1. Inhibition of VEGFR-2 reverses type 1 diabetes in NOD mice by abrogating insulitis and restoring islet function
- Author
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Rolf A. Brekken, Jeffrey A. Bluestone, Mark A. Atkinson, Jiena Lang, Robert H. Arch, Boris Calderon, Samantha Kubeck, Gregory L. Szot, S. Armando Villalta, Nicholas Pullen, Clive Wasserfall, and Beniwende Kabre
- Subjects
Indoles ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,Nod ,Medical and Health Sciences ,Receptor tyrosine kinase ,Mice ,0302 clinical medicine ,Mice, Inbred NOD ,Sunitinib ,2.1 Biological and endogenous factors ,Aetiology ,NOD mice ,Original Research ,Pediatric ,0303 health sciences ,geography.geographical_feature_category ,Diabetes ,Islet ,3. Good health ,medicine.anatomical_structure ,5.1 Pharmaceuticals ,embryonic structures ,Female ,Development of treatments and therapeutic interventions ,medicine.symptom ,Type 1 ,medicine.medical_specialty ,endocrine system ,030209 endocrinology & metabolism ,Inflammation ,Biology ,Autoimmune Disease ,Endocrinology & Metabolism ,03 medical and health sciences ,Islets of Langerhans ,Internal medicine ,Diabetes Mellitus ,Internal Medicine ,medicine ,Animals ,Humans ,Pyrroles ,Pancreas ,Protein Kinase Inhibitors ,Metabolic and endocrine ,030304 developmental biology ,geography ,Type 1 diabetes ,Pancreatic islets ,medicine.disease ,Vascular Endothelial Growth Factor Receptor-2 ,Endocrinology ,Diabetes Mellitus, Type 1 ,Hyperglycemia ,biology.protein ,Inbred NOD ,Immunology and Transplantation ,Insulitis - Abstract
The dysregulation of receptor tyrosine kinases (RTKs) in multiple cell types during chronic inflammation is indicative of their pathogenic role in autoimmune diseases. Among the many RTKs, vascular endothelial growth factor receptor (VEGFR) stands out for its multiple effects on immunity, vascularization, and cell migration. Herein, we examined whether VEGFR participated in the pathogenesis of type 1 diabetes (T1D) in nonobese diabetic (NOD) mice. We found that RTK inhibitors (RTKIs) and VEGF or VEGFR-2 antibodies reversed diabetes when administered at the onset of hyperglycemia. Increased VEGF expression promoted islet vascular remodeling in NOD mice, and inhibition of VEGFR activity with RTKIs abrogated the increase in islet vascularity, impairing T-cell migration into the islet and improving glucose control. Metabolic studies confirmed that RTKIs worked by preserving islet function, as treated mice had improved glucose tolerance without affecting insulin sensitivity. Finally, examination of human pancreata from patients with T1D revealed that VEGFR-2 was confined to the islet vascularity, which was increased in inflamed islets. Collectively, this work reveals a previously unappreciated role for VEGFR-2 signaling in the pathogenesis of T1D by controlling T-cell accessibility to the pancreatic islets and highlights a novel application of VEGFR-2 antagonists for the therapeutic treatment of T1D. © 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
- Published
- 2013