Objective To observe the changes of bone formation in type 2 diabetes mellitus (T2DM) mice and the effect of different exercises on their cAMP/CREB/Atf4 pathway and bone formation.Methods Forty four-week-old C57BL/6 male mice were randomly divided into a normal control group (ZC) of 10 and a T2DM group of 30.T2DM was induced using the high-fat diet and injection of streptozotocin.Then,the T2DM mice were randomly divided into a T2DM control group (TC),a T2DM swimming group (TS) and a T2DM downhill running group (TD),each of 10.The TS and TD groups were trained for eight weeks as their group names indicated.Then the concentration of cAMP in serum was tested using the enzyme-linked immunosorbent assay (ELISA).The reverse transcription-polymerase chain reaction (RT-PCR) was used to test the mRNA expression of the cAMP-response element binding protein (CREB),activate transcription factor 4 (ATF4),osteocalcin (OC),bone gla-protein (OCN)and bone sialoprotein (BSP) in the left tibia,and Western blotting was employed to test the protein expression of CREB in the right femur.The bone marrow mesenchymal stem cells (BMSCs) were taken and induced to differentiate into osteoblasts (OBs) and dyed using the alkaline phosphatase (ALP) solution.The left side hindlimb bone was taken and scanned the bone mineral density (BMD) of the distal end using the Skyscan Micro-CT.Results Compared with group ZC,the concentration of cAMP declined in group TC.Moreover,the mRNA expression of CREB,ATF4,OC,OCN and BSP as well as the protein expression of CREB of group TC were significantly down-regulated(P＜0.01 or P＜0.05),together with the OB osteogenic capacity and BMD (P＜0.01) compared to group ZC.Compared with group TC,significant increase was observed in the mRNA expression of OC and OCN (P＜0.01 or P＜0.05),as well as the OB osteogenic capacity of group TS.The concentration of cAMP of group TD decreased,the mRNA expression of CREB,ATF4,OC and OCN,as well as the protein expression of CREB were all significantly up-regulated (P＜0.01 or P＜0.05) compared with group TD.The OB osteogenic capacity and BMD(P＜0.05) of group TD also increased significantly.Compared with group TS,the concentration of cAMP(P＜0.05) and the OB osteogenic capacity increased,and the mRNA expression of CREB,ATF4 and OC of group TD increased significantly(P＜0.01 or P＜0.05).Conclusion The bone formation metabolism of type 2 diabetic mice is inhibited.The downhill running is superior to swimming in promoting the osteoblast differentiation and bone formation,as well as the bone mineral density through activating the cAMP/CREB/Atf4 pathway in the bone of T2DM mice.