Eri Mukai1, Takeshi Ohta2, Harukiyo Kawamura3, Eun-Young Lee3, Asuka Morita3, Tomohiko Sasase2, Katsuhiro Miyajima2, Nobuya Inagaki4, Toshihiko Iwanaga5, Takashi Miki6. 1. 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. 2. Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan. 3. Department of Medical Physiology, Graduate School of Medicine, Chiba University, Chiba, Japan. 4. Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan. 5. Laboratory of Histology and Cytology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan. 6. Department of Medical Physiology, Graduate School of Medicine, Chiba University, Chiba, Japan. Electronic address: tmiki@faculty.chiba-u.jp.
Abstract
AIMS: 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.
AIMS: 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: Ali Mahdi; Tong Jiao; Yahor Tratsiakovich; Bernhard Wernly; Jiangning Yang; Claes-Göran Östenson; A H Jan Danser; John Pernow; Zhichao Zhou Journal: Pharmacology Date: 2021-12-20 Impact factor: 2.547
Authors: Brittany M Duggan; Kevin P Foley; Brandyn D Henriksbo; Joseph F Cavallari; Akhilesh K Tamrakar; Jonathan D Schertzer Journal: Sci Rep Date: 2017-05-08 Impact factor: 4.379