Aim: Studies both in vitro and ex vivo of rodent skeletal muscle have highlighted the potential involvement of neuregulin 1 (NRG1) in glucose metabolism regulation, yet nothing is known of the role of NRG1 in systemic glucose homoeostasis. For this reason, it was hypothesized that systemic delivery of NRG1 might improve glucose tolerance and that the effect might be age-dependent Methods: Glucose tolerance tests were performed in 6-month-old (adult) and 22-month-old (old) male Wistar rats 15 min after a single injection of either NRG1 (50 μg/kg) or saline (controls). Skeletal muscle and liver samples were also collected 30 min after the acute NRG1 or saline treatment, while the phosphorylation status of ErbB receptors and AKT was assessed by Western blotting Results:Acute NRG1 treatment decreased the glycaemic response to an oral glucose load in both adult and old rats. NRG1 injection did not activate ErbB receptors in skeletal muscle, whereas phosphorylation of ErbB3 and AKT was markedly increased in the liver of NRG1-treated adult and old rats compared with controls Conclusion:This study shows that NRG1 has a possible glucose-lowering effect in the liver and via an ErbB3/AKT signaling pathway. This NRG1 effect is also maintained in old rats, suggesting that the NRG1/ErbB signaling pathway might represent a promising therapeutic target in insulin resistance states