Enhanced vascular endothelial growth factor signaling in islets contributes to β cell injury and consequential diabetes in spontaneously diabetic Torii rats.

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.

• Authors: Eri Mukai, Takeshi Ohta, Harukiyo Kawamura, Eun-Young Lee, Asuka Morita, Tomohiko Sasase, Katsuhiro Miyajima, Nobuya Inagaki, Toshihiko Iwanaga, Takashi Miki
• Journal: Diabetes research and clinical practice (Diabetes Res Clin Pract) Vol. 106 Issue 2 Pg. 303-11 (Nov 2014) ISSN: 1872-8227 [Electronic] Ireland
• PMID: 25262109 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Crotalid Venoms
• Interleukin-1beta
• Vascular Endothelial Growth Factor A

Topics

• Animals
• Cell Death (drug effects)
• Crotalid Venoms (pharmacology)
• Diabetes Mellitus, Experimental (etiology, metabolism, pathology)
• Diabetes Mellitus, Type 2 (etiology, metabolism, pathology)
• Hemorrhage (chemically induced)
• Insulin-Secreting Cells (drug effects, metabolism, pathology)
• Interleukin-1beta (metabolism)
• Islets of Langerhans (blood supply, drug effects, metabolism, pathology)
• Male
• Rats
• Signal Transduction
• Trimeresurus
• Vascular Endothelial Growth Factor A (pharmacology, physiology)