Glycemic Control by Umbilical Cord-Derived Mesenchymal Stem Cells Promotes Effects of Fasting-Mimicking Diet on Type 2 Diabetes

Background Hepatic steatosis is a big hurdle to treat type 2 diabetes (T2D). Fasting-mimicking diet (FMD) has been shown to be an effective intervention in dyslipidemia of T2D. However, fasting might impair the normal glucose metabolism. Human umbilical cord-derived mesenchymal stem cells (UC-MSCs) transplantation has been discovered to regulate immune reactions and reduce hyperglycemia in diabetes. However, the effects of UC-MSCs on improving the lipid metabolism disorder are not quite satisfactory. We have investigated the efficacy comparison and interaction between two typical therapies of FMD and UC-MSC infusion, aiming to pave an avenue for their synergistic use, establish effective T2D therapies and explore its mechanism.Methods C57/BL6 mice were fed with high-fat diet (HFD) for 16 weeks to induce a diet-induced obese (DIO) mouse model. Six-week-old leptin-receptor-deficient (db/db) mice were used for follow-up experiments. DIO or db/db mice were divided into 4 groups: PBS, UC-MSCs (1*106), FMD (entails 4-day FMD and 7-day of refeeding (RF)) and UC-MSCs + FMD. At the end of the study period, mice were fasted for 6 h with the measurement of blood glucose and body weight, and then sacrificed. Blood was collected to determine levels of HbA1c, serum insulin, and cytokines. In addition, the fresh liver, skin and white adipose tissue were analyzed by histology.Results FMD restored the lipid metabolism in DIO mice, whereas its capacity to rescue hyperglycemia was uncertain. Infusion of UC-MSCs was effective in T2D glycemic control but the impact on dyslipidemia was insufficient. Furthermore, both the glucose and the lipid alterations of DIO and db/db mice recovered after UC-MSCs combined with FMD. It was proved that UC-MSCs promoted FMD effects on ameliorating hyperglycemia and restoring the lipid metabolism in T2D mice, while FMD had little promotion effect on UC-MSCs. Mechanistically, we discovered that UC-MSC infusion significantly modulated systematic inflammatory microenvironment, which contributed to concerted actions with FMD.Conclusions We established a strategy that combined UC-MSC infusion and FMD were effective in treating T2D, which synergistically attenuated hyperglycemia and improved the lipid metabolism through immunoregulation. The significance of the work is to provide potential approaches for developing novel clinical T2D therapies.