Jin Long, Lim Sun Woo, Doh Kyoung Chan, Piao Shang Guo, Jin Jian, Heo Seong Beom, Chung Byung Ha, Yang Chul Woo
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.
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.
PLoS One. 2014 Jun 24;9(6):e100798. doi: 10.1371/journal.pone.0100798. eCollection 2014.
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.
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.
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.
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.
他克莫司（TAC）诱导的胰岛损伤是移植受者新发糖尿病的重要原因之一。本研究旨在评估二肽基肽酶IV（DPP IV）抑制剂是否能通过减轻胰岛损伤有效改善TAC诱导的糖尿病。
大鼠皮下注射TAC（1.5mg/kg）并经口灌胃给予DPP IV抑制剂MK-0626（10或20mg/kg），持续4周。通过评估胰岛功能、组织病理学来评价MK-0626对TAC诱导糖尿病的作用。还基于葡萄糖负荷后血清中活性胰高血糖素样肽-1（GLP-1）水平检测TAC诱导的肠促胰岛素功能障碍。通过测量氧化应激、抗氧化和凋亡标志物来评估MK-0626的保护作用。为确定增强的GLP-1信号传导是否与这些保护作用相关，我们检测了GLP-1受体（GLP-1R）的表达以及GLP-1类似物艾塞那肽-4对分离胰岛细胞活力和氧化应激的影响。
MK-0626治疗减轻了TAC诱导的胰岛功能障碍和胰岛形态改变。TAC治疗导致活性GLP-1分泌缺陷；然而，MK-0626逆转了这些作用。TAC治疗增加了8-羟基-2'-脱氧鸟苷（8-OHdG）水平、凋亡死亡数量和活性半胱天冬酶-3水平，并降低了锰超氧化物歧化酶和血红素加氧酶-1水平；MK-0626治疗逆转了这些变化。MK-0626治疗恢复了GLP-1R的表达，并且向分离的胰岛直接给予艾塞那肽-4减少了TAC诱导的细胞死亡和8-OHdG表达。
DPP IV抑制剂MK-0626是一种有效的抗糖尿病药物，通过增强GLP-1信号传导在TAC诱导的糖尿病中发挥抗氧化和抗凋亡作用。
