Dipeptidyl Peptidase IV Inhibitor MK-0626 Attenuates Pancreatic Islet Injury in Tacrolimus-Induced Diabetic Rats

摘要

Background: Tacrolimus (TAC)-induced pancreatic islet injury is one of the important causes of new onset of diabetes in transplant recipients. This study was performed to evaluate whether a dipeptidyl peptidase (DPP) IV inhibitor is effective in improving TAC-induced diabetes mellitus by reducing pancreatic islet injury. Methods: Rats were treated with TAC (1.5mg/kg, subcutaneously) and DPP IV inhibitor MK-0626 (10 or 20mg/kg, oral gavage) for 4 weeks. The effect of MK-0626 on TAC-induced diabetes was evaluated by assessing pancreatic islet function, histopathology. TAC-induced incretin dysfunction was also examined with the serum active glucagon like peptide (GLP)-1 level after glucose loading. Protective effect of MK-0626 was evaluated by measuring markers for oxidative stress, oxidative resistance, and apoptosis. To reveal whether enhanced GLP-1 signaling is associated with these protective effects, we measured the expression of GLP-1 receptor (GLP-1R) and effect of GLP-1 analogue exendin-4 on cell viability and oxidative stress in isolated islets. Results: MK-0626 treatment attenuated TAC-induced pancreatic islet dysfunctions and islet morphology. TAC treatment showed defective in active GLP-1 secretion; however, MK-0626 recovered these effects. TAC treatment increased the level of 8-hydroxy-2'deoxyguanosine (8-OHdG), number of apoptotic cell death, active caspase-3 and decreased the level of manganese superoxide dismutase and heme oxygenase-1, and MK-0626 treatment reversed these changes. MK-0626 treatment restored the expression of GLP-1R and direct exendin-4 treatment in isolated islet reduced TAC-induced cell death and 8-OHdG expression. Conclusions: DPP IV inhibitor MK-0626 is an effective anti-diabetic agent with antioxidative and antiapoptotic properties by enhanced GLP-1 signaling in TAC-induced diabetics. These beneficial effects of DPP IV inhibitor could be helpful to a delay in the new onset of diabetes in transplant recipients.