title: Enhanced vascular endothelial growth factor signaling in islets contributes to β cell injury and consequential diabetes in spontaneously diabetic Torii rats.
abstract: OBJECTIVE
  Spontaneously diabetic Torii (SDT) rats exhibit vascular abnormalities in pancreatic islets as the initial changes at pre-diabetes stage (8 weeks old), which is followed by β cell deterioration. In the present study, we investigated pathophysiological interactions between β cells and intra-islet microvasculature of SDT rats at pre- and peri-onset of diabetes.
  
  
  METHODS
  SDT rats were treated with Habu snake venom (HSV) to assess its hemorrhagic effects in glomeruli and pancreatic islets. SDT rats were treated with streptozotocin (STZ) to assess acute β cell fragility toward cytotoxic insult and the late-stage consequence of β cell ablation in neighboring structures. The receptor tyrosine kinase inhibitor sunitinib was administered to SDT rats to examine its therapeutic effect.
  
  
  RESULTS
  HSV administration at 5 weeks old induced severe hemorrhage in and around islets in SDT rats. By contrast, precedent β cell depletion using STZ ameliorated hemorrhage, inflammation, and fibrosis around the islets at 13 weeks old, which is normally seen in SDT rats of this age. Blockade of vascular endothelial growth factor (VEGF)-like activity attenuated HSV-induced hemorrhage in SDT islets. VEGF release from SDT islets was increased at 13 weeks old but not at 5 weeks old, while interleukin-1β release was increased as early as 5 weeks old. Sunitinib treatment started at 5 weeks of age inhibited the onset of intra-islet hemorrhage, β cell loss, and hyperglycemia in SDT rats.
  
  
  CONCLUSIONS
  Enhanced VEGF signaling in islets contributes to β cell injury, microvascular failure, and consequential diabetes in SDT rats.
authors.affiliation: Department of Medical Physiology, Graduate School of Medicine, Chiba University, Chiba, Japan; Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Mukai
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ohta
authors.affiliation: Department of Medical Physiology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Harukiyo
authors.initials: H
authors.lastname: Kawamura
authors.affiliation: Department of Medical Physiology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Lee
authors.affiliation: Department of Medical Physiology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Morita
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Sasase
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Miyajima
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Inagaki
authors.affiliation: Laboratory of Histology and Cytology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Iwanaga
authors.affiliation: Department of Medical Physiology, Graduate School of Medicine, Chiba University, Chiba, Japan. Electronic address: tmiki@faculty.chiba-u.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Miki
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D003435:Crotalid Venoms / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D006470:Hemorrhage / Q000139:chemically induced; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D053583:Interleukin-1beta / Q000378:metabolism; D007515:Islets of Langerhans / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051381:Rats; D015398:Signal Transduction; D017841:Trimeresurus; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology / Q000502:physiology*
chemical_list: D003435:Crotalid Venoms; D053583:Interleukin-1beta; D042461:Vascular Endothelial Growth Factor A
keywords: Islet vasculature; SDT rats; VEGF; VEGFR; β Cells