title: Dipeptidyl peptidase- IV inhibitor alogliptin improves stress-induced insulin resistance and prothrombotic state in a murine model.
abstract: Stress evokes lipolytic release of free fatty acid (FFA) and low-grade inflammation in visceral adipose tissue, mediated by increased adipokine secretion, and contributes to glucose metabolism disorder and prothrombotic state. We tested the hypothesis that alogliptin, a dipeptidyl peptidase-4 inhibitor, can ameliorate the biological effects of chronic stress in mice.
  
  
  
  C57BL/6J mice were subjected to 2-week intermittent restraint stress and orally treated with vehicle or alogliptin (dose: 15 or 45mg/kg/day). Plasma levels of lipids, proinflammatory cytokines (monocyte chemoattractant protein-1, tumor necrosis factor-α, and interleukin-6), and 8-hydroxydeoxyguanosine were measured with enzyme-linked immunosorbent assay. Monocyte/macrophage accumulation in inguinal white adipose tissue (WAT) was examined by CD11b-positive cell count and mRNA expression of CD68 and F4/80 was examined by immunohistochemistry and RT-PCR, respectively. The mRNA levels of the above-mentioned proinflammatory cytokines, NADPH oxidase 4, adiponectin, and coagulation factors (plasminogen activation inhibitor-1 and tissue factor) in WAT were also assessed with RT-PCR. Glucose metabolism was assessed by glucose and insulin tolerance tests, plasma levels of DPP-4 activity, glucagon-like peptide-1, expression of DPP-4, insulin receptor substrate-1 and glucose transporter 4 in WAT and skeletal muscle. Alogliptin administration suppressed stress-induced FFA release, oxidative stress, adipose tissue inflammation, DPP-4 activation, and prothrombotic state in a dose-dependent manner, and improved insulin sensitivity in stressed mice.
  
  
  
  The results indicate that alogliptin improves stress-induced prothrombotic state and insulin resistance; suggesting that alogliptin could have beneficial therapeutic effects against cardiovascular complications in diabetic patients under stress.
authors: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Maimaiti
authors: M
authors: Yisireyili
authors: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Clinical Laboratory, Nagoya University Hospital, Nagoya, Japan. Electronic address: kyousuke@med.nagoya-u.ac.jp.
authors: Kyosuke
authors: K
authors: Takeshita
authors: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Motoharu
authors: M
authors: Hayashi
authors: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Hongxian
authors: H
authors: Wu
authors: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Yasuhiro
authors: Y
authors: Uchida
authors: Department of Blood Transfusion, Nagoya University Hospital, Nagoya, Japan.
authors: Koji
authors: K
authors: Yamamoto
authors: Department of Clinical Laboratory, Nagoya University Hospital, Nagoya, Japan.
authors: Ryosuke
authors: R
authors: Kikuchi
authors: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Chang-Ning
authors: CN
authors: Hao
authors: Department of Blood Transfusion, Aichi Medical University Hospital, Nagakute, Japan.
authors: Takayuki
authors: T
authors: Nakayama
authors: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Xian Wu
authors: XW
authors: Cheng
authors: Department of Clinical Laboratory, Nagoya University Hospital, Nagoya, Japan; Department of Blood Transfusion, Nagoya University Hospital, Nagoya, Japan.
authors: Tadashi
authors: T
authors: Matsushita
authors: Department of Pathology, Nagoya University Hospital, Nagoya, Japan.
authors: Shigeo
authors: S
authors: Nakamura
authors: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Toyoaki
authors: T
authors: Murohara
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D007249:Inflammation / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010880:Piperidines / Q000494:pharmacology*; D013315:Stress, Psychological / Q000150:complications*; D019851:Thrombophilia / Q000188:drug therapy* / Q000209:etiology; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D010880:Piperidines; D014498:Uracil; D018819:Dipeptidyl Peptidase 4; C520853:alogliptin
keywords: Adipose tissue inflammation; DPP-4 Inhibitor; Insulin resistance; Reactive oxygen species; Restraint stress