Reciprocal Interactions of Insulin and Insulin-Like Growth Factor I in Receptor-Mediated Transport across the Blood-Brain Barrier

Abstract

Although the blood-brain barrier limits free passage of peptides and proteins from the peripheral circulation to the central nervous system, specific transport systems for insulin and IGF-I have been identified. To further determine whether insulin and IGF-I share the same transport system, and if not, whether the two transport systems interact with each other, we performed multiple-time regression analysis in mice after iv injection and in situ brain perfusion of these peptides. Insulin and IGF-I caused reciprocal inhibition of each other's transport, although the effect of insulin was detected only by the in situ brain perfusion system. The interaction took place mainly at the step of cell surface binding as seen in cultured rat brain endothelium 4 brain microvessel endothelial cells. Further studies in 3T3 cells stably overexpressing the insulin receptor showed that the sharing of the transport systems was only partial. We conclude that insulin and IGF-I are mainly transported by their own transport systems, but a small amount can enter the brain by their "noncognate" transporters. The redundancy of their transport systems illustrates the regulatory function of the blood-brain barrier and reflects the importance of blood-borne insulin and IGF-I in the central nervous system.