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1 Department of Internal Medicine, University of Virginia Health System, Charlottesville, Virginia, United States
* To whom correspondence should be addressed. E-mail: ejb8x{at}virginia.edu.
The pathways by which insulin exits the vasculature to muscle interstitium has not been characterized. In the present study we infused FITC-labeled insulin to trace morphologically (using confocal immunohistochemical methods) insulin transport into rat skeletal muscle. We biopsied rectus muscle at 0, 10, 30, and 60 min of continuous (10 mU/min/kg) FITC-insulin infusion (with euglycemia maintained). The FITC-insulin distribution was compared to that of insulin receptors (IR), IGF-1 receptors (IGF-1R) and caveolin -1 (a marker for caveolae) in skeletal muscle vasculature. Within 10 min muscle endothelium stained more strongly for FITC-insulin than any other cellular elements in muscle and this persisted to 60 min. Insulin receptors, IGF-1R and caveolin-1 were also detected immunohistochemically in muscle endothelial cells. We compared their intracellular distribution with that of FITC-insulin in bovine aortic endothelial cells (BAECs). Considerable co-localization of IR or IGF-1R with FITC-insulin was noted. There was some but less overlap of IR or IGF-1R or FITC-insulin with caveolin-1. Immunoprecipitation of IR co-precipitated caveolin-1 and conversely, precipitation of caveolin-1 brought down IR. Furthermore, insulin increased the tyrosine phosphorylation of caveolin-1 while filipin (which inhibits caveolae formation) blocked insulin uptake. Finally, the ability of insulin, IGF-1 and IGF-1 blocking antibody to diminish insulin transport across BAEC monolayers suggested that IGF-IR in addition to IR can also mediate trans-endothelial insulin transit. We conclude that endothelial cells rapidly take up and concentrate insulin relative to plasma and muscle interstitium and that IGF-IRs like IRs may mediate insulin transit through endothelial cells in a process involving caveolae.
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