AIM: To compare the therapeutic effects of transplantation of human umbilical cord mesenchymal stem cells (hUCMSC) through different ways on diabetic mice.METHODS: hUCMSCs were labeled with enhanced green fluorescent protein (EGFP) and luciferase (Luc) reporter gene, and then the cells were transplanted into the diabetic mice through pancreas or tail vein to monitor the migration of the hUCMSCs in vivo.The pathological changes of pancreas tissue sections were determined by HE staining.Weight and blood glucose of the mice were measured dynamically.To compare the therapeutic effects, serum insulin levels were analyzed and glucose tolerance test were also performed.RESULTS: In vivo bioluminescence imaging results showed that the hUCMSCs transplanted into pancreatic capsule was mainly located in the pancreas while the hUCMSCs transplanted through vein tail injection was mainly located in the lung.HE staining illustrated that islet cells presented distinctive boundary and no infiltration of inflammatory cells in pancreatic capsule transplantation group was observed, but a little inflammatory cell infiltration and fibrosis formation in tail vein injection group were seen.A significant decrease in blood glucose level and a significant increase in serum insulin level in pancreas transplantation group were showed as compared with vein tail injection group.CONCLUSION: Transplantation of hUCMSCs through different approaches demonstrates different effects.The transplantation of hUCMSCs into pancreatic capsule is more effective on hyperglycemia reversion, insulin secretion and improvement of beta-cell function than that through tail vein.