Acute Effects Of Sitagliptin On Progenitor Cells And Its Potential Mechanism In Type 2 Diabetes

Objectives（1）The aim of this study was to investigate the changes of circulating EPCs in peripheral blood of patients with type 2 diabetes mellitus（T2DM）by a short-term treatment of sitagliptin--a DPP-4 inhibitor.（2）The aim of this study was to investigate the changes of ET-1,NO,SDF-1a and GLP-1 levels in peripheral blood of patients with type 2 diabetes mellitus before and after the short-term treatment of sitagliptin.（3）The aim of this study was to investigate whether changes in the number of circulating endothelial progenitor cells before and after the short-term treatment of sitagliptin are related to changes in the concentrations of these mediators.MethodsFrom January to March 2017,60 patients with type 2 diabetes mellitus（T2DM）who met in-group criteria were enrolled in xx department,xx Hospital,and randomized according to 1:1:1 For the three groups:sitagliptin group was given oral sitagliptin100mg once daily for three days;metformin group was given metformin 500mg three times daily for three days;combination group was given oral metformin 500mg daily Three times+sitagliptin 100mg once daily for three consecutive days.Flow cytometry was used to detect the numbers of circulating endothelial progenitor cells(including CD34⁺KDR^+,CD133⁺KDR⁺and CD34⁺CD133⁺KDR⁺endothelial progenitor cells)before and after treatment in three groups.Serum levels of GLP-1,NO,ET-1,SDF-1αbefore and after treatment were measured by enzyme-linked immunosorbent assay.At the same time,the clinical parameters of the three groups before and after treatment of glucose and lipid metabolism were collected and measured.Pearson correlation analysis and multivariate linear regression analysis were used to understand the relationship between changes of peripheral blood progenitor cells and changes of related clinical parameters before and after treatment.Results（1）Before the drug intervention,there was no significant difference in age,gender composition,body mass index,glycated hemoglobin,blood pressure,smoking history,medication history,and diabetic complications among the three groups（P>0.05）.（2）Compared with pretreatment,the number of EPCs and GLP-1,SDF-1α,and NO levels in the sitagliptin group were significantly increased after treatment（P<0.05）.Fasting blood glucose,serum cholesterol,triglyceride,low-density lipoprotein cholesterol,high-density lipoprotein cholesterol,and ET-1 levels were not significantly different before and after treatment（P>0.05）.（3）The number of EPCs in metformin group,fasting blood glucose,serum cholesterol,triglyceride,low-density lipoprotein cholesterol,high-density lipoprotein cholesterol,and peripheral blood ET-1,GLP-1,SDF-1αThere was no significant difference in NO levels before and after treatment（P>0.05）.（4）Compared with pretreatment,the number of CD34+CD133+KDR+EPCs in the combinationgroupincreasedsignificantlyafteradministrationfrom（1.365±1.085）%/mononuclear cells to（1.730±1.157）%/Mononuclear cells,the difference was statistically significant（P<0.05）,while the number of CD34+KDR+EPCs and CD133+KDR+EPCs were not significantly changed（P>0.05）.In addition,the levels of SDF-1αand GLP-1 in peripheral blood were significantly increased after administration,and fasting blood glucose,serum cholesterol,triglyceride,low-density lipoprotein cholesterol,high-density lipoprotein cholesterol,and ET-1 were compared with those before treatment.There was no significant difference in NO levels before and after treatment（P>0.05）.（5）Pearson correlation analysis showed that△EPC and△FPG,△TC,△TG,△HDL-C,△LDL-C,△NO,△ET-1 were all in the whole group（including three groups of subjects）.Correlation（P>0.05）was positively correlated with△SDF-αand△GLP-1（r=0.630,0.254,P<0.05）.Further analysis found that there was no correlation betweenΔEPC and other clinical parameters in the metformin group（P>0.05）.In the sitagliptin group,△EPC was positively correlated with△SDF-αand△GLP-1（r=0.717,0.525,P<0.05）,but had no correlation with other clinical parameters（P>0.05）.In the combination therapy group,there was a positive correlation between△EPC and△SDF-αand△GLP-1（r=0.634,0.394,P<0.05）,but no correlation with other clinical parameters△（P>0.05）.（6）Pearson correlation analysis showed that there was a positive correlation between△EPC and△SDF-αand△GLP-1 in both sitagliptin and combination groups;multiple linear regression analysis suggested that△GLP-1 is Two groups of△EPC independent factors.Conclusions（1）Short-term use of sitagliptin increases the number of peripheral blood progenitor cells in patients with type 2 diabetes mellitus,this change is not related with changes in blood glucose and blood lipid levels before and after treatment（2）The effect of short-term use of sitagliptin to increase the number of EPC was related to the change of SDF-1αconcentration before and after treatment.The increase of bioactivity and mobilization of SDF-1αmay be one of the ways to change the number of EPCs.（3）The effect of short-term increase in the amount of EPC induced by sitagliptin is related to the change of GLP-1 concentration before and after treatment,and it is an independent factor.The direct or indirect pathway dependent on GLP-1 may be one of the main mechanisms of EPC number changes.