Background: Apelin plays a key beneficial role in energy metabolism by increasing glucose uptake and insulin sensitivity; however, apelin has a short half-life because it is rapidly cleared from the circulation limiting its therapeutic benefit. The aim of this study is to create a new approach to treat type 2 diabetes by inducing prolonged expression of apelin in Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs). Methods: A type 2 diabetic rat model was given a high-fat diet combined with low-dose streptozotocin (STZ) injection. The human WJ-MSCs were isolated and subsequently transduced with apelin-expressing lentiviral particles (WJMSCs-apelin), and expression was verified by flow cytometry, Western blot, ELISA, and RT-PCR analysis. Type 2 diabetic rats were infused with either WJMSCs-apelin (2 × 106 cells) or an equivalent dose of saline through the tail vein injection 7 days after STZ injection. The therapeutic effects of each infusion group were evaluated by monitoring plasma glucose levels and performing glucose tolerance tests (OGTTs), insulin tolerance tests (IPITTs), confocal microscopy, and immunocytochemical analysis for quantitating islet beta cells. Plasma inflammatory cytokines IL-6 and TNF-α and anti-inflammatory factors adiponectin were measured as well. Results: Type 2 diabetic rats infused with WJ-MSCs-apelin significantly decreased levels of blood glucose (from 26.03 ± 2.83 to 15.85 ± 2.13 mmol/L on 7 days P < 0.001, and to 9.41 ± 2.05 on 14 days, P < 0.001). Infusion of WJMSCs-apelin not only improved significantly insulin sensitivity and glucose disposal, but also promoted endogenous pancreatic ß cell proliferation (9.6-fold increase compared to the control group). Furthermore, infusion of the WJMSCs-apelin consistently increased insulin and C-peptide levels in the plasma, and the above effects persisted up to 42 days. The inflammatory cytokines IL-6 and TNF-α were significantly decreased, whereas anti-inflammatory factor adiponectin was significantly increased after WJ-MSC-apelin infusion. Conclusion: In this study, we report a novel approach to treat type 2 diabetic rats that combines apelin gene therapy with WJ-MSC cell therapy, which could provide a promising therapeutic option for management of type 2 diabetes clinically.Keywords: Apelin; Lentiviral transduction; Mesenchymal stem cells; Type 2 diabetes; Wharton’s jelly; ß cell proliferation.