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

Abstract

BackgroundSepsis 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.MethodsTwo-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.ResultsAt 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.ConclusionIn 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.

Which one is more effective for the treatment of rat sepsis model: thalidomide or etanercept?

“…Shin et al (29) consistently observed systemic infl ammatory responses such as higher concentrations of proinfl ammatory cytokines TNF-α and IL-6 with LPS, in comparison to control rats. Yanay et al found signifi cantly higher levels of TNF-α, IL-6 and IL-1β in the LPS group than the sham group (30). Our study obtained similar results.…”

Rationale for and Design of the Study of Early Enteral Dextrose in Sepsis: A Pilot Placebo‐Controlled Randomized Clinical Trial

“…Incretin-based therapies have revolutionized the care of patients with diabetes mellitus, 4,29,30 and preclinical studies demonstrate anti-inflammatory effects of incretins and suggest benefits in septic animal models. 16,[31][32][33][34] Early clinical trials of exogenous incretin administration to critically ill patients have demonstrated beneficial effects on glycemic control, 35,36 and in this trial we extend those observations to test whether endogenous incretin stimulation can be targeted through provision of enteral dextrose. We hypothesize that increasing circulating incretins using enteral dextrose will decrease systemic inflammation.…”

“…The SEEDS trial is novel in its focus on endogenous stimulation of incretin hormones in sepsis. Incretin‐based therapies have revolutionized the care of patients with diabetes mellitus, and preclinical studies demonstrate anti‐inflammatory effects of incretins and suggest benefits in septic animal models . Early clinical trials of exogenous incretin administration to critically ill patients have demonstrated beneficial effects on glycemic control, and in this trial we extend those observations to test whether endogenous incretin stimulation can be targeted through provision of enteral dextrose.…”

The effect of intrauterine inflammation on mTOR signaling in mouse fetal brain

“…Emerging evidence indicates that inflammation caused by LPS could affect the status of maternal nutrition and placental nutrient transfer. LPS itself has been shown to induce hypoglycemia (Tweedell et al., 2011; Yanay, Bailey, Kernan, Zimmerman, & Osborne, 2015). Wu et al (2018) reported that after intrauterine injection of LPS, magnetic resonance imaging (MRI) showed significantly decreased placental perfusion, and the placental capability in response to maternal glucose challenge was impaired.…”