title: Dipeptidyl peptidase IV inhibitor MK-0626 attenuates pancreatic islet injury in tacrolimus-induced diabetic rats.
abstract: BACKGROUND
  Tacrolimus (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.
  
  
  METHODS
  Rats 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.
  
  
  RESULTS
  MK-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.
  
  
  CONCLUSIONS
  The DPP IV inhibitor MK-0626 was an effective antidiabetic agent that exerted antioxidative and antiapoptotic effects via enhanced GLP-1 signaling in TAC-induced diabetics.
authors: Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea; Transplant Research Center, The Catholic University of Korea, Seoul, Korea.
authors: Long
authors: L
authors: Jin
authors: Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea; Transplant Research Center, The Catholic University of Korea, Seoul, Korea.
authors: Sun Woo
authors: SW
authors: Lim
authors: Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea; Transplant Research Center, The Catholic University of Korea, Seoul, Korea.
authors: Kyoung Chan
authors: KC
authors: Doh
authors: Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea; Transplant Research Center, The Catholic University of Korea, Seoul, Korea.
authors: Shang Guo
authors: SG
authors: Piao
authors: Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea; Transplant Research Center, The Catholic University of Korea, Seoul, Korea.
authors: Jian
authors: J
authors: Jin
authors: Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea; Transplant Research Center, The Catholic University of Korea, Seoul, Korea.
authors: Seong Beom
authors: SB
authors: Heo
authors: Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea; Transplant Research Center, The Catholic University of Korea, Seoul, Korea; Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.
authors: Byung Ha
authors: BH
authors: Chung
authors: Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea; Transplant Research Center, The Catholic University of Korea, Seoul, Korea; Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.
authors: Chul Woo
authors: CW
authors: Yang
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D004249:DNA Damage / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000097:blood / Q000652:urine; D003921:Diabetes Mellitus, Experimental; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000473:pathology; D008297:Male; D020011:Protective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016559:Tacrolimus / Q000009:adverse effects*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D020011:Protective Agents; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine; D016559:Tacrolimus