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

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.

Effects of addition of a dipeptidyl peptidase IV inhibitor to metformin on sirolimus-induced diabetes mellitus

“…The whole-blood SRL concentration was measured using a microparticle enzyme immunoassay (Abbott Diagnostics, Abbott Park, M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT In vitro study. As shown in our previous study, the protective effects of DPP IV inhibitors are associated with activation of glucagon-like peptide 1 (GLP-1) (18). To investigate the exact role of the combined treatment with a DPP IV inhibitor and MET on SRL-induced pancreatic beta cell injury, we applied the GLP-1 analog exendin-4 (EXD) (0.01nM; SigmaAldrich, St Louis, MO) and MET (10ng/mL) to INS-1 cells, which was donated by Dr. Yoon 50 µM β-mercaptoethanol, 100 U/mL penicillin, and 100 mg/mL streptomycin (except for FBS, all were from Sigma-Aldrich).…”

“…Therefore, the ideal antidiabetic drugs to treat SRLinduced DM should work by improving impaired insulin signaling and protecting against islet cell injury. We tested the combination of MET and a DPP IV inhibitor after considering previous reports showing that MET improves the insulin signaling pathway by activating AMP-activated protein kinase (44) and that DPP IV inhibitors can protect against pancreatic islet cell injury caused by diverse injuries (9), including tacrolimus-induced renal and pancreatic islet injuries (18,19). Thus, we hypothesized that the combination of MET and a DPP IV inhibitor would provide better control of SRL-induced DM compared with each drug alone.…”

Endogenous GLP-1 as a key self-defense molecule against lipotoxicity in pancreatic islets

“…Exendin-4, another GLP-1R agonist, protects endothelial cells from palmitate-induced apoptosis by modulating stress-sensitive signaling pathways ( 40 ). In a previous study, in rats with tacrolimus-induced diabetes, the dipeptidyl peptidase-4 (DPP4) inhibitor, MK-0626, decreased the levels of 8-OHdG (a marker of oxidative DNA damage) and increased the levels of manganese superoxide dismutase and heme oxygenase-1 ( 41 ). In rats with streptozotocin-induced diabetes, liraglutide was shown to directly protect the rats against oxidative stress through the inhibition of NAD(P)H oxidases ( 11 ).…”

Ginseng extract reduces tacrolimus-induced oxidative stress by modulating autophagy in pancreatic beta cells

“…Oxidative stress has an important role in the pathogenesis of Tac-induced pancreatic islet injury. 4,13 Therefore, we evaluated the effect of KRGE on mitochondria, which are susceptible to oxidative damage and are one of the major cellular sources of ROS generation. 14,15 In this study, Tac decreased overall mitochondrial function, demonstrated by increased mitochondrial ROS, superoxide anion production, mitochondrial membrane depolarization, and reduced mitochondrial bioenergetics.…”