Effects of imatinib on vascular insulin sensitivity and free fatty acid transport in early weight gain.

<h4>Background</h4>Vascular endothelial dysfunction is an essential part of the pathophysiology of type 2 diabetes and its complications. In type 2 diabetes, endothelial dysfunction is characterized by reduced insulin signaling and increased transendothelial transport of fatty acids (FA)...

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Autores principales:	Camiel V J Box, Amandeep K Sandhu, Alexander H Turaihi, Pan Xiaoké, Geesje Dallinga-Thie, Jurjan Aman, Etto C Eringa
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b52e4e84200e452998820cf83d68f834
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spelling	oai:doaj.org-article:b52e4e84200e452998820cf83d68f8342021-12-02T20:05:14ZEffects of imatinib on vascular insulin sensitivity and free fatty acid transport in early weight gain.1932-620310.1371/journal.pone.0250442https://doaj.org/article/b52e4e84200e452998820cf83d68f8342021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0250442https://doaj.org/toc/1932-6203<h4>Background</h4>Vascular endothelial dysfunction is an essential part of the pathophysiology of type 2 diabetes and its complications. In type 2 diabetes, endothelial dysfunction is characterized by reduced insulin signaling and increased transendothelial transport of fatty acids (FA). As the Abl kinase inhibitor imatinib was previously shown to reverse type 2 diabetes and to inhibit VEGF signaling via Abl kinases, we studied the effect of imatinib on vascular insulin sensitivity and fatty acid transport in vivo and in vitro.<h4>Methods</h4>C57/BL6J mice were fed a chow diet or Western diet (WD), and received daily imatinib injections for two weeks. Insulin-mediated vasoreactivity of resistance arteries was studied using intravital microscopy, and metabolic insulin sensitivity using the hyperinsulinemic-euglycemic clamp. The effect of imatinib on triglyceride content in skeletal muscle and heart in vivo was also determined. In vitro, the effect of imatinib on fatty acid transport was studied in human umbilical vein endothelial cells (HUVECs) by evaluating the effect of imatinib on fluorescently labeled FA uptake both under basal and VEGF-B-stimulated conditions.<h4>Results</h4>Imatinib prevented the WD-induced weight gain in mice, independently from food intake. In line with this, imatinib enhanced insulin-mediated vasoreactivity of resistance arteries in the WD-fed mice. However, imatinib did not affect triglyceride content in muscle. In cultured endothelial cells, VEGF-B stimulation resulted in a time-dependent uptake of fatty acids in parallel with increased phosphorylation of the Abl kinase substrate Crk-like protein (CrkL) at Tyr207. Although imatinib effectively prevented VEGF-B-mediated Abl kinase activation, it had no effect on VEGF-B mediated endothelial FA uptake.<h4>Conclusion</h4>Imatinib prevents weight gain and preserves insulin-mediated vasodilation in WD-fed mice, but does not affect endothelial FA transport despite inhibiting VEGF-B signaling. The beneficial effect of imatinib on insulin-mediated vasodilation may contribute to the anti-diabetic effects of imatinib.Camiel V J BoxAmandeep K SandhuAlexander H TuraihiPan XiaokéGeesje Dallinga-ThieJurjan AmanEtto C EringaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 7, p e0250442 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Camiel V J Box Amandeep K Sandhu Alexander H Turaihi Pan Xiaoké Geesje Dallinga-Thie Jurjan Aman Etto C Eringa Effects of imatinib on vascular insulin sensitivity and free fatty acid transport in early weight gain.
description	<h4>Background</h4>Vascular endothelial dysfunction is an essential part of the pathophysiology of type 2 diabetes and its complications. In type 2 diabetes, endothelial dysfunction is characterized by reduced insulin signaling and increased transendothelial transport of fatty acids (FA). As the Abl kinase inhibitor imatinib was previously shown to reverse type 2 diabetes and to inhibit VEGF signaling via Abl kinases, we studied the effect of imatinib on vascular insulin sensitivity and fatty acid transport in vivo and in vitro.<h4>Methods</h4>C57/BL6J mice were fed a chow diet or Western diet (WD), and received daily imatinib injections for two weeks. Insulin-mediated vasoreactivity of resistance arteries was studied using intravital microscopy, and metabolic insulin sensitivity using the hyperinsulinemic-euglycemic clamp. The effect of imatinib on triglyceride content in skeletal muscle and heart in vivo was also determined. In vitro, the effect of imatinib on fatty acid transport was studied in human umbilical vein endothelial cells (HUVECs) by evaluating the effect of imatinib on fluorescently labeled FA uptake both under basal and VEGF-B-stimulated conditions.<h4>Results</h4>Imatinib prevented the WD-induced weight gain in mice, independently from food intake. In line with this, imatinib enhanced insulin-mediated vasoreactivity of resistance arteries in the WD-fed mice. However, imatinib did not affect triglyceride content in muscle. In cultured endothelial cells, VEGF-B stimulation resulted in a time-dependent uptake of fatty acids in parallel with increased phosphorylation of the Abl kinase substrate Crk-like protein (CrkL) at Tyr207. Although imatinib effectively prevented VEGF-B-mediated Abl kinase activation, it had no effect on VEGF-B mediated endothelial FA uptake.<h4>Conclusion</h4>Imatinib prevents weight gain and preserves insulin-mediated vasodilation in WD-fed mice, but does not affect endothelial FA transport despite inhibiting VEGF-B signaling. The beneficial effect of imatinib on insulin-mediated vasodilation may contribute to the anti-diabetic effects of imatinib.
format	article
author	Camiel V J Box Amandeep K Sandhu Alexander H Turaihi Pan Xiaoké Geesje Dallinga-Thie Jurjan Aman Etto C Eringa
author_facet	Camiel V J Box Amandeep K Sandhu Alexander H Turaihi Pan Xiaoké Geesje Dallinga-Thie Jurjan Aman Etto C Eringa
author_sort	Camiel V J Box
title	Effects of imatinib on vascular insulin sensitivity and free fatty acid transport in early weight gain.
title_short	Effects of imatinib on vascular insulin sensitivity and free fatty acid transport in early weight gain.
title_full	Effects of imatinib on vascular insulin sensitivity and free fatty acid transport in early weight gain.
title_fullStr	Effects of imatinib on vascular insulin sensitivity and free fatty acid transport in early weight gain.
title_full_unstemmed	Effects of imatinib on vascular insulin sensitivity and free fatty acid transport in early weight gain.
title_sort	effects of imatinib on vascular insulin sensitivity and free fatty acid transport in early weight gain.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/b52e4e84200e452998820cf83d68f834
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Effects of imatinib on vascular insulin sensitivity and free fatty acid transport in early weight gain.

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