Preservation of the pancreatic beta-cell population is required for the development of therapies for diabetes, which is caused by a decrease in beta-cells. Here, we demonstrate the antidiabetic effects of substance P (SP) in type 1 diabetes (T1D) mice induced with streptozotocin. SP enhanced the compensatory proliferation of beta-cells in order to restore beta-cells in response to acute injury induced by a single high-dose of streptozotocin. However, SP affected neither the basal proliferation of beta-cells nor their apoptosis. In vitro studies by using the INS-1 pancreatic beta-cell line showed that SP mediated the increase in the proliferation of beta-cells via the activation of Akt. Chronic systemic treatment with SP restored the mass of beta-cells and inhibited insulitis in T1D mice induced with multiple low-doses of streptozotocin. Therefore, systemic treatment with SP may be a promising therapeutic strategy for treating diabetes in patients with loss of functional beta-cells. (C) 2017 Elsevier Inc. All rights reserved.