title: Chemerin in peritoneal sepsis and its associations with glucose metabolism and prognosis: a translational cross-sectional study.
abstract: BACKGROUND
  Stress hyperglycaemia (SHG) is a common complication in sepsis associated with poor outcome. Chemerin is an adipocytokine associated with inflammation and impaired glucose homeostasis in metabolic diseases such as type 2 diabetes (T2D). We aimed to investigate how alterations of circulating chemerin levels and corresponding visceral adipose tissue (VAT) expression are linked to glucose metabolism and prognosis in sepsis.
  
  
  METHODS
  Clinical data and tissue samples were taken from a cross-sectional study including control, T2D and sepsis patients, all undergoing laparotomy. A second independent patient cohort of patients with sepsis was included to evaluate associations with prognosis. This was complemented by a murine model of peritoneal infection and a high-fat diet. We analysed circulating chemerin by enzyme-linked immunosorbent assay and VAT messenger RNA (mRNA) expression by real-time polymerase chain reaction.
  
  
  RESULTS
  Circulating chemerin was increased in sepsis 1.69-fold compared with controls (p = 0.012) and 1.47-fold compared with T2D (p = 0.03). Otherwise, chemerin VAT mRNA expression was decreased in patients with sepsis (p = 0.006) and in septic diabetic animals (p = 0.009). Circulating chemerin correlated significantly with intra-operative glucose (r = 0.662; p = 0.01) and in trend with fasting glucose (r = 0.528; p = 0.052). After adjusting for body mass index or haemoglobin A1c, chemerin correlated in trend with insulin resistance evaluated using the logarithmised homeostasis model assessment of insulin resistance (r = 0.539, p = 0.071; r = 0.553, p = 0.062). Chemerin was positively associated with Acute Physiology and Chronic Health Evaluation II score in patients with sepsis (p = 0.036) and with clinical severity in septic mice (p = 0.031). In an independent study population, we confirmed association of chemerin with glucose levels in multivariate linear regression analysis (β = 0.556, p = 0.013). In patients with sepsis with SHG, non-survivors had significantly lower chemerin levels than survivors (0.38-fold, p = 0.006), while in patients without SHG, non-survivors had higher chemerin levels, not reaching significance (1.64-fold, p = 0.089). No difference was apparent in patients with pre-existing T2D (p = 0.44).
  
  
  CONCLUSIONS
  We show, for the first time to our knowledge, that chemerin is increased in sepsis and that it associates with impaired glucose metabolism and survival in these patients. It could be further evaluated as a biomarker to stratify mortality risk of patients with SHG.
authors.affiliation: Integrated Research and Treatment Centre, Centre for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany. paul.horn@med.uni-jena.de.|Department of Anaesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany. paul.horn@med.uni-jena.de.
authors.forename: Paul
authors.initials: P
authors.lastname: Horn
authors.affiliation: Integrated Research and Treatment Centre, Centre for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany. barbara.schaller@med.uni-jena.de.|Department of Anaesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany. barbara.schaller@med.uni-jena.de.
authors.forename: Uta Barbara
authors.initials: UB
authors.lastname: Metzing
authors.affiliation: Integrated Research and Treatment Centre, Centre for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany. ricardo.steidl@med.uni-jena.de.|Department of Anaesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany. ricardo.steidl@med.uni-jena.de.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Steidl
authors.affiliation: Section of Neuropathology, Department of Pathology, Jena University Hospital, Jena, Germany. bernd.romeike@med.uni-jena.de.
authors.forename: Bernd
authors.initials: B
authors.lastname: Romeike
authors.affiliation: Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena, Germany. falk.rauchfuss@med.uni-jena.de.
authors.forename: Falk
authors.initials: F
authors.lastname: Rauchfuß
authors.affiliation: Integrated Research and Treatment Centre, Centre for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany. christoph.sponholz@med.uni-jena.de.|Department of Anaesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany. christoph.sponholz@med.uni-jena.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Sponholz
authors.affiliation: Integrated Research and Treatment Centre, Centre for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany. daniel.thomas@med.uni-jena.de.|Department of Anaesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany. daniel.thomas@med.uni-jena.de.
authors.forename: Daniel
authors.initials: D
authors.lastname: Thomas-Rüddel
authors.affiliation: Integrated Research and Treatment Centre, Centre for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany. katrin.ludewig@med.uni-jena.de.|Department of Anaesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany. katrin.ludewig@med.uni-jena.de.
authors.forename: Katrin
authors.initials: K
authors.lastname: Ludewig
authors.affiliation: Section of Metabolic and Vascular Medicine, Medical Clinic III, University Hospital Carl Gustav Carus, Dresden, Germany. andreas.birkenfeld@uniklinikum-dresden.de.|German Centre for Diabetes Research (DZD e.V.), Neuherberg, Germany. andreas.birkenfeld@uniklinikum-dresden.de.|Section of Diabetes and Nutritional Sciences, Rayne Institute, King's College London, London, UK. andreas.birkenfeld@uniklinikum-dresden.de.
authors.forename: Andreas L
authors.initials: AL
authors.lastname: Birkenfeld
authors.affiliation: Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena, Germany. utz.settmacher@med.uni-jena.de.
authors.forename: Utz
authors.initials: U
authors.lastname: Settmacher
authors.affiliation: Integrated Research and Treatment Centre, Centre for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany. michael.bauer@med.uni-jena.de.|Department of Anaesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany. michael.bauer@med.uni-jena.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Bauer
authors.affiliation: Integrated Research and Treatment Centre, Centre for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany. ralf.claus@med.uni-jena.de.
authors.forename: Ralf Alexander
authors.initials: RA
authors.lastname: Claus
authors.affiliation: Integrated Research and Treatment Centre, Centre for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany. christian.von_loeffelholz@med.uni-jena.de.|Department of Anaesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany. christian.von_loeffelholz@med.uni-jena.de.
authors.forename: Christian
authors.initials: C
authors.lastname: von Loeffelholz
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D007003:Hypoglycemia / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010538:Peritonitis / Q000378:metabolism* / Q000401:mortality*; D011379:Prognosis; D018805:Sepsis / Q000378:metabolism / Q000401:mortality*
chemical_list: D015415:Biomarkers; D018925:Chemokines; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; C478630:RARRES2 protein, human; D005947:Glucose