Effects of exendin-4, a glucagon like peptide-1 receptor agonist, on neutrophil count and inflammatory cytokines in a rat model of endotoxemia

• Published in: Journal of inflammation research Vol. 8; no. default; pp. 129 - 135
• Main Authors: Yanay, Ofer, Bailey, Adam L, Kernan, Kelly, Zimmerman, Jerry J, Osborne, William R
• Format: Journal Article
• Language: English
• Published: New Zealand Dove Medical Press Limited 01-01-2015; Taylor & Francis Ltd; Dove Medical Press
• Subjects: Blood tests; Care and treatment; Cell growth; Complications and side effects; Critical care; Cytokines; Development and progression; Diabetes; Glucose; Health aspects; Hyperglycemia; Hypoglycemia; Inflammation; Insulin; Insulin secretion; Ischemia; Lipopolysaccharides; Neutrophils; Original Research; Peptides; Risk factors; Rodents; Sepsis; Type 2 diabetes; United States; United States > US; glucagon like peptide-1; inflammation; exendin-4; neutrophils; sepsis; endotoxemia
• ISSN: 1178-7031; 1178-7031
• DOI: 10.2147/jir.s84993

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.
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.
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.
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.