA, Messenger; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D019344:Lactic Acid; D005947:Glucose; D004837:Epinephrine