Yi Zhang1, Younan Chen2, Jingqiu Cheng2, Zhiguang Guo3, Yanrong Lu2, Bole Tian4. 1. Department of Hepatobiliopancreatic Surgery, West China Hospital, Sichuan University, Chengdu 610041, PR China. 2. Laboratory of Transplant Engineering and Immunology, Regenerative Medicine Research Center, West China Hospital, Sichaun University, Chengdu 610041, PR China. 3. International Diabetes Institute, University of Minnesota, USA. 4. Department of Hepatobiliopancreatic Surgery, West China Hospital, Sichuan University, Chengdu 610041, PR China. Electronic address: tianbole2013@163.com.
Abstract
BACKGROUND: To evaluate the protective effect of the DPP IV inhibitor in STZ-induced islet injury and to identify the molecular events that protect islet against apoptosis. METHODS: 4 diabetic monkeys were treated with streptozotocin (70 mg/kg) in the presence or absence of the DPP IV inhibitor (Sitagliptin), continuing administered for 4 weeks after STZ. The monkeys were evaluated by plasma DPP IV activity, serum active GLP-1 response, blood glucose, insulin and C-P levels, the insulin resistance index (HOMA-IR), and the expression of insulin, caspase-3, IGF receptor (IGFR), p-Akt and p-mTOR in pancreas islets tissues. To test that DPP IV inhibitors might against islets apoptosis via IGFR/Akt/mTOR signaling pathways, the isolated islets from the normal monkeys were pre-treated with or without 10mM STZ for 1h, followed by GLP-1 (10 μM) in the presence or absence of NVP-AEW541 or Wortmannin for 24h, to determined islets function and islet apoptosis. RESULTS: DPP IV inhibitors treatment showed depressing the degradation of GLP-1 and significantly increased serum GLP-1 levels in DM monkeys. Moreover, treatment of diabetic monkeys with the DPP IV inhibitor or treatment of isolated islets with GLP-1 can decrease islet apoptosis, and enhanced islet function and survival, and the expression of IGF receptor, p-Akt and p-mTOR in islets. When the IGFR/Akt/mTOR signaling pathways was blocked by NVP-AEW541 or Wortmannin, the protective effects of GLP1 on STZ-induced islets injury were inhibited in vitro. CONCLUSIONS: Our data provides evidence that DPP IV inhibitors confer resistance to STZ-induced islet injury. The protective effects of DPP IV inhibitor on STZ-induced islets injury were dependent on activation of the IGFR/Akt/mTOR signaling pathways by GLP-1 in islets of monkeys.
BACKGROUND: To evaluate the protective effect of the DPP IV inhibitor in STZ-induced islet injury and to identify the molecular events that protect islet against apoptosis. METHODS: 4 diabetic monkeys were treated with streptozotocin (70 mg/kg) in the presence or absence of the DPP IV inhibitor (Sitagliptin), continuing administered for 4 weeks after STZ. The monkeys were evaluated by plasma DPP IV activity, serum active GLP-1 response, blood glucose, insulin and C-P levels, the insulin resistance index (HOMA-IR), and the expression of insulin, caspase-3, IGF receptor (IGFR), p-Akt and p-mTOR in pancreas islets tissues. To test that DPP IV inhibitors might against islets apoptosis via IGFR/Akt/mTOR signaling pathways, the isolated islets from the normal monkeys were pre-treated with or without 10mM STZ for 1h, followed by GLP-1 (10 μM) in the presence or absence of NVP-AEW541 or Wortmannin for 24h, to determined islets function and islet apoptosis. RESULTS:DPP IV inhibitors treatment showed depressing the degradation of GLP-1 and significantly increased serum GLP-1 levels in DM monkeys. Moreover, treatment of diabetic monkeys with the DPP IV inhibitor or treatment of isolated islets with GLP-1 can decrease islet apoptosis, and enhanced islet function and survival, and the expression of IGF receptor, p-Akt and p-mTOR in islets. When the IGFR/Akt/mTOR signaling pathways was blocked by NVP-AEW541 or Wortmannin, the protective effects of GLP1 on STZ-induced islets injury were inhibited in vitro. CONCLUSIONS: Our data provides evidence that DPP IV inhibitors confer resistance to STZ-induced islet injury. The protective effects of DPP IV inhibitor on STZ-induced islets injury were dependent on activation of the IGFR/Akt/mTOR signaling pathways by GLP-1 in islets of monkeys.