Insulin receptor-mediated transcytosis

SECs are normally able to internalize only small particles (up to 0.23 pm). In conditions of impaired KC function, however, they have also been found to phagocytose larger particles [23]. They are also responsible for the receptor-mediated transcytosis of several compounds, such as insulin [24] and transferrin [25]. 

Polypeptides are substrates for receptor-mediated transcytosis. Cerebral insulin reaches the brain from the circulation via receptor-mediated transcytosis through the BBB on the brain endothelial insulin receptor. This receptor is upregulated in development and downregulated in streptozotocin-induced diabetes mellitus. Similarly a BBB transferrin receptor mediates the transcytosis of transferrin across the BBB and this explains how the brain is able to extract iron from the circulation. Other RMT pathways consituting portals of entry to the brain for circulating peptides include receptors for insulin-like growth factors, cationic proteins, lectins, acetyl-low density lipoprotein and leptin. 

Another method of delivery of insulin is to conjugate the protein with transferrin. Oral administration of the insulin-transferrin complex and insulin in streptozotocin-induced diabetic mice lowered the blood glucose levels by 28 and 5%, respectively. The blood glucose level was further decreased to 40% when the mice were pretreated with brefeldin A, a fungal metabolite, before the administration of the insulin-transferrin complex. The potentiation by brefeldin A indicated that insulin absorption could be accomplished through a transferrin receptor-mediated transcytosis in the intestinal wall. 

PMN binding to and migration across endothelium initiates a sequence of events that resembles that following histamine treatment [14,30], namely, an increase in the permeability of the EC monolayer. For anionic plasma macromolecules, the plasmalemmal vesicles and transendothelial channels are suitable candidates for exit from the vessel lumen. Indeed, receptor-mediated transcytosis of insulin and transferrin has been identified for brain capillaries [31-33]. The insulin carriers have not yet been identified, but it is speculated that they could be coated vesicles and/or plasmalemmal vesicles. Transferrin [34] as well as ceruloplasmin [35,36] binding has been localized to coated pits and vesicles in the endothelium of bone marrow and liver capillary endothelium, respectively. 

Certain proteins, such as insulin, transferrin, and insulin-like growth factors, cross the blood-brain barrier by receptor-mediated transcytosis. Once the protein binds to its membrane receptor, the membrane containing the receptor-protein complex is endocytosed into the endothelial cell to form a vesicle. It is released on the other side of the endothelial cell. Absorptive-mediated transcytosis also can occur. It differs from receptor-mediated transcytosis in that the protein binds nonspecifically to the membrane and not to a distinct receptor. 

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