Abstract: Objective To investigate the therapeutic effects of multiple intravenous infusions of umbilical cord derived mesenchymal stem cells (UC-MSCs) in type 2 diabetic rats and explore the possible mechanisms of stem cells in the treatment of type 2 diabetes(T2D). Methods The T2D rats were randomly divided into two groups, the stem cells treatment group (MSC group, n=10) and the diabetic group (DM group, n=10), with a control group (N group) including 10 healthy rats. Rats in MSC group were treated with 3×10⁶ UC-MSCs suspended in 0.5 ml of phosphate-buffered saline (PBS) through the tail vein. Rats in N group and DM group were infused with the same amount of PBS via the tail vein. Infusion was performed every two weeks, and a total of four infusions were administered. After 4 times of treatment, 3 rats were randomly selected from each group for intravenous infusion of CM-Dil dye labeled UC-MSCs. After 72 hours, these animals were sacrificed and the distribution of CM-Dil-labeled UC-MSCs in various organs was explored by laser scanning confocal microscope. Results After four times of infusion of UC-MSCs, the blood glucose of MSC group maintained at 23.9±3.7 mmol/L, which was significantly lower than that of DM group (28.2±2.9 mmol/L). The glucose tolerance level of MSC group was superior to that of group DM at each time point. The average weight of N group was about 695 g, significantly higher than 582 g in DM group, and 599 g in MSC group. While MSC group was significantly improved in weight loss compared to DM group. Compared to DM group (46%), the glomerular sclerosis rate of group MSC was 16%, indicating that multiple infusions of UC-MSCs could effectively reduce the degree of glomerular sclerosis in diabetic rats. In addition, the degree of fatty liver and the pathological state of pancreas in MSC group were better than those in DM group. The results of counting CM-Dil positive UC-MSCs showed that UC-MSCs were mainly found in the spleen at 72 hours after infusion, and there was no significant difference in the number of homing stem cells between the three groups (all P＞ 0.05). Only few stem cells were found in the kidney and liver, but the number of stem cells in DM group was greater than those in N group and MSC group (all P＜ 0.05). No CM-Dil positive cell was found in the pancreatic tissue in the three groups. Conclusion Multiple infusions of UC-MSCs has obvious therapeutic effects on type 2 diabetic rats. The amounts of UC-MSCs homing to liver, kidney and pancreas are rare, while a large number of stem cells are detected in the spleen.