Abstract
BackgroundTacrolimus (TAC)-induced pancreatic islet injury is one of the important causes of new-onset diabetes in transplant recipients. This study was performed to evaluate whether a dipeptidyl peptidase IV (DPP IV) inhibitor is effective in improving TAC-induced diabetes mellitus by reducing pancreatic islet injury.MethodsRats were treated with TAC (1.5 mg/kg, subcutaneously) and the DPP IV inhibitor MK-0626 (10 or 20 mg/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 based on active glucagon-like peptide-1 (GLP-1) levels in the serum after glucose loading. The protective effect of MK-0626 was evaluated by measuring markers of oxidative stress, oxidative resistance, and apoptosis. To determine whether enhanced GLP-1 signaling is associated with these protective effects, we measured the expression of the GLP-1 receptor (GLP-1R) and the effect of the GLP-1 analog exendin-4 on cell viability and oxidative stress in isolated islets.ResultsMK-0626 treatment attenuated TAC-induced pancreatic islet dysfunction and islet morphology. TAC treatment led to a defect in active GLP-1 secretion; however, MK-0626 reversed these effects. TAC treatment increased the level of 8-hydroxy-2′-deoxyguanosine (8-OHdG), the number of apoptotic death, and the level of active caspase-3, and decreased the level of manganese superoxide dismutase and heme oxygenase-1; MK-0626 treatment reversed these changes. MK-0626 treatment restored the expression of GLP-1R, and direct administration of exendin-4 to isolated islets reduced TAC-induced cell death and 8-OHdG expression.ConclusionsThe DPP IV inhibitor MK-0626wasan effective antidiabetic agent that exerted antioxidative and antiapoptotic effects via enhanced GLP-1 signaling in TAC-induced diabetics.
Highlights
Tacrolimus (TAC) is a widely used maintenance immunosuppressant in renal transplant recipients (KTR)
The pathogenesis of new-onset diabetes after transplantation (NODAT) caused by TAC remains undetermined, this condition is partly related to the direct toxic effect of TAC on pancreatic b cells, and oxidative stress plays a pivotal role in TACinduced pancreatic islet dysfunction [3,4]
Selective dipeptidyl peptidase IV (DPP IV) inhibitors are quite different from conventional antidiabetic agents and control hyperglycemia by stimulating insulin production via the prevention of the degradation of two major incretins, the glucagon-like peptide-1 (GLP-1) and the glucose inhibitory peptide (GIP) [5,6,7]
Summary
Tacrolimus (TAC) is a widely used maintenance immunosuppressant in renal transplant recipients (KTR). New-onset diabetes after transplantation (NODAT), which occurs in 10%– 25% of the patients receiving TAC, has emerged as a major adverse event of this drug [1,2]. This condition leads to serious consequences, including reduced graft survival and increased risk of infectious and cardiovascular diseases. DPP IV inhibitors have protective effects against inflammation, oxidative injury, and apoptotic cell death in various disease models [8,9,10,11,12] Considering their antidiabetic and tissueprotective effects, the use of DPP IV inhibitors may be ideal in patients with TAC-induced diabetes. This study was performed to evaluate whether a dipeptidyl peptidase IV (DPP IV) inhibitor is effective in improving TAC-induced diabetes mellitus by reducing pancreatic islet injury
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