title: DPP IV inhibitor suppresses STZ-induced islets injury dependent on activation of the IGFR/Akt/mTOR signaling pathways by GLP-1 in monkeys.
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.
authors.affiliation: Department of Hepatobiliopancreatic Surgery, West China Hospital, Sichuan University, Chengdu 610041, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Laboratory of Transplant Engineering and Immunology, Regenerative Medicine Research Center, West China Hospital, Sichaun University, Chengdu 610041, PR China.
authors.forename: Younan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Laboratory of Transplant Engineering and Immunology, Regenerative Medicine Research Center, West China Hospital, Sichaun University, Chengdu 610041, PR China.
authors.forename: Jingqiu
authors.initials: J
authors.lastname: Cheng
authors.affiliation: International Diabetes Institute, University of Minnesota, USA.
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Laboratory of Transplant Engineering and Immunology, Regenerative Medicine Research Center, West China Hospital, Sichaun University, Chengdu 610041, PR China.
authors.forename: Yanrong
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Hepatobiliopancreatic Surgery, West China Hospital, Sichuan University, Chengdu 610041, PR China. Electronic address: tianbole2013@163.com.
authors.forename: Bole
authors.initials: B
authors.lastname: Tian
mesh_terms: D000818:Animals; D017209:Apoptosis; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008253:Macaca mulatta; D018384:Oxidative Stress; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction; D013311:Streptozocin; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007328:Insulin; D013311:Streptozocin; D052216:Glucagon-Like Peptide 1; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D005947:Glucose
keywords: DPP IV inhibitors; Glucagon-like peptide-1; IGF receptor; Islets injury