Abstract
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. 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. 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. 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.
Highlights
Type 2 diabetes is a progressive metabolic disease that leads to multiple complications, mainly of cardiovascular origin [1]
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
To investigate the effects of imatinib on metabolic insulin sensitivity, we quantified insulin-induced whole-body glucose uptake as the glucose infusion rate (GIR) during the hyperinsulinemic-euglycemic clamp in mice fed either standard chow diet or Western diet (WD)
Summary
Type 2 diabetes is a progressive metabolic disease that leads to multiple complications, mainly of cardiovascular origin [1]. With an estimated worldwide prevalence of over 300 million patients, type 2 diabetes constitutes a major global health problem [2] It is characterized by decreased insulin sensitivity and a relative insulin deficiency, resulting in increasing blood glucose levels [3]. Vascular insulin resistance impairs transendothelial transport of insulin to muscle cells [10, 11], as well as insulin-mediated vasodilation [12,13,14,15], which in turn determines muscle perfusion These endothelial functions regulate the access of insulin to myocytes, which is correlated to insulin sensitivity [16], the cornerstone of type 2 diabetes pathophysiology. In type 2 diabetes, endothelial dysfunction is characterized by reduced insulin signaling and increased transendothelial transport of fatty acids (FA).
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