Hyperinsulinemia Impairs Clathrin-Mediated Endocytosis of the Insulin Receptor and Activation of Endothelial Nitric Oxide Synthase in Brain Endothelial Cells

Adequate perfusion of cerebral tissues, which is necessary for the preservation of optimal brain health, depends on insulin signaling within brain endothelial cells. Proper insulin signaling relies on the regulated internalization of insulin bound to the insulin receptor, a process which is disrupte...

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Bibliographic Details
Published in:International journal of molecular sciences 2023-09, Vol.24 (19), p.14670
Main Authors: DiLucia, Stephanie G, Kendrick, B Jacob, Sims-Robinson, Catrina
Format: Article
Language:English
Subjects:
Brain - metabolism
Clathrin
Clathrin - metabolism
Endocytosis - physiology
Endothelial Cells - metabolism
Endothelium
Ethylenediaminetetraacetic acid
Humans
Hyperinsulinism - metabolism
Insulin
Insulin - metabolism
Insulin resistance
Kinases
Nitric oxide
Nitric Oxide Synthase Type III - metabolism
Obesity
Phosphorylation
Receptor, Insulin - metabolism
Variance analysis
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Summary:Adequate perfusion of cerebral tissues, which is necessary for the preservation of optimal brain health, depends on insulin signaling within brain endothelial cells. Proper insulin signaling relies on the regulated internalization of insulin bound to the insulin receptor, a process which is disrupted by hyperinsulinemia via an unknown mechanism. Thus, the goal of this study was to characterize the impact of hyperinsulinemia on the regulation of molecular targets involved in cerebral blood flow and insulin receptor internalization into brain endothelial cells. The phosphorylation of molecular targets associated with cerebral blood flow and insulin receptor internalization was assessed in hyperinsulinemic brain endothelial cells. Insulin receptor uptake into cells was also examined in the setting of endocytosis blockade. Our data demonstrate that hyperinsulinemia impairs the activation of endothelial nitric oxide synthase. These data correspond with an impairment in clathrin-mediated endocytosis of the insulin receptor and dysregulated phosphorylation of key internalization effectors. We conclude that hyperinsulinemia alters the phosphorylation of molecular targets involved in clathrin-mediated endocytosis, disrupts signaling through the insulin receptor, and hinders the capacity for blood flow regulation by brain endothelial cells.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms241914670