title: Association of diabetes and diabetes treatment with the host response in critically ill sepsis patients.
abstract: BACKGROUND
  Diabetes is associated with chronic inflammation and activation of the vascular endothelium and the coagulation system, which in a more acute manner are also observed in sepsis. Insulin and metformin exert immune modulatory effects. In this study, we aimed to determine the association of diabetes and preadmission insulin and metformin use with sepsis outcome and host response.
  
  
  METHODS
  We evaluated 1104 patients with sepsis, admitted to the intensive care unit and stratified according to the presence or absence of diabetes mellitus. The host response was examined by a targeted approach (by measuring 15 plasma biomarkers reflective of pathways implicated in sepsis pathogenesis) and an unbiased approach (by analyzing whole genome expression profiles in blood leukocytes).
  
  
  RESULTS
  Diabetes mellitus was not associated with differences in sepsis presentation or mortality up to 90 days after admission. Plasma biomarker measurements revealed signs of systemic inflammation, and strong endothelial and coagulation activation in patients with sepsis, none of which were altered in those with diabetes. Patients with and without diabetes mellitus, who had sepsis demonstrated similar transcriptional alterations, comprising 74 % of the expressed gene content and involving over-expression of genes associated with pro-inflammatory, anti-inflammatory, Toll-like receptor and metabolic signaling pathways and under-expression of genes associated with T cell signaling pathways. Amongst patients with diabetes mellitus and sepsis, preadmission treatment with insulin or metformin was not associated with an altered sepsis outcome or host response.
  
  
  CONCLUSIONS
  Neither diabetes mellitus nor preadmission insulin or metformin use are associated with altered disease presentation, outcome or host response in patients with sepsis requiring intensive care.
authors: Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Room G2-130, 1105, AZ, Amsterdam, The Netherlands. l.a.vanvught@amc.uva.nl.|the Center for Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. l.a.vanvught@amc.uva.nl.
authors: Lonneke A
authors: LA
authors: van Vught
authors: Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Room G2-130, 1105, AZ, Amsterdam, The Netherlands.|the Center for Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Brendon P
authors: BP
authors: Scicluna
authors: Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Room G2-130, 1105, AZ, Amsterdam, The Netherlands.|the Center for Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Arie J
authors: AJ
authors: Hoogendijk
authors: Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Room G2-130, 1105, AZ, Amsterdam, The Netherlands.|the Center for Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Maryse A
authors: MA
authors: Wiewel
authors: Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.|Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.|Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Peter M C
authors: PM
authors: Klein Klouwenberg
authors: Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Olaf L
authors: OL
authors: Cremer
authors: Department of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Janneke
authors: J
authors: Horn
authors: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors: Peter
authors: P
authors: Nürnberg
authors: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Marc M J
authors: MM
authors: Bonten
authors: Department of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Laboratory of Experimental Intensive Care and Anesthesiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Marcus J
authors: MJ
authors: Schultz
authors: Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Room G2-130, 1105, AZ, Amsterdam, The Netherlands.|the Center for Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Tom
authors: T
authors: van der Poll
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000032:analysis / Q000097:blood; D054428:Chemokine CX3CL1 / Q000032:analysis / Q000097:blood; D016638:Critical Illness / Q000401:mortality / Q000628:therapy; D003920:Diabetes Mellitus / Q000188:drug therapy*; D019040:E-Selectin / Q000032:analysis / Q000097:blood; D005260:Female; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy; D007249:Inflammation / Q000150:complications; D007328:Insulin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007362:Intensive Care Units / Q000458:organization & administration / Q000706:statistics & numerical data; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000097:blood; D007371:Interferon-gamma / Q000032:analysis / Q000097:blood; D016753:Interleukin-10 / Q000032:analysis / Q000097:blood; D053583:Interleukin-1beta / Q000032:analysis / Q000097:blood; D015850:Interleukin-6 / Q000032:analysis / Q000097:blood; D016209:Interleukin-8 / Q000032:analysis / Q000097:blood; D008297:Male; D008687:Metformin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008875:Middle Aged; D011446:Prospective Studies; D018805:Sepsis / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000097:blood
chemical_list: D015415:Biomarkers; C515538:CX3CL1 protein, human; D054428:Chemokine CX3CL1; D019040:E-Selectin; C508609:IL10 protein, human; C508600:IL6 protein, human; D007328:Insulin; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; C546936:SELE protein, human; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10; D007371:Interferon-gamma; D008687:Metformin
keywords: Biomarker; Critically ill; Diabetes; Host response; Intensive care unit; MARS study; Sepsis