Mechanism Of Adipose-derived Mesenchymal Stem Cells On Ameliorated Hyperglycemia Through Regulating Hepatic Glucose Metabolism In Type 2 Diabetes

With the increasing of incidence of diabetes, type 2 diabetic mellitus (T2DM) has become a major metabolic disease that poses a great threat to human health. At present,the clinical drugs to treat diabetes did not focus on the key pathogenesis of diabetes.Mesenchymal stem cells (MSCs) ,emerged in the biomedical field for their proliferative capacity and the multi-potential differentiation, are particularly good candidates for cell-therapy which being widely used in treatment of various diseases already represents an attractive strategy for diabetes management. A large number of studies have shown that infusion of MSCs can relatively improve hyperglycemia through multiple mechanisms, including promoting b-cell function, improving insulin sensitivity. In previous studies, results demonstrated that MSCs administration could contribute to amelioration of hyperglycemia in T2DM rats during the early (day 7),multiple infusion can maintain a long-term blood glucose decline in T2D rats. , At the same time,we also surprised to see a rapid glucose-lowering effect within 24 hours after MSCs infusion. The mechanism involved rapid and short time glucose-lowering effect of MSCs has not been adequately explained by these cells' potential role in modulating system insulin sensitivity and islet regeneration, the improvement of system insulin resistance and islet function need relatively long process. So the further research on mechanism of MSCs hypoglycemic effect is necessary, and it can provide more theoretical basis for the clinic application of MSCs infusion. In this study, we extract Adipose-derived mesenchymal stem cells (ASCs) from inguinal adipose tissue of normal rats, induced a type 2 diabetic rat model by high-fat diet and low dose streptozotocin (STZ) administration. Then we infuse ASCs to T2DM rats through tail vein, emphatically observed the change of blood glucose and the situation of insulin resistance within 24 hours after the ASCs infusion. By the dynamic observation, we found that ASCs significantly lower blood glucose within 3 hours after infusion,continued until 24 hours, In addition, ASCs injection restored the expression of PI3K and p-AKT in different times and to different degrees in the liver of type 2 diabetic rats,however, we did not observe the remarkable effect of ASCs on system insulin resistance in IPGTT, IPITT experiments and HOMA-IR index value. Furthermore, we found that ASCs infusion promote hepatic glycogen synthesis, increase the expression of glycolysis-related enzymes (GcK, PK, PLK) and inhibit the expression of gluconeogenesis-related enzymes (PEPCK, G6Pase, PGC-1?) within 24 h after infusion in T2DM rats. The above results revealed that ASCs produced significantly lower blood glucose via regulating hepatic glucose production within 24 h after infusion in T2DM rats. In vitro, HepG2 cells treated with palmitate (PA) were used as a model of hepatic glucose metabolism disorder to confirm that ASCs stimulates the phosphorylation of hepatic AMP-activated protein kinase (AMPK) to restores hepatic glucose metabolism in type 2 diabetes. In summary, this study indicated that ASCs improve hyperglycemia via regulating hepatic glucose metabolism. Additionally, the effect of ASCs on hepatic glucose metabolism depended on the AMPK signaling pathway. Thus, this is the new research of the molecular mechanisms of MSCs administration to improve glucose metabolism, and it may indicate a new treatment target of MSCs in T2DM.