title: Effects of exendin-4, a glucagon like peptide-1 receptor agonist, on neutrophil count and inflammatory cytokines in a rat model of endotoxemia.
abstract: BACKGROUND
  Sepsis remains a major cause of morbidity and mortality. A variety of strategies targeting modulation of the pro-inflammatory response associated with early sepsis have been reported without clinical success. GLP-1 enhances glucose-stimulated insulin secretion. In addition, it was shown to have anti-inflammatory effects. We hypothesized that treatment with exendin-4, a GLP-1 receptor agonist, would attenuate inflammation and improve glucose control in a lipopolysaccharide (LPS) rat model of inflammation.
  
  
  METHODS
  Two-month-old male Wistar rats were randomly assigned to one of the following four groups: 1) treatment: intraperitoneal (IP) injection of LPS 10 mg/kg followed by exendin-4, 30 μg/kg, 10 minutes later; 2) control-1: IP injection of LPS 10 mg/kg, followed by normal saline (NS); 3) control-2: IP NS injection followed by exendin-4; 4) sham: IP injection of NS followed by another NS injection. Glucose concentration, total white blood count with absolute neutrophil count, and pro- and anti-inflammatory cytokine concentrations were measured at 0, 3, 6, and 10 hours following LPS injection.
  
  
  RESULTS
  At 3 hours, rats injected with LPS developed neutropenia, elevated pro- and anti-inflammatory cytokines, and mild hypoglycemia. Treatment with exendin-4 significantly modulated neutropenia, and decreased pro-inflammatory cytokine concentrations (IL-1α, IL-1β, IL-6, TNFα, and IFNγ). However, exendin-4 had no effect on IL-10 concentrations. LPS injection led to mild hypoglycemia, that was not observed in rats treated with exendin-4. Sham animals exhibited no significant change from baseline in all parameters.
  
  
  CONCLUSIONS
  In this LPS model of acute early phase inflammation, treatment with exendin-4 decreased pro-inflammatory cytokine concentrations without changing IL-10 blood levels and improved neutropenia. Following LPS injection, rats developed a tendency toward hypoglycemia that improved with exendin-4. Overall our data suggest that exogenous exendin-4 mediates anti-inflammatory effects early in this rat model of endotoxin-induced inflammation.
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA, USA ; Division of Pediatric Critical Care Medicine, Seattle Children's Hospital, Seattle, WA, USA.
authors.forename: Ofer
authors.initials: O
authors.lastname: Yanay
authors.affiliation: Medical Scientist Training Program, University of Wisconsin, Madison, WI, USA.
authors.forename: Adam L
authors.initials: AL
authors.lastname: Bailey
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Kernan
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA, USA ; Division of Pediatric Critical Care Medicine, Seattle Children's Hospital, Seattle, WA, USA.
authors.forename: Jerry J
authors.initials: JJ
authors.lastname: Zimmerman
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Osborne
keywords: endotoxemia; exendin-4; glucagon like peptide-1; inflammation; neutrophils; sepsis