title: Effects of addition of a dipeptidyl peptidase IV inhibitor to metformin on sirolimus-induced diabetes mellitus.
abstract: The guideline for the management of new-onset diabetes after transplantation recommends metformin (MET) as a first-line drug, and addition of a second-line drug is needed to better control of hyperglycemia. We tested the effect of addition of a dipeptidyl peptidase IV (DPP IV) inhibitor to MET on sirolimus (SRL)-induced diabetes mellitus (DM). In animal model of SRL-induced DM, MET treatment improved pancreatic islet function (blood glucose level and insulin secretion) and attenuated oxidative stress and apoptotic cell death. Addition of a DPP IV inhibitor to MET improved these parameters more than MET alone. An in vitro study showed that SRL treatment increased pancreas beta cell death and production of reactive oxygen species (ROS), and pretreatment of ROS inhibitor, or p38MAPK inhibitor effectively decreased SRL-induced islet cell death. Exendin-4 (EXD), a substrate of DPP IV or MET significantly improved cell viability and decreased ROS production compared with SRL treatment, and combined treatment with the 2 drugs improved both parameters. At the subcellular level, impaired mitochondrial respiration by SRL were partially improved by MET or EXD and much improved further after addition of EXD to MET. Our data suggest that addition of a DPP IV inhibitor to MET decreases SRL-induced oxidative stress and improves mitochondrial respiration. This finding provides a rationale for the combined use of a DPP IV inhibitor and MET in treating SRL-induced DM.
authors.affiliation: Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Transplant Research Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Long
authors.initials: L
authors.lastname: Jin
authors.affiliation: Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Transplant Research Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Sun Woo
authors.initials: SW
authors.lastname: Lim
authors.affiliation: Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Transplant Research Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
authors.affiliation: Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Transplant Research Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Byung Ha
authors.initials: BH
authors.lastname: Chung
authors.affiliation: Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Transplant Research Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. Electronic address: yangch@catholic.ac.kr.
authors.forename: Chul Woo
authors.initials: CW
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D000077270:Exenatide; D006943:Hyperglycemia / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007515:Islets of Langerhans / Q000187:drug effects; D008297:Male; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D018384:Oxidative Stress / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology; D010881:Piperidones / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D020123:Sirolimus; D014688:Venoms / Q000494:pharmacology
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; C534891:LC15-0444; D010455:Peptides; D010881:Piperidones; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D014688:Venoms; D008687:Metformin; D000077270:Exenatide; D020123:Sirolimus